tag:blogger.com,1999:blog-42761749332806037312024-03-12T15:03:38.220-07:00My MediNotesxar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.comBlogger83125tag:blogger.com,1999:blog-4276174933280603731.post-11021715372110441192015-05-10T08:26:00.001-07:002015-05-10T08:26:34.606-07:00Abandoned Painkiller Makes a Comeback In 2006, in the midst of a growing opioid epidemic, the FDA approved the new narcotic painkiller Opana.<br /><br />
<br />
It was a familiar drug.<br /><br />
<br />
Under the name Numorphan, it had been abused in the 1960s and 1970s <br />
until it was removed from the market. When injected, the drug is 10 <br />
times as potent as morphine.<br /><br />
<br />
And now there is a familiar problem.<br /><br />
<br />
Known generically as oxymorphone, the FDA approved the new version of<br />
the drug -- made by Endo Pharmaceuticals -- in 2006 as both an <br />
immediate-release and extended-release pill. Then in December 2011, the <br />
agency approved a new abuse-deterrent version -- but users have been <br />
able to foil the anti-injection mechanism and have been shooting up <br />
Opana.<br /><br />
<br />
In addition to overdose risk, abuse of Opana by injection has been tied to a recent <a href="http://www.medpagetoday.com/InfectiousDisease/PublicHealth/51182" target="_blank">outbreak of HIV in rural Indiana</a> as well as a surge in <a href="http://www.medpagetoday.com/InfectiousDisease/Hepatitis/51419" target="_blank">hepatitis C infections in several Appalachian states</a>.<br /><br />
<br />
It also has been associated with <a href="http://www.medpagetoday.com/Psychiatry/Addictions/51449" target="_blank">a blood-clotting disorder and permanent organ damage</a> -- a problem that didn't occur with injection abuse of generics and the earlier version of the drug.<br /><br />
<br />
When Opana was approved, it joined more than a dozen other narcotic painkillers on the market.<br /><br />
<br />
"There certainly didn't seem to be a need for it," said <a href="https://www.drexelmed.edu/Home/AboutOurFaculty/JamesRoberts.aspx" target="_blank">James Roberts, MD</a>,<br />
a professor of emergency medicine at Drexel University College of <br />
Medicine in Philadelphia. "There are plenty of narcotics around for pain<br />
relief."<br /><br />
<br />
As Numorphan, the drug's popularity among addicts was due to its quick and sustained effect, according to the 1974 report <a href="https://www.documentcloud.org/documents/2074330-dalopana.html#document/p247/a216832" target="_blank">"Drugs and Addict Lifestyle" by the National Institute on Drug Abuse</a>.<br /><br />
<br />
The report said the drug -- which carried a street name of "blues" <br />
-- was used primarily by white males and highlighted 309 Philadelphia <br />
area addicts who were interviewed about their Numorphan abuse in 1970. <br />
Many of the addicts said they preferred the drug over heroin.<br /><br />
<br />
Originally approved in 1959, FDA records indicate the pill form of <br />
Numorphan was taken off the market in 1979 for what is described as "<a href="https://www.documentcloud.org/documents/2073943-fda-medical-review.html#document/p4/a216831" target="_blank">commercial reasons</a>." Its intravenous and suppository formulations were allowed to remain on the market.<br /><br />
<br />
In an email, FDA spokesman Eric Pahon said opioids, including Opana, <br />
are important medications for the treatment of pain, when used properly.<br /><br />
<br />
"The FDA is concerned about the misuse and abuse of prescription <br />
opioids, which is a serious public health challenge, and is working in <br />
many ways to help prescribers and patients make the best possible <br />
choices about how to use these powerful drugs," he said. "We must <br />
balance this effort, however, with ensuring prescribers and patients <br />
maintain access to these medications and a variety of treatment options <br />
are available."<br /><br />
<br />
Opana ER generated 756,000 prescriptions and sales of $385 million in<br />
2013, according to data supplied by IMS Health, a drug market research <br />
firm. Since 2009, its annual sales have ranged from $246 million to $640<br />
million.<br /><br />
<br />
In an email, Endo spokesperson Heather Zoumas Lubeski said the drug <br />
"was approved by the FDA based upon its demonstration of safety and <br />
effectiveness in clinical trials and its successful submission of an <br />
application for approval."<br /><br />
<br />
<strong>Meetings Impact Approval?</strong><br /><br />
<br />
A <em>Milwaukee Journal Sentinel/MedPage Today</em> examination found<br />
oxymorphone's re-appearance on the market followed a pattern identified<br />
in past investigations, including cozy relationships between regulators<br />
and drug company executives and the use of questionable clinical <br />
testing methods allowed by the FDA.<br /><br />
<br />
Endo was a frequent participant at meetings of an organization funded<br />
by pain drug companies that brought together pharmaceutical executives <br />
and federal regulators during the 2000s, records show.<br /><br />
<br />
The group, known as IMMPACT, was the subject of <a href="http://www.medpagetoday.com/PainManagement/PainManagement/42103" target="_blank">a 2013 <em>Journal Sentinel/MedPage Today</em> investigation</a>.<br /><br />
<br />
The story highlighted how federal health industry officials, members <br />
of academia, and executives of companies that make pain drugs held <br />
private meetings at expensive hotels at least once a year beginning in <br />
2002, according to emails obtained through a public records request.<br /><br />
<br />
Each year, a handful of drug companies paid up to $35,000 each to <br />
send a representative to the meetings where they could discuss clinical <br />
trial design with FDA officials.<br /><br />
<br />
The arrangement was criticized as appearing to be pay-for-play <br />
connection between regulators and companies anxious to get products onto<br />
the multibillion-dollar-a-year pain market.<br /><br />
<br />
In 2014, <a href="http://www.medpagetoday.com/PainManagement/PainManagement/44510" target="_blank">two U.S. senators wrote to the medical school dean at the University of Rochester</a> demanding financial records related to the IMMPACT meetings. A researcher at the school was a co-founder of the group.<br /><br />
<br />
Sen. Joe Manchin (D-W.Va.) and Sen. David Vitter (R-La.) wrote that <br />
they were "deeply troubled by allegations that the FDA gave <br />
manufacturers of prescription drugs the opportunity to pay thousands of <br />
dollars to the University of Rochester Medical Center for the privilege <br />
to attend private meetings with FDA officials."<br /><br />
<br />
FDA spokesman Pahon said it is misleading to imply that the IMMPACT <br />
meetings were private meetings between FDA officials and members of <br />
industry.<br /><br />
<br />
Though the meetings were invitation-only, he said, they were attended<br />
by a variety of government officials, academics, and pain advocates.<br /><br />
<br />
"These were large scientific meetings at which the outside experts <br />
almost always outnumbered the attending companies," he said. "We are not<br />
aware of any separate, private meetings between FDA and pharmaceutical <br />
companies during or as a result of IMMPACT meetings."<br /><br />
<br />
He said the meetings had no bearing on the approval of Opana and did <br />
not include the discussion of any particular product or the standards <br />
for FDA approval of pain products.<br /><br />
<br />
<strong>Stacking the Deck?</strong><br /><br />
<br />
The IMMPACT meetings helped develop a new approach to winning approval of drugs known as enriched enrollment.<br /><br />
<br />
The approach allows drugs companies to weed out people who don't <br />
respond well to a drug or who can't tolerate taking it before an actual <br />
clinical trial for the drug begins.<br /><br />
<br />
Independent doctors say that approach makes it much more likely a <br />
drug will be found effective and possibly win FDA approval. It's also <br />
cheaper for drug companies to conduct such trials.<br /><br />
<br />
Critics say the approach essentially stacks the deck in favor of the <br />
drug. More importantly, experts say, drugs tested that way are not <br />
likely to reflect what will happen when a medication gets on the market <br />
and is prescribed for large numbers of people.<br /><br />
<br />
When Endo tried to get Opana approved in 2003, the FDA said the drug <br />
didn't appear effective enough in clinical trials. It also raised safety<br />
concerns after several postoperative pain patients overdosed on the <br />
drug and had to be revived with naloxone.<br /><br />
<br />
So Endo conducted <a href="https://www.documentcloud.org/documents/2074336-oxymorphone-enriched-enrollment-metaanalysis.html" target="_blank">new clinical trials using enriched enrollment</a>.<br /><br />
<br />
In those trials, only the patients who initially responded to the <br />
drug were entered into a randomized, controlled trial, where they were <br />
given either Opana or a placebo. The idea is that the drug's effects can<br />
be clearly demonstrated in comparison with placebo because it is <br />
already known to work for all of the patients.<br /><br />
<br />
The results of those trials helped get the drug approved by the FDA <br />
in 2006. But the FDA's own medical review of the drug acknowledged that,<br />
given the enriched study design, "one could argue that the results may <br />
not be generalizable to the wider chronic pain population."<br /><br />
<br />
"The FDA should be in the business of requiring high-quality evidence and not short-cut evidence," said <a href="http://nyulangone.org/doctors/1639164635/lewis-s-nelson" target="_blank">Lewis Nelson, MD</a>,<br />
a medical toxicologist at NYU Langone Medical Center. "Unfortunately, <br />
they're under pressure to make pharmaceuticals available to the general <br />
public."<br /><br />
<br />
Nelson said the enriched trials "find the people who are most likely to respond to a drug and not suffer from side effects."<br /><br />
<br />
"I don't think enriched enrollment studies are truly valid," he added.<br /><br />
<br />
FDA spokesman Pahon said companies use a variety of strategies to <br />
select those in the general population in which the effect of a drug can<br />
be more readily shown.<br /><br />
<br />
He would not say whether the FDA encouraged Endo to use enriched enrollment for Opana.<br /><br />
<br />
"You'll need to FOIA [apply under the Freedom of Information Act to see] those pre-approval meeting minutes," he said.<br /><br />
<br />
Opana is not the only opioid approved using enriched enrollment. In 2013, drugmaker Zogenix used the strategy to <a href="http://www.medpagetoday.com/PainManagement/PainManagement/42510" target="_blank">win approval for Zohydro</a>, a high-dose, hydrocodone-only drug that was originally approved without any abuse-deterrent mechanisms.<br /><br />
<a href="http://www.medpagetoday.com/Psychiatry/Addictions/51448"> | Medpage Today</a>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com1tag:blogger.com,1999:blog-4276174933280603731.post-7757298566519245962015-04-26T03:32:00.001-07:002015-04-26T03:32:44.753-07:00Radically Rethinking Medical Education : Shots<a href="http://www.npr.org/blogs/health/2015/04/26/401254790/would-doctors-be-better-if-they-didnt-have-to-memorize?utm_medium=RSS&utm_campaign=news"><span></span><br />
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<div id="res401992956"> <div> <div class="readableLargeImageContainer"><img alt="Katherine Streeter for NPR" height="359" src="http://media.npr.org/assets/img/2015/04/24/medschool1_wide-d5caa24d3bb60c91be8355706c199745dca15520-s800-c85.jpeg" title="Katherine Streeter for NPR" width="640" /></div><a href="http://www.npr.org/blogs/health/2015/04/26/401254790/would-doctors-be-better-if-they-didnt-have-to-memorize?utm_medium=RSS&utm_campaign=news#" target="_blank" title="Enlarge">i</a><br />
</div><div> <br />
<br />
<br />
Katherine Streeter for NPR<br />
<br />
<br />
</div></div>Poor old Dr. Krebs. His painstaking Nobel-winning <a href="http://www.nobelprize.org/nobel_prizes/medicine/laureates/1953/krebs-bio.html" target="_blank">work</a> on cellular metabolism, called the Krebs cycle, has made him the symbol for what's ailing medical education.<br /><br />
"Why do I need to know this stuff?" medical students ask me.<br /><br />
"How many times have <em>you</em> used the Krebs Cycle lately?" senior doctors jokingly reminisce.<br /><br />
For decades, first-year medical students have had to cram the details of the <a href="http://sustainabilityworkshop.autodesk.com/sites/default/files/styles/large/public/core-page-inserted-images/krebs_cycle_from_wikimedia-tweaked.jpg" target="_blank">Krebs cycle</a> into their heads. Now the biomedical model of educating doctors, based largely on a century-old <a href="http://www.npr.org/blogs/health/2015/04/09/390440465/medical-schools-reboot-for-21st-century" target="_blank">document</a> called <em>The Flexner Report,</em> is coming under fire.<br /><br />
From one end, our long-standing medical education model is attacked as out of tune with the information age. By some <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116346/pdf/tacca122000048.pdf" target="_blank">estimates</a>, our entire body of medical knowledge doubles every three or four years.<br /><br />
<br />
<br />
<br />
Critics say med students can't possibly master so much <br />
information, which quickly becomes outdated anyway. Instead, the new <br />
theory goes, students should be taught and evaluated on their ability to<br />
find, assess and synthesize knowledge. And they should be educated in <a href="http://www.ihi.org/communities/blogs/_layouts/ihi/community/blog/itemview.aspx?List=0f316db6-7f8a-430f-a63a-ed7602d1366a&ID=29" target="_blank">teams</a> to help prepare them for what goes on in the real world.<br /><br />
From<br />
another angle, critics of the Flexner model correctly point out that <br />
Flexner himself, an educational theorist with no medical training, was <br />
silent on issues such as poverty, housing, nutrition and other factors <br />
that we now call the social determinants of health.<br /><br />
We now know these factors collectively affect our overall health more than even the $3 trillion health care industry.<br /><br />
Many<br />
times I've seen patients and found the tools I was trained to use <br />
aren't nearly enough to provide help. No physical exam or X-ray can find<br />
a homeless person a bed. No lab test or medication can provide a <br />
laid-off worker with job training or education.<br /><br />
It took more <br />
than a decade for me to learn to ask patients about hunger. I found out <br />
that many of the people I've cared for suffer from food insecurity – not<br />
knowing where their next meal will come from.<br /><br />
"But what can <em>I</em> do about those problems?" my students ask. "Isn't that just social work?"<br /><br />
The answer may surprise you.<br /><br />
In my role as a medical educator, I attended the Beyond Flexner <a href="http://www.medicaleducationfutures.org/projects/beyond-flexner/beyond-flexner-2015/about" target="_blank">conference</a> in Albuquerque, N.M., in early April. The main theme of the meeting, sponsored by the <a href="https://www.wkkf.org/who-we-are/overview" target="_blank">W.K. Kellogg Foundation</a> and others, was this question: "What is the social mission of medical education?"<br /><br />
The conference came about as an outgrowth of a 2010 <a href="http://www.medicaleducationfutures.org/sites/default/files/article-internal/Social%20Mission%20of%20Medical%20Education.pdf" target="_blank">paper</a> that ranked medical schools by their social commitment rather than their research dollars or <em>U.S. News and World Report</em><br />
scores. It began as something of a shot across the bow to organized <br />
medicine, challenging orthodoxy, such as making students memorize the <br />
Krebs cycle.<br /><br />
Over the years since then, more research has shed light on the economic and health impact of social determinants. The <a href="http://www.npr.org/series/389312217/what-shapes-health" target="_blank">media</a> has caught on to this as well.<br /><br />
Nearly<br />
400 medical educators, activists, policymakers and students turned up <br />
to share ideas, hash out strategy and plan a road map for changing <br />
medical education.<br /><br />
Our hosts from the University of New Mexico <br />
demonstrated that medical schools that are serious about community <br />
engagement build strong partnerships that take social determinants into <br />
account. We heard how community health workers and a re-imagination of <br />
the <a href="http://healthextensiontoolkit.org/" target="_blank">agricultural extension</a> model for health education are improving the health of New Mexicans.<br /><br />
To<br />
me, the most surprising aspect of the meeting was just how many medical<br />
schools are now getting serious about the importance of social <br />
determinants.<br /><br />
Many of the sessions at the conference explored <br />
obstacles that stand in the way of a culture change in medical <br />
education. At the top of the list: How to deal with a payment system <br />
that still prioritizes the <em>quantity</em> of medical care over <em>quality</em>? A <a href="http://www.hhs.gov/news/press/2015pres/01/20150126a.html" target="_blank">decision</a><br />
by Medicare earlier this year to base a large proportion of future <br />
payments on quality and value has convinced many of us that the health <br />
system is on the path of change.<br /><br />
I left the conference with new<br />
ideas and fresh energy. I also was left wondering what will replace the<br />
Krebs cycle in the medical education pantheon.<br /><br />
My bet? It will<br />
be a team of students finding ways to break the vicious cycle of <br />
poverty that contributes to so much suffering, illness and early loss of<br />
life.<br /><br />
<em>John Henning Schumann is a writer and doctor in <br />
Tulsa, Okla. He was recently named interim president of the University <br />
of Oklahoma, Tulsa. He also hosts Public Radio Tulsa's</em> <a href="http://kwgs.org/term/medical-matters" target="_blank">Medical Matters</a>. <em>He's on Twitter:</em> <a href="https://twitter.com/GlassHospital" target="_blank">@GlassHospital</a><br /><br />
<a href="http://www.npr.org/blogs/health/2015/04/26/401254790/would-doctors-be-better-if-they-didnt-have-to-memorize?utm_medium=RSS&utm_campaign=news"> : NPR</a>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com1tag:blogger.com,1999:blog-4276174933280603731.post-21160334939443768532015-04-03T08:12:00.001-07:002015-04-03T08:12:39.115-07:00Safety Communications > Olympus Validates New Reprocessing Instructions for Model TJF-Q180V Duodenoscopes<strong>Medical Specialties:</strong> Gastroenterology, Infection Control<br /><br />
<strong>Device:</strong> Olympus Duodenoscope model TJF-Q180V<br /><br />
Olympus<br />
has issued new, validated manual reprocessing instructions for the <br />
TJF-Q180V duodenoscope to replace those provided in the original <br />
labeling. The FDA has reviewed these new reprocessing instructions and <br />
the validation data as part of its ongoing review of the 510(k), and <br />
recommends that any facilities that are using Olympus’ TJF-Q180V <br />
duodenoscope train staff on the new instructions and implement them as <br />
soon as possible.<br /><br />
<strong>Summary of Problem and Scope:</strong><br /><br />
As noted in FDA’s <a href="http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm434871.htm" target="_blank">February 2015 Safety Communication</a>,<br />
the complex design of ERCP endoscopes (also called duodenoscopes) may <br />
impede effective reprocessing. Reprocessing is a detailed, multistep <br />
process to clean and disinfect or sterilize reusable devices. Recent <br />
medical publications and adverse event reports associate <br />
multidrug-resistant bacterial infections in patients who have undergone <br />
ERCP with reprocessed duodenoscopes, even when manufacturer reprocessing<br />
instructions are followed correctly. FDA has been working with <br />
duodenoscope manufacturers as they modify and validate their <br />
reprocessing instructions to further enhance the safety margin of their <br />
devices and show with a high degree of assurance that their reprocessing<br />
instructions, when followed correctly, effectively clean and disinfect <br />
the duodenoscopes.<br /><br />
In September 2014, Olympus initiated testing to<br />
validate new reprocessing instructions. The cleaning validation reports<br />
were provided to FDA in October 2014. While FDA found Olympus’ cleaning<br />
validation data acceptable, initial high level disinfection reports did<br />
not demonstrate an adequate safety margin, and so Olympus conducted <br />
additional testing. At the end of February 2015, Olympus submitted new <br />
high level disinfection validation data to FDA. The agency has reviewed <br />
this data and believes that, when followed, the new, validated <br />
reprocessing instructions for the Olympus TJF-Q180V duodenoscope are <br />
robust, and demonstrate consistent and reliable cleaning and high-level <br />
disinfection. At FDA’s request, Olympus has issued the new, validated <br />
instructions for reprocessing the TJF-Q180V duodenoscope.<br /><br />
To <br />
validate reprocessing instructions for duodenoscopes, manufacturers <br />
should soil their device with bacteria to simulate use in a procedure <br />
and then demonstrate that the device can be adequately disinfected <br />
through a sufficient reduction in microbes when the reprocessing <br />
instructions are correctly followed. To support high level disinfection <br />
of duodenoscopes, the disinfectant should result in a six-log reduction <br />
in the number of microbes at each of several locations on the scope – <br />
that is a one million-fold reduction; or a reduction of 99.9999%.<br /><br />
The<br />
FDA is closely monitoring the possible association between reprocessed <br />
duodenoscopes and the transmission of infectious agents, including <br />
multidrug-resistant bacterial infections caused by Carbapenem-Resistant <br />
Enterobacteriaceae (CRE) such as Klebsiella species and Escherichia <br />
coli. If not properly reprocessed, residual body fluids and organic <br />
debris may remain in microscopic crevices of the device following an <br />
attempted cleaning and high level disinfection. If these residual fluids<br />
contain microbial contamination, subsequent patients may be exposed to <br />
serious infections. The FDA’s investigation into the possible <br />
association between inadequately reprocessed duodenoscopes and patient <br />
infections, including the agency’s recommendations for health care <br />
facilities, is more fully discussed in its <a href="http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm434871.htm" target="_blank">February 2015 Safety Communication</a>.<br /><br />
Olympus sent <a href="http://medical.olympusamerica.com/sites/default/files/pdf/150326_TJF-Q180V_Customer_letter.pdf" target="_blank">letters dated March 26, 2015</a><br />
to health care facilities and other users of the TJF-Q180V outlining <br />
the new, validated reprocessing instructions, and will soon be <br />
distributing revised user manuals.<br /><br />
Please note the key changes to the reprocessing procedure for Olympus’ TJF-Q180V duodenoscope:<br /><br />
<strong>Precleaning:</strong><br /><br />
<ul><li>During immersion, raise and lower the elevator three times</li>
</ul><strong>Manual Cleaning:</strong><br /><br />
<ul><li>Additional brushing of the forceps elevator recess area <ul><li>The<br />
revised cleaning procedure requires brushing of the forceps elevator <br />
recess with two different-sized brushes. In addition to the brush that <br />
is currently used to clean the elevator recess area, the MAJ-1888 brush <br />
(or MAJ-1888 equivalent) will be provided for further cleaning of this <br />
area. Olympus anticipates shipping the MAJ-1888 brushes to facilities no<br />
later than May 8, 2015.</li>
</ul></li>
<li>Additional flushing of forceps elevator recess area</li>
<li>Additional raising/lowering the forceps elevator</li>
</ul><strong>Manual High Level Disinfection:</strong><br /><br />
<ul><li>Additional manual flushing steps and increased flushing volume of each endoscope channel, as well as the elevator recess area</li>
<li>Additional raising/lowering the forceps elevator</li>
</ul>In addition, FDA has the following recommendations for facilities and staff that use and reprocess the Olympus TJF-Q180V:<br /><br />
<ul><li>Implement<br />
the new manual cleaning and high level disinfection procedures for the <br />
Olympus TJF-Q180V duodenoscope in accordance with the manufacturer’s <br />
reprocessing instructions <ul><li>Implement the new TJF-Q180V high level<br />
disinfection procedure immediately. The high level disinfection <br />
procedure does not require additional equipment for implementation.</li>
<li>Implement<br />
the new TJF-Q180V manual cleaning procedure as soon as possible. It <br />
involves the use of a new, smaller bristle cleaning brush (model <br />
MAJ-1888) which Olympus anticipates shipping to facilities no later than<br />
May 8, 2015. Continue using the existing cleaning procedure for manual <br />
cleaning of the TJF-Q180V until the new brush is available.</li>
</ul></li>
<li>Train appropriate staff on Olympus’ new reprocessing instructions and implement them as soon as possible.</li>
<li>Contact<br />
Olympus directly with specific questions and concerns or to schedule a <br />
site visit with their Endoscopy Support Specialists: <ul><li>Technical Assistance Center (TAC), 1-800-848-9024, option 1 Monday - Friday between 7AM EST - 8 PM EST.</li>
</ul></li>
</ul>FDA’s<br />
recommendations are based on currently available information. If new, <br />
important information becomes available, FDA will update its <br />
recommendations.<br /><br />
As noted in<a href="http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/ReprocessingofReusableMedicalDevices/UCM436588.pdf" target="_blank">FDA’s Updated Information for Healthcare Providers Regarding Duodenoscopes</a><br />
issued March 4, 2015, Olympus has a pending 510(k) application for its <br />
TJF-Q180V duodenoscope and the company continues to market its device <br />
while its application is under review. The removal of its device from <br />
the market could lead to an insufficient number of available <br />
duodenoscopes to meet the clinical demand in the United State of <br />
approximately 500,000 procedures per year.<br /><br />
<strong>FDA Activities: </strong><br /><br />
The<br />
FDA is actively engaged with other government agencies, including <br />
Centers for Disease Control and Prevention (CDC), and the manufacturers <br />
of duodenoscopes used in the United States to identify the causes and <br />
risk factors for transmission of infectious agents and develop solutions<br />
to further increase the safety margin of reprocessed devices and <br />
minimize patient exposure to infectious agents.<br /><br />
The agency will convene a public <a href="http://www.fda.gov/AdvisoryCommittees/Calendar/ucm437500.htm" target="_blank">Advisory Committee Meeting</a><br />
on May 14th and 15th, 2015 to seek expert scientific and clinical <br />
opinion related to reprocessing of duodenoscopes and other endoscopes, <br />
as well as use of automated endoscope reprocessors for duodenoscope <br />
reprocessing, based on available scientific information. The committee <br />
will make recommendations on: (1) The effectiveness of cleaning, high <br />
level disinfection, and sterilization methods; (2) the amount and type <br />
of premarket validation data and information needed to support labeling <br />
claims and technical instructions; (3) the appropriate use of other risk<br />
mitigations, such as surveillance cultures; (4) best practices and <br />
guidelines for reprocessing duodenoscopes and endoscopes at user <br />
facilities to minimize the transmission of infections; and (5) <br />
recommended approaches for ensuring patient safety during ERCP <br />
procedures, including a discussion of appropriate patient selection. <br />
Recommendations on these issues will assist FDA in minimizing patient <br />
exposure to infectious agents that may result from reprocessed <br />
duodenoscopes and endoscopes.<br /><br />
The FDA is also working closely with<br />
the manufacturers of reusable medical devices such as duodenoscopes to <br />
ensure that their reprocessing instructions are adequate to clean and <br />
disinfect the devices. The FDA continues to actively monitor this <br />
situation and will provide updates as appropriate.<br /><br />
<strong>Reporting Problems to the FDA: </strong><br /><br />
Device manufacturers and user facilities must comply with the applicable <a href="http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequirements/ReportingAdverseEvents/ucm2005737.htm" target="_blank">Medical Device Reporting (MDR) regulations</a>.<br /><br />
Health care personnel employed by facilities that are subject to the <a href="http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequirements/ReportingAdverseEvents/ucm2005737.htm" target="_blank">FDA's user facility reporting requirements</a> should follow the reporting procedures established by their facilities.<br /><br />
Prompt<br />
reporting of adverse events can help the FDA identify and better <br />
understand the risks associated with medical devices. Health care <br />
providers should submit voluntary reports of the transmission of an <br />
infection due to an inadequately cleaned duodenoscope to the agency via <br />
the <a href="http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/ucm2005291.htm" target="_blank">Medical Device Reporting (MDR)</a> process.<br /><br />
If<br />
a health care provider suspects bacterial contamination—either because <br />
of an increase in infections after ERCP, or because of the results of <br />
bacterial surveillance culturing of duodenoscopes—we encourage the <br />
health care provider to file a voluntary report through <a href="http://www.fda.gov/Safety/MedWatch/HowToReport/ucm2007306.htm" target="_blank">MedWatch, the FDA Safety Information and Adverse Event Reporting program</a>.<br /><br />
<a href="http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm439999.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery">Model TJF-Q180V Duodenoscopes</a>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-65869137766656947572015-04-03T07:57:00.001-07:002015-04-03T07:57:22.188-07:00GastroBreak: White House War on 'Superbugs,' CMS Hep C $$<h2>The latest news and research in gastroenterology.</h2>The White House <a href="https://www.whitehouse.gov/the-press-office/2015/03/27/fact-sheet-obama-administration-releases-national-action-plan-combat-ant" target="_blank">published an extensive plan</a> to slow the emergence and spread of antibiotic-resistant bacteria, including carbapenem-resistant <i>Enterobacteriaceae</i> (CRE), methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), and <i>Clostridium difficile</i>.<br /><br />
Olympus has issued new <a href="http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm439999.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery" target="_blank">disinfecting instructions</a> for its duodenoscopes, which are unapproved by the FDA and have been linked to carbapenem-resistant <i>Enterobacteriaceae</i> (CRE) infections at UCLA Medical Center.<br /><br />
Medicare spent $4.5 billion in 2014 on hepatitis C drugs, a 15-fold <br />
increase compared with 2013's spending on earlier generation <br />
medications, reported <a href="http://www.washingtonpost.com/national/health-science/medicare-spent-45-billion-on-new-hepatitis-c-drugs-last-year-data-shows/2015/03/29/66952dde-d32a-11e4-a62f-ee745911a4ff_story.html" target="_blank">ProPublica</a>.<br /><br />
Nearly two-thirds of patients with colorectal cancer have survival <br />
rates of greater than 5 years, due to improvements in early detection <br />
and treatment, according to a <a href="http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6409a1.htm?s_cid=mm6409a1_w" target="_blank">CDC report</a>.<br /><br />
But one-third of adults are still not getting the recommended screening for colon cancer. One gastroenterologist <a href="http://www.medpagetoday.com/HematologyOncology/ColonCancer/50750" target="_blank">explains</a> how to decrease that number.<br /><br />
Patients with inflammatory bowel disease who are on immunosuppressive<br />
therapy have a less robust response to routine vaccinations, reported <br />
researchers in <a href="http://link.springer.com/article/10.1007%2Fs10620-015-3631-y" target="_blank"><i>Digestive Diseases and Sciences</i></a>.<br /><br />
Three alcoholic drinks per day can cause liver cancer, while coffee may have a protective effect, according to a <a href="http://www.wcrf.org/sites/default/files/Liver-Cancer-2015-Report.pdf" target="_blank">report</a> published by the <a href="http://www.wcrf.org/int/research-we-fund/continuous-update-project-findings-reports" target="_blank">Continuous Update Project</a>.<br /><br />
<a href="http://www.medpagetoday.com/Gastroenterology/GeneralGastroenterology/50759?isalert=1&uun=g482252d3826R5578564u&utm_source=breaking-news&utm_medium=email&utm_campaign=breaking-news&xid=NL_breakingnews_2015-04-01"> | Medpage Today</a>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-55636142004731578012015-03-04T07:52:00.001-08:002015-03-04T07:52:13.089-08:00Clinical Practice Guidelines for the Medical Management of Non-Hospitalized Ulcerative Colitis: The Toronto Consensus - Gastroenterology<h3>Background & Aims</h3>The medical management of ulcerative <br />
colitis (UC) has improved through the development of new therapies and <br />
novel approaches that optimize existing drugs. Previous Canadian <br />
consensus guidelines addressed the management of severe UC in the <br />
hospitalized patient. We now present consensus guidelines for the <br />
treatment of ambulatory patients with mild-to-severe active UC.<br /><br />
<h3>Methods</h3>A<br />
systematic literature search identified studies on the management of <br />
UC. The quality of evidence and strength of recommendations were rated <br />
according to the Grading of Recommendation Assessment, Development, and <br />
Evaluation (GRADE) approach. Statements were developed through an <br />
iterative online platform, then finalized and voted on by a working <br />
group of specialists.<br /><br />
<h3>Results</h3>The participants concluded <br />
that the goal of therapy is complete remission defined as both <br />
symptomatic and endoscopic remission without corticosteroids. The <br />
consensus includes 34 statements focused on five main drug classes, <br />
5-aminosalicylate (ASA), corticosteroids, immunosuppressants, anti-tumor<br />
necrosis factor-alpha (TNF) therapies, and other therapies. Oral and <br />
rectal 5-ASAs are recommended first-line therapy for mild-to-moderate <br />
UC, with corticosteroid therapy for those who fail to achieve remission.<br />
Patients with moderate-to-severe UC, should undergo a course of oral <br />
corticosteroids, with transition to 5-ASA, thiopurines, anti-TNF therapy<br />
(with or without thiopurines or methotrexate), or vedolizumab <br />
maintenance therapy in those who successfully achieve symptomatic <br />
remission. For patients with corticosteroid-resistant/dependent UC, <br />
anti-TNF therapies or vedolizumab are recommended. Timely assessments of<br />
response and remission are critical to ensuring optimal outcomes.<br /><br />
<h3>Conclusions</h3>Optimal<br />
management of UC requires careful patient assessment, evidence-based <br />
use of existing therapies, and thorough assessment to define treatment <br />
success.<br /><br />
<a href="http://www.gastrojournal.org/article/S0016-5085(15)00303-0/abstract?rss=yes">- Gastroenterology</a>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-84175517410611457962015-02-22T03:04:00.001-08:002015-02-22T03:07:06.491-08:00Smartphones, tablets can do damage to overall health in unexpected ways<div dir="ltr" style="text-align: left;" trbidi="on">
Despite the many benefits of having information at your fingertips, smartphones and tablets can do damage to your body and <br />
overall health in unexpected ways.<br />
<br />
<div class="primary-image">
</div>
<a href="http://cdn2.pcpro.co.uk/sites/pcpro/files/styles/thumbnail_large/public/9/22//tablets.jpg?itok=ctRy2ZmA" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="Tiled tablets" border="0" src="http://cdn2.pcpro.co.uk/sites/pcpro/files/styles/thumbnail_large/public/9/22//tablets.jpg?itok=ctRy2ZmA" title="Tiled tablets" /></a>You may not realize it, but all that time spent with your head down <br />
checking email and texting may be creating more than a social gap — you <br />
may also be harming your spine. Research suggests that spinal pressure <br />
actually doubles with each inch you bend your head down.<br />
<br />
Smartphone users spend an average of two to four hours per day <br />
hunched over, says Kenneth Hansraj, chief of spine surgery at New York <br />
Spine Surgery & Rehabilitation Medicine, in his recent report for <br />
Surgical Technology International. As a result, back and neck pain have <br />
increased among users of electronic gadgets, and the effects may linger <br />
for years.<br />
<br />
"Poor posture is easy to spot in the hunched over forms of older <br />
adults who have carried bad habits for a lifetime," said Stephen <br />
Gubernick, Doctor of Chiropractic at The Joint Chiropractic. "However, <br />
few people realize that there are health implications that make good <br />
posture essential for healthy living at any age."<br />
<br />
Dr. Gubernick explained that a misalignment of your spine can affect <br />
your overall health and well-being. Your spine protects your nervous <br />
system, which controls and coordinates all the different functions of <br />
your body. Any disruption in nerve communication to your organs and <br />
tissues may result in abnormal function. "There are countless benefits <br />
from simply improving the alignment of the spine," he added.<br />
<br />
Poor posture negatively impacts your muscles and ligaments, as well <br />
as your spine, which can lead to a host of health problems ranging from <br />
neck and back pain to gastrointestinal problems and even hyperkyphosis —<br />
a condition in which the spine curvature is significantly exaggerated, <br />
with increased risk of pulmonary and arterial health problems.<br />
<br />
When posture or other factors cause a misalignment, a spinal <br />
adjustment is one way to help restore normal nerve function and <br />
communication, thereby allowing your body to work normally and <br />
naturally.<br />
<br />
In addition to recommending exercises that strengthen your core <br />
postural muscles in an effort to sustain and improve posture, a <br />
chiropractor can also assist you with identifying proper posture <br />
techniques to use during daily activities that help reduce the risk of <br />
injury.<br />
<br />
Why Posture Matters<br />
<br />
There are many benefits to practicing good posture. According to the <br />
American Chiropractic Association, keeping your spine aligned properly:<br />
<br />
<ul>
<li>Ensures bones and joints are correctly aligned. This helps the <br />
muscles to be used properly, diminishing the abnormal wear which can <br />
cause degenerative arthritis and joint pain.</li>
<li>Places less stress on the ligaments which link the spinal joints, decreasing the chance of injury.</li>
<li>Creates efficiency within the muscle groups, helping the body use less energy and avoid fatigue.</li>
<li>Reduces the likelihood of back and muscular pain, overuse disorders and muscle strain.</li>
</ul>
Maintaining Good Posture<br />
<br />
Ditching your smartphone probably isn't a practical solution for <br />
improving your posture, so instead work to keep your posture in check <br />
with these tips:<br />
<br />
<ul>
<li>To protect your posture while using your phone and other electronic<br />
devices, avoid angling your head down for prolonged periods. Raise the <br />
device closer to eye level, or use a stand to prop the screen.</li>
<li>Treat back and neck pain, which may signal a posture problem or <br />
worsen poor posture habits, with regular chiropractic adjustments to <br />
keep your body balanced and flexible.</li>
<li>When sitting, avoid crossing your legs and keep your knees at or <br />
below hip level. Use a back pillow to support your lower and middle <br />
back. Relax your shoulders and avoid sitting in the same position for <br />
extended periods of time.</li>
<li>While standing, keep your feet shoulder width apart and your knees <br />
slightly bent. Stand straight with your shoulders pulled back and your <br />
stomach tucked in.</li>
</ul>
<div>
<div>
Source:</div>
<div>
Family Features Editorial Syndicate</div>
</div>
</div>
xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-58883100597803331832015-02-20T09:17:00.001-08:002015-02-20T09:17:32.870-08:00CRE outbreak: You're due to go in for a procedure. Should you be worried? - CNN.com<section id="large-media"><div><div><div id="media__video_large-media_0--wrapper"><div id="large-media_0--thumbnail"><div class="readableLargeImageContainer"><img alt="UCLA narrows cause of superbug infection to 2 tools" height="359" src="http://i2.cdn.turner.com/cnnnext/dam/assets/150219172223-superbug-lead-gfx-02-19-exlarge-169.jpg" width="640" /></div><div><span>UCLA narrows cause of superbug infection to 2 tools</span> <span>01:15</span></div></div></div></div></div></section><div><cite> (CNN)</cite>You're due to go in for a medical procedure. But after what happened at a UCLA hospital, you're a little apprehensive. </div>Two<br />
patients died at the Ronald Reagan UCLA Medical Center in a superbug <br />
CRE outbreak, caused by two medical scopes that still carried the <br />
bacteria even after they were disinfected. <br /><br />
In addition to the two<br />
victims, seven hospital patients were infected with the deadly superbug<br />
between October and January. The medical center has contacted 179 <br />
others who had endoscopic procedures between October and January and is <br />
offering them home tests to screen for the bacteria.<br /><br />
The superbug, carbapenem-resistant Enterobacteriaceae, or CRE, can kill up to half the patients who contract them, the <a href="http://www.cdc.gov/HAI/organisms/cre/" target="_blank">Centers for Disease Control and Prevention says</a>. <br /><br />
So, should you cancel your procedure?<br /><br />
Here's what you need to know: <br /><br />
<strong>1. What type of equipment caused these horrible infections? </strong><br /><br />
They're called duodenoscopes. <br /><br />
The<br />
UCLA hospital was using a duodenoscope made by Olympus Corp. of the <br />
Americas, but the Food and Drug Administration is also reviewing data <br />
from the two other U.S. companies that make the devices, Fujifilm USA <br />
and Pentax Medical.<br /><br />
Duodenoscopes are most commonly used for <br />
procedures on the gallbladder, pancreatic ducts, and the bile ducts, <br />
which are a series of thin tubes that reach from the liver to the small <br />
intestine. <br /><br />
<strong>2. I'm scheduled to get a colonoscopy soon. Should I be worried? </strong><br /><br />
No. Duodenoscopes are not used for colonoscopies. <br /><br />
<strong>3. How common are these infections, and why do they happen? </strong><br /><br />
More<br />
than half a million duodenoscope procedures are done every year in the <br />
United States, and there have been fewer than 100 known cases of <br />
transmission of the CRE bacteria, <a href="http://www.prnewswire.com/news-releases/gastroenterology-societies-discuss-patient-safety-in-gastrointestinal-endoscopy-300024113.html" target="_blank">according to the American Society for Gastrointestinal Endoscopy</a>. <br /><br />
The problem is this: A part of the scope called "the elevator" can be tough to clean because it has many small moving parts.<br /><br />
According to the FDA, the cleaning instructions that come with duodenoscopes say to brush the elevator area -- but <a href="http://www.hopkinsmedicine.org/gastroenterology_hepatology/clinical_services/advanced_endoscopy/endoscopic_retrograde_cholangiopancreatography.html" target="_blank">that might not be enough</a>.<br /><br />
"The<br />
moving parts of the elevator mechanism contain microscopic crevices <br />
that may not be reached with a brush," the FDA said Thursday. "Residual <br />
body fluids and organic debris may remain in these crevices after <br />
cleaning and disinfection. If these fluids contain microbial <br />
contamination, subsequent patients may be exposed to serious <br />
infections." <br /><br />
<strong>4. Yech. I'm supposed to have a procedure with a duodenoscope. Should I cancel it? </strong><br /><br />
No.<br />
A procedure with a duodenoscope can be lifesaving. It can remove <br />
gallstones, for example, or insert a stent into a blocked bile duct. If <br />
you need it, you need it. <br /><br />
<strong>5. OK. My doctor says I need it. So how do I make sure I'm safe? </strong><br /><br />
Remind your doctor that following the manufacturer's cleaning instructions on a duodenoscope might not be enough. <br /><br />
Show your doctor <a href="http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm434871.htm" target="_blank">this advisory from the FDA</a><br />
that recommends additional cleaning practices, including meticulously <br />
cleaning the elevator mechanism by hand. Many hospitals already do this.<br />
<br /><br />
Also, show your doctor <a href="http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6251a4.htm" target="_blank">this article from the Centers for Disease Control</a>:<br />
A hospital in Illinois put a stop to duodenoscope infections by using a<br />
technique called gas sterilization. Other hospitals have started <br />
testing their scopes for bacteria and only using them when the results <br />
come back negative. <br /><br />
<a href="http://edition.cnn.com/2015/02/20/health/cre-outbreak-patient-questions/index.html?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2Fcnn_health+%28RSS%3A+Health%29">- CNN.com</a>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com3tag:blogger.com,1999:blog-4276174933280603731.post-20194440844553160562015-02-19T06:43:00.001-08:002015-02-19T06:43:29.198-08:00Why Your Doctor Might Not Be the Best Nutritional Resource<div class="readableLargeImageContainer"><img alt="Why Your Doctor Might Not Be the Best Nutritional Resource" src="http://i.kinja-img.com/gawker-media/image/upload/s--qTcnpnSx--/c_fit,fl_progressive,q_80,w_636/et7xo1jntuwbibruhnzl.jpg" /></div>Your doctor is one of the most important people to your wellbeing, <br />
and rightfully so. While you should trust their advice on certain <br />
matters, it's also important to understand the boundaries of their <br />
training, and when you should seek outside help.<br />
<br /><br />
I grew up obese despite the fact that both my parents were medical <br />
doctors, and fit ones at that. The few conversations we had about my <br />
weight were essentially lectures on moderation (or simply <a href="http://vitals.lifehacker.com/why-eat-less-move-more-is-the-least-helpful-diet-adv-1686146359" target="_blank">"eat less, move more"</a>).<br /><br />
I always figured the lack of intervention was probably because they <br />
assumed I'd grow out of the chub. Besides, it can't be easy for someone <br />
to dual as parent and diet coach.<br /><br />
Fast forward two decades, and the story is completely different. My <br />
father is now overweight, pops countless (medical) pills for breakfast. <br />
He doesn't know the first thing about losing weight, nor does he care to<br />
learn. Contrastingly, my mother is in great shape, thanks to becoming <br />
an avid consumer of fitness information following my own transformation.<br />
<br /><br />
Looking back, I now know that their silence wasn't because they were <br />
hesitant or unwilling to help me lose weight. It was because they had no<br />
clue <i>how to</i> help me lose weight.<br /><br />
My parents are just n=2, but in my coaching experience, many clients <br />
have reported a similar gap in their own GP's knowledge. Sure, their <br />
doctor can tell them when to lose weight, but dispense poor advice to <br />
help them achieve it. This is unsurprising.<br /><br />
<h3><b>What Doctors Know: Disease vs. Health</b></h3><div class="readableLargeImageContainer"><img alt="Why Your Doctor Might Not Be the Best Nutritional Resource" src="http://i.kinja-img.com/gawker-media/image/upload/s--8FPe3xRG--/lgkmd9aueip6jklo7arw.jpg" /></div>Most doctors spend at least 11 years in school: four years in an <br />
undergraduate program, four years in medical school, and at least three <br />
years in residency (depending on chosen area of expertise). Basically, <br />
doctors learn a whole lot about a whole bunch of stuff, for a long time.<br />
But in all those years, and all those textbooks, very little of that is<br />
about nutrition—<a href="http://vitals.lifehacker.com/exercise-vs-diet-which-is-more-important-for-weight-l-1677532039" target="_blank">the biggest factor in weight loss, </a>and debatably one of the most important factors for overall health.<br /><br />
Of the <a href="https://benbrownmd.wordpress.com/" target="_blank">40,000 hours that doctors spend on training</a>, typically only 19 of those <a href="http://articles.chicagotribune.com/2013-03-26/health/ct-met-heart-nutrition-20130326_1_mediterranean-style-diet-heart-disease-diet-and-nutrition" target="_blank">are devoted to studying nutrition</a>. According to the<a href="http://articles.chicagotribune.com/2013-03-26/health/ct-met-heart-nutrition-20130326_1_mediterranean-style-diet-heart-disease-diet-and-nutrition" target="_blank"> Chicago Tribune</a>, this number is steadily decreasing:<br /><br />
<blockquote>On average, doctors receive 19 hours of total nutrition education in <br />
medical school; in 2004 the average was 22.3 hours, according to the <br />
study, conducted as part of the Nutrition in Medicine project at UNC. In<br />
2009, 27 percent of the schools met the minimum standard of nutrition <br />
training, compared with 38 percent in 2004.</blockquote>As such, it shouldn't be surprising that <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779722/" target="_blank">a study from The Journal of the American College of Nutrition</a><br />
shows that only 14% of internal medicine interns feel they can <br />
adequately talk to their patients about nutrition, while 94% feel it's <br />
their responsibility to do so. Yet, if Dr. Oz's popularity ratings are <br />
any indication, society still considers doctors to be weight loss <br />
authorities.<br />
<br /><br />
To be clear, this is a systematic failing of the medical educational <br />
system, and not the fault of our doctors. Between seeing patients and <i>fixing</i> them—something that they <i>are</i><br />
incredibly knowledgeable about—there's not a lot of time to make up for<br />
their educational shortcomings. Still, it seems silly to <a href="http://www.nytimes.com/2010/09/16/health/16chen.html?_r=0" target="_blank">look to medicine </a>to reduce incidence of disease, when dietary intervention may have prevented some of these in the first place.<br />
<br /><br />
<h3><b>The Problem with Defaulting to Doctors for Nutritional Advice</b></h3><div class="readableLargeImageContainer"><img alt="Why Your Doctor Might Not Be the Best Nutritional Resource" src="http://i.kinja-img.com/gawker-media/image/upload/s--gg3earrh--/yjjhodouzkhzhkejf7tn.jpg" /></div>The nutrition and fitness industry is full of shi—err...<a href="http://lifehacker.com/why-theres-so-much-confusion-over-nutrition-and-fitness-1572870867#_ga=1.163337276.1252495578.1419650584" target="_blank">incredibly confusing</a>,<br />
which is in no way helped by the apparent paralysis of relevant <br />
regulatory parties. Case in point: despite decades of outcry from the <br />
scientific community, the FDA is only <a href="http://vitals.lifehacker.com/the-us-is-finally-dropping-its-outdated-guideline-again-1686339755" target="_blank">now relaxing its message on the dangers of dietary cholesterol</a>.<br /><br />
With conflicting information abound, people deal with confusion in different ways. Some are <i>autodidacts,</i><br />
or self-learners, who read voraciously until they can navigate through <br />
the noise. Most people, however, naturally default to someone they trust<br />
to tell them what to do.<br /><br />
Human beings are subject to something called <a href="http://en.wikipedia.org/wiki/Bounded_rationality" target="_blank">bounded rationality</a>—the<br />
idea that, in the face of complexity, humans sacrifice calculating the <br />
purely rational choice by making mental shortcuts. For most people, <br />
doctors are the gatekeepers of health information. They know doctors are<br />
educated in their profession, and generally trustworthy. Therefore, it <br />
seemingly follows that a doctor's health advice must be reliable.<br /><br />
The problem is that too many people think that "curing disease" is <br />
the same thing as "preventing disease." In reality, these are two <br />
completely different areas of expertise. As my friend Dr. Joseph <br />
Lightfoot once told me: "In medical school, I learned about disease, but<br />
I did not learn about health."<br /><br />
In spite of this, it's hard to imagine a doctor's typical nutritional<br />
recommendations could be harmful, after all how dangerous could an <br />
abundance of cruciferous vegetables be?However, the utility of their <br />
advice is undermined by one of medicine's most basic tenets: "First do <br />
no harm." In other words, they must make sure that any treatment does <br />
not make a patient's situation worse. For nutrition, this often <br />
translates into stock-standard dietary advice.<br /><br />
For example, let's say a doctor is faced with the choice of giving a <br />
recommendation that's in line with the status quo, such as limiting <br />
sodium, or going against the grain by saying that you shouldn't worry <br />
about salt intake. In the doctor's eyes, which is more likely to "do no <br />
harm?" Most doctors would avoid the controversy and just tell their <br />
patient to limit their salt intake, because that's what everyone has <br />
always said. Their assumption is that this advice "does no harm."<br /><br />
The problem is that it <i>does</i> do harm. It increases their <br />
patient's chances of failure, thereby precluding them from the benefits <br />
of maintaining a healthy weight and an enjoyable lifestyle. Quite <br />
simply, research shows that the <a href="http://jama.jamanetwork.com/article.aspx?articleid=1900510" target="_blank">best diet is one you can stick to</a>. By creating <a href="http://dicktalens.com/the-word-healthy-sucks/" target="_blank">false restrictions</a><br />
and limiting choice, you state that there is only one path for success <br />
(the doctor's)—a low sodium, low saturated fat, low cholesterol, <br />
alcohol-free one—when in reality there are many.<br /><br />
According to obesity specialist and frequent Lifehacker contributor <a href="http://drspencer.com/" target="_blank">Dr. Spencer Nadolsky</a>:<br /><br />
<blockquote>Unless trained through ABOM (American Board of Obesity Medicine), <br />
ABPNS (American Board of Physician Nutrition Specialists ), or similar <br />
training/experience, the typical doctor isn't as well equipped to help <br />
with dietary guidance. This doesn't mean the doctor is bad, it just <br />
means it wasn't in their training. </blockquote><h3><b>How to Find a Doctor That Can Help You</b></h3><div class="readableLargeImageContainer"><img alt="Why Your Doctor Might Not Be the Best Nutritional Resource" src="http://i.kinja-img.com/gawker-media/image/upload/s--xCL6m4in--/pxhjok1iophnnoouskeq.jpg" /></div>Of course there are plenty of doctors with abundant nutritional knowledge, like Dr. Nadolsky or <a href="http://www.weightymatters.ca/" target="_blank">Dr. Yoni Freedhoff</a>,<br />
another frequent Vitals contributor. In fact, because of their <br />
multi-domain expertise, these doctors have unique insights around <br />
preventative health <i>and</i> disease that few others possess. The danger, however, is that assuming that all medical doctors have this same expertise.<br /><br />
Here's how to find out if your doctor can help you with your own nutrition and fitness endeavors:<br /><br />
<ul><li><b>Research the latest evidence on topics</b> such as saturated fat, protein intake, and dietary cholesterol. <a href="http://examine.com/faq/" target="_blank">Examine.com's FAQ</a><br />
is a good place to start. Ask your doctor questions about these topics,<br />
such as "Is a high protein diet right for me?" or "Are eggs bad for my <br />
health?" If they default to outdated wisdom without batting an eyelash, <br />
then you may want to seek nutritional guidance elsewhere.</li>
<li><b>Pay close attention to whether or not their advice is specific and actionable.</b><br />
Are their recommendations vague, such as "eat healthy" and "do things <br />
in moderation?" or do they go into specific recommendations, such as <br />
"keep a food journal and track calories."</li>
<li><b>Look at other credentials other than the "Dr." in front of their name.</b> You can <a href="http://library.fsmb.org/pdf/GRPOL_Physician_Profiling.pdf" target="_blank">use this handy PDF</a><br />
to search for a physician's certifications by any state. Are they <br />
trained by the American Board of Obesity Medicine, the American Board of<br />
Physician Nutrition Specialists, or something similar?</li>
<li><b>Be realistic about how well you get along with your doctor.</b> Knowledge isn't everything. Your doctor can be the most knowledgeable in the world, <a href="http://www.schwarzenegger.com/fitness/post/everything-that-you-know-about-motivating-others-is-wrong" target="_blank">but their advice can backfire</a> if you feel that they are overly judgmental or lack empathy.</li>
</ul>At the end of the day, the onus is on you to make sure that you have <br />
the resources you need in order to get (or stay) healthy and fit. Stay <br />
as informed as you can on the latest nutritional research. Don't expect <br />
your doctor's knowledge about medicine to apply to other domains. After <br />
all—like you—they are only human.<br /><br />
<i><small>Images by <a href="http://www.shutterstock.com/pic-197685221/stock-vector-as-a-health-care-and-medicine-icon-with-snakes-crawling-on-a-pole-with-wings-on-golden-metal.html?src=id&ws=1" target="_blank">LalithHerath</a> (Shutterstock), <a href="http://www.shutterstock.com/pic-109532660/stock-vector-two-doctors-vector-illustration.html?src=id&ws=1" target="_blank">murphy81</a> (Shutterstock), <a href="http://www.shutterstock.com/pic-139321682/stock-vector-exercise-equipment-seamless-pattern.html?src=id&ws=1" target="_blank">katherinarspb</a> (Shutterstock), <a href="https://www.flickr.com/photos/caliorg/" target="_blank">caliorg</a>, <a href="https://www.flickr.com/photos/jeremywong01/" target="_blank">Jeremy Wong</a>, and <a href="https://www.flickr.com/photos/115089924@N02/" target="_blank">Ilmicrofono Oggiono</a>.</small></i><br /><br />
<a href="http://vitals.lifehacker.com/why-your-doctor-might-not-be-the-best-nutritional-resou-1686688922?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+lifehacker%2Ffull+%28Lifehacker%29">Why Your Doctor Might Not Be the Best Nutritional Resource</a>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-46419054241809712892015-02-09T18:24:00.001-08:002015-02-09T18:24:46.431-08:006 habits to improve healing after surgery <div><section id="large-media"><div><div class="readableLargeImageContainer"><img alt="A successful surgery depends on a number of factors -- a few of them you can control." height="360" src="http://i2.cdn.turner.com/cnnnext/dam/assets/140902125517-surgery-stock-horizontal-large-gallery.jpg" width="640" /></div><div>A successful surgery depends on a number of factors -- a few of them you can control.</div></div></section><div><cite> (CNN)</cite>The winter is surgery season.</div>People<br />
get into skiing accidents and need to replace knees, or they slip on <br />
ice and need to fix a hip, or they just want to get ready for bikini <br />
weather and schedule a nip here and an enlargement there. <br /><br />
Surgeons are particularly busy these days, but Dr. <a href="http://www.kelsey-seybold.com/find-a-houston-doctor/pages/jamal-bullocks.aspx" target="_blank">Jamal M. Bullocks</a>, a surgeon from the Kelsey-Seybold Clinic in Houston, has advice if you do need surgery. <br /><br />
A successful surgery depends on a number of factors -- a few of them you can control.<br /><br />
Even<br />
minor surgery may pose some risk that has long-term implications. So, <br />
for those considering surgery, there are six habits you need to commit <br />
to right now to help your body heal.<br /><br />
Here's how Bullocks suggests you can improve your chances of recovering more quickly if you do go under the knife: <br /><br />
<h3>Quit smoking</h3>I<br />
shouldn't even have to tell you this. If you smoke, you know this habit<br />
can cause irreparable damage to your organs. It increases your chances <br />
for heart attack and stroke. <br /><br />
Smoking can significantly hamper <br />
the success of your procedure. While in surgery, the damage from smoking<br />
to your airway and lungs makes it more difficult to control your <br />
breathing while you are under anesthesia.<br /><br />
Additionally, because <br />
smoking damages your vascular system, it can bring on complications in <br />
wound healing that may lead to infection and wound breakdown. <br /><br />
If<br />
you smoke and have plans to go under the knife, talk to your physician <br />
about smoking-cessation programs and products and follow his or her <br />
advice. <br /><br />
Use this surgery as an opportunity to improve your overall health by quitting smoking. <br /><br />
<h3>Improve your diet</h3>Malnutrition and the effects of poor eating habits can negatively alter how your body reacts to surgery. <br /><br />
Malnutrition<br />
is a serious condition that can affect overall health and is a concern <br />
for many older adults since senior citizens are at particular risk. <br /><br />
Malnutrition<br />
can weaken your immune system, cause muscle weakness that can decrease <br />
cardiac and respiratory function and may negatively affect wound <br />
healing. <br /><br />
Talk to your physician about your eating habits, and if <br />
he or she determines you need help improving your diet, work with a <br />
registered dietitian before surgery.<br /><br />
<h3>Consider supplements</h3>Even<br />
if you eat a well-balanced diet, your diet may still be lacking in <br />
important vitamins and protein that promote healing after surgery. <br /><br />
Supplemental<br />
vitamins (such as vitamins A, E and C) and protein can promote acute <br />
wound healing -- and despite looking and feeling healthy, your body may <br />
need a boost. <br /><br />
Ask your physician to confirm that you are not <br />
deficient in any vitamins and to test your protein building capacity and<br />
work with him or her to determine an appropriate supplement regimen <br />
before surgery. <br /><br />
<h3>Manage your weight</h3>This is easier said than done. <br /><br />
Being<br />
overweight or obese raises your risk because many people with this <br />
condition have other risk factors such as cardiovascular disease, <br />
respiratory abnormalities, heart failure, hypertension, pulmonary <br />
embolism and deep vein thrombosis.<br /><br />
If you are overweight or obese <br />
and considering a nonurgent surgery, work with your physician to develop<br />
a weight-loss plan and try to attain a healthier weight. <br /><br />
It may help improve your overall condition as well as lower your surgery risk.<br /><br />
<h3>Manage chronic conditions</h3>Diabetes,<br />
kidney disease and hypertension are just a few examples of chronic <br />
conditions that may increase the chances of complications during and <br />
after surgery. <br /><br />
It is important to be in the best possible condition before undergoing surgery. <br /><br />
If<br />
you have a chronic condition that is not well-controlled, work with <br />
your care team to help improve your outcomes before an elective surgery.<br />
<br /><br />
<h3>Follow your doctor's orders</h3>You've chosen your surgeon <br />
to guide you through this experience based on a lot of things. You did <br />
research on this procedure, and he or she came highly recommended. Such a<br />
surgeon may have special credentials or certifications that make you <br />
feel more confident. <br /><br />
You trusted your surgeon enough to start <br />
down the path of preparing for this surgery, so why won't you listen <br />
when we give you special instructions to follow beforehand? <br /><br />
Surgeons<br />
are like every other kind of doctor; they want to help patients improve<br />
their health, but they also want to minimize the risk of a condition <br />
worsening as a result of the surgery. <br /><br />
This is a team effort, and <br />
it is imperative you do your part to eliminate potential problems and <br />
help with a successful outcome. <br /><br />
Follow your surgeon's instructions before surgery -- and <em>always</em> ask questions if something is confusing or unclear. </div><a href="http://edition.cnn.com/2015/02/09/health/surgery-improve-healing/index.html?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2Fcnn_health+%28RSS%3A+Health%29"> - CNN.com</a>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-90147511332473887492014-11-07T09:39:00.001-08:002014-11-07T09:39:54.889-08:00Dabigatran: More Bleeds in Practice Than Expected<div style="text-align: justify;"><br /><br />
<aside><div><a class="readableLinkWithLargeImage" href="http://www.medpagetoday.com/Cardiology/Prevention/48425#" target="_blank"></a><br /><br />
<div class="readableLargeImageContainer"><a class="readableLinkWithLargeImage" href="http://www.medpagetoday.com/Cardiology/Prevention/48425#" target="_blank"><img src="http://www.medpagetoday.com/upload/2014/11/5/48425_wide.jpg" height="480" width="640" /></a></div><a class="readableLinkWithLargeImage" href="http://www.medpagetoday.com/Cardiology/Prevention/48425#" target="_blank"><br />
</a><br /><br />
<div>Discussant: Judy Mackall, MD <br /><br />
Please click the bottom right corner for full screen.</div><br /><br />
<section><header><h2>Action Points</h2></header></section></div></aside></div><div style="text-align: justify;">Dabigatran<br />
(Pradaxa) was associated with higher risk of bleeding than warfarin <br />
(Coumadin) in a large Medicare population sample, unlike the equal risk <br />
seen in the pivotal RE-LY trial.</div><div style="text-align: justify;">The relative risk was 30% higher for any bleeding with the direct thrombin inhibitor than warfarin and <a href="http://archinte.jamanetwork.com/article.aspx?articleid=1921753" target="_blank">58% higher for major bleeding </a>(propensity adjusted rate 9.0% versus 5.9%, <i>P</i><0.001), <a href="http://www.healthpolicyinstitute.pitt.edu/node/374" target="_blank">Yuting Zhang, PhD</a>, of the University of Pittsburgh, and colleagues reported online in <i>JAMA Internal Medicine</i>.</div><div style="text-align: justify;">By contrast, the pivotal <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa0905561#t=articleResults" target="_blank">RE-LY trial had shown no difference in major bleeding risk</a><br />
between the two drugs, with an annual rate of 3.36% for warfarin versus<br />
3.11% with the approved 150-mg dose of dabigatran, for a relative risk <br />
of 0.93 (<i>P</i>=0.31).</div><div style="text-align: justify;">The nationally-representative, <br />
5%-sample Medicare analysis did agree qualitatively with the trial <br />
results on higher risk of GI bleeds and lower likelihood of intracranial<br />
bleeding than warfarin.</div><div style="text-align: justify;">The hazard ratio for GI bleeding on <br />
dabigatran was 1.85 (95% confidence interval 1.64-2.07) versus warfarin,<br />
whereas the hazard ratio for intracranial hemorrhage of 0.32 (95% CI <br />
0.20-0.50) favored dabigatran over the older drug. In RE-LY, the hazard <br />
ratio for major GI bleeding with the 150-mg dabigatran dose versus <br />
warfarin was considerably lower, at 1.50.</div><div style="text-align: justify;">A prior FDA analysis of <br />
Medicare data had agreed with the trial on overall bleeding risk, but <br />
Zhang's group argued that its lack of adjustment for patient factors was<br />
a major flaw.</div><div style="text-align: justify;">"Dabigatran and warfarin users are very different <br />
in several factors that directly affect the risk of bleeding, and <br />
failing to adjust would bias the results, as our unadjusted estimates <br />
indicate," they wrote.</div><div style="text-align: justify;">Their results were propensity weighted to <br />
account for demographic variables (age, sex, race, and Medicaid <br />
eligibility) and clinical characteristics, including the stroke risk <br />
CHADS<sub>2</sub> score, chronic kidney disease, hypertension, history <br />
of stroke or transient ischemic attack, history of acute myocardial <br />
infarction, diabetes, congestive heart failure, acquired hypothyroidism,<br />
the number of other CMS-priority comorbidities, and history of bleeding<br />
in the year prior to treatment initiation.</div><div style="text-align: justify;">And there was a <br />
significantly higher prevalence of chronic kidney disease, congestive <br />
heart failure, diabetes, and history of stroke or transient ischemic <br />
attack in those who took warfarin. Propensity score weighting balanced <br />
out those characteristics.</div><div style="text-align: justify;">The retrospective analysis of pharmacy <br />
and medical claims from a random 5% sample of Medicare beneficiaries <br />
newly diagnosed with atrial fibrillation from Oct. 1, 2010, through Oct.<br />
31, 2011 included 1,302 starting on dabigatran and 8,102 initiating <br />
warfarin within 60 days of initial diagnosis.</div><div style="text-align: justify;"><b>Clinical Implications</b></div><div style="text-align: justify;">"Thus, dabigatran should be prescribed with caution, especially among high-risk patients," they cautioned.</div><div style="text-align: justify;">The<br />
risk of major bleeding on dabigatran was particularly high for African <br />
Americans (HR 2.12, 95% confidence interval 1.39-3.24) and patients with<br />
chronic kidney disease (HR 2.07, 95% CI 1.66-2.58).</div><div style="text-align: justify;">The findings were cause for concern, according to an editor's note accompanying the paper from <a href="http://www.ucsfhealth.org/rita.redberg" target="_blank">Rita F. Redberg, MD</a>, calling the bleeding risks of dabigatran "significantly greater than originally appeared at the time of the FDA approval."</div><div style="text-align: justify;">"Dabigatran<br />
was approved by the FDA in 2010 via the accelerated pathway after a <br />
6-month review. The haste to approve novel drugs places an increasing <br />
importance on post-approval data to help better understand risks and <br />
benefits," wrote Redberg, a cardiologist at the University of California<br />
San Francisco.</div><div style="text-align: justify;">"This study reminds us of the importance of <br />
postmarketing data and of having adequate data on risks and benefits to <br />
advise our patients accurately."</div><div style="text-align: justify;"><a href="http://www.uhhospitals.org/find-a-doctor/mackall-judith-864" target="_blank">Judy Mackall, MD</a>,<br />
section chief for cardiac electrophysiology at University Hospitals <br />
Case Medical Center in Cleveland, was less convinced that the data were <br />
influential for practice.</div><div style="text-align: justify;">"A lot of what's in this study we were already aware of from RE-LY study," she told <i>MedPage Today</i>.</div><div style="text-align: justify;">As far as the increased risk of GI bleeding, Mackall pointed to one theory.</div><div style="text-align: justify;">"Dabigatran<br />
is delivered as a pro-drug," she said. "About 6% gets absorbed and the <br />
rest passes through the GI tract as an inactive anticoagulant."</div><div style="text-align: justify;">But the lower risk of intracranial bleeding outweighs the concern about GI bleeds, she suggested.</div><div style="text-align: justify;">"GI<br />
bleed is significant, yes, it's treatable most often. Getting a lower <br />
risk of intracranial bleeding is a big safety concern," she said. <br />
"Intracranial bleeding is the major bleeding that we worry about because<br />
that's not easily correctable."</div><div style="text-align: justify;">The researchers urged that <br />
because of the GI bleeding risk across all subgroups "it is important <br />
for physicians to explain to patients how to detect gastrointestinal <br />
bleeding so that it can be controlled as early as possible."</div><div style="text-align: justify;">But <br />
"intracranial hemorrhage is the most feared complication associated with<br />
warfarin," they agreed, "thus, patients at high risk of intracranial <br />
hemorrhage may be willing to accept the higher risk of other bleeding <br />
events associated with dabigatran for a lower likelihood of intracranial<br />
bleeding. Arguably, this is the subgroup in which dabigatran is most <br />
likely to be a favorable choice in terms of safety."</div><hr style="margin-left: 0px; margin-right: 0px;" /><a href="https://www.pinterest.com/pin/create/extension/" style="background-color: transparent; background-image: url("data:image/png; border: medium none; cursor: pointer; display: none; height: 20px; opacity: 0.85; position: absolute; width: 40px; z-index: 8675309;"></a>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-25495622618592989012014-10-27T06:53:00.001-07:002014-10-27T06:53:32.618-07:00Medical Technology Needs Better Apps… Stat! <div> <div class="readableLargeImageContainer"><img height="266" src="https://openstandard.mozilla.org/files/2014/10/Health1-770x321.jpg?8954f8" width="640" /></div><div> Patients will expect hospitals to solve IT problems <br />
that can add costs and stifle disclosure. Credit: Flickr/Jason Howie <br />
</div></div><h2>Patients are increasingly tech savvy but hospitals need to pick up their pace.</h2><hr /> <br />
<br />
Easy access to health care data is critical. But as <br />
hospitals move to adopt new gadgets and systems that promise to make <br />
them work faster and better, too often medical teams are instead stuck <br />
working with a patchwork of old and new technology that doesn’t save <br />
time, money or sanity.<br /><br />
<br />
In September, West Health CEO Nick Valeriani sounded an alarm over the state of medical technology in the U.S. In an <a href="http://medcitynews.com/2014/09/keeping-interoperability/" target="_blank">op-ed</a><br />
for MedCity News, the former Johnson & Johnson executive wrote, <br />
“healthcare workers spend, on average, a third of their time <br />
transcribing data from medical devices because most machines don’t share<br />
data.” He reported that the nation pays more than $30 billion annually <br />
because of laborious information transfers from instruments such as a <br />
blood pressure gauge or thermometer to a patient’s electronic health <br />
record (EHR).<br /><br />
<br />
<strong>Nurses feel left out, too</strong><br /><br />
<br />
Valeriani isn’t the only one dissatisfied with the status quo. The data comparison firm Black Book <a href="http://www.healthitoutcomes.com/doc/nurses-hate-ehrs-too-0001" target="_blank">polled</a><br />
13,650 registered nurses and found 85 percent reported struggling daily<br />
with their hospitals’ EHR systems. Still more reported feeling excluded<br />
from decisions relating to their hospitals’ EHR systems — even though <br />
they are the primary users.<br /><br />
<br />
<blockquote>“Healthcare workers spend, on average, a third of their <br />
time transcribing data from medical devices because most machines don’t <br />
share data”</blockquote>There’s another digital divide. Outside the walls of hospitals, <br />
consumers turn to a wealth of online medical information — much of it <br />
now reliable and well-sourced — for prevention or self-education before <br />
contacting a medical professional. Your fitness tracker might connect to<br />
an app, which connects to a personal health record that keeps all of <br />
your vital stats and emergency information and allows you to share it <br />
with relatives and doctors. Patients are left wondering when their <br />
medical offices will ditch that clipboard and catch up.<br /><br />
<br />
Hospitals and health organizations alike are beginning to take on <br />
that challenge and improve communication between devices, and between <br />
doctors and patients, with easy-access communication systems, medical <br />
monitoring tools and mobile technology.<br /><br />
<br />
The proliferation of mobile devices like tablets and increasingly <br />
tablet-like smart phones has sparked creation of tools that can change <br />
how, and how often, doctors and patients visit. As the efficiency and <br />
transparency of medical information grows, the costs of services are <br />
better controlled.<br /><br />
<br />
<strong>Smart Pill Bottles</strong><br /><br />
<br />
On such company is <a href="http://adheretech.com/" target="_blank">AdhereTech</a>,<br />
which developed smart, wireless pill bottles that track whether <br />
patients are sticking to their prescribed pill regimen. That gives <br />
doctors more accurate, real time information, reminds patients to <br />
actually take their pills or get more, and ultimately saves hospitals <br />
money. Sotera Wireless’ <a href="http://www.visimobile.com/" target="_blank">Visi Mobile</a><br />
System includes a wearable touch screen monitor that sends real-time <br />
vital sign statistics such as pulse rate, blood pressure and temperature<br />
to clinicians.<br /><br />
<br />
One of the leaders in improving records access for medical providers <br />
and patients alike is is Seattle-based Group Health Cooperative. It’s a <br />
non-profit insurance and health care system that been <a href="http://www.oregonlive.com/health/index.ssf/2009/08/nw_nonprofit_health_care_plans.html" target="_blank">hailed as a model</a> nationwide, in part for developing a cohesive health records system that includes the patient service, <a href="http://mygrouphealth.com/" target="_blank">mygrouphealth.com</a>.<br />
Group Health members use it to make appointments, review their medical <br />
history, test results and prescriptions, and to talk with their doctors <br />
via email and see what upcoming wellness checks they need.<br /><br />
<br />
<a href="http://www.myopennotes.org/" target="_blank">Open Notes</a> <br />
is a national initiative to give patients free access to the notes their<br />
doctors write via online portals. “The clinical note has historically <br />
been a way for doctors to communicate amongst themselves about patient <br />
care; the notes were not written with patient viewing in mind,” says <br />
Joann Elmore, M.D., MPH, professor at the University of Washington <br />
School of Medicine and Harborview Medical Center. “Before electronic <br />
notes were available, patients had to jump through hoops to get their <br />
notes.”<br /><br />
<br />
<strong>Putting doctors’ notes online</strong><br /><br />
<br />
Three hospitals, in Massachusetts, Pennsylvania and Washington, <br />
participated in an initial 12-month study, in which patients reported <br />
that as a result of being able to read doctors’ notes online, they felt <br />
more in control of their care, better understood their health <br />
conditions, better recalled their care plan and were likely to take <br />
their medications as prescribed<br /><br />
<br />
Elmore says that doctors were initially less enthusiastic about the <br />
idea of Open Notes, worrying it would create more work. “Many of us are <br />
already struggling with the ever-increasing workload of documentation <br />
and having to type notes and navigate the electronic health record <br />
systems. However, after the 12-month experiment, doctors were <br />
re-surveyed and reported that OpenNotes had much less impact on their <br />
work flow than they anticipated.” Ninety-nine percent of patients wanted<br />
to continue sharing visit notes.<br /><br />
<br />
The Health Information Technology for Economic and Clinical Health <a href="http://www.hhs.gov/ocr/privacy/hipaa/understanding/coveredentities/hitechnprm.html" target="_blank">(HITECH) Act</a><br />
has been nudging electronic medical records open for several years, <br />
encouraging hospitals to use online electronic medical records and <br />
requiring them to allow patients to request and get their information <br />
electronically.<br /><br />
<br />
But it doesn’t address how systems can talk to each other, leaving <br />
medical professionals frustrated and private companies inventing ever <br />
more groundbreaking devices — while more patients shop between systems <br />
and keep and manage their own medical data.<br /><br />
<a href="https://openstandard.mozilla.org/medical-technology-needs-better-apps-stat/">| The Open Standard</a>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-65241623478969726862014-09-08T07:49:00.000-07:002014-09-08T07:49:00.043-07:00Why ab workouts are a waste of time - CNN.com<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="Bad advice and outdated research could be putting a kink in your workout efforts. Here are some fitness myths that have proved to be just that. " src="http://i2.cdn.turner.com/cnn/dam/assets/140320120551-fitness-myths-1-horizontal-gallery.jpg" id="articleGalleryPhoto001" /></div>
<cite id="galleryCaption001">Bad advice and outdated research could be <br />
putting a kink in your workout efforts. Here are some fitness myths that<br />
have proved to be just that. </cite><br />
<br /></div>
<div>
<div class="readableLargeImageContainer">
<img alt="Crunches do tone a small portion of your abs, but you may get better results from moves engaging your entire core." src="http://i2.cdn.turner.com/cnn/dam/assets/140320120713-fitness-myths-2-horizontal-gallery.jpg" id="articleGalleryPhoto002" /></div>
<cite id="galleryCaption002">Crunches do tone a small portion of your abs, but you may get better results from moves engaging your entire core.</cite><br />
<br /></div>
<div>
<div class="readableLargeImageContainer">
<img alt="Sweating doesn't equate to calories burned. It might be the result of a hot room, the weather or your physiology." src="http://i2.cdn.turner.com/cnn/dam/assets/140320120735-fitness-myths-3-horizontal-gallery.jpg" id="articleGalleryPhoto003" /></div>
<cite id="galleryCaption003">Sweating doesn't equate to calories burned. It might be the result of a hot room, the weather or your physiology.</cite><br />
<br /></div>
<div>
<div class="readableLargeImageContainer">
<img alt="Running is safer on your joints than contact sports, but it's not totally harmless. A total-body workout at least twice a week along with regular jogs can build up muscles supporting the knees." src="http://i2.cdn.turner.com/cnn/dam/assets/140320120804-fitness-myths-4-horizontal-gallery.jpg" id="articleGalleryPhoto004" /></div>
<cite id="galleryCaption004">Running is safer on your joints than <br />
contact sports, but it's not totally harmless. A total-body workout at <br />
least twice a week along with regular jogs can build up muscles <br />
supporting the knees.</cite><br />
<br /></div>
<div>
<div class="readableLargeImageContainer">
<img alt="Stretching after exercise won't completely reduce soreness or speed muscle tissue repair, but can increase joint flexibility. " src="http://i2.cdn.turner.com/cnn/dam/assets/140320121001-fitness-myths-5-horizontal-gallery.jpg" id="articleGalleryPhoto005" /></div>
<cite id="galleryCaption005">Stretching after exercise won't completely reduce soreness or speed muscle tissue repair, but can increase joint flexibility. </cite><br />
<br /></div>
<div>
<div class="readableLargeImageContainer">
<img alt="More and more studies are pointing to the power of short workouts rather than longer ones. Some research even suggests quickie sessions might be better." src="http://i2.cdn.turner.com/cnn/dam/assets/140320121329-fitness-myths-6-horizontal-gallery.jpg" id="articleGalleryPhoto006" /></div>
<cite id="galleryCaption006">More and more studies are pointing to the <br />
power of short workouts rather than longer ones. Some research even <br />
suggests quickie sessions might be better.</cite><br />
<br /></div>
<div>
<div>
<div class="readableLargeImageContainer">
<img alt="Scheduling rest days is crucial. Working out every day can lead to injury or overtraining, which keeps your muscles from rebounding and your body from improving." src="http://i2.cdn.turner.com/cnn/dam/assets/140320121356-fitness-myths-7-vertical-gallery.jpg" id="articleGalleryPhoto007" /></div>
</div>
<cite id="galleryCaption007">Scheduling rest days is crucial. Working <br />
out every day can lead to injury or overtraining, which keeps your <br />
muscles from rebounding and your body from improving.</cite><br />
<br /></div>
<div>
<div class="readableLargeImageContainer">
<img alt="Research has shown that skipping sleep may lead to weight gain. Even partial sleep deprivation ups production of the hormone ghrelin, which triggers hunger." src="http://i2.cdn.turner.com/cnn/dam/assets/140320121422-fitness-myths-8-horizontal-gallery.jpg" id="articleGalleryPhoto008" /></div>
<cite id="galleryCaption008">Research has shown that skipping sleep may <br />
lead to weight gain. Even partial sleep deprivation ups production of <br />
the hormone ghrelin, which triggers hunger.</cite><br />
<br /></div>
<div>
<div class="readableLargeImageContainer">
<img alt="Yoga improves strength and flexibility, but it doesn't burn as many calories as aerobic exercise, researchers say." src="http://i2.cdn.turner.com/cnn/dam/assets/140320121447-fitness-myths-9-horizontal-gallery.jpg" id="articleGalleryPhoto009" /></div>
<cite id="galleryCaption009">Yoga improves strength and flexibility, but it doesn't burn as many calories as aerobic exercise, researchers say.</cite><br />
<br /></div>
<div>
<div class="readableLargeImageContainer">
<img alt="Women have less muscle tissue and produce lower levels of testosterone than men, so they're less likely to bulk up from lifting weights." src="http://i2.cdn.turner.com/cnn/dam/assets/140320121540-fitness-myths-10-horizontal-gallery.jpg" id="articleGalleryPhoto0010" /></div>
<cite id="galleryCaption0010">Women have less muscle tissue and produce <br />
lower levels of testosterone than men, so they're less likely to bulk up<br />
from lifting weights.</cite><br />
<br /></div>
<div id="gallerySlideTitle001">
Fitness: Myths vs. facts</div>
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</div>
</div>
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<i><b>Editor's note:</b> Personal trainer Steve Steinberg is the owner of <a href="http://www.blackbeltfitness.com/" target="_blank">Black Belt Fitness Personal Training </a>and author of "Fix Your Body, Fix Your Swing."</i><br />
<br />
<br />
<b>(CNN)</b> -- You've been trying forever to get that <br />
elusive six-pack: the holy grail of fitness goals. None of the gizmos <br />
and doodads advertised online or on TV have worked, so you figure it's <br />
time to sign up for that 30-minute abs class at the gym.<br />
<br />
<br />
Heck, what could be better for getting washboard abs than doing 9 <br />
million crunches, reverse crunches, twisting crunches, crunches with <br />
someone holding your feet, crunches with someone sitting on your chest, <br />
crunches with a cinderblock on your forehead, right?<br />
<br />
<br />
Wrong.<br />
<br />
<br />
"Everyone already has a six-pack. It's just hidden under layers of <br />
body fat," said personal trainer Lecia Whitlock, an instructor at the <br />
National Personal Training Institute. "The key to getting a lean <br />
midsection is to reduce your overall percentage of body fat. And <br />
crunches just aren't a very effective way to do that."<br />
<br />
<br />
<a href="http://www.cnn.com/2013/12/27/health/workout-habits/" target="_blank">7 workout habits to drop now</a><br />
<br />
<br />
Losing body fat -- whether it's in your arms, legs, hips or abs -- is<br />
done by creating a daily caloric deficit so your body has to tap into <br />
stored energy, or body fat, to feed your muscles and keep you going.<br />
<br />
<br />
To do this, you'll want to launch a three-pronged attack.<br />
<br />
<br />
<div id="expand18">
<br />
<img src="http://i2.cdn.turner.com/cnn/dam/assets/120714064006-nr-nathanson-ab-workout-00015618-story-body.jpg" height="120" width="214" /><cite>Great abs without the crunches</cite></div>
<div id="expand28">
<br />
<img src="http://i2.cdn.turner.com/cnn/dam/assets/120324073145-mobile-apps-that-help-you-lose-weight-00005214-story-body.jpg" height="120" width="214" /><cite>Mobile apps that help you lose weight</cite></div>
<div id="expand38">
<br />
<img src="http://i2.cdn.turner.com/cnn/dam/assets/111028051351-mxp-lbn-core-workout-00005830-story-body.jpg" height="120" width="214" /><cite>Trainer: work your core, you can do more</cite></div>
Building lean muscle through resistance training will force your body<br />
to burn more calories daily. Muscle is living tissue. The more of it <br />
you have and the more of it you use on regularly, the more calories your<br />
body requires to function properly.<br />
<br />
<br />
Adding multiple bouts of intense cardiovascular work -- 30-minute <br />
sessions three to four times per week -- is a quick way to burn big <br />
chunks of calories in a short time.<br />
<br />
<br />
<a href="http://www.cnn.com/2010/HEALTH/12/28/fastest.fat.burners/" target="_blank">51 fastest fat burners</a><br />
<br />
<br />
Finally, you'll want to make sure that your diet isn't loaded with a <br />
lot of extra, empty calories. For the most part, the more calories that <br />
you take in, the more you'll have to burn to lose weight.<br />
<br />
<br />
"Most people underestimate how much they eat and overestimate how <br />
much they've exercised, and that's a lethal combination for someone <br />
trying to lose weight," said Whitlock.<br />
<br />
<br />
What's nice is that the work you'll be doing in the gym -- whether <br />
it's strength training or cardio -- can be just as much of a workout for<br />
your midsection as any "abs blaster" class at your gym. And choosing <br />
movements that engage the abs and other core muscles will actually help <br />
you in your quest for a trimmer waistline.<br />
<br />
<br />
Try doing your chest presses while lying on a stability ball instead <br />
of on a bench. Replace the leg presses you do using a machine with just <br />
about any type of lunge.<br />
<br />
<br />
<br />
"As your core becomes stronger, it allows you to build your other <br />
muscles more effectively," Whitlock explaned. "And by building those <br />
other muscles, you'll be increasing your metabolism, which is one of the<br />
keys to lowering your overall body fat."<br />
<br />
<br />
<a href="http://www.cnn.com/2013/02/12/health/easy-ways-kickstart-metabolism/" target="_blank">7 easy ways to kickstart your metabolism</a><br />
<br />
<br />
Conveniently, when it comes to cardio, the exercises that challenge <br />
your midsection are also the ones that have the highest rates of calorie<br />
burn.<br />
<br />
<br />
Think about a kickboxing or Latin dance class. Even choosing standing<br />
exercises like the elliptical or treadmill over seated exercises like <br />
the stationary bike will cause you to burn more calories per minute and <br />
force your midsection to work harder.<br />
<br />
<br />
"When most people think about their core, they only think about their<br />
abs," said Whitlock. "In reality, the core is made up of all the <br />
muscles that control, move and stabilize the hips and lower torso."<br />
<br />
<br />
So by incorporating a variety of different movements into your <br />
workout, you'll also make sure you're strengthening your entire core.<br />
<br />
<br />
Weakness or muscular imbalances in the core can lead to everything <br />
from lower back pain to issues with your knees and posture. By ditching <br />
your abs class in favor of a full-body workout, you'll not only be <br />
heading in a straighter direction toward your six-pack, but you'll also <br />
be working to prevent potential injuries down the road.</div>
xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-76518482399361701012014-09-07T07:50:00.000-07:002014-09-07T07:50:00.520-07:00Stick Your Tongue Out to Release Tension From Your Body<div dir="ltr" style="text-align: left;" trbidi="on">
<div class="readableLargeImageContainer">
<img alt="Stick Your Tongue Out to Release Tension From Your Body" src="http://i.kinja-img.com/gawker-media/image/upload/s---56ol8Q3--/cxoum4b2aleb2lmey4tq.jpg" /></div>
When<br />
we get stressed, we tense our muscles. Our neck, shoulders and back <br />
all feel tight. One way to release that tension is an exercise that <br />
involves sticking out your tongue.<br />
<br />
Entrepreneur contributor Arthur Joseph has an exercise (that you'll probably want to do in private) to help you loosen up a bit:<br />
<br />
<blockquote>
In front of a mirror, release your tongue and jaw and neck and <br />
shoulder tension by placing two fingertips in your mouth under your <br />
tongue and gently release. Your tongue should appear relaxed, not <br />
concave or convex, simply flaccid (the feeling of drooling). Place your <br />
other hand right under your lip line, forming a V between your thumb and<br />
index finger and gently pull your jaw down a half to one inch.<br />
<br />
While<br />
observing yourself, you will likely see that your tongue pulls back, <br />
your head dips down and your neck and shoulders are tense. As you <br />
consistently do this exercise, you will not only feel more relaxed and <br />
confident, you will appear that way as well.</blockquote>
Sure, it<br />
feels and looks a bit strange, but it's another quick exercise you can <br />
do anywhere and relax a bit more. I'd suggest you wash your hands before<br />
trying this tip.<br />
<br />
<a href="http://www.entrepreneur.com/article/235302" target="_blank">Develop the Body Language of a Leader With These 5 Exercises</a> | Entrepreneur </div>
xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-10391186940112539162014-08-20T16:52:00.000-07:002014-08-20T16:52:00.299-07:00'Trojan horse' gold nanoparticles treatment could beat brain tumors<div dir="ltr" style="text-align: left;" trbidi="on">
<article><figure>
<div>
<div class="readableLargeImageContainer">
<img alt="'Trojan horse' treatment could beat brain tumors" src="http://cdn.phys.org/newman/gfx/news/2014/trojanhorset.jpg" /></div>
<a href="http://cdn.phys.org/newman/gfx/news/hires/2014/trojanhorset.jpg" target="_blank" title="A cancer cell containing the nanoparticles. The nanoparticles are colored green, and have entered the nucleus, which is the area in blue. Credit: M. Welland">Enlarge</a></div>
<figcaption><br />
A cancer cell containing the nanoparticles. The nanoparticles are <br />
colored green, and have entered the nucleus, which is the area in blue. <br />
Credit: M. Welland</figcaption> </figure><figure>A "Trojan horse" treatment for an aggressive form of brain cancer, </figure><section>
which involves using tiny nanoparticles of gold to kill tumour cells, <br />
has been successfully tested by scientists.<br />
<br />
The ground-breaking technique could eventually be used to treat <a href="http://phys.org/tags/glioblastoma/" target="_blank">glioblastoma</a><br />
multiforme, which is the most common and aggressive brain tumour in <br />
adults, and notoriously difficult to treat. Many sufferers die within a <br />
few months of diagnosis, and just six in every 100 patients with the <br />
condition are alive after five years.<br /><br />
The research involved engineering nanostructures containing both gold<br />
and cisplatin, a conventional chemotherapy drug. These were released <br />
into tumour cells that had been taken from glioblastoma patients and <br />
grown in the lab.<br />
<br />
Once inside, these "nanospheres" were exposed to radiotherapy. This <br />
caused the gold to release electrons which damaged the cancer cell's DNA<br />
and its overall structure, thereby enhancing the impact of the <br />
chemotherapy drug.<br />
<br />
The process was so effective that 20 days later, the cell culture <br />
showed no evidence of any revival, suggesting that the tumour cells had <br />
been destroyed.<br /><br />
While further work needs to be done before the same technology can be<br />
used to treat people with glioblastoma, the results offer a highly <br />
promising foundation for future therapies. Importantly, the research was<br />
carried out on cell lines derived directly from glioblastoma patients, <br />
enabling the team to test the approach on evolving, drug-resistant <br />
tumours.<br /><br />
The study was led by Mark Welland, Professor of Nanotechnology and a <br />
Fellow of St John's College, University of Cambridge, and Dr Colin <br />
Watts, a clinician scientist and honorary consultant neurosurgeon at the<br />
Department of Clinical Neurosciences. Their work is reported in the <br />
Royal Society of Chemistry journal, <i>Nanoscale</i>.<br />
<br />
"The combined therapy that we have devised appears to be incredibly <br />
effective in the live cell culture," Professor Welland said. "This is <br />
not a cure, but it does demonstrate what nanotechnology can achieve in <br />
fighting these aggressive cancers. By combining this strategy with <br />
cancer cell-targeting materials, we should be able to develop a therapy <br />
for glioblastoma and other challenging cancers in the future."<br /><br />
<figure><div>
<div class="readableLargeImageContainer">
<img alt="'Trojan horse' treatment could beat brain tumors" src="http://cdn.phys.org/newman/gfx/news/2014/1-trojanhorset.jpg" /></div>
<a href="http://cdn.phys.org/newman/gfx/news/hires/2014/1-trojanhorset.jpg" target="_blank" title="A diagram showing the composition of the nanosphere. Credit: M. Welland">Enlarge</a></div>
<figcaption><br />
diagram showing the composition of the nanosphere. Credit: M. Welland</figcaption></figure>
To date, <a href="http://phys.org/tags/glioblastoma+multiforme/" target="_blank">glioblastoma multiforme</a> (GBM) has proven very resistant to treatments. One reason for this is that the <a href="http://phys.org/tags/tumour+cells/" target="_blank">tumour cells</a> invade surrounding, healthy brain tissue, which makes the surgical removal of the tumour virtually impossible.<br />
<br />
Used on their own, <a href="http://phys.org/tags/chemotherapy+drugs/" target="_blank">chemotherapy drugs</a><br />
can cause a dip in the rate at which the tumour spreads. In many cases,<br />
however, this is temporary, as the cell population then recovers.<br />
<br />
"We need to be able to hit the cancer cells directly with more than <br />
one treatment at the same time" Dr Watts said. "This is important <br />
because some cancer cells are more resistant to one type of treatment <br />
than another. Nanotechnology provides the opportunity to give the cancer<br />
cells this 'double whammy' and open up new treatment options in the <br />
future."<br /><br />
In an effort to beat tumours more comprehensively, scientists have <br />
been researching ways in which gold nanoparticles might be used in <br />
treatments for some time. Gold is a benign material which in itself <br />
poses no threat to the patient, and the size and shape of the particles <br />
can be controlled very accurately.<br />
<br />
When exposed to radiotherapy, the particles emit a type of low energy<br />
electron, known as Auger electrons, capable of damaging the diseased <br />
cell's DNA and other intracellular molecules. This low energy emission <br />
means that they only have an impact at short range, so they do not cause<br />
any serious damage to healthy cells that are nearby.<br /><br />
In the new study, the researchers first wrapped gold nanoparticles <br />
inside a positively charged polymer, polyethylenimine. This interacted <br />
with proteins on the cell surface called proteoglycans which led to the <br />
nanoparticles being ingested by the cell.<br /><br />
<br />
Once there, it was possible to excite it using standard radiotherapy,<br />
which many GBM patients undergo as a matter of course. This released <br />
the electrons to attack the cell DNA.<br /><br />
While gold nanospheres, without any accompanying drug, were found to <br />
cause significant cell damage, treatment-resistant cell populations did <br />
eventually recover several days after the radiotherapy. As a result, the<br />
researchers then engineered a second nanostructure which was suffused <br />
with cisplatin.<br />
<br />
The chemotherapeutic effect of cisplatin combined with the radiosensitizing effect of <a href="http://phys.org/tags/gold+nanoparticles/" target="_blank">gold nanoparticles</a><br />
resulted in enhanced synergy enabling a more effective cellular damage.<br />
Subsequent tests revealed that the treatment had reduced the visible <br />
cell population by a factor of 100 thousand, compared with an untreated <br />
cell culture, within the space of just 20 days. No population renewal <br />
was detected.<br />
<br />
The researchers believe that similar models could eventually be used <br />
to treat other types of challenging cancers. First, however, the method <br />
itself needs to be turned into an applicable treatment for GBM patients.<br />
This process, which will be the focus of much of the group's <br />
forthcoming research, will necessarily involve extensive trials. Further<br />
work needs to be done, too, in determining how best to deliver the <br />
treatment and in other areas, such as modifying the size and surface <br />
chemistry of the nanomedicine so that the body can accommodate it <br />
safely.<br /><br />
Sonali Setua, a PhD student who worked on the project, said: "It was <br />
hugely satisfying to chase such a challenging goal and to be able to <br />
target and destroy these aggressive <a href="http://phys.org/tags/cancer+cells/" target="_blank">cancer cells</a>.<br />
This finding has enormous potential to be tested in a clinical trial in<br />
the near future and developed into a novel treatment to overcome <br />
therapeutic resistance of glioblastoma."<br /><br />
Welland added that the significance of the group's results to date <br />
was partly due to the direct collaboration between nanoscientists and <br />
clinicians. "It made a huge difference, as by working with surgeons we <br />
were able to ensure that the nanoscience was clinically relevant," he <br />
said. "That optimises our chances of taking this beyond the lab stage, <br />
and actually having a clinical impact."<br /><br />
</section></article></div>
xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-47957641584065506732014-08-19T09:16:00.001-07:002014-09-01T07:51:26.232-07:00Steroids vs Dietary Therapy to Treat Eosinophilic Esophagitis<div dir="ltr" style="text-align: left;" trbidi="on">
<h3>
<img alt="http://www.mclno.org/webresources/kbase/cellatlas/cell%20images/Eosinophil.jpg" class="decoded" src="http://www.mclno.org/webresources/kbase/cellatlas/cell%20images/Eosinophil.jpg" /> </h3>
<h3>
</h3>
<h3>
Abstract and Introduction</h3>
<h4>
Abstract</h4>
<b>Purpose of Review</b>. Eosinophilic esophagitis (EoE) is a condition characterized by dense mucosal <a href="http://emedicine.medscape.com/article/199879-overview?src=wgt_edit_news_lsm&lc=int_mb_1001" target="_blank">eosinophilia</a><br />
in conjunction with symptoms of esophageal dysfunction. Since both the <br />
incidence and prevalence of EoE are on the rise in both children and <br />
adults, understanding the various treatment options available is <br />
imperative in choosing the proper treatment for each patient. This <br />
article will highlight the major strides in both medical and dietary <br />
treatment of EoE in the past year.<br />
<br />
<br />
<br />
<b>Recent Findings</b>. Whereas prior <br />
studies have shown that medical therapy with topical corticosteroids is <br />
effective in treating EoE, this more recent literature highlights some <br />
of the limitations of this approach, raising awareness that development <br />
of better drug delivery models is greatly needed. The review also <br />
describes the recent advances in the field of dietary therapy for this <br />
disease, particularly in adults, and further supports the notion that <br />
the pathophysiology of this disease in children and adults is similar, <br />
with food antigens driving this disease.<br />
<br />
<br />
<br />
<b>Summary</b>. Both medical and dietary <br />
therapy are effective for treating adults and children with EoE. <br />
Choosing the optimal treatment approach should be individualized based <br />
both on patient goals and on available local resources. Future <br />
prospective clinical trials comparing these two treatment modalities are<br />
needed to help understand comparable effectiveness as well as to help <br />
understand potential predictors of response to treatment and identify <br />
optimal therapeutic endpoints.<br />
<br />
<br />
<br />
<br />
<h4>
Introduction</h4>
Recent consensus guidelines define <br />
eosinophilic esophagitis (EoE) as a chronic, immune/antigen-mediated <br />
esophageal disease characterized clinically by symptoms related to <br />
esophageal dysfunction and histologically by eosinophil-predominant <br />
inflammation.<sup><a href="https://www.blogger.com/null" target="_blank">[1]</a></sup> The most common symptoms of adults with this condition include dysphagia and food impaction.<sup><a href="https://www.blogger.com/null" target="_blank">[1,2]</a></sup><br />
Involvement of allergic mechanisms in the pathogenesis of EoE has been <br />
supported by prior studies demonstrating esophageal tissue expression of<br />
allergic mediators such as IgE, eotaxin-3, IL-13, IL-5 and esophageal <br />
involvement by immune cells, including mast cells, dendritic cells and <br />
eosinophils.<sup><a href="https://www.blogger.com/null" target="_blank">[3]</a></sup> Furthermore, esophageal eosinophilia is induced in a murine model following allergen exposure.<sup><a href="https://www.blogger.com/null" target="_blank">[4]</a></sup><br />
Given the immunological reactivity of the disease, treatment with <br />
anti-inflammatory medications such as oral corticosteroids and swallowed<br />
topical corticosteroids has been shown to be efficacious in both <br />
children and adults.<sup><a href="https://www.blogger.com/null" target="_blank">[5–8]</a></sup><br />
<br />
<br />
<br />
The concept of food allergens as the main antigenic trigger in EoE <br />
was introduced in a landmark study by Kelly and Sampson in pediatric <br />
patients with symptoms of gastroesophageal reflux disease (GERD) and <br />
histologic features of esophageal eosinophilia, both of which were <br />
unresponsive to acid suppression or fundoplication. After treatment with<br />
an elemental or amino acid based formula, both symptoms and histologic <br />
eosinophilia resolved.<sup><a href="https://www.blogger.com/null" target="_blank">[9,10]</a></sup><br />
Since this landmark study, numerous series have replicated this <br />
association of food allergens as a trigger in EoE in both the adult and <br />
the pediatric population.<sup><a href="https://www.blogger.com/null" target="_blank">[2,5,11–13]</a></sup><br />
Common food triggers found to cause EoE in both children and adults <br />
include milk, wheat, soy, egg, nuts/peanuts, and fish/shellfish.<sup><a href="https://www.blogger.com/null" target="_blank">[11,12]</a></sup><br />
<br />
<br />
<br />
The feasible goals of treatment in EoE are still evolving, but <br />
typically include resolution of clinical symptoms, and the achievement <br />
and maintenance of histologic remission. Other important goals include <br />
prevention of complications of the disease (including fibrostenotic <br />
changes such as strictures), avoidance of food bolus impaction and <br />
avoidance of esophageal perforation, which can occur either <br />
spontaneously (from retching during a food impaction) or iatrogenically <br />
(from stricture dilation). Other important therapeutic endpoints include<br />
improvement in the patient's quality of life, improvement of <br />
nutritional deficits in those treated with dietary restrictions, and <br />
prevention of harmful side effects of medications used to treat the <br />
disease. This study highlights the recent strides in both dietary and <br />
medical therapy over the past year.<br />
<br />
<br />
<br />
<div id="articleContent">
<br />
<br />
<br />
<br />
<h3 class="sectionTitle">
Comparison of Different Formulations of Topical Corticosteroids</h3>
As mentioned, few studies have tried to <br />
identify differences in the effectiveness of EoE medications based on <br />
changes in their formulation or methods of drug delivery. Dellon <i>et al</i>.<sup><a href="https://www.blogger.com/null">[15]</a></sup> performed a randomized trial comparing nebulized and viscous topical steroid preparations in a cohort of adult patients.<br />
Patients received budesonide 1 mg twice daily, either in an aerosolized<br />
form swallowed from a nebulizer or as an oral viscous slurry, for a <br />
total of 8 weeks. Study endpoints included dysphagia improvement based <br />
on MDQ score, reduction in eosinophil counts, and mucosal medication <br />
contact time, which was measured by nuclear scintigraphy with tagged <br />
radiocontrast. The authors found that histologic improvement was <br />
significantly higher in the oral viscous budesonide group (64%) than in <br />
the swallowed nebulizer solution group (27%), although both groups had <br />
comparable improvement in their dysphagia scores. Nuclear scintigraphy <br />
showed that mucosal contact time was much higher in patients treated <br />
with the oral viscous budesonide than the nebulizer solution. This study<br />
showed that the frequency of histologic improvement may be directly <br />
related to mucosal contact time, and has highlighted the importance of <br />
appropriate drug delivery methods in treatment of this disease. It also <br />
shows that complete histologic resolution was achieved in only 64% of <br />
the oral viscous budesonide group, which is a lower percentage than has <br />
been found in prior studies.<br />
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<br />
<br />
<br />
<h3 class="sectionTitle">
Topical Corticosteroids Versus Acid Suppression</h3>
In the past year, several studies have <br />
confirmed the effectiveness of medical therapy for EoE, but also have <br />
highlighted some limitations of the current treatment approach. Moawad <i>et al</i>.<sup><a href="https://www.blogger.com/null">[14]</a></sup> recently performed a randomized controlled trial of swallowed fluticasone versus <span class="mandelbrot_refrag"><a class="mandelbrot_refrag" data-ls-seen="1" href="http://reference.medscape.com/drug/nexium-nexium-24hr-esomeprazole-341998?src=wgt_edit_news_lsm&lc=int_mb_1001">esomeprazole</a></span> for the treatment of esophageal <span class="mandelbrot_refrag"><a class="mandelbrot_refrag" data-ls-seen="1" href="http://emedicine.medscape.com/article/199879-overview?src=wgt_edit_news_lsm&lc=int_mb_1001">eosinophilia</a></span>.<br />
In this study, 42 patients suspected of having EoE (defined by clinical<br />
symptoms of esophageal dysfunction and >15 eos/hpf) underwent <br />
esophageal pH testing with 24 h pH/impedance monitoring. Patients were <br />
then stratified by the presence of GERD and randomized to receive either<br />
fluticasone 440 μg twice daily or esomeprazole 40 mg once daily for 8 <br />
weeks. Repeat endoscopy was performed, and the primary outcome was a <br />
histologic response of less than 7 eos/hpf. Secondary outcomes included <br />
clinical change in symptoms using the Mayo Dysphagia Questionnaire (MDQ)<br />
score and interval change in endoscopic features. The investigators <br />
showed that there was no difference in the frequency of resolution of <br />
esophageal eosinophilia between the fluticasone and esomeprazole groups <br />
(19 versus 33%; <i>P</i> = 0.484). They also found that patients with <br />
established GERD (based on pH testing) were much more likely to respond <br />
to proton pump inhibitor (PPI) than fluticasone. Interestingly, they <br />
also found that symptoms improved with PPI treatment, but not with <br />
fluticasone. They concluded that the histologic response with both <br />
treatment options was similar and significantly less than expected <br />
(based on prior studies). This study raises concern about the limited <br />
efficacy of some formulations of swallowed aerosolized topical <br />
corticosteroids, and highlights the importance of using acid suppression<br />
as part of the initial diagnostic and therapeutic strategy for patients<br />
with esophageal symptoms and eosinophilia.<br />
<br />
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<br />
<br />
<br />
<h3 class="sectionTitle">
Medical Therapy in Eosinophilic Esophagitis</h3>
While prior studies have shown the efficacy <br />
of both systemic and topical corticosteroids in the treatment of EoE, <br />
currently there is no medication specifically approved by the US Food <br />
and Drug Administration (US FDA) for the disease. There have also been <br />
few studies comparing the effectiveness of different types of <br />
pharmacologic therapies. The two most common steroid medications used <br />
for treatment of EoE have been fluticasone and budesonide. Fluticasone <br />
is typically delivered via a metered-dose inhaler whereby the medication<br />
is puffed into the mouth and then swallowed. Starting doses in <br />
published studies have ranged from 440 to 880 μg b.i.d. Budesonide has <br />
been used in the form of oral viscous budesonide, which is a suspension <br />
of the drug in a sucralose binder. Patients are typically counseled on <br />
mixing this medication with multiple packets of sucralose to make a <br />
viscous solution that is swallowed twice daily. A typical starting dose <br />
in adults is 1 mg twice daily.<br />
<br />
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<br />
<br />
<br />
<br />
<h3 class="sectionTitle">
Placebo-controlled Trials of Swallowed Topical Corticosteroids</h3>
Other adult studies also have shown limitations with the use of swallowed topical corticosteroids. For example, Alexander <i>et al</i>.<sup><a href="https://www.blogger.com/null">[16]</a></sup><br />
performed a double-blind, randomized, placebo-controlled trial of <br />
fluticasone in 42 adult patients with EoE. Patients in the treatment arm<br />
swallowed 880 μg of aerosolized fluticasone (four puffs) twice daily <br />
for 6 weeks. Their therapeutic endpoints were symptomatic (based on the <br />
MDQ-30) and histologic response (based on a criteria of >90% decrease<br />
in mean eosinophil count). They reported complete histologic response <br />
in 11/15 (62%) patients receiving 6 weeks of fluticasone compared with <br />
none of the 15 patients receiving placebo (<i>P</i> < 0.001, based <br />
on intention-to-treat analysis). Dysphagia was reduced in only 57% of <br />
patients receiving fluticasone compared with 33% receiving placebo <br />
therapy (<i>P</i> = 0.22 by intention-to-treat analysis), and esophageal <span class="mandelbrot_refrag"><a class="mandelbrot_refrag" data-ls-seen="1" href="http://emedicine.medscape.com/article/213853-overview?src=wgt_edit_news_lsm&lc=int_mb_1001">candidiasis</a></span><br />
was found in 26% of patients treated with fluticasone. These results <br />
highlight the fact that topical corticosteroids result in less <br />
histologic response than suggested by earlier studies, and have higher <br />
rates of important side effects, including candidiasis, than previously <br />
reported. As in the prior study, the decreased histologic response is <br />
likely due to problems in drug delivery with attempting to swallow an <br />
aerosolized medication, as well as insufficient mucosal contact time.<br />
<br />
<br />
These recent pharmacologic studies in EoE demonstrate that medical <br />
therapy can result in histologic remission in some patients, but the <br />
limitations shown by the above studies highlight the important unmet <br />
need to identify better medications for the treatment of EoE.</div>
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<br />
<br />
<br />
<h3 class="sectionTitle">
Dietary Therapy in Eosinophilic Esophagitis</h3>
Dietary therapy has long been accepted as <br />
first-line therapy in children with EoE, and recently has been shown to <br />
be effective in adults as well. Three approaches to dietary elimination <br />
in EoE patients have evolved. The first is total elimination of all food<br />
allergens by placing patients on an elemental or amino acid-based <br />
formula as their primary nutrition. Patients are usually placed on this <br />
diet for at least 6 weeks. Another approach to dietary therapy has been <br />
allergy-directed diets using the information gained from allergy testing<br />
(e.g. skin prick) to help guide the foods that are to be restricted. <br />
While this approach has been shown to be helpful in some pediatric <br />
cohorts,<sup><a href="https://www.blogger.com/null">[11]</a></sup><br />
it had limited utility in adult populations due to the lack of <br />
correlation between foods identified by allergy testing and food <br />
triggers in individual patients.<sup><a href="https://www.blogger.com/null">[1,2,13,17]</a></sup><br />
The last approach of empiric dietary elimination (e.g. six-food <br />
elimination diet) has been shown to be equally effective in children and<br />
adults.<sup><a href="https://www.blogger.com/null">[2,12]</a></sup><br />
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<br />
<br />
<br />
<h3 class="sectionTitle">
Goals of Diet Therapy</h3>
Knowing that dietary therapy is effective in <br />
adults provides the rationale for offering this treatment approach as an<br />
alternative to swallowed topical corticosteroids. It is important to <br />
emphasize that the goals of the dietary therapy are not to stay on a <br />
restrictive diet indefinitely, but, rather, to undergo a process of food<br />
trigger identification to help tailor the diet for long-term <br />
maintenance therapy. Dietary elimination with serial food reintroduction<br />
enables the identification of the actual food triggers of the disease. <br />
This treatment plan should be individualized based on individual <br />
patients and their goals.<br />
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</div>
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<br />
<h3 class="sectionTitle">
Effectiveness of Empiric Elimination Diets in Adults</h3>
While dietary therapy has been well <br />
established as an effective first-line therapy in pediatrics for EoE, <br />
this approach has not been extensively studied in adults. Recently, <br />
empiric dietary elimination has been shown to have comparable <br />
effectiveness in adults. Gonsalves <i>et al</i>. prospectively studied<br />
the efficacy of the six-food elimination diet (SFED) in 50 adults (25 <br />
M/25 F) with EoE. Seventy percent of patients had histologic response of<br />
less than 10 eos/hpf, 94% had symptomatic improvement and 74% had <br />
endoscopic improvement after completing the diet for 6 weeks. Serial <br />
food reintroduction was undertaken in patients who responded to the <br />
diet. When food triggers were identified, symptoms typically recurred <br />
within 5 days and esophageal eosinophil counts returned to pretreatment <br />
values (<i>P</i> < 0.0001) on follow-up endoscopy. Common food <br />
allergens identified during this process were wheat (60%), milk (50%), <br />
soy (10%), nuts (10%) and egg (5%). The majority of patients had only <br />
one food trigger. Skin prick testing for food allergens was undertaken <br />
prior to the elimination diet, but was predictive of food triggers in <br />
only 13% of cases.<br />
<br />
<br />
Subsequent to the publication of this study, Lucendo <i>et al</i>.<sup><a href="https://www.blogger.com/null">[13]</a></sup><br />
from Spain demonstrated similar results in 67 adults with EoE after <br />
empiric elimination of wheat, rice, corn, legumes, peanuts, soy, egg, <br />
milk, fish and shellfish for a similar duration. This approach resulted <br />
in histologic improvement of less than 15 eos/hpf in 73% of the <br />
patients, but required additional foods to be removed.<sup><a href="https://www.blogger.com/null">[11]</a></sup><br />
Food reintroduction in this study identified the common triggers as <br />
milk (61%), wheat (28%), eggs (26%) and legumes (23%). Unlike the prior <br />
study, the majority of patients in this study were found to have <br />
multiple food antigens as their triggers. A single offending food <br />
antigen was identified in only 36%, two food triggers were found in 31%,<br />
and three or more triggers were found in 33% of patients. Results of <br />
allergy testing in this cohort were also not predictive of their food <br />
triggers. The investigators also found that continued elimination of the<br />
food triggers was effective in maintaining remission.<br />
<br />
<br />
Noting that milk was one of the most common food triggers in their pediatric cohort, Kagalwalla <i>et al</i>.<sup><a href="https://www.blogger.com/null">[18]</a></sup><br />
investigated the utility of a single food elimination diet in their EoE<br />
patients. In this retrospective study conducted between 2006 and 2011, <br />
17 patients who had empirically eliminated cow's milk protein from the <br />
diet and had a follow-up endoscopy were included. Sixty-five per cent of<br />
these patients achieved remission as defined by less than 15 eos/hpf <br />
after therapy.<sup><a href="https://www.blogger.com/null">[18]</a></sup><br />
Although this study has encouraging results, further prospective <br />
studies will be needed in both pediatrics and adults to assess the <br />
generalizability of the approach of single food elimination.<br />
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<br />
<h3 class="sectionTitle">
Effectiveness of Allergy-directed Diets in Adults</h3>
One of the first studies to attempt a form of<br />
allergy-directed diet in adults was pursued in a small number of adult <br />
patients in Switzerland by Simon <i>et al</i>.<sup><a href="https://www.blogger.com/null">[19]</a></sup><br />
In this study, based on results of IgE testing to certain foods, few <br />
foods were eliminated from the diet. Despite elimination of these foods,<br />
patients did not respond symptomatically. The one patient who completed<br />
endoscopic evaluation after dietary therapy also did not show a <br />
histologic response. A more recent study undertaken by Molina-Infante <i>et al</i>.<sup><a href="https://www.blogger.com/null">[20]</a></sup><br />
studied the outcome of an allergy-directed diet using a multimodal <br />
approach including skin prick testing, prick-prick testing and atopy <br />
patch testing to identify allergens in their adult EoE cohort of 22 <br />
patients. Disappointingly, they found only a 26% improvement with this <br />
approach. Likewise, allergy testing was not found to be predictive of <br />
food triggers in either the Gonsalves or the Lucendo study. Taken <br />
together, these studies suggest that current allergic testing methods <br />
are not reliable for identifying food triggers in adults with EoE and <br />
should not be used to guide dietary intervention.<br />
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<br />
<h3 class="sectionTitle">
Effectiveness of Elemental Diets in Adults</h3>
A recent study by Peterson <i>et al</i>.<sup><a href="https://www.blogger.com/null">[21]</a></sup><br />
evaluated the effectiveness of an elemental diet in a small group of <br />
adults. They found that 50% of adults responded histologically to the <br />
diet with eosinophil counts less than 5 eos/hpf, and 72% had less than <br />
10 eos/hpf, with eosinophil levels on average dropping from 54 to 10 <br />
after the diet. Interestingly, patients did not demonstrate symptomatic <br />
improvement, but that may be due to limitations in the dysphagia <br />
assessment tool used in this study. The authors also suspected that the <br />
limited efficacy of elemental diet in this study compared with pediatric<br />
studies might have resulted from poor adherence to the diet in their <br />
adult patient population.<br />
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<h3 class="sectionTitle">
Potential Development of Tolerance After Dietary Therapy</h3>
Once a food trigger is identified in EoE, the<br />
mainstay of therapy is continued avoidance of that particular food. <br />
There have not been systematic studies evaluating recurrent food <br />
challenges and the possible development of tolerance over time. One of <br />
the first studies to address this issue was by Leung <i>et al</i>.,<sup><a href="https://www.blogger.com/null">[22]</a></sup><br />
who performed a retrospective review of their pediatric EoE patients <br />
who were known to have milk as their food trigger. They identified 15 <br />
patients who had subsequently reintroduced baked milk back into their <br />
diets for at least 6 weeks, and 11 of them (73%) had maintained <br />
histologic remission despite the reintroduction of baked milk products. <br />
The study did not mention the precise time when reintroduction of baked <br />
milk products occurred in these patients. Despite this limitation, this <br />
study suggests that, over time, some patients with cow's milk-induced <br />
EoE may be able to tolerate milk reintroduction in the form of baked <br />
milk, which would allow a considerable broadening of the diet.<br />
<br />
<br />
Another study exploring this concept was performed by Lucendo <i>et al</i>.<sup><a href="https://www.blogger.com/null">[23]</a></sup> in adults. This group evaluated the use of a cow's milk-based hydrolyzed formula in patients with cow's milk-induced EoE.<sup><a href="https://www.blogger.com/null">[23]</a></sup><br />
Seventeen adult patients with cow's milk-induced EoE were administered <br />
this formula over a period of 8 weeks, and repeat endoscopy was <br />
performed. At that time, 88% of patients maintained histologic remission<br />
as defined by less than 15 eos/hpf. This study suggests that some <br />
patients with EoE triggered by a cow's milk protein may tolerate <br />
reintroduction of milk in this reduced antigenic state. While these <br />
formulas are not readily available, this study does provide insight into<br />
the pathophysiologic mechanisms of food allergy that trigger EoE, and <br />
suggests that some patients are tolerant to less antigenic preparations <br />
of their food triggers.<br />
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<br />
<h3 class="sectionTitle">
Potential Advantages of Medical Therapy in Adults</h3>
Medical therapy has been shown to effectively<br />
induce both symptomatic and histologic remission in some patients with <br />
EoE. Advantages of this approach include the ease of administration of <br />
the medications as well as the limited impact of this treatment approach<br />
on lifestyle. This treatment plan allows patients to eat normally, and <br />
does not mandate dietary restrictions. While an endoscopy after <br />
treatment institution often is performed to ensure that the medication <br />
is working, the medical treatment approach does not require multiple <br />
additional endoscopies, as are often performed in dietary therapy. <br />
Medical therapy does, however, require chronic daily use of medications <br />
with potential side effects.<br />
<br />
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<br />
<h3 class="sectionTitle">
Potential Advantages of Dietary Therapy</h3>
Dietary therapy in adults with EoE has a <br />
number of practical advantages. As prior studies have shown, <br />
discontinuation of swallowed topical corticosteroids in the treatment of<br />
EoE can cause symptomatic and histologic recurrence which may <br />
necessitate chronic daily therapy. Avoidance of food allergens <br />
eliminates the need for chronic medication/corticosteroids to help <br />
control the disease. Oral and esophageal <span class="mandelbrot_refrag"><a class="mandelbrot_refrag" data-ls-seen="1" href="http://emedicine.medscape.com/article/213853-overview?src=wgt_edit_news_lsm&lc=int_mb_1001">candidiasis</a></span><br />
may occur in 5–30% of patients treated with steroids. Other rare side <br />
effects of topical corticosteroids include growth failure in children, <br />
cataracts and adrenal suppression. Unfortunately, these medications have<br />
not been US FDA-approved to be swallowed, which raises concern about <br />
their long-term safety. In addition, long-term use of these medications <br />
may result in a considerable cost to patients with this chronic <br />
condition.<br />
<br />
<br />
The effectiveness of elimination diet in adults supports the <br />
conceptual definition that EoE is an antigen or immune-mediated <br />
esophageal disease. Therefore, dietary therapy has the advantage of <br />
getting to the root cause of the disease (i.e. food allergen avoidance) <br />
rather than symptom and histologic control with topical corticosteroids.<br />
Current consensus guidelines suggest continued avoidance of food <br />
allergens in patients who are managed with diet therapy,<sup><a href="https://www.blogger.com/null">[1,2,5,11,12]</a></sup><br />
and a targeted, individualized approach to nutrition therapy is <br />
essential to success. Recent studies have suggested that food <br />
reintroduction with altered forms of the food trigger may induce <br />
tolerance and allow more food products to be added. While repeated <br />
endoscopies often are recommended during the food reintroduction <br />
process, recent studies have suggested that other noninvasive testing <br />
methods may become available soon.<sup><a href="https://www.blogger.com/null">[24]</a></sup><br />
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<br />
<br />
<br />
<h3 class="sectionTitle">
Medical Versus Dietary Therapy: Which to Choose?</h3>
When discussing options for therapy with <br />
patients, it is important to review the pros and cons of each treatment <br />
plan and try to identify goals of treatment. It is important to <br />
underscore that the goals of dietary therapy are not to stay on the <br />
elemental diet or SFED indefinitely, but, rather, to undergo a process <br />
of food trigger identification to help tailor the diet for long-term <br />
maintenance therapy. The goals of medical therapy are to help control <br />
symptoms and histology with minimal disruption to daily routine, but <br />
will likely require maintenance therapy to achieve these goals. The <br />
choice on proceeding with medical or dietary therapy should be <br />
individualized based on patient preference as well as available local <br />
resources.<br />
<br />
</div>
<div id="articleContent">
<div id="articleContent">
<br />
<br />
<br />
<br />
<h3 class="sectionTitle">
Conclusion</h3>
Medical and dietary therapy both are <br />
effective treatments for patients with EoE. While previous studies have <br />
demonstrated the effectiveness of topical corticosteroids, research over<br />
this past year has highlighted limitations of this approach. These <br />
studies have underscored the unmet need for additional therapeutic <br />
options with better drug delivery systems that are specific for EoE. <br />
They have also highlighted the need to better define therapeutic <br />
endpoints (i.e. symptomatic, histologic, or endoscopic response or a <br />
combination of all three). Research is underway to help answer these <br />
basic questions and to develop an important disease activity index <br />
specifically for EoE. Over the past year, several studies have also <br />
highlighted the effectiveness of dietary therapy in adults with EoE, and<br />
have demonstrated that this treatment approach should be considered as <br />
first-line therapy in adults, as it is in children. Knowing that both <br />
medical and dietary therapy is effective provides options for patients, <br />
and highlights the need to individualize treatment plans based on <br />
patient preferences.<br />
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xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-52590901513434999972014-08-15T20:09:00.001-07:002014-08-15T20:09:57.768-07:00CDC Accidentally Ships Deadly Virus, Hopes No One Will Notice<div class="readableLargeImageContainer"><img alt="CDC Accidentally Ships Deadly Virus, Hopes No One Will Notice" src="http://i.kinja-img.com/gawker-media/image/upload/s--gg3S7ZoO--/c_fit,fl_progressive,q_80,w_636/858312628783952166.jpg" /></div><br />That wacky CDC is up to its old, potentially fatal-virus-spreading tricks again. But instead of <a href="http://gizmodo.com/vials-full-of-smallpox-were-just-found-in-an-unapproved-1601807269" target="_blank">anthrax</a> or <a href="http://gizmodo.com/vials-full-of-smallpox-were-just-found-in-an-unapproved-1601807269/1606228938/+ashleyfeinberg" target="_blank">dengue</a>,<br />
this time, the Centers for Disease Control brought a deadly strain of <br />
bird flu into its revolving cast of highly contagious characters. While <br />
rushing to get to a meeting, a CDC scientist <a href="http://bigstory.ap.org/article/report-cdc-scientist-kept-quiet-about-flu-blunder" target="_blank">accidentally tainted a tamer strain of bird flu with a far more deadly one</a>—and then sent it out to another unsuspecting lab. Whoops.<br /><br />
This<br />
most recent set of hijinks took place at CDC Prevention headquarters in<br />
Atlanta in January, when a lab scientist accidentally mixed the two <br />
samples, sending what <em>should</em> have been a benign (at least to <br />
humans) strain of the virus to another lab. Except, you know, it wasn't.<br />
So when that very same virus concoction was given to some unsuspecting <br />
chickens as part of a USDA study in March, and all those chickens <br />
proceeded to immediately die, the USDA officials knew something wasn't <br />
right. <br /><br />
The CDC lab responsible for the deadly mixed sample then confirmed that, yes, that virus <em>was</em> actually wildly dangerous but told, well, no one. No one until June, that is, when a <em>second</em> lab reported a similar problem, and CDC Director Dr. Tom Frieden was finally notified. <br /><br />
Apparently,<br />
the lab scientist who had originally contaminated the sample completed <br />
what should have been 90 minutes of work (with both the tame and deadly <br />
viruses) in 51 minutes, in an attempt to make the noon meeting. Whether <br />
that meeting actually did begin as scheduled, though, remains <br />
inconclusive. <br /><br />
To the CDC's credit, "<a href="http://bigstory.ap.org/article/report-cdc-scientist-kept-quiet-about-flu-blunder" target="_blank">the viral mix was at all times contained in specialized laboratories and was never a threat to the public</a>," according to an internal report. But then <a href="http://gizmodo.com/vials-full-of-smallpox-were-just-found-in-an-unapproved-1601807269/1606228938/+ashleyfeinberg" target="_blank">that's what they said last time, too</a>. And <a href="http://gizmodo.com/vials-full-of-smallpox-were-just-found-in-an-unapproved-1601807269" target="_blank">the time before that</a>. Here's to hoping<a href="http://gizmodo.com/why-you-shouldnt-freak-out-about-ebola-patients-coming-1614788513" target="_blank"> Ebola's not next</a>. [<a href="http://bigstory.ap.org/article/report-cdc-scientist-kept-quiet-about-flu-blunder" target="_blank">AP</a>]xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-72784231384016732432014-08-12T15:45:00.001-07:002014-08-12T15:45:09.694-07:00Sigmoidoscopy Does Cut Risk of Dying From Colon Cancer: Study <div style="text-align: justify;"><a href="http://www.webmd.com/colorectal-cancer/news/20140812/sigmoidoscopy-does-cut-risk-of-dying-from-colon-cancer-study?src=RSS_PUBLIC">Colon cancer screening done by sigmoidoscopy -- a less invasive, <br />
cheaper alternative to colonoscopy -- does cut people's risk of <br />
developing or dying from the disease, a new clinical trial finds.</a></div><div style="text-align: justify;">Experts said the study, conducted in Norway and reported in the Aug. 13 issue of the <i>Journal of the American Medical Association</i>, confirms the value of sigmoidoscopy screening.</div><div style="text-align: justify;">But<br />
in the United States, where few doctors even perform sigmoidoscopy, the<br />
results are unlikely to make a difference in everyday practice.</div><div style="text-align: justify;">"Sigmoidoscopy<br />
is definitely second-best to colonoscopy," said Dr. James Church, a <br />
colorectal surgeon at the Cleveland Clinic in Ohio.</div><div style="text-align: justify;">That's mainly <br />
because sigmoidoscopy looks only at the lower portion -- or "left side" <br />
-- of the colon, said Church, who was not involved in the study. <br />
Colonoscopy gives doctors a view of the entire colon.</div><div style="text-align: justify;">Both <br />
procedures not only detect cancer but also help prevent it -- by <br />
allowing doctors to remove potentially precancerous growths called <br />
polyps. But colonoscopy can pick up polyps throughout the colon.</div><div style="text-align: justify;">"Colonoscopy is not perfect, by any means," Church said. But, he added, "if you don't want to get <a href="http://www.webmd.com/colorectal-cancer/default.htm" target="_blank">colon cancer</a>, colonoscopy is the best option."</div><div style="text-align: justify;">The<br />
new trial was conducted in Norway, where there is no routine colon <br />
cancer screening, explained lead researcher Dr. Oyvind Holme, of <br />
Sorlandet Hospital in Kristiansand, Norway.</div><div style="text-align: justify;">That allowed the <br />
researchers to offer one-time sigmoidoscopy screening to over 20,000 50-<br />
to 64-year-old adults, then compare them with 78,000 people the same <br />
age who were not offered any kind of colon cancer screening.</div><div style="text-align: justify;">Half <br />
of the sigmoidoscopy group also received a stool test to look for hidden<br />
blood -- another option for colon cancer screening.</div><div style="text-align: justify;">Holme's team <br />
found that people who underwent screening were 27 percent less likely to<br />
die of colon cancer over the next decade, versus the unscreened group.</div><div style="text-align: justify;">According to Holme, the findings bolster evidence that sigmoidoscopy is a "valuable tool" for colon cancer screening.</div><div style="text-align: justify;">But,<br />
he said, they don't mean that sigmoidoscopy is the best tool. "We did <br />
not compare flexible sigmoidoscopy to other screening methods," Holme <br />
pointed out.</div><div style="text-align: justify;">In the United States, experts advise most people to begin colon cancer screening at age 50.</div><div style="text-align: justify;">The<br />
U.S. Preventive Services Task Force recommends three choices: an annual<br />
stool test; sigmoidoscopy every five years, along with stool testing <br />
every three years; or colonoscopy every 10 years.</div><div style="text-align: justify;">In practice, though, colonoscopy is by far the most common test in the United States.</div><div style="text-align: justify;">Sigmoidoscopy<br />
does have a number of advantages over colonoscopy, Holme said. The <br />
pre-exam bowel cleanse is easier to take, and the procedure itself is <br />
faster, does not require sedation and can be done by a primary care <br />
doctor or trained nurse -- whereas colonoscopies are done by <br />
gastroenterologists.</div><div style="text-align: justify;">Sigmoidoscopy is also much cheaper: In the United States, it costs about $150 to $300, versus $1,000 or more for a colonoscopy.</div><div style="text-align: justify;">But<br />
some of those advantages are not as good as they sound, according to <br />
Church. Since patients are not sedated for sigmoidoscopy, he said, it's <br />
actually more uncomfortable than colonoscopy, for example.</div><div style="text-align: justify;">What <br />
this study shows, Church said, is that sigmoidoscopy is better than no <br />
screening -- for preventing cancers on the left side of the colon.</div><div style="text-align: justify;">Among<br />
patients who were screened, there were 113 cancers per 100,000 people <br />
each year of the study. That compared with 141 per 100,000 in the <br />
unscreened group. But the difference was mostly seen in cancers in the <br />
left side of the colon.</div><div style="text-align: justify;">"For right-sided colon cancer, sigmoidoscopy is, statistically, the same as doing nothing," Church said.</div><div style="text-align: justify;">In<br />
the end, questions over how sigmoidoscopy fits into colon cancer <br />
screening could actually be moot in the near future, according to an <br />
editorial published with the study.</div><div style="text-align: justify;">New DNA stool tests, which are<br />
much more precise than standard stool tests, have the potential to <br />
reduce routine colonoscopies, writes Dr. Allan Brett, of the University <br />
of South Carolina School of Medicine in Columbia.</div><div style="text-align: justify;">"Fecal DNA tests<br />
could change the way we think about stool testing," Church said. <br />
"They're so much better than what we have now."</div><div style="text-align: justify;">Just yesterday, <br />
the U.S. Food and Drug Administration approved a DNA-based stool test <br />
that detects colon cancer with more than 90 percent accuracy. Still, <br />
experts said, the test is not intended to replace colonoscopies -- and <br />
any positive result would have to be followed up with a colonoscopy to <br />
confirm the diagnosis.</div><div style="text-align: justify;">The hope is that new and better options <br />
will encourage more people to get screened. A recent government study <br />
found that one-third of Americans eligible for colon cancer screening <br />
aren't doing it.</div>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-11850407198164175992014-08-11T09:07:00.001-07:002014-08-11T09:07:26.529-07:00Report: Ebola outbreak started in 2-year-old in Guinea <b>(CNN)</b> -- The worst outbreak of Ebola, which has <br />
killed 961 people and triggered an international public health <br />
emergency, may have started with a 2-year-old patient in a village in <br />
Guinea.<br /><br />
About eight months ago, the toddler, whom researchers believe may <br />
have been Patient Zero, suffered fever, black stool and vomiting. Just <br />
four days after showing the painful symptoms, the child died on December<br />
6, 2013, <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1404505#t=article" target="_blank">according to a report published in The New England Journal of Medicine. </a><br /><br />
Scientists don't know exactly how the toddler contracted the virus. <br />
Ebola is spread from animals to humans through infected fluids or <br />
tissue, <a href="http://www.who.int/mediacentre/factsheets/fs103/en/" target="_blank">according to the World Health Organization</a>.<br /><br />
"In Africa, infection has been documented through the handling of <br />
infected chimpanzees, gorillas, fruit bats, monkeys, forest antelope and<br />
porcupines," WHO says, though researchers think fruit bats are what <br />
they call the virus's "natural host."<br /><br />
<div id="expand15"><div><div id="photoContainer15"><img alt="Photos: Ebola outbreak in West Africa" src="http://i2.cdn.turner.com/cnn/dam/assets/140808073707-restricted-01-ebola-0807-horizontal-gallery.jpg" height="360" id="photo15" width="640" /><br />
<cite id="cite15">Photos: Ebola outbreak in West Africa</cite><br />
</div></div></div><div id="expand25"><img src="http://i2.cdn.turner.com/cnn/dam/assets/140728224431-ac-dr-gupta-on-ebola-00014216-story-body.jpg" height="120" width="214" /><cite>Ebola coverage: informing vs. overhyping</cite><br />
</div><div id="expand35"><img src="http://i2.cdn.turner.com/cnn/dam/assets/140808222757-ac-dnt-mckenzie-ebola-health-emergency-00001214-story-body.jpg" height="120" width="214" /><cite>Delayed response cause Ebola to spread? </cite><br />
</div><div id="expand45"><img src="http://i2.cdn.turner.com/cnn/dam/assets/140808185514-dnt-man-loses-family-members-to-ebola-00003301-story-body.jpg" height="120" width="214" /><cite>Man loses 7 relatives to Ebola</cite><br />
</div>Researchers who published the paper this year found a chain of illnesses in the toddler's family.<br /><br />
After the child's death, the mother suffered bleeding symptoms and <br />
died on December 13, according to the report. Then, the toddler's <br />
3-year-old sister died on December 29, with symptoms including fever, <br />
vomiting and black diarrhea. The illness subsequently affected the <br />
toddler's grandmother, who died on January 1, in the family's village of<br />
Meliandou in Guéckédou.<br /><br />
The area in southern Guinea is close to the Sierra Leone and Liberia borders.<br /><br />
The illness spread outside their village after several people attended the grandmother's funeral.<br /><br />
Funerals tend to bring people in close contact with the body. <a href="http://www.cnn.com/2014/04/11/health/ebola-fast-facts/index.html" target="_blank">Ebola</a><br />
spreads from person to person through contact with organs and bodily <br />
fluids such as blood, saliva, urine and other secretions of infected <br />
people. It has no known cure.<br /><br />
<a href="http://amanpour.blogs.cnn.com/2014/07/02/scientist-who-discovered-ebola-this-is-unprecedented/" target="_blank">READ: 'This is unprecedented'</a><br /><br />
Two of the funeral attendees appeared to bring back the virus to <br />
their village, and it spread to health care workers and other family <br />
members who took care of infected patients.<br /><br />
"A health care worker from Guéckédou with suspected disease, seems to<br />
have triggered the spread of the virus to Macenta, Nzérékoré, and <br />
Kissidougou in February 2014," stated the report, noting that more <br />
Guinea towns were affected.<br /><br />
Clusters of the disease popped up in early 2014 in these areas, with <br />
the initial patients suffering fever, vomiting and severe diarrhea, <br />
according to the report. Hemorrhaging was less frequent, the report <br />
noted.<br /><br />
In early March, the Ministry of Health in Guinea and Doctors Without Borders in Guinea were notified about the disease clusters.<br /><br />
Health investigators arrived that month and began tracing the disease<br />
by examining hospital documents and conducting interviews with affected<br />
families and villagers.<br /><br />
Ebola has now spread to <a href="http://www.cnn.com/2013/10/29/world/liberia-fast-facts/index.html" target="_blank">Liberia</a>, Sierra Leone and Nigeria, prompting global concerns.<br /><br />
The report about the emergence of Ebola in Guinea was authored by <br />
dozens of international doctors and researchers from institutions in <br />
France, Germany, Guinea, WHO and Doctors Without Borders.<br /><br />
<a href="http://edition.cnn.com/2014/08/11/health/ebola-patient-zero/index.html?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2Fcnn_health+%28RSS%3A+Health%29"> - CNN.com</a>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-2939849155185381272014-08-10T10:43:00.001-07:002014-08-10T10:43:57.571-07:00PRAGUE CRITERIA - For Endoscopically Suspected Oesophageal Columnar Metaplasia / Barrett’s Oesophagus <div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgdL59K79jIY00rq-1FQzue1T78S3gPvN20FSuPQUNAkRKlaREYfJ38aDsWHc-QuJ6zqIJVX4nHt5eEmpC9dmEuRh8j34QjXmqSijzwmkGCJy-TKMfoKe50uhcDKyn0y61ohU3RrU6by6Gi/s1600/PRAGUE+CRITERIA+(1).jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgdL59K79jIY00rq-1FQzue1T78S3gPvN20FSuPQUNAkRKlaREYfJ38aDsWHc-QuJ6zqIJVX4nHt5eEmpC9dmEuRh8j34QjXmqSijzwmkGCJy-TKMfoKe50uhcDKyn0y61ohU3RrU6by6Gi/s1600/PRAGUE+CRITERIA+(1).jpg" height="640" width="452" /></a></div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">In the past, criteria for the diagnosis and grading of the severity of esophageal mucosal consequences of gastroesophageal reflux disease (GERD) have been postulated with insufficient consultation and critical evaluation. The result has been a confusion of inadequately defined criteria, which impairs the quality of communication about endoscopic findings in both routine patient care and research studies. Endoscopists were unable to recognize these changes with acceptable agreement. The result was a lack of consensus on how to assess the presence and extent of CLE in clinical practice. The grading systems which have been proposed previously include:</div><ol style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; list-style: none; margin: -1em 0px 1.5em 1.5em; padding: 0px; vertical-align: baseline;"><li style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; list-style-position: outside; list-style-type: decimal; margin: 0px; padding: 0px; vertical-align: baseline;"><div style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; padding: 0px; vertical-align: baseline;">The classification of CLE into long (≥ 3 cm) and short (<3 cm) segments: this system seems clinically irreverent because it was documented that even SSBE may undergo progression to dysplasia as well as adenocarcinoma.<span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">[4-7]</span></div></li>
<li style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; list-style-position: outside; list-style-type: decimal; margin: 0px; padding: 0px; vertical-align: baseline;"><div style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; padding: 0px; vertical-align: baseline;">The Z-line appearance (ZAP) classification: this was developed to describe the endoscopic extent of CLE with particular reference to SSBE.<span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">[26]</span> The ZAP was found to correlate with the prevalence of IM at the SCJ; however, this system also uses a threshold of 3 cm to distinguish between grades II and III CLE making it insufficiently precise for documenting progression or regression of CLE.</div></li>
</ol><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Several years of research and deliberations by the International Working Group For The Classification Of Esophagitis (IWGCO) have led to the development and validation of explicit, consensus-driven criteria for the endoscopic diagnosis and grading of CLE called the Prague C & M Criteria for CLE (Fig. 1).<span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">[27]</span> The Prague C & M Criteria is a new grading system for CLE, and it was so named because it was first introduced by the IWGCO at the 11th United European Gastroenterology Week meeting in Prague, Czech Republic in 2004. The purpose of these criteria is to simplify and standardize endoscopic characterization of the extent and length of CLE. The new system emphasizes the use of esophageal landmarks to assess the circumference (C) and maximal (M) extent of the endoscopically visualized CLE segment. The key steps in Prague C & M Criteria are: (i) identify the GEJ as at the tops of the gastric mucosal folds; if hiatus hernia is present, do not confuse with the diaphragmatic hiatal impression for the GEJ; (ii) for circumferential columnar-appearing mucosa above the GEJ, define this extent in centimeters above the GEJ: report as the <i style="border: 0px; font-family: inherit; font-size: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">C</i>-value; and (iii) for any tongue-like areas of columnar-appearing mucosa, measure the maximum extent in centimeters above the GEJ: report as the <i style="border: 0px; font-family: inherit; font-size: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">M</i>-value.<span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">[27]</span> The primary validation study for these criteria was published by Sharma <i style="border: 0px; font-family: inherit; font-size: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">et al</i>.<span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">[28]</span> in November 2006. The criteria are simple, reliable, reproducible and memorable. It is expected to be a practical clinical tool for characterizing the severity of CLE and for evaluating its progression over time. Now there is a need to build experience in the use of these criteria. As there is no widely used method of grading CLE currently, the Prague C & M Criteria are expected to be used worldwide.<span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">[29]</span> The most important weakness of this grading system appears to be in patients with short segment CLE. The kappa measures of interobserver agreement fell markedly when the length of tissue involvement was less than 1 cm.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 0px !important; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding: 0px; vertical-align: baseline;"><div style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin-bottom: 0px !important; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding: 0px; vertical-align: baseline;"><div style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; padding: 0px; vertical-align: baseline;">Prague C & M Criteria for Endoscopically Suspected Esophageal Columnar Metaplasia/Barrett's Esophagus. (Reproduced with permission from the International Working Group for the Classification of Oesophagitis (IWGCO) <a href="http://www.iwgco.com/" style="border: 0px; color: #1f0909; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">http://www.iwgco.com</a> )</div></div></div>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-66453463326764715942014-08-06T15:40:00.001-07:002014-08-06T15:40:43.658-07:00Ebola Virus: How Contagious?<a href="http://www.webmd.com/news/20140806/ebola-virus-how-contagious?src=RSS_PUBLIC">Two Americans stricken with the </a><a href="http://www.webmd.com/a-to-z-guides/ebola-fever-virus-infection" target="_blank">Ebola</a><br />
virus amid a record outbreak in West Africa are now being treated in <br />
Atlanta, which has triggered fears of a potential outbreak in the United<br />
States.<br /><br />
Infectious disease experts say they don’t expect that to <br />
happen for several reasons. Ebola is hard to contract, they say, and <br />
good infection-control practices can stop its spread.<br /><br />
What's more, Ebola is much less contagious than many other more common diseases. The virus, much like HIV or <a href="http://www.webmd.com/hepatitis/default.htm" target="_blank">hepatitis</a>, is spread through blood or bodily fluids and is not airborne.<br /><br />
Many<br />
factors play into how contagious a disease is thought to be, say Jeff <br />
Duchin, MD, an infectious disease expert at the University of <br />
Washington, Seattle, and Amesh Adalja, MD, an infectious disease expert <br />
at the University of Pittsburgh.<br /><br />
Among those factors:<br /><br />
<ul><li>How it’s transmitted (airborne, bodily fluids, other)</li>
<li>Infection-control practices in place</li>
<li>Extent of contact an infected person has with others</li>
<li>Percent of the population that has been vaccinated (if a <a href="http://www.webmd.com/vaccines/default.htm" target="_blank">vaccine</a> exists)</li>
</ul>To<br />
gauge how contagious different diseases are, experts take these and <br />
other things into account and estimate the average number of people <br />
likely to catch the illness from a single infected person. They call <br />
this the basic reproductive rate or number. The number is an average, a <br />
scientific guess, experts say, and it is likely to vary from country to <br />
country.<br /><br />
"I would anticipate the reproductive rate for Ebola in the U.S. to be zero," Adalja says.<br /><br />
By comparison, <a href="http://www.webmd.com/children/tc/measles-rubeola-topic-overview" target="_blank">measles</a>, diphtheria, and <a href="http://www.webmd.com/children/guide/whooping-cough-symptoms-treatment" target="_blank">whooping cough</a><br />
are all airborne, and they can be transmitted by "just being in <br />
face-to-face contact with an infected patient, without touching them,” <br />
Duchin says. When that person coughs or sneezes, others may become <br />
infected after breathing in the organisms.<br /><br />
Here are the estimated,<br />
overall, basic reproductive rates for Ebola and other infectious <br />
diseases, along with how they're spread.<br /><br />
<b>Measles</b><br /><br />
Airborne -- reproductive rate 12 to 18<br /><br />
The<br />
measles virus spreads through the air when infected people breathe, <br />
cough, or sneeze. Any person exposed to the virus who is not immune <br />
generally gets the disease. It is less common in countries with good <br />
vaccination coverage.<br /><br />
The virus typically grows in the cells lining the lungs and the back of the throat, leading to <a href="http://www.webmd.com/first-aid/fevers-causes-symptoms-treatments" target="_blank">fever</a>, <a href="http://www.webmd.com/allergies/postnasal-drip" target="_blank">runny nose</a>, <a href="http://www.webmd.com/cold-and-flu/tc/coughs-topic-overview" target="_blank">cough</a>, and an extensive rash.<br /><br />
Measles<br />
was declared eliminated in the U.S. nearly 15 years ago, according to <br />
the CDC. Even so, outbreaks still happen. In 2014, 288 people were <br />
confirmed to have had measles as of May 23. No deaths have occurred this<br />
year in the U.S. from measles.<br /><br />
<br /><br />
<b><a href="http://www.webmd.com/children/pertussis-whooping-cough-10/slideshow-prevent-pertussis" target="_blank">Pertussis</a> (whooping cough)</b><br /><br />
Droplets, airborne -- reproductive rate 12 to 17<br /><br />
Whooping<br />
cough is highly contagious. The bacteria that cause the disease attach <br />
to the tiny hair-like extensions (known as cilia) in the <a href="http://www.webmd.com/lung/how-we-breathe" target="_blank">respiratory system</a>, leading to the violent coughing that can make it hard to breathe.<br /><br />
It's spread when infected people cough or sneeze and others breathe in the bacteria.<br /><br />
Vaccination<br />
protects people, but outbreaks still happen. In 2012, for instance, <br />
more than 48,000 people with whooping cough were reported to the CDC, <br />
with 20 deaths. Most deaths were in infants younger than 3 months. <br />
Vaccination should begin at age 2 months, the CDC advises. Adults, <br />
especially those who will be around infants, also need a pertussis <br />
booster.<br /><br />
<b>Diphtheria</b><br /><br />
Respiratory droplets -- reproductive rate 6 to 7<br /><br />
Diphtheria is an infection caused by bacteria that are spread from person to person, usually by coughing or sneezing.<br /><br />
Diphtheria<br />
is not typically a concern in the U.S., Adalja says, due to routine <br />
vaccination. When it does occur, diphtheria can kill 1 in 10 affected, <br />
according to the CDC.<br /><br />
<b><a href="http://www.webmd.com/children/vaccines/polio-vaccine-ipv" target="_blank">Polio</a></b><br /><br />
Person to person -- reproductive rate 5 to 7<br /><br />
The polio virus spreads from person to person and invades the brain and spinal cord, sometimes leading to paralysis.<br /><br />
The<br />
virus is spread from the stool of an infected person or from droplets <br />
from a sneeze or cough. Toys and other objects contaminated with the <br />
virus can also spread the disease.<br /><br />
Most people infected don't have any symptoms. Others have <a href="http://www.webmd.com/cold-and-flu/default.htm" target="_blank">flu</a>-like symptoms that go away.<br /><br />
Only 1 in 100 people infected develop the weakness or paralysis, according to the CDC.<br /><br />
Of<br />
those people who are paralyzed, up to 10% die when the paralysis <br />
affects the breathing muscles. Vaccination has wiped out polio from <br />
some, but not all, of the world. Only three countries in the world -- <br />
Nigeria, Pakistan, and Afghanistan -- have not stopped the spread of <br />
polio, according to the WHO. Stumbling blocks have included resistance <br />
to vaccinations and the reluctance of some leaders to back vaccination <br />
efforts. <br /><br />
<b><a href="http://www.webmd.com/children/tc/mumps-topic-overview" target="_blank">Mumps</a></b><br /><br />
Droplets of saliva, mucus; contaminated objects -- reproductive rate 4 to 7<br /><br />
Mumps is a viral illness. It's spread by droplets of mucus or saliva when an infected person coughs, sneezes, or talks.<br /><br />
Vaccination<br />
prevents the disease, but outbreaks have still been seen, including in <br />
the U.S. Most people who get mumps recover fully, the CDC says.<br /><br />
<b>HIV</b><br /><br />
Sharing needles, sexual contact -- reproductive rate 1 to 4<br /><br />
HIV is the virus that can lead to <a href="http://www.webmd.com/hiv-aids/default.htm" target="_blank">AIDS</a>. The body can't get rid of the virus, so once infected, a person has HIV for life.<br /><br />
HIV is spread mainly by having sex with or sharing needles or other drug equipment with an infected person.<br /><br />
The<br />
estimated reproductive number, 1 to 4, can vary greatly, Adalja says. <br />
It would typically be much lower if someone infected with HIV is on an <br />
antiretroviral drug, does not inject drugs, and does not take part in <br />
other risky behaviors, he says.<br /><br />
<div class="pageSeparator"><div class="pageSeparatorLabel"><em>page 3</em></div></div><div class="page" id="page3"><div class="page_content"><h3> continued...</h3>AIDS<br />
is still a killer in the U.S. According to the CDC, 15,500 people with <br />
AIDS died in 2010, the latest year for the statistics.<br /><br />
<b>Ebola Virus</b><br /><br />
Bodily fluids, exposure to contaminated needles and other objects -- reproductive rate 1 to 4<br /><br />
Ebola<br />
was first discovered in 1976. Outbreaks have surfaced from time to time<br />
ever since. Ebola is particularly deadly, though. In the current <br />
outbreak, about 60% of those infected have died, according to the CDC.<br /><br />
Experts believe the virus hosts are animals, probably bats.<br /><br />
While<br />
Ebola and HIV have a similar reproductive number, they are different in<br />
many ways, Duchin says. "HIV and Ebola both are present in the blood, <br />
but the ways they infect cells, where they live in the body, are very <br />
different."<br /><br />
Compared to the airborne organisms spread by casual <br />
contact, "it takes effort to get infected with both of these viruses <br />
[HIV and Ebola]," Adalja says.<br /><br />
<div><div>© 2014 WebMD, LLC. All rights reserved.</div></div></div></div>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-65589944547574367092014-08-03T07:33:00.001-07:002014-08-03T07:33:17.255-07:00EASL Recommendations on Treatment of Hepatitis C 2014 .:. Latest news .:. EASL - EUROPEAN ASSOCIATION FOR THE STUDY OF THE LIVER<a href="http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-C/index.html#p=I" target="_blank">EASL Recommendations on Treatment of Hepatitis C 2014 .:. Latest news .:. EASL - EUROPEAN ASSOCIATION FOR THE STUDY OF THE LIVER</a><a href="http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-C/index.html#p=I"></a>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-63444166031019600662014-08-03T07:30:00.001-07:002014-08-03T07:30:35.450-07:00Guidelines for Colonoscopy Surveillance After Cancer Resection<h1><span style="font-size: small;">Guidelines for Colonoscopy Surveillance After Cancer Resection: A Consensus Update by the American Cancer Society and the US Multi-Society Task Force on Colorectal Cancer</span></h1> <br /><br />
Recommendations (<a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#tbl1" id="back-tbl1" target="_blank">Table 1</a>Table<br />
1) on the use of surveillance colonoscopy after resection of <br />
colorectal cancer were produced jointly by the US Multi-Society Task <br />
Force on Colorectal Cancer and the American Cancer Society (ACS). They <br />
constitute the updated recommendations of both organizations. The <br />
rationale for combined guidelines by organizations is discussed in the <br />
accompanying joint recommendations on postpolypectomy surveillance.<sup><a href="https://www.blogger.com/null" id="back-bib1" target="_blank">1</a></sup>Winawer,<br />
S.J., Zauber, A.G., Fletcher, R.H., Stillman, J.S., O’Brien, M.J., <br />
Levin, B., Smith, R.A., Lieberman, D.A., Burt, R.W., Levin, T.R., Bond, <br />
J.H., Brooks, D., Byers, T., Hyman, N., Kirk, L., Thorson, A., Simmang, <br />
C., Johnson, D., and Rex, D.K. Guidelines for Colonoscopy Surveillance <br />
After Polypectomy (a consensus update by the US Multi-Society Task Force<br />
on Colorectal Cancer and the American Cancer Society) . <br />
Gastroenterology. ;<br />
: 1872–1885<br /><br /><a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_1_2&dbid=4&doi=10.1053/j.gastro.2006.03.013&key=10.1053%2Fj.gastro.2006.03.012&cf=abstract&site=ygast-site" target="_blank">Abstract</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_1_2&dbid=4&doi=10.1053/j.gastro.2006.03.013&key=10.1053%2Fj.gastro.2006.03.012&cf=fulltext&site=ygast-site" target="_blank">Full Text</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_1_2&dbid=4&doi=10.1053/j.gastro.2006.03.013&key=10.1053%2Fj.gastro.2006.03.012&cf=pdf&site=ygast-site" target="_blank">Full Text PDF</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_1_2&dbid=8&doi=10.1053/j.gastro.2006.03.013&key=16697750&cf=" target="_blank">PubMed</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_1_2&dbid=137438953472&doi=10.1053/j.gastro.2006.03.013&key=2-s2.0-33646361037&cf=" target="_blank">Scopus (437)</a><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#references" target="_blank">See all References</a><br />
These guidelines were endorsed by the Colorectal Cancer Advisory <br />
Committee of the ACS and by the governing boards of the American College<br />
of Gastroenterology, the American Gastroenterological Association <br />
Institute, and the American Society for Gastrointestinal Endoscopy.<br /><br />
<div><div id="tbl1"><table><caption>Table 1Postcancer Resection Surveillance Colonoscopy Recommendations</caption><tbody>
<tr><td>1.<br />
Patients with colon and rectal cancer should undergo high-quality <br />
perioperative clearing. In the case of nonobstructing tumors, this can <br />
be done by preoperative colonoscopy. In the case of obstructing colon <br />
cancers, computed tomography colonography with intravenous contrast or <br />
double-contrast barium enema can be used to detect neoplasms in the <br />
proximal colon. In these cases, a colonoscopy to clear the colon of <br />
synchronous disease should be considered 3 to 6 months after the <br />
resection if no unresectable metastases are found during surgery. <br />
Alternatively, colonoscopy can be performed intraoperatively.</td></tr>
<tr><td>2.<br />
Patients undergoing curative resection for colon or rectal cancer <br />
should undergo a colonoscopy 1 year after the resection (or 1 year <br />
following the performance of the colonoscopy that was performed to clear<br />
the colon of synchronous disease). This colonoscopy at 1 year is in <br />
addition to the perioperative colonoscopy for synchronous tumors.</td></tr>
<tr><td>3.<br />
If the examination performed at 1 year is normal, then the interval <br />
before the next subsequent examination should be 3 years. If that <br />
colonoscopy is normal, then the interval before the next subsequent <br />
examination should be 5 years.</td></tr>
<tr><td>4. Following the <br />
examination at 1 year, the intervals before subsequent examinations may <br />
be shortened if there is evidence of hereditary nonpolyposis colorectal <br />
cancer or if adenoma findings warrant earlier colonoscopy.<sup><a href="https://www.blogger.com/null" id="back-bib1" target="_blank">1</a></sup>Winawer,<br />
S.J., Zauber, A.G., Fletcher, R.H., Stillman, J.S., O’Brien, M.J., <br />
Levin, B., Smith, R.A., Lieberman, D.A., Burt, R.W., Levin, T.R., Bond, <br />
J.H., Brooks, D., Byers, T., Hyman, N., Kirk, L., Thorson, A., Simmang, <br />
C., Johnson, D., and Rex, D.K. Guidelines for Colonoscopy Surveillance <br />
After Polypectomy (a consensus update by the US Multi-Society Task Force<br />
on Colorectal Cancer and the American Cancer Society) . <br />
Gastroenterology. ;<br />
: 1872–1885<br /><br /><a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_1_2&dbid=4&doi=10.1053/j.gastro.2006.03.013&key=10.1053%2Fj.gastro.2006.03.012&cf=abstract&site=ygast-site" target="_blank">Abstract</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_1_2&dbid=4&doi=10.1053/j.gastro.2006.03.013&key=10.1053%2Fj.gastro.2006.03.012&cf=fulltext&site=ygast-site" target="_blank">Full Text</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_1_2&dbid=4&doi=10.1053/j.gastro.2006.03.013&key=10.1053%2Fj.gastro.2006.03.012&cf=pdf&site=ygast-site" target="_blank">Full Text PDF</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_1_2&dbid=8&doi=10.1053/j.gastro.2006.03.013&key=16697750&cf=" target="_blank">PubMed</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_1_2&dbid=137438953472&doi=10.1053/j.gastro.2006.03.013&key=2-s2.0-33646361037&cf=" target="_blank">Scopus (437)</a><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#references" target="_blank">See all References</a></td></tr>
<tr><td>5.<br />
Periodic examination of the rectum for the purpose of identifying local<br />
recurrence, usually performed at 3- to 6-month intervals for the first 2<br />
or 3 years, may be considered after low anterior resection of rectal <br />
cancer. The techniques utilized are typically rigid proctoscopy, <br />
flexible proctoscopy, or rectal endoscopic ultrasound. These <br />
examinations are independent of the colonoscopic examinations described <br />
above for detection of metachronous disease.</td></tr>
</tbody></table></div></div><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#tbl2" id="back-tbl2" target="_blank">Table 2</a>Table 2 summarizes the differences in this guideline from previous guidelines on postcancer resection surveillance colonoscopy.<br /><br />
<table><caption>Table 2Differences Between This Guideline and Previous Guidelines on Postcancer Resection Surveillance Colonoscopy</caption><tbody>
<tr><td>In<br />
addition to careful perioperative clearing of the colorectum for <br />
synchronous lesions, a colonoscopy is recommended 1 year after surgical <br />
resection because of high yields of detecting early second, apparently <br />
metachronous cancers</td></tr>
<tr><td>Clinicians can consider periodic <br />
examination of the rectum for the purpose of identifying local <br />
recurrence after low anterior resection of rectal cancer. <br /><section id="Candidates for Postcancer Resection Surveillance Colonoscopy"><h3>Candidates for Postcancer Resection Surveillance Colonoscopy</h3><div>In<br />
general, patients who undergo surgical resection of Stage I, II, or III<br />
colon and rectal cancers or curative-intent resection of Stage IV <br />
cancers are candidates for surveillance colonoscopy. Patients who <br />
undergo curative endoscopic resection of Stage I colon cancers are also <br />
candidates for surveillance colonoscopy. Patients with Stage IV colon or<br />
rectal cancer that is unresectable for cure are generally not <br />
candidates for surveillance colonoscopy because their chance of survival<br />
from their primary cancer is low, and the risks of surveillance <br />
outweigh any potential benefit.<br /><br />
<br /><br />
<a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_27_2&dbid=8&doi=10.1053/j.gastro.2006.03.013&key=11869629&cf=" target="_blank">PubMed</a><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#references" target="_blank">See all References</a><br />
In summary, performance of annual colonoscopy for the purpose of <br />
detecting recurrent disease does not have an established survival <br />
benefit for patients with colorectal cancer. (However, as noted below, <br />
there is a rationale for surveillance of the rectum after resection of <br />
rectal cancer for the detection of local recurrence.) The primary goal <br />
of surveillance colonoscopy after resection of colorectal cancer is the <br />
detection of metachronous neoplasms.<br /><br />
<br /><br />
<h3>Distinguishing Rectal Cancer Versus Colon Cancer Follow-up</h3>Although<br />
there is no established benefit from endoscopic surveillance for the <br />
purpose of detecting early recurrences of the original cancer, in <br />
clinical practice many clinicians distinguish between rectal and colon <br />
cancer in this regard. The distinction is based on differences in the <br />
rates of local recurrence of rectal vs colon cancer. Specifically, in <br />
the case of colon cancer, recurrence at the anastomosis occurs in only <br />
2%–4% of patients.<sup><a href="https://www.blogger.com/null" id="back-bib2" target="_blank">2</a></sup>Barillari,<br />
P., Ramacciato, G., Manetti, G., Bovino, A., Sammartino, P., and <br />
Stipa, V. Surveillance of colorectal cancer (effectiveness of early <br />
detection of intraluminal recurrences on prognosis and survival of <br />
patients treated for cure) . Dis Colon Rectum. ;<br />
: 388–393</div><div><h3>Detection of Metachronous Neoplasms</h3>A second potential <br />
benefit of surveillance colonoscopy is the detection of metachronous <br />
cancers at a surgically curable stage, as well as the prevention of <br />
metachronous cancers via identification and removal of adenomatous <br />
polyps. The incidence of metachronous cancers, the timing at which <br />
metachronous cancers occur, and the stage of these cancers at <br />
presentation or identification by surveillance colonoscopy should <br />
determine the optimal intervals for performance of surveillance <br />
colonoscopy directed toward metachronous disease. The evidence from <br />
published studies of postcancer resection surveillance in colonoscopy <br />
was reviewed to determine what these rates and timing of metachronous <br />
cancers are (<a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#tbl3" id="back-tbl3" target="_blank">Table 3</a>Table 3). Limitations in interpretation of this literature were described earlier.<br /><br />
<div><div id="tbl3"><table><caption>Table 3Metachronous Cancers in Postcancer Resection Surveillance Colonoscopy Studies</caption><tbody>
<tr><th>Study</th><th>N</th><th>Colonoscopies</th><th>Metachronous CRCs (all)</th><th>Metachronous CRCs (within 24 mo)</th><th>Dukes’ A or B</th><th>Number asymptomatic</th><th>Reoperation for cure</th></tr>
<tr><td>Barillari</td><td>481</td><td><br /></td><td>12</td><td>6<a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#tblfn1" id="back-tblfn1" target="_blank"><sup>a</sup></a></td><td>9</td><td>6<a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#tblfn2" id="back-tblfn2" target="_blank"><sup>b</sup></a></td><td>7</td></tr>
<tr><td>Barrier</td><td>61<a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#tblfn3" id="back-tblfn3" target="_blank"><sup>c</sup></a></td><td><br /></td><td>0</td><td><br /></td><td><br /></td><td><br /></td><td><br /></td></tr>
<tr><td>Carlsson</td><td>129</td><td>546</td><td>1</td><td>0</td><td>NS</td><td>NS</td><td>NS</td></tr>
<tr><td>Castells</td><td>199</td><td><br /></td><td>0</td><td><br /></td><td><br /></td><td><br /></td><td><br /></td></tr>
<tr><td>Chen</td><td>231</td><td><br /></td><td>4</td><td>0</td><td>NS</td><td>4</td><td>4</td></tr>
<tr><td>Eckardt</td><td>212</td><td><br /></td><td>0</td><td><br /></td><td><br /></td><td><br /></td><td><br /></td></tr>
<tr><td>Granqvist</td><td>390</td><td>600</td><td>12</td><td>7</td><td>5<a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#tblfn4" id="back-tblfn4" target="_blank"><sup>d</sup></a></td><td>6<a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#tblfn4" id="back-tblfn4" target="_blank"><sup>d</sup></a></td><td>10</td></tr>
<tr><td>Green</td><td>3278</td><td><br /></td><td>42</td><td>24</td><td>23</td><td>NS</td><td>NS</td></tr>
<tr><td>Juhl</td><td>133</td><td>316</td><td>4</td><td>0</td><td>4</td><td>4</td><td>4</td></tr>
<tr><td>Khoury</td><td>389</td><td>3889</td><td>2</td><td>1</td><td>NS</td><td>NS</td><td>NS</td></tr>
<tr><td>Kjeldsen</td><td>597</td><td><br /></td><td>10</td><td>NS</td><td>NS</td><td>8</td><td>8</td></tr>
<tr><td>Kronborg</td><td>239</td><td>710</td><td>4</td><td>3</td><td>4</td><td>NS</td><td>4</td></tr>
<tr><td>Makela</td><td>106</td><td><br /></td><td>1</td><td>NS</td><td>NS</td><td>NS</td><td>1</td></tr>
<tr><td>McFarland</td><td>74</td><td>237</td><td>0</td><td><br /></td><td><br /></td><td><br /></td><td><br /></td></tr>
<tr><td>Obrand</td><td>444</td><td><br /></td><td>0</td><td><br /></td><td><br /></td><td><br /></td><td><br /></td></tr>
<tr><td>Ohlsson</td><td>53<a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#tblfn5" id="back-tblfn5" target="_blank"><sup>e</sup></a></td><td><br /></td><td>0</td><td><br /></td><td><br /></td><td><br /></td><td><br /></td></tr>
<tr><td>Patchett</td><td>132</td><td><br /></td><td>2</td><td>NS</td><td>NS</td><td>0</td><td>NS</td></tr>
<tr><td>Pietra</td><td>207</td><td><br /></td><td>1</td><td>NS</td><td>NS</td><td>NS</td><td>NS</td></tr>
<tr><td>Schoemaker</td><td>325</td><td>733</td><td>8</td><td>5</td><td>5</td><td>1</td><td>NS</td></tr>
<tr><td>Skaife</td><td>611</td><td>609<a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#tblfn6" id="back-tblfn6" target="_blank"><sup>f</sup></a></td><td>5</td><td>1</td><td>NS</td><td>NS</td><td>NS</td></tr>
<tr><td>Stigliano</td><td>322</td><td><br /></td><td>5</td><td>0</td><td>NS</td><td>NS</td><td>NS</td></tr>
<tr><td>Togashi</td><td>341</td><td>1570</td><td>22</td><td>9</td><td>17</td><td>NS</td><td>22</td></tr>
<tr><td>Weber</td><td>75</td><td>197</td><td>2</td><td>1</td><td>2</td><td>NS</td><td>2</td></tr>
<tr><td>Total</td><td>9029</td><td>9407</td><td>137</td><td>57</td><td>69</td><td>29</td><td>62</td></tr>
</tbody></table><div id="tblfn1"><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#back-tblfn1" target="_blank">a</a>Report states that “more than one half” arose in first 24 months.</div><div id="tblfn2"><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#back-tblfn2" target="_blank">b</a>Reports<br />
46 combined local recurrences with metachronous tumors, of which 22 <br />
were asymptomatic; number calculated assumes similar proportion for <br />
metachronous cancers.</div><div id="tblfn3"><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#back-tblfn3" target="_blank">c</a>Subgroup who underwent perioperative colonoscopy.</div><div id="tblfn4"><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#back-tblfn4" target="_blank">d</a>Reports<br />
26 combined local recurrences with metachronous tumors, of which 10 <br />
were Dukes’ A or B and 14 were asymptomatic; numbers calculated assume <br />
similar proportion for metachronous cancers.</div><div id="tblfn5"><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#back-tblfn5" target="_blank">e</a>Intensive surveillance subgroup (control group did not undergo routine colonoscopy).</div><div id="tblfn6"><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#back-tblfn6" target="_blank">f</a>Two patients underwent barium enema for completion of incomplete colonoscopy.</div></div></div>From<br />
2% to 7% of patients with colorectal cancer have 1 or more synchronous <br />
cancers in the colon and rectum at the time of initial diagnosis.<sup><a href="https://www.blogger.com/null" id="back-bib3" target="_blank">3</a></sup>Barrier,<br />
A., Houry, S., and Huguier, M. The appropriate use of colonoscopy in <br />
the curative management of colorectal cancer. Int J Colorectal Dis. ;<br />
: 93–98</div><div><h2>Alternatives to Colonoscopy for Surveillance</h2>Colonoscopy<br />
is considered the test of choice for detection of metachronous <br />
neoplasms in the postcancer resection surveillance colonoscopy setting (<a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#tbl4" id="back-tbl4" target="_blank">Table 4</a>Table<br />
4). Double-contrast barium enema was less sensitive than colonoscopy <br />
for large and small polyp detection after resection of adenomas.<sup><a href="https://www.blogger.com/null" id="back-bib59" target="_blank">59</a></sup>National<br />
Polyp Study Work Group, Winawer, S.J., Stewart, E.T., Zauber, A.G., <br />
Bond, J.H., Ansel, H., Waye, J.D., Hall, D., Hamlin, J.A., Schapiro, M.,<br />
O’Brien, M.J., Sternberg, S.S., and Gottlieb, L.A. A comparison of <br />
colonoscopy and double-contrast barium enema for surveillance after <br />
polypectomy. N Engl J Med. ;<br />
: 1766–1772<br /><br /><a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_59_2&dbid=16&doi=10.1053/j.gastro.2006.03.013&key=10.1056%2FNEJM200006153422401&cf=" target="_blank">CrossRef</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_59_2&dbid=8&doi=10.1053/j.gastro.2006.03.013&key=10852998&cf=" target="_blank">PubMed</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_59_2&dbid=137438953472&doi=10.1053/j.gastro.2006.03.013&key=2-s2.0-0034660436&cf=" target="_blank">Scopus (437)</a><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#references" target="_blank">See all References</a><br /><br />
<div><div id="tbl4"><table><caption>Table 4Additional Recommendations Regarding Postcancer Resection Surveillance Colonoscopy</caption><tbody>
<tr><td>1. These recommendations assume that colonoscopy is complete to the cecum and that bowel preparation is adequate</td></tr>
<tr><td>2.<br />
There is clear evidence that the quality of examinations is highly <br />
variable; continuous quality improvement process is critical to the <br />
effective application of colonoscopy in colorectal cancer prevention<sup><a href="https://www.blogger.com/null" id="back-bib50" target="_blank">50</a></sup>Rex,<br />
D., Cummings, O., and Ulbright, T. Coming to terms with pathologists <br />
over colon polyps with cancer or high-grade dysplasia. J Clin <br />
Gastroenterol. ;<br />
: <br /><br /><a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_50_2&dbid=16&doi=10.1053/j.gastro.2006.03.013&key=10.1097%2F01.mcg.0000145495.83928.0d&cf=" target="_blank">CrossRef</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_50_2&dbid=8&doi=10.1053/j.gastro.2006.03.013&key=15599200&cf=" target="_blank">PubMed</a><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#references" target="_blank">See all References</a></td></tr>
<tr><td>3. Endoscopists should make clear recommendations to primary care physicians about when the next colonoscopy is indicated</td></tr>
<tr><td>4. Performance of fecal occult blood text is discouraged in patients undergoing colonoscopic surveillance</td></tr>
<tr><td>5.<br />
Discontinuation of surveillance colonoscopy should be considered in <br />
persons with advanced age or comorbidities (<10 years life <br />
expectancy), according to the clinician’s judgment</td></tr>
<tr><td>6. Surveillance guidelines are intended for asymptomatic people; new symptoms may need diagnostic work-up</td></tr>
<tr><td>7. Chromoendoscopy (dye-spraying) and magnification endoscopy are not established as essential to screening or surveillance</td></tr>
<tr><td>8. Computed tomography colonography (virtual colonoscopy) is not established as a surveillance modality</td></tr>
</tbody></table></div></div>CT colonography has not been evaluated adequately in the surveillance setting, and results for polyp detection are quite mixed.<sup><a href="https://www.blogger.com/null" id="back-bib60" target="_blank">60</a></sup>Rockey, D., Paulson, E., Favis, W. et al. Multicenter prospective comparison of colon imaging tests. (abstr)Gastroenterology. ;<br />
: A2004<br /><br /><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#references" target="_blank">See all References</a><sup>, </sup><sup><a href="https://www.blogger.com/null" id="back-bib61" target="_blank">61</a></sup>Johnson,<br />
C.D., Harmsen, W.S., Wilson, L.A., McCarty, R.L., Welch, T.J., Ilstrup,<br />
D.M., and Ahlquist, D.A. Prospective blinded evaluation of computed <br />
tomographic colonography for screen detection of colorectal polyps. <br />
Gastroenterology. ;<br />
: 311–319<br /><br /><a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_61_2&dbid=4&doi=10.1053/j.gastro.2006.03.013&key=10.1016%2FS0016-5085%2803%2900894-1&cf=abstract&site=ygast-site" target="_blank">Abstract</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_61_2&dbid=4&doi=10.1053/j.gastro.2006.03.013&key=10.1016%2FS0016-5085%2803%2900894-1&cf=fulltext&site=ygast-site" target="_blank">Full Text</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_61_2&dbid=4&doi=10.1053/j.gastro.2006.03.013&key=10.1016%2FS0016-5085%2803%2900894-1&cf=pdf&site=ygast-site" target="_blank">Full Text PDF</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_61_2&dbid=8&doi=10.1053/j.gastro.2006.03.013&key=12891530&cf=" target="_blank">PubMed</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_61_2&dbid=137438953472&doi=10.1053/j.gastro.2006.03.013&key=2-s2.0-0041530278&cf=" target="_blank">Scopus (289)</a><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#references" target="_blank">See all References</a><sup>, </sup><sup><a href="https://www.blogger.com/null" id="back-bib62" target="_blank">62</a></sup>Cotton,<br />
P.B., Durkalski, V.L., Pineau, B.C., Palesch, Y.Y., Mauldin, P.D., <br />
Hoffman, B., Vining, D.J., Small, W.C., Affronti, J., Rex, D.K. et al. <br />
Computed tomographic colonography (virtual colonoscopy). A multicenter <br />
comparison with standard colonoscopy for detection of colorectal <br />
neoplasia. . ;<br />
: 1713–1719<br /><br /><a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_62_2&dbid=16&doi=10.1053/j.gastro.2006.03.013&key=10.1001%2Fjama.291.14.1713&cf=" target="_blank">CrossRef</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_62_2&dbid=8&doi=10.1053/j.gastro.2006.03.013&key=15082698&cf=" target="_blank">PubMed</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_62_2&dbid=137438953472&doi=10.1053/j.gastro.2006.03.013&key=2-s2.0-11144358036&cf=" target="_blank">Scopus (512)</a><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#references" target="_blank">See all References</a><sup>, </sup><sup><a href="https://www.blogger.com/null" id="back-bib63" target="_blank">63</a></sup>Pickhardt,<br />
P.J., Choi, J.R., Hwang, I., Butler, J.A., Puckett, M.L., Hildebrandt, <br />
H.A., Wong, R.K., Nugent, P.A., Mysliwiec, P.A., and Schindler, W.R. <br />
Computed tomographic virtual colonoscopy to screen for colorectal <br />
neoplasia in asymptomatic adults. N Engl J Med. ;<br />
: 2191–2200<br /><br /><a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_63_2&dbid=16&doi=10.1053/j.gastro.2006.03.013&key=10.1056%2FNEJMoa031618&cf=" target="_blank">CrossRef</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_63_2&dbid=8&doi=10.1053/j.gastro.2006.03.013&key=14657426&cf=" target="_blank">PubMed</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_63_2&dbid=137438953472&doi=10.1053/j.gastro.2006.03.013&key=2-s2.0-0345690179&cf=" target="_blank">Scopus (1288)</a><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#references" target="_blank">See all References</a><br />
Guaiac-based fecal occult blood testing generally has been considered <br />
to have very low positive predictive value after clearing colonoscopy. <br />
This was confirmed for the first 5 years after colonoscopy in a recent <br />
large study.<sup><a href="https://www.blogger.com/null" id="back-bib64" target="_blank">64</a></sup>Finkelstein,<br />
S. and Bini, E.J. Annual fecal occult blood testing can be safely <br />
suspended for up to 5 years after a negative colonoscopy in asymptomatic<br />
average-risk patients. Gastrointest Endosc. ;<br />
: AB250<br /><br /><a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_64_2&dbid=4&doi=10.1053/j.gastro.2006.03.013&key=10.1016%2FS0016-5107%2805%2901335-0&cf=abstract&site=ymge-site" target="_blank">Abstract</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_64_2&dbid=4&doi=10.1053/j.gastro.2006.03.013&key=10.1016%2FS0016-5107%2805%2901335-0&cf=fulltext&site=ymge-site" target="_blank">Full Text</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_64_2&dbid=4&doi=10.1053/j.gastro.2006.03.013&key=10.1016%2FS0016-5107%2805%2901335-0&cf=pdf&site=ymge-site" target="_blank">Full Text PDF</a><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#references" target="_blank">See all References</a> Immunochemical fecal occult blood testing warrants additional evaluation as an adjunct to colonoscopy<sup><a href="https://www.blogger.com/null" id="back-bib65" target="_blank">65</a></sup>Bampton,<br />
P.A., Sandford, J.J., Cole, S.R., Smith, A., Marcon, J., Cadd, B., and<br />
Young, G.P. Interval faecal occult blood testing in a colonoscopy based<br />
screening programme detects additional pathology. . ;<br />
: 803–806<br /><br /><a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_65_2&dbid=16&doi=10.1053/j.gastro.2006.03.013&key=10.1136%2Fgut.2004.043786&cf=" target="_blank">CrossRef</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_65_2&dbid=8&doi=10.1053/j.gastro.2006.03.013&key=15888788&cf=" target="_blank">PubMed</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_65_2&dbid=137438953472&doi=10.1053/j.gastro.2006.03.013&key=2-s2.0-19544365737&cf=" target="_blank">Scopus (45)</a><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#references" target="_blank">See all References</a> in this setting. Fecal DNA testing<sup><a href="https://www.blogger.com/null" id="back-bib66" target="_blank">66</a></sup>Imperiale,<br />
T.F., Ransohoff, D.F., Itzkowitz, S.H., Turnbull, B.A., and Ross, M.E.<br />
Fecal DNA versus fecal occult blood for colorectal-cancer screening in <br />
an average-risk population. N Engl J Med. ;<br />
: 2704–2714<br /><br /><a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_66_2&dbid=16&doi=10.1053/j.gastro.2006.03.013&key=10.1056%2FNEJMoa033403&cf=" target="_blank">CrossRef</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_66_2&dbid=8&doi=10.1053/j.gastro.2006.03.013&key=15616205&cf=" target="_blank">PubMed</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_66_2&dbid=137438953472&doi=10.1053/j.gastro.2006.03.013&key=2-s2.0-10844281210&cf=" target="_blank">Scopus (486)</a><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#references" target="_blank">See all References</a> has not been evaluated for postcancer resection surveillance and is not recommended for this indication.<br /><br />
<h3>Key Research Questions</h3>There<br />
are a number of questions that cannot be addressed fully by currently <br />
available evidence. Some of these key research questions are listed in <a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#tbl5" id="back-tbl5" target="_blank">Table 5</a>Table 5.<sup><a href="https://www.blogger.com/null" id="back-bib55" target="_blank">55</a></sup>Lieberman,<br />
D., Weiss, D., Bond, J., Ahnen, D., Garewal, H., and Chejfec, G. 380. <br />
VACSG. Use of colonoscopy to screen asymptomatic adults for colorectal <br />
cancer. N Engl J Med. ;<br />
: 162–168<br /><br /><a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_55_2&dbid=16&doi=10.1053/j.gastro.2006.03.013&key=10.1056%2FNEJM200007203430301&cf=" target="_blank">CrossRef</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_55_2&dbid=8&doi=10.1053/j.gastro.2006.03.013&key=10900274&cf=" target="_blank">PubMed</a> | <a href="http://www.gastrojournal.org/servlet/linkout?suffix=e_1_5_1_2_55_2&dbid=137438953472&doi=10.1053/j.gastro.2006.03.013&key=2-s2.0-0034691827&cf=" target="_blank">Scopus (1219)</a><a href="http://www.gastrojournal.org/article/S0016-5085%2806%2900562-2/fulltext#references" target="_blank">See all References</a><br /><br />
<table><caption>Table 5Key Research Questions Regarding Surveillance of the Colorectum After Resection of Colorectal Cancer</caption><tbody>
<tr><td>1.<br />
What clinical, genetic, or biologic markers predict development of <br />
metachronous cancers (ie, stratify risk) in colorectal cancer patients <br />
without hereditary nonpolyposis colorectal cancer?</td></tr>
<tr><td>2. <br />
Are new colorectal cancers in the short-term interval after surgical <br />
resection true metachronous cancers or missed synchronous lesions?</td></tr>
<tr><td>3.<br />
Do follow-up procedures (flexible sigmoidoscopy, endoscopic ultrasound)<br />
after resection of rectal cancer improve any outcomes?</td></tr>
<tr><td>4.<br />
Should the treatment of rectal cancer (eg, neoadjuvant chemoradiation, <br />
total mesorectal excision) influence whether follow-up evaluation for <br />
local recurrence is justified?</td></tr>
<tr><td>5. Should adjunctive <br />
testing (eg, immunochemical fecal occult blood testing) be added to <br />
colonoscopy in the surveillance of patients who have undergone resection<br />
of colorectal cancer?</td></tr>
</tbody></table></div></section></td><td> </td><td> </td><td> </td><td> </td><td> </td><td><br /></td></tr>
</tbody></table>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-24235907927333322892014-08-03T05:32:00.001-07:002014-08-03T05:32:00.929-07:00Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver - Vilstrup - 2014 - Hepatology - Wiley Online Library<div style="text-align: justify;"><br /><br />
<section id="hep27210-sec-0080">The<br />
AASLD/EASL Practice Guideline Subcommittee on Hepatic Encephalopathy <br />
are: Jayant A. Talwalkar (Chair, AASLD), Hari S. Conjeevaram, Michael <br />
Porayko, Raphael B. Merriman, Peter L.M. Jansen, and Fabien Zoulim. This<br />
guideline has been approved by the American Association for the Study <br />
of Liver Diseases and the European Association for the Study of the <br />
Liver and represents the position of both associations.</section><section id="hep27210-sec-0001"><h2>Preamble</h2>These<br />
recommendations provide a data-supported approach. They are based on <br />
the following: (1) formal review and analysis of the recently published <br />
world literature on the topic; (2) guideline policies covered by the <br />
American Association for the Study of Liver Diseases/European <br />
Association for the Study of the Liver (AASLD/EASL) Policy on the Joint <br />
Development and Use of Practice Guidelines; and (3) the experience of <br />
the authors in the specified topic.<br /><br />
Intended for use by <br />
physicians, these recommendations suggest preferred approaches to the <br />
diagnostic, therapeutic, and preventive aspects of care. They are <br />
intended to be flexible, in contrast to standards of care, which are <br />
inflexible policies to be followed in every case. Specific <br />
recommendations are based on relevant published information.<br /><br />
To <br />
more fully characterize the available evidence supporting the <br />
recommendations, the AASLD/EASL Practice Guidelines Subcommittee has <br />
adopted the classification used by the Grading of Recommendation <br />
Assessment, Development, and Evaluation (GRADE) workgroup, with minor <br />
modifications (Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0001" target="_blank" title="Link to table">1</a>).<br />
The classifications and recommendations are based on three categories: <br />
the source of evidence in levels I through III; the quality of evidence <br />
designated by high (A), moderate (B), or low quality (C); and the <br />
strength of recommendations classified as strong (1) or weak (2).<br /><br />
<div><table id="hep27210-tbl-0001" style="margin-left: 0px; margin-right: 0px; text-align: left;"><caption>Table 1. GRADE System for Evidence</caption><thead>
<tr><th>Grade</th><th>Evidence</th></tr>
</thead><tbody>
<tr><td>I</td><td>Randomized, controlled trials</td></tr>
<tr><td>II-1</td><td>Controlled trials without randomization</td></tr>
<tr><td>II-2</td><td>Cohort or case-control analytic studies</td></tr>
<tr><td>II-3</td><td>Multiple time series, dramatic uncontrolled experiments</td></tr>
<tr><td>III</td><td>Opinions of respected authorities, descriptive epidemiology</td></tr>
</tbody></table><table id="hep27210-tbl-0001" style="margin-left: 0px; margin-right: 0px; text-align: left;"><thead>
<tr><th>Evidence</th><th>Description</th></tr>
</thead><tbody>
<tr><td>High quality</td><td>Further research is very unlikely to change our confidence in the estimated effect.</td><td>A</td></tr>
<tr><td>Moderate</td><td>Further research is likely to have an important impact on our confidence in the estimate effect and may change the estimate.</td><td>B</td></tr>
<tr><td>Low quality</td><td>Further<br />
research is likely to have an important impact on our confidence in the<br />
estimate effect and is likely to change the estimate. Any change of <br />
estimate is uncertain.</td><td>C</td></tr>
</tbody></table><table id="hep27210-tbl-0001" style="margin-left: 0px; margin-right: 0px; text-align: left;"><thead>
<tr><th colspan="3">Recommendation</th></tr>
</thead><tbody>
<tr><td>Strong</td><td>Factors<br />
influencing the strength of recommendation included the quality of <br />
evidence, presumed patient-important outcomes, and costs.</td><td>1</td></tr>
<tr><td>Weak</td><td>Variability<br />
in preferences and values, or more uncertainty. Recommendation is made <br />
with less certainty, higher costs, or resource consumption.</td><td>2</td></tr>
</tbody></table></div></section><section id="hep27210-sec-0002"><h2>Literature Review and Analysis</h2>The<br />
literature databases and search strategies are outlined below. The <br />
resulting literature database was available to all members of the <br />
writing group (i.e., the authors). They selected references within their<br />
field of expertise and experience and graded the references according <br />
to the GRADE system.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0001" target="_blank" title="Link to bibliographic citation">1</a>]<br />
The selection of references for the guideline was based on a validation<br />
of the appropriateness of the study design for the stated purpose, a <br />
relevant number of patients under study, and confidence in the <br />
participating centers and authors. References on original data were <br />
preferred and those that were found unsatisfactory in any of these <br />
respects were excluded from further evaluation. There may be limitations<br />
in this approach when recommendations are needed on rare problems or <br />
problems on which scant original data are available. In such cases, it <br />
may be necessary to rely on less-qualified references with a low <br />
grading. As a result of the important changes in the treatment of <br />
complications of cirrhosis (renal failure, infections, and variceal <br />
bleeding [VB]), studies performed more than 30 years ago have generally <br />
not been considered for these guidelines.</section><section id="hep27210-sec-0003"><h2>Introduction</h2>Hepatic<br />
encephalopathy (HE) is a frequent complication and one of the most <br />
debilitating manifestations of liver disease, severely affecting the <br />
lives of patients and their caregivers. Furthermore, cognitive <br />
impairment associated with cirrhosis results in utilization of more <br />
health care resources in adults than other manifestations of liver <br />
disease.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0002" target="_blank" title="Link to bibliographic citation">2</a>]<br />
Progress in the area has been hindered by the complex pathogenesis that<br />
is not yet fully elucidated. Apart from such biological factors, there <br />
remains the larger obstacle that there are no universally accepted <br />
standards for the definition, diagnosis, classification, or treatment of<br />
HE, mostly as a result of insufficient clinical studies and <br />
standardized definitions. Clinical management tends to be dependent on <br />
local standards and personal views. This is an unfavorable situation for<br />
patients and contrasts with the severity of the condition and the high <br />
level of standardization in other complications of cirrhosis. The lack <br />
of consistency in the nomenclature and general standards renders <br />
comparisons among studies and patient populations difficult, introduces <br />
bias, and hinders progress in clinical research for HE. The latest <br />
attempts to standardize the nomenclature were published in 2002 and <br />
suggestions for the design of HE trials in 2011. Because there is an <br />
unmet need for recommendations on the clinical management of HE, the <br />
EASL and the AASLD jointly agreed to create these practice guidelines. <br />
It is beyond the scope of these guidelines to elaborate on the theories <br />
of pathogenesis of HE, as well as the management of encephalopathy <br />
resulting from acute liver failure (ALF), which has been published as <br />
guidelines recently. Rather, its aim is to present standardized <br />
terminology and recommendations to all health care workers who have <br />
patients with HE, regardless of their medical discipline, and focus on <br />
adult patients with chronic liver disease (CLD), which is, by far, the <br />
most frequent scenario.<br /><br />
As these guidelines on HE were created, <br />
the authors found a limited amount of high-quality evidence to extract <br />
from the existing literature. There are many reasons for this; the <br />
elusive character of HE is among them, as well as the lack of generally <br />
accepted and utilized terms for description and categorization of HE. <br />
This makes a practice guideline all the more necessary for future <br />
improvement of clinical studies and, subsequently, the quality of <br />
management of patients with HE. With the existing body of evidence, <br />
these guidelines encompass the authors' best, carefully considered <br />
opinions. Although not all readers may necessarily agree with all <br />
aspects of the guidelines, their creation and adherence to them is the <br />
best way forward, with future adjustments when there is emergence of new<br />
evidence.</section><section id="hep27210-sec-0004"><h2>Definition of the Disease/Condition</h2><section id="hep27210-sec-0005"><h3>Overview</h3>Advanced<br />
liver disease and portosystemic shunting (PSS), far from being an <br />
isolated disorder of the liver, have well-known consequences on the body<br />
and, notably, on brain functioning. The alterations of brain <br />
functioning, which can produce behavioral, cognitive, and motor effects,<br />
were termed portosystemic encephalopathy (PSE)[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0003" target="_blank" title="Link to bibliographic citation">3</a>] and later included in the term HE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0004" target="_blank" title="Link to bibliographic citation">4</a>]<br /><br />
Unless the underlying liver disease is successfully treated, HE is associated with poor survival and a high risk of recurrence.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0005" target="_blank" title="Link to bibliographic citations">5, 6</a>] Even in its mildest form, HE reduces health-related quality of life and is a risk factor for bouts of severe HE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0007" target="_blank" title="Link to bibliographic citations">7-9</a>]</section><section id="hep27210-sec-0006"><h3>Definition of HE</h3><i>Hepatic<br />
encephalopathy is a brain dysfunction caused by liver insufficiency <br />
and/or PSS; it manifests as a wide spectrum of neurological or <br />
psychiatric abnormalities ranging from subclinical alterations to coma</i>.<br /><br />
This definition, in line with previous versions,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0010" target="_blank" title="Link to bibliographic citations">10, 11</a>] is based on the concept that encephalopathies are “diffuse disturbances of brain function”[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0005" target="_blank" title="Link to bibliographic citation">5</a>] and that the adjective “hepatic” implies a causal connection to liver insufficiency and/or perihepatic vascular shunting.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0006" target="_blank" title="Link to bibliographic citation">6</a>]</section><section id="hep27210-sec-0007"><h3>Epidemiology</h3>The incidence and prevalence of HE are related to the severity of the underlying liver insufficiency and PSS.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0012" target="_blank" title="Link to bibliographic citations">12-15</a>]<br />
In patients with cirrhosis, fully symptomatic overt HE (OHE) is an <br />
event that defines the decompensated phase of the disease, such as VB or<br />
ascites.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0007" target="_blank" title="Link to bibliographic citation">7</a>] Overt hepatic encephalopathy is also reported in subjects without cirrhosis with extensive PSS.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0008" target="_blank" title="Link to bibliographic citations">8, 9</a>]<br /><br />
The<br />
manifestation of HE may not be an obvious clinical finding and there <br />
are multiple tools used for its detection, which influences the <br />
variation in the reported incidence and prevalence rates.<br /><br />
The prevalence of OHE at the time of diagnosis of cirrhosis is 10%-14% in general,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0016" target="_blank" title="Link to bibliographic citations">16-18</a>] 16%-21% in those with decompensated cirrhosis,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0007" target="_blank" title="Link to bibliographic citations">7, 19</a>] and 10%-50% in patients with transjugular intrahepatic portosystemic shunt (TIPS).[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0020" target="_blank" title="Link to bibliographic citations">20, 21</a>]<br />
The cumulated numbers indicate that OHE will occur in 30%-40% of those <br />
with cirrhosis at some time during their clinical course and in the <br />
survivors in most cases repeatedly.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0022" target="_blank" title="Link to bibliographic citation">22</a>] Minimal HE (MHE) or covert HE (CHE) occurs in 20%-80% of patients with cirrhosis.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0023" target="_blank" title="Link to bibliographic citations">23-27, 81</a>] The prevalence of HE in prehepatic noncirrhotic portal hypertension (PH) is not well defined.<br /><br />
The<br />
risk for the first bout of OHE is 5%-25% within 5 years after cirrhosis<br />
diagnosis, depending on the presence of risk factors, such as other <br />
complications to cirrhosis (MHE or CHE, infections, VB, or ascites) and <br />
probably diabetes and hepatitis C.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0028" target="_blank" title="Link to bibliographic citations">28-32</a>] Subjects with a previous bout of OHE were found to have a 40% cumulative risk of recurring OHE at 1 year,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0033" target="_blank" title="Link to bibliographic citation">33</a>]<br />
and subjects with recurrent OHE have a 40% cumulative risk of another <br />
recurrence within 6 months, despite lactulose treatment. Even <br />
individuals with cirrhosis and only mild cognitive dysfunction or mild <br />
electroencephalography (EEG) slowing develop approximately one bout of <br />
OHE per 3 years of survival.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0034" target="_blank" title="Link to bibliographic citations">34, 35</a>]<br /><br />
After TIPS, the median cumulative 1-year incidence of OHE is 10%-50%[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0036" target="_blank" title="Link to bibliographic citations">36, 37</a>] and is greatly influenced by the patient selection criteria adopted.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0038" target="_blank" title="Link to bibliographic citation">38</a>] Comparable data were obtained by PSS surgery.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0039" target="_blank" title="Link to bibliographic citation">39</a>]<br /><br />
It<br />
gives an idea of the frequent confrontation of the health care system <br />
by patients with HE that they accounted for approximately 110,000 <br />
hospitalizations yearly (2005-2009)[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0040" target="_blank" title="Link to bibliographic citation">40</a>]<br />
in the United States. Though numbers in the European Union (EU) are not<br />
readily available, these predictions are expected to be similar. <br />
Furthermore, the burden of CLD and cirrhosis is rapidly increasing,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0041" target="_blank" title="Link to bibliographic citations">41, 42</a>] and more cases will likely be encountered to further define the epidemiology of HE.</section><section id="hep27210-sec-0008"><h3>Clinical Presentation</h3>Hepatic encephalopathy produces a wide spectrum of nonspecific neurological and psychiatric manifestations.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0010" target="_blank" title="Link to bibliographic citation">10</a>] In its lowest expression,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0043" target="_blank" title="Link to bibliographic citations">43, 44</a>]<br />
HE alters only psychometric tests oriented toward attention, working <br />
memory (WM), psychomotor speed, and visuospatial ability, as well as <br />
electrophysiological and other functional brain measures.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0045" target="_blank" title="Link to bibliographic citations">45, 46</a>]<br /><br />
As<br />
HE progresses, personality changes, such as apathy, irritability, and <br />
disinhibition, may be reported by the patient's relatives,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0047" target="_blank" title="Link to bibliographic citation">47</a>]<br />
and obvious alterations in consciousness and motor function occur. <br />
Disturbances of the sleep-wake cycle with excessive daytime sleepiness <br />
are frequent,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0048" target="_blank" title="Link to bibliographic citation">48</a>] whereas complete reversal of the sleep-wake cycle is less consistently observed.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0049" target="_blank" title="Link to bibliographic citations">49, 50</a>]<br />
Patients may develop progressive disorientation to time and space, <br />
inappropriate behavior, and acute confusional state with agitation or <br />
somnolence, stupor, and, finally, coma.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0051" target="_blank" title="Link to bibliographic citation">51</a>]<br />
The recent ISHEN (International Society for Hepatic Encephalopathy and <br />
Nitrogen Metabolism) consensus uses the onset of disorientation or <br />
asterixis as the onset of OHE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0065" target="_blank" title="Link to bibliographic citation">65</a>]<br /><br />
In<br />
noncomatose patients with HE, motor system abnormalities, such as <br />
hypertonia, hyper-reflexia, and a positive Babinski sign, can be <br />
observed. In contrast, deep tendon reflexes may diminish and even <br />
disappear in coma,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0052" target="_blank" title="Link to bibliographic citation">52</a>] although pyramidal signs can still be observed. Rarely, transient focal neurological deficits can occur.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0053" target="_blank" title="Link to bibliographic citation">53</a>] Seizures are very rarely reported in HE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0054" target="_blank" title="Link to bibliographic citations">54-56</a>]<br /><br />
Extrapyramidal<br />
dysfunction, such as hypomimia, muscular rigidity, bradykinesia, <br />
hypokinesia, monotony and slowness of speech, parkinsonian-like tremor, <br />
and dyskinesia with diminished voluntary movements, are common findings;<br />
in contrast, the presence of involuntary movements similar to tics or <br />
chorea occur rarely.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0052" target="_blank" title="Link to bibliographic citations">52, 57</a>]<br /><br />
Asterixis<br />
or “flapping tremor” is often present in the early to middle stages of <br />
HE that precede stupor or coma and is, in actuality, not a tremor, but a<br />
negative myoclonus consisting of loss of postural tone. It is easily <br />
elicited by actions that require postural tone, such as hyperextension <br />
of the wrists with separated fingers or the rhythmic squeezing of the <br />
examiner's fingers. However, asterixis can be observed in other areas, <br />
such as the feet, legs, arms, tongue, and eyelids. Asterixis is not <br />
pathognomonic of HE because it can be observed in other diseases[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0057" target="_blank" title="Link to bibliographic citation">57</a>] (e.g., uremia).<br /><br />
Notably,<br />
the mental (either cognitive or behavioral) and motor signs of HE may <br />
not be expressed, or do not progress in parallel, in each individual, <br />
therefore producing difficulties in staging the severity of HE.<br /><br />
Hepatic myelopathy (HM)[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0058" target="_blank" title="Link to bibliographic citation">58</a>]<br />
is a particular pattern of HE possibly related to marked, long-standing<br />
portocaval shunting, characterized by severe motor abnormalities <br />
exceeding the mental dysfunction. Cases of paraplegia with progressive <br />
spasticity and weakness of lower limbs with hyper-reflexia and <br />
relatively mild persistent or recurrent mental alterations have been <br />
reported and do not respond to standard therapy, including ammonia <br />
lowering, but may reverse with liver transplantation (LT).[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0059" target="_blank" title="Link to bibliographic citation">59</a>]<br /><br />
Persistent<br />
HE may present with prominent extrapyramidal and/or pyramidal signs, <br />
partially overlapping with HM, in which postmortem brain examination <br />
reveals brain atrophy.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0060" target="_blank" title="Link to bibliographic citation">60</a>]<br />
This condition was previously called acquired hepatolenticular <br />
degeneration, a term currently considered obsolete. However, this <br />
cirrhosis-associated parkinsonism is unresponsive to ammonia-lowering <br />
therapy and may be more common than originally thought in patients with <br />
advanced liver disease, presenting in approximately 4% of cases.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0061" target="_blank" title="Link to bibliographic citation">61</a>]<br /><br />
Apart<br />
from these less-usual manifestations of HE, it is widely accepted in <br />
clinical practice that all forms of HE and their manifestations are <br />
completely reversible, and this assumption still is a well-founded <br />
operational basis for treatment strategies. However, research on <br />
liver-transplanted HE patients and on patients after resolution of <br />
repeated bouts of OHE casts doubt on the full reversibility. Some mental<br />
deficits, apart from those ascribable to other transplantation-related <br />
causes, may persist and are mentioned later under transplantation.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0135" target="_blank" title="Link to bibliographic citation">135</a>] Likewise, episodes of OHE may be associated with persistent cumulative deficits in WM and learning.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0014" target="_blank" title="Link to bibliographic citation">14</a>]</section><section id="hep27210-sec-0009"><h3>Classification</h3>Hepatic encephalopathy should be classified according to all of the following four factors.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0010" target="_blank" title="Link to bibliographic citation">10</a>]<br /><br />
<ol id="hep27210-list-0001"><li id="hep27210-li-0001"> <b>According to the underlying disease,</b> HE is subdivided into <br /><br />
<ul id="hep27210-list-0002"><li id="hep27210-li-0002">Type A resulting from ALF</li>
<li id="hep27210-li-0003">Type B resulting predominantly from portosystemic bypass or shunting</li>
<li id="hep27210-li-0004">Type C resulting from cirrhosis</li>
</ul>The<br />
clinical manifestations of types B and C are similar, whereas type A <br />
has distinct features and, notably, may be associated with increased <br />
intracranial pressure and a risk of cerebral herniation. The management <br />
of HE type A is described in recent guidelines on ALF[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0062" target="_blank" title="Link to bibliographic citations">62, 63</a>] and is not included in this document.</li>
<li id="hep27210-li-0005"> <b>According to the severity of manifestations</b>.<br />
The continuum that is HE has been arbitrarily subdivided. For clinical <br />
and research purposes, a scheme of such grading is provided (Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0002" target="_blank" title="Link to table">2</a>).<br />
Operative classifications that refer to defined functional impairments <br />
aim at increasing intra- and inter-rater reliability and should be used <br />
whenever possible.</li>
<li id="hep27210-li-0006"> <b>According to its time course</b>, HE is subdivided into <br /><br />
<ul id="hep27210-list-0003"><li id="hep27210-li-0007"><b>Episodic HE</b></li>
<li id="hep27210-li-0008"><b>Recurrent HE</b> denotes bouts of HE that occur with a time interval of 6 months or less.</li>
<li id="hep27210-li-0009"><b>Persistent HE</b> denotes a pattern of behavioral alterations that are always present and interspersed with relapses of overt HE.</li>
</ul></li>
<li id="hep27210-li-0010"> <b>According to the existence of precipitating factors</b>, HE is subdivided into <br /><br />
<ul id="hep27210-list-0004"><li id="hep27210-li-0011"><b>Nonprecipitated</b> or</li>
<li id="hep27210-li-0012"><b>Precipitated</b>,<br />
and the precipitating factors should be specified. Precipitating <br />
factors can be identified in nearly all bouts of episodic HE type C and <br />
should be actively sought and treated when found (Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0003" target="_blank" title="Link to table">3</a>).</li>
</ul></li>
</ol><div><table id="hep27210-tbl-0002" style="margin-left: 0px; margin-right: 0px; text-align: left;"><caption>Table 2. WHC and Clinical Description</caption><thead>
<tr><th>WHC Including MHE</th><th>ISHEN</th><th>Description</th><th>Suggested Operative Criteria</th><th>Comment</th></tr>
</thead><tfoot>
<tr><td colspan="5"><ol><li id="hep27210-note-0004"> All conditions are required to be related to liver insufficiency and/or PSS.</li>
</ol></td></tr>
</tfoot><tbody>
<tr><td colspan="2">Unimpaired</td><td>No encephalopathy at all, no history of HE</td><td>Tested and proved to be normal</td><td></td></tr>
<tr><td>Minimal</td><td rowspan="2">Covert</td><td>Psychometric<br />
or neuropsychological alterations of tests exploring psychomotor <br />
speed/executive functions or neurophysiological alterations without <br />
clinical evidence of mental change</td><td>Abnormal results of established psychometric or neuropsychological tests without clinical manifestations</td><td>No universal criteria for diagnosis<br /><br />
Local standards and expertise required</td></tr>
<tr><td>Grade I</td><td>• Trivial lack of awareness<br /><br />
• Euphoria or anxiety<br /><br />
• Shortened attention span<br /><br />
• Impairment of addition or subtraction<br /><br />
• Altered sleep rhythm</td><td>Despite<br />
oriented in time and space (see below), the patient appears to have <br />
some cognitive/behavioral decay with respect to his or her standard on <br />
clinical examination or to the caregivers</td><td>Clinical findings usually not reproducible</td></tr>
<tr><td>Grade II</td><td rowspan="3">Overt</td><td>• Lethargy or apathy<br /><br />
• Disorientation for time<br /><br />
• Obvious personality change<br /><br />
• Inappropriate behavior<br /><br />
• Dyspraxia<br /><br />
• Asterixis</td><td>Disoriented<br />
for time (at least three of the followings are wrong: day of the month,<br />
day of the week, month, season, or year) ± the other mentioned symptoms</td><td>Clinical findings variable, but reproducible to some extent</td></tr>
<tr><td>Grade III</td><td>• Somnolence to semistupor<br /><br />
• Responsive to stimuli<br /><br />
• Confused<br /><br />
• Gross disorientation<br /><br />
• Bizarre behavior</td><td>Disoriented<br />
also for space (at least three of the following wrongly reported: <br />
country, state [or region], city, or place) ± the other mentioned <br />
symptoms</td><td>Clinical findings reproducible to some extent</td></tr>
<tr><td>Grade IV</td><td>Coma</td><td>Does not respond even to painful stimuli</td><td>Comatose state usually reproducible</td></tr>
</tbody></table></div><div><table id="hep27210-tbl-0003" style="margin-left: 0px; margin-right: 0px; text-align: left;"><caption>Table 3. Precipitating Factors for OHE by Decreasing Frequency</caption><thead>
<tr><th>Episodic</th><th>Recurrent</th></tr>
</thead><tfoot>
<tr><td colspan="2"><ol><li id="hep27210-note-0005"> Modified<br />
from Strauss E, da Costa MF. The importance of bacterial infections as <br />
precipitating factors of chronic hepatic encephalopathy in cirrhosis. <br />
Hepatogastroenterology 1998;45:900-904.</li>
<li id="hep27210-note-0006"><sup><i>a</i></sup> More recent unpublished case series confirm the dominant role of infections.</li>
</ol></td></tr>
</tfoot><tbody>
<tr><td>Infections<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-note-0006" target="_blank" title="Link to note">a</a></td><td>Electrolyte disorder</td></tr>
<tr><td>GI bleeding</td><td>Infections</td></tr>
<tr><td>Diuretic overdose</td><td>Unidentified</td></tr>
<tr><td>Electrolyte disorder</td><td>Constipation</td></tr>
<tr><td>Constipation</td><td>Diuretic overdose</td></tr>
<tr><td>Unidentified</td><td>GI bleeding</td></tr>
</tbody></table></div>A<br />
fifth classification, according to whether or not the patient has <br />
acute-on-chronic liver failure (ACLF), has recently been suggested.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0064" target="_blank" title="Link to bibliographic citation">64</a>] Although the management, mechanism, and prognostic impact differ, this classification is still a research area.</section><section id="hep27210-sec-0010"><h3>Differential Diagnoses</h3>The<br />
diagnosis requires the detection of signs suggestive of HE in a patient<br />
with severe liver insufficiency and/or PSS who does not have obvious <br />
alternative causes of brain dysfunction. The recognition of <br />
precipitating factors for HE (e.g., infection, bleeding, and <br />
constipation) supports the diagnosis of HE. The differential diagnosis <br />
should consider common disorders altering the level of consciousness <br />
(Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0004" target="_blank" title="Link to table">4</a>).<br /><br />
<div><table id="hep27210-tbl-0004" style="margin-left: 0px; margin-right: 0px; text-align: left;"><caption>Table 4. Differential Diagnosis of HE</caption><tfoot>
<tr><td colspan="1"><ol><li id="hep27210-note-0007"> Hyponatremia and sepsis can both produce encephalopathy <i>per se</i><br />
and precipitate HE by interactions with the pathophysiological <br />
mechanisms. In end-stage liver disease, uremic encephalopathy and HE may<br />
overlap.</li>
</ol></td></tr>
</tfoot><tbody>
<tr><td><i>Overt HE or acute confusional state</i></td></tr>
<tr><td>Diabetic (hypoglycemia, ketoacidosis, hyperosmolar, lactate acidosis)</td></tr>
<tr><td>Alcohol (intoxication, withdrawal, Wernicke)</td></tr>
<tr><td>Drugs (benzodiazepines, neuroleptics, opioids)</td></tr>
<tr><td>Neuroinfections</td></tr>
<tr><td>Electrolyte disorders (hyponatremia and hypercalcemia)</td></tr>
<tr><td>Nonconvulsive epilepsy</td></tr>
<tr><td>Psychiatric disorders</td></tr>
<tr><td>Intracranial bleeding and stroke</td></tr>
<tr><td>Severe medical stress (organ failure and inflammation)</td></tr>
<tr><td><i>Other presentations</i></td></tr>
<tr><td>Dementia (primary and secondary)</td></tr>
<tr><td>Brain lesions (traumatic, neoplasms, normal pressure hydrocephalus)</td></tr>
<tr><td>Obstructive sleep apnea</td></tr>
</tbody></table></div></section><section id="hep27210-sec-0011"><h3>Recommendations:</h3><b><i>1.<br />
Hepatic encephalopathy should be classified according to the type of <br />
underlying disease, severity of manifestations, time course, and <br />
precipitating factors (GRADE III, A, 1)</i></b>.<br /><br />
<b><i>2. A diagnostic workup is required, considering other disorders that can alter brain function and mimic HE (GRADE II-2, A, 1)</i></b>.<br /><br />
Every<br />
case and bout of HE should be described and classified according to all<br />
four factors, and this should be repeated at relevant intervals <br />
according to the clinical situation. The recommendations are summarized <br />
in Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0005" target="_blank" title="Link to table">5</a>.<br /><br />
<div><table id="hep27210-tbl-0005" style="margin-left: 0px; margin-right: 0px; text-align: left;"><caption>Table 5. HE Description and Clinical Example</caption><thead>
<tr><th>Type</th><th colspan="2">Grade</th><th>Time Course</th><th>Spontaneous or Precipitated</th></tr>
</thead><tfoot>
<tr><td colspan="5"><ol><li id="hep27210-note-0008"> The<br />
HE patient should be characterized by one component from each of the <br />
four columns. Example of a recommended description of a patient with HE:<br />
“The patient has HE, Type C, Grade 3, Recurrent, Precipitated (by <br />
urinary tract infection).” The description may be supplemented with <br />
operative classifications (e.g., the Glasgow Coma Score or psychometric <br />
performance).</li>
</ol></td></tr>
</tfoot><tbody>
<tr><td rowspan="2">A</td><td>MHE</td><td rowspan="2">Covert</td><td rowspan="2">Episodic</td><td rowspan="2">Spontaneous</td></tr>
<tr><td>B</td><td>2</td><td rowspan="3">Overt</td><td>Recurrent</td><td rowspan="3">Precipitated (specify)</td></tr>
<tr><td rowspan="2">C</td><td>3</td><td rowspan="2">Persistent</td></tr>
</tbody></table></div></section></section><section id="hep27210-sec-0012"><h2>Diagnosis and Testing</h2><section id="hep27210-sec-0013"><h3>Clinical Evaluation</h3>Judging and measuring the severity of HE is approached as a continuum.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0065" target="_blank" title="Link to bibliographic citation">65</a>]<br />
The testing strategies in place range from simple clinical scales to <br />
sophisticated psychometric and neurophysiological tools; however, none <br />
of the current tests are valid for the entire spectrum.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0011" target="_blank" title="Link to bibliographic citations">11, 66</a>]<br />
The appropriate testing and diagnostic options differ according to the <br />
acuity of the presentation and the degree of impairment.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0067" target="_blank" title="Link to bibliographic citation">67</a>]</section><section id="hep27210-sec-0014"><h3>Diagnosis and Testing for OHE</h3>The<br />
diagnosis of OHE is based on a clinical examination and a clinical <br />
decision. Clinical scales are used to analyze its severity. Specific <br />
quantitative tests are only needed in study settings. The gold standard <br />
is the West Haven criteria (WHC; Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0002" target="_blank" title="Link to table">2</a>,<br />
including clinical description). However, they are subjective tools <br />
with limited interobserver reliability, especially for grade I HE, <br />
because slight hypokinesia, psychomotor slowing, and a lack of attention<br />
can easily be overlooked in clinical examination. In contrast, the <br />
detection of disorientation and asterixis has good inter-rater <br />
reliability and thus are chosen as marker symptoms of OHE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0067" target="_blank" title="Link to bibliographic citation">67</a>] Orientation or mixed scales have been used to distinguish the severity of HE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0068" target="_blank" title="Link to bibliographic citations">68, 69</a>] In patients with significantly altered consciousness, the Glasgow Coma Scale (GCS; Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0006" target="_blank" title="Link to table">6</a>) is widely employed and supplies an operative, robust description.<br /><br />
<div><table id="hep27210-tbl-0006" style="margin-left: 0px; margin-right: 0px; text-align: left;"><caption>Table 6. GCS[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0169" target="_blank" title="Link to bibliographic citation">169</a>]</caption><thead>
<tr><th colspan="7">GCS</th></tr>
<tr><th>1</th><th>2</th><th>3</th><th>4</th><th>5</th><th>6</th></tr>
</thead><tfoot>
<tr><td colspan="7"><ol><li id="hep27210-note-0009"> The<br />
scale comprises three tests: eyes, verbal, and motor responses. The <br />
three values separately as well as their sum are considered. The lowest <br />
possible GCS (the sum) is 3 (deep coma or death), whereas the highest is<br />
15 (fully awake person).</li>
<li id="hep27210-note-0010"> Abbreviation: N/A, not applicable.</li>
</ol></td></tr>
</tfoot><tbody>
<tr><td>Eyes</td><td>Does not open eyes</td><td>Opens eyes in response to painful stimuli</td><td>Opens eyes in response to voice</td><td>Opens eyes spontaneously</td><td>N/A</td><td>N/A</td></tr>
<tr><td>Verbal</td><td>Makes no sounds</td><td>Incomprehensible sounds</td><td>Utters inappropriate words</td><td>Confused, disoriented</td><td>Oriented, converses normally</td><td>N/A</td></tr>
<tr><td>Motor</td><td>Makes no movements</td><td>Extension to painful stimuli (decerebrate response)</td><td>Abnormal flexion to painful stimuli (decorticate response)</td><td>Flexion/withdrawal to painful stimuli</td><td>Localizes painful stimuli</td><td>Obeys commands</td></tr>
</tbody></table></div>Diagnosing<br />
cognitive dysfunction is not difficult. It can be established from <br />
clinical observation as well as neuropsychological or neurophysiological<br />
tests. The difficulty is to assign them to HE. For this reason, OHE <br />
still remains a diagnosis of exclusion in this patient population that <br />
is often susceptible to mental status abnormalities resulting from <br />
medications, alcohol abuse, drug use, effects of hyponatremia, and <br />
psychiatric disease (Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0004" target="_blank" title="Link to table">4</a>).<br />
Therefore, as clinically indicated, exclusion of other etiologies by <br />
laboratory and radiological assessment for a patient with altered mental<br />
status in HE is warranted.</section><section id="hep27210-sec-0015"><h3>Testing for MHE and CHE</h3>Minimal<br />
hepatic encephalopathy and CHE is defined as the presence of <br />
test-dependent or clinical signs of brain dysfunction in patients with <br />
CLD who are not disoriented or display asterixis. The term “minimal” <br />
conveys that there is no clinical sign, cognitive or other, of HE. The <br />
term “covert” includes minimal and grade 1 HE. Testing strategies can be<br />
divided into two major types: psychometric and neurophysiological.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0070" target="_blank" title="Link to bibliographic citations">70, 71</a>]<br />
Because the condition affects several components of cognitive <br />
functioning, which may not be impaired to the same degree, the ISHEN <br />
suggests the use of at least two tests, depending on the local <br />
population norms and availability, and preferably with one of the tests <br />
being more widely accepted so as to serve as a comparator.<br /><br />
Testing<br />
for MHE and CHE is important because it can prognosticate OHE <br />
development, indicate poor quality of life and reduced socioeconomic <br />
potential, and help counsel patients and caregivers about the disease. <br />
The occurrence of MHE and CHE in patients with CLD seems to be as high <br />
as 50%,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0072" target="_blank" title="Link to bibliographic citation">72</a>] so, ideally, every patient at risk should be tested. However, this strategy may be costly,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0073" target="_blank" title="Link to bibliographic citation">73</a>]<br />
and the consequences of the screening procedure are not always clear <br />
and treatment is not always recommended. An operational approach may be <br />
to test patients who have problems with their quality of life or in whom<br />
there are complaints from the patients and their relatives.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0074" target="_blank" title="Link to bibliographic citation">74</a>] Tests positive for MHE or CHE before stopping HE drug therapy will identify patients at risk for recurrent HE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0033" target="_blank" title="Link to bibliographic citations">33, 75</a>] Furthermore, none of the available tests are specific for the condition,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0076" target="_blank" title="Link to bibliographic citation">76</a>]<br />
and it is important to test only patients who do not have confounding <br />
factors, such as neuropsychiatric disorders, psychoactive medication, or<br />
current alcohol use.<br /><br />
Testing should be done by a trained examiner<br />
adhering to scripts that accompany the testing tools. If the test <br />
result is normal (i.e., negative for MHE or CHE), repeat testing in 6 <br />
months has been recommended.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0077" target="_blank" title="Link to bibliographic citation">77</a>] A diagnosis of MHE or CHE does not automatically mean that the affected subject is a dangerous driver.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0078" target="_blank" title="Link to bibliographic citation">78</a>]<br />
Medical providers are not trained to formally evaluate fitness to drive<br />
and are also not legal representatives. Therefore, providers should act<br />
in the best interests of both the patient and society while following <br />
the applicable local laws.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0078" target="_blank" title="Link to bibliographic citation">78</a>]<br />
However, doctors cannot evade the responsibility of counseling patients<br />
with diagnosed HE on the possible dangerous consequences of their <br />
driving, and, often, the safest advice is to stop driving until the <br />
responsible driving authorities have formally cleared the patient for <br />
safe driving. In difficult cases, the doctor should consult with the <br />
authorities that have the expertise to test driving ability and the <br />
authority to revoke the license.<br /><br />
A listing of the most established<br />
testing strategies is given below. The test recommendation varies <br />
depending on the logistics, availability of tests, local norms, and <br />
cost.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0065" target="_blank" title="Link to bibliographic citations">65, 66, 71</a>] <br /><br />
<ol id="hep27210-list-0006"><li id="hep27210-li-0015">Portosystemic<br />
encephalopathy (PSE) syndrome test. This test battery consists of five <br />
paper-pencil tests that evaluate cognitive and psychomotor processing <br />
speed and visuomotor coordination. The tests are relatively easy to <br />
administer and have good external validity.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0076" target="_blank" title="Link to bibliographic citation">76</a>]<br />
The test is often referred to as the Psychometric Hepatic <br />
Encephalopathy Score (PHES), with the latter being the sum score from <br />
all subtests of the battery. It can be obtained from Hannover Medical <br />
School (Hannover, Germany), which holds the copyright <a href="mailto:%28Weissenborn.karin@mh-hannover.de%29." target="_blank">(Weissenborn.karin@mh-hannover.de).</a><br />
The test was developed in Germany and has been translated for use in <br />
many other countries. For illiterate patients, the figure connection <br />
test has been used as a subtest instead of the number connection test.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0079" target="_blank" title="Link to bibliographic citation">79</a>]</li>
<li id="hep27210-li-0016">The<br />
Critical Flicker Frequency (CFF) test is a psychophysiological tool <br />
defined as the frequency at which a fused light (presented from 60 Hz <br />
downward) appears to be flickering to the observer. Studies have shown <br />
its reduction with worsening cognition and improvement after therapy. <br />
The CFF test requires several trials, intact binocular vision, absence <br />
of red-green blindness, and specialized equipment.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0080" target="_blank" title="Link to bibliographic citations">80, 81</a>]</li>
<li id="hep27210-li-0017">The<br />
Continuous Reaction Time (CRT) test. The CRT test relies on repeated <br />
registration of the motor reaction time (pressing a button) to auditory <br />
stimuli (through headphones). The most important test result is the CRT <br />
index, which measures the stability of the reaction times. The test <br />
result can differentiate between organic and metabolic brain impairment <br />
and is not influenced by the patient's age or gender, and there is no <br />
learning or tiring effect. Simple software and hardware are required.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0082" target="_blank" title="Link to bibliographic citation">82</a>]</li>
<li id="hep27210-li-0018">The Inhibitory Control Test (ICT) is a computerized test of response inhibition and working memory[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0083" target="_blank" title="Link to bibliographic citation">83</a>] and is freely downloadable at <a href="http://www.hecme.tv/" target="_blank" title="Link to external resource: http://www.hecme.tv">www.hecme.tv</a>.<br />
The ICT test has been judged to have good validity, but requires highly<br />
functional patients. The norms for the test have to be elaborated <br />
beyond the few centers that have used it.</li>
<li id="hep27210-li-0019">The<br />
Stroop test evaluates psychomotor speed and cognitive flexibility by <br />
the interference between recognition reaction time to a colored field <br />
and a written color name. Recently, mobile application software (“apps” <br />
for a smartphone or tablet computer) based on the test has been shown to<br />
identify cognitive dysfunction in cirrhosis compared to paper-pencil <br />
tests.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0084" target="_blank" title="Link to bibliographic citation">84</a>] Further studies are under way to evaluate its potential for screening for MHE and CHE.</li>
<li id="hep27210-li-0020">The<br />
SCAN Test is a computerized test that measures speed and accuracy to <br />
perform a digit recognition memory task of increasing complexity. The <br />
SCAN Test has been shown to be of prognostic value.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0085" target="_blank" title="Link to bibliographic citation">85</a>]</li>
<li id="hep27210-li-0021">Electroencephalography<br />
examination can detect changes in cortical cerebral activity across the<br />
spectrum of HE without patient cooperation or risk of a learning <br />
effect.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0070" target="_blank" title="Link to bibliographic citation">70</a>]<br />
However, it is nonspecific and may be influenced by accompanying <br />
metabolic disturbances, such as hyponatremia as well as drugs. Possibly,<br />
the reliability of EEG analysis can increase with quantitative <br />
analysis. This specifically should include the background frequency with<br />
mean dominant frequency or spectral band analysis.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0060" target="_blank" title="Link to bibliographic citation">60</a>]<br />
Also, in most situations, EEG requires an institutional setup and <br />
neurological expertise in evaluation, and the cost varies among <br />
hospitals.</li>
</ol>Although the above-described tests have been used<br />
to test for MHE and CHE, there is, most often, a poor correlation <br />
between them because HE is a multidimensional dysfunction.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0086" target="_blank" title="Link to bibliographic citation">86</a>]<br />
Learning effect is often observed with psychometric tests and it is <br />
unclear whether current HE therapy plays a role in the test performance.<br />
Therefore, interpretation of these tests and consideration of the <br />
results for further management need an understanding of the patient's <br />
history, current therapy, and effect on the patient's daily activities, <br />
if signs of HE are found. For multicenter studies, the diagnosis of MHE <br />
or CHE by consensus should utilize at least two of the current validated<br />
testing strategies: paper-pencil (PHES) and one of the following: <br />
computerized (CRT, ICT, SCAN, or Stroop) or neurophysiological (CFF or <br />
EEG).[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0066" target="_blank" title="Link to bibliographic citation">66</a>]<br />
In the clinical routine or single-center studies, investigators may use<br />
tests for assessing the severity of HE with which they are familiar, <br />
provided that normative reference data are available and the tests have <br />
been validated for use in this patient population.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0066" target="_blank" title="Link to bibliographic citation">66</a>]</section><section id="hep27210-sec-0016"><h3>Laboratory Testing</h3>High blood-ammonia levels alone do not add any diagnostic, staging, or prognostic value in HE patients with CLD.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0087" target="_blank" title="Link to bibliographic citation">87</a>]<br />
However, in case an ammonia level is checked in a patient with OHE and <br />
it is normal, the diagnosis of HE is in question. For ammonia-lowering <br />
drugs, repeated measurements of ammonia may be helpful to test the <br />
efficacy. There may be logistic challenges to accurately measure blood <br />
ammonia, which should be taken into consideration. Ammonia is reported <br />
either in venous, arterial blood, or plasma ammonia, so the relevant <br />
normal should be used. Multiple methods are available, but measurements <br />
should only be employed when laboratory standards allow for reliable <br />
analyses.</section><section id="hep27210-sec-0017"><h3>Brain Scans</h3>Computed<br />
tomography (CT) or magnetic resonance (MR) or other image modality <br />
scans do not contribute diagnostic or grading information. However, the <br />
risk of intracerebral hemorrhage is at least 5-fold increased in this <br />
patient group,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0088" target="_blank" title="Link to bibliographic citation">88</a>]<br />
and the symptoms may be indistinguishable, so a brain scan is usually <br />
part of the diagnostic workup of first-time HE and on clinical suspicion<br />
of other pathology.</section><section id="hep27210-sec-0018"><h3>Recommendations:</h3><b><i>3.<br />
Hepatic encephalopathy should be treated as a continuum ranging from <br />
unimpaired cognitive function with intact consciousness through coma <br />
(GRADE III, A, 1)</i></b>.<br /><br />
<b><i>4. The diagnosis of HE is through exclusion of other causes of brain dysfunction (GRADE II-2, A, 1)</i></b>.<br /><br />
<b><i>5.<br />
Hepatic encephalopathy should be divided into various stages of <br />
severity, reflecting the degree of self-sufficiency and the need for <br />
care (GRADE III, B, 1)</i></b>.<br /><br />
<b><i>6. Overt hepatic <br />
encephalopathy is diagnosed by clinical criteria and can be graded <br />
according the WHC and the GCS (GRADE II-2, B, 1)</i></b>.<br /><br />
<b><i>7.<br />
The diagnosis and grading of MHE and CHE can be made using several <br />
neurophysiological and psychometric tests that should be performed by <br />
experienced examiners (GRADE II-2, B, 1)</i></b>.<br /><br />
<b><i>8. <br />
Testing for MHE and CHE could be used in patients who would most benefit<br />
from testing, such as those with impaired quality of life or <br />
implication on employment or public safety (GRADE III, B, 2)</i></b>.<br /><br />
<b><i>9.<br />
Increased blood ammonia alone does not add any diagnostic, staging, or <br />
prognostic value for HE in patients with CLD. A normal value calls for <br />
diagnostic reevaluation (GRADE II-3, A, 1)</i></b>.</section></section><section id="hep27210-sec-0019"><h2>Treatment</h2><section id="hep27210-sec-0020"><h3>General Principles</h3>At this time, only OHE is routinely treated.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0010" target="_blank" title="Link to bibliographic citation">10</a>]<br />
Minimal hepatic encephalopathy and CHE, as its title implies, is not <br />
obvious on routine clinical examination and is predominantly diagnosed <br />
by techniques outlined in the previous section. Despite its subtle <br />
nature, MHE and CHE can have a significant effect on a patient's daily <br />
living. Special circumstances can prevail where there may be an <br />
indication to treat such a patient (e.g., impairment in driving skills, <br />
work performance, quality of life, or cognitive complaints). Liver <br />
transplantation is mentioned under the treatment recommendations.</section><section id="hep27210-sec-0140"><h3>Recommendations:</h3><b><i>General recommendations for treatment of episodic OHE type C include the following:</i></b><br /><br />
<b><i>10. An episode of OHE (whether spontaneous or precipitated) should be actively treated (GRADE II-2, A, 1)</i></b>.<br /><br />
<b><i>11. Secondary prophylaxis after an episode for overt HE is recommended (GRADE I, A, 1)</i></b>.<br /><br />
<b><i>12.<br />
Primary prophylaxis for prevention of episodes of OHE is not required, <br />
except in patients with cirrhosis with a known high risk to develop HE <br />
(GRADE II-3, C, 2)</i></b>.<br /><br />
<b><i>13. Recurrent intractable OHE, together with liver failure, is an indication for LT (GRADE I)</i></b>.</section><section id="hep27210-sec-0021"><h3>Specific Approach to OHE Treatment</h3><b><i>A four-pronged approach to management of HE is recommended (GRADE II-2, A, 1):</i></b><br /><br />
<b><i>14. Initiation of care for patients with altered consciousness</i></b><br /><br />
<b><i>15. Alternative causes of altered mental status should be sought and treated</i></b>.<br /><br />
<b><i>16. Identification of precipitating factors and their correction</i></b><br /><br />
<b><i>17. Commencement of empirical HE treatment</i></b></section><section id="hep27210-sec-0022"><h3>Comments on Management Strategy</h3>Patients<br />
with higher grades of HE who are at risk or unable to protect their <br />
airway need more intensive monitoring and are ideally managed in an <br />
intensive care setting. Alternative causes of encephalopathy are not <br />
infrequent in patients with advanced cirrhosis. Technically, if other <br />
causes of encephalopathy are present, then the episode of encephalopathy<br />
may not be termed HE. In the clinical setting, what transpires is <br />
treatment of both HE and non-HE.<br /><br />
Controlling precipitating factors<br />
in the management of OHE is of paramount importance, because nearly 90%<br />
of patients can be treated with just correction of the precipitating <br />
factor.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0089" target="_blank" title="Link to bibliographic citation">89</a>] Careful attention to this issue is still the cornerstone of HE management.</section><section id="hep27210-sec-0023"><h3>Therapy for Episodes of OHE</h3>In<br />
addition to the other elements of the four-pronged approach to <br />
treatment of HE, specific drug treatment is part of the management. Most<br />
drugs have not been tested by rigorous randomized, controlled studies <br />
and are utilized based on circumstantial observations. These agents <br />
include nonabsorbable disaccharides, such as lactulose, and antibiotics,<br />
such as rifaximin. Other therapies, such as oral branched-chain amino <br />
acids (BCAAs), intravenous (IV) L-ornithine L-aspartate (LOLA), <br />
probiotics, and other antibiotics, have also been used. In the hospital,<br />
a nasogastric tube can be used to administer oral therapies in patients<br />
who are unable to swallow or have an aspiration risk.<br /><br />
<section id="hep27210-sec-0024"><h4>Nonabsorbable Disaccharides</h4>Lactulose<br />
is generally used as initial treatment for OHE. A large meta-analysis <br />
of trial data did not completely support lactulose as a therapeutic <br />
agent for treatment of OHE, but for technical reasons, it did not <br />
include the largest trials, and these agents continue to be used <br />
widely.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0090" target="_blank" title="Link to bibliographic citation">90</a>]<br />
Lack of effect of lactulose should prompt a clinical search for <br />
unrecognized precipitating factors and competing causes for the brain <br />
impairment. Though it is assumed that the prebiotic effects (the drug <br />
being a nondigestible substance that promotes the growth of beneficial <br />
microorganisms in the intestines) and acidifying nature of lactulose <br />
have an additional benefit beyond the laxative effect, <br />
culture-independent studies have not borne those out.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0075" target="_blank" title="Link to bibliographic citations">75, 91</a>]<br />
In addition, most recent trials on lactulose have been open label in <br />
nature. Cost considerations alone add to the argument in support of <br />
lactulose.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0092" target="_blank" title="Link to bibliographic citation">92</a>] In some centers, lactitol is preferred to lactulose, based on small meta-analyses of even smaller trials.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0093" target="_blank" title="Link to bibliographic citations">93, 94</a>]<br /><br />
In populations with a high prevalence of lactose intolerance, the use of lactose has been suggested.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0095" target="_blank" title="Link to bibliographic citation">95</a>]<br />
However, the only trial to show that stool-acidifying enemas (lactose <br />
and lactulose) were superior to tap-water enemas was underpowered.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0096" target="_blank" title="Link to bibliographic citation">96</a>] The use of polyethylene glycol preparation[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0097" target="_blank" title="Link to bibliographic citation">97</a>] needs further validation.<br /><br />
The dosing of lactulose should be initiated[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0098" target="_blank" title="Link to bibliographic citation">98</a>]<br />
when the three first elements of the four-pronged approach are <br />
completed, with 25 mL of lactulose syrup every 1-2 hours until at least <br />
two soft or loose bowel movements per day are produced. Subsequently, <br />
the dosing is titrated to maintain two to three bowel movements per day.<br />
This dose reduction should be implemented. It is a misconception that <br />
lack of effect of smaller amounts of lactulose is remedied by much <br />
larger doses. There is a danger for overuse of lactulose leading to <br />
complications, such as aspiration, dehydration, hypernatremia, and <br />
severe perianal skin irritation, and overuse can even precipitate HE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0099" target="_blank" title="Link to bibliographic citation">99</a>]</section><section id="hep27210-sec-0025"><h4>Rifaximin</h4>Rifaximin has been used for the therapy of HE in a number of trials[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0100" target="_blank" title="Link to bibliographic citation">100</a>]<br />
comparing it with placebo, other antibiotics, nonabsorbable <br />
disaccharides, and in dose-ranging studies. These trials showed effect <br />
of rifaximin that was equivalent or superior to the compared agents with<br />
good tolerability. Long-term cyclical therapy over 3-6 months with <br />
rifaximin for patients with OHE has also been studied in three trials <br />
(two compared to nonabsorbable disaccharides and one against neomycin) <br />
showing equivalence in cognitive improvement and ammonia lowering. A <br />
multinational study[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0101" target="_blank" title="Link to bibliographic citation">101</a>]<br />
with patients having two earlier OHE bouts to maintain remission showed<br />
the superiority of rifaximin versus placebo (in the background of 91% <br />
lactulose use). No solid data support the use of rifaximin alone.</section><section id="hep27210-sec-0026"><h4>Other Therapies</h4>Many<br />
drugs have been used for treatment of HE, but data to support their use<br />
are limited, preliminary, or lacking. However, most of these drugs can <br />
safely be used despite their limited proven efficacy.</section><section id="hep27210-sec-0027"><h4>BCAAs</h4>An<br />
updated meta-analysis of eight randomized, controlled trials (RCTs) <br />
indicated that oral BCAA-enriched formulations improve the <br />
manifestations of episodic HE whether OHE or MHE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0102" target="_blank" title="Link to bibliographic citations">102, 130</a>] There is no effect of IV BCAA on the episodic bout of HE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0127" target="_blank" title="Link to bibliographic citation">127</a>]</section><section id="hep27210-sec-0028"><h4>Metabolic Ammonia Scavengers</h4>These<br />
agents, through their metabolism, act as urea surrogates excreted in <br />
urine. Such drugs have been used for treatment of inborn errors of the <br />
urea cycle for many years. Different forms are available and currently <br />
present as promising investigational agents. Ornithine phenylacetate has<br />
been studied for HE, but further clinical reports are awaited.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0103" target="_blank" title="Link to bibliographic citation">103</a>] Glyceryl phenylbutyrate (GPB) was tested in a recent RCT[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0104" target="_blank" title="Link to bibliographic citation">104</a>]<br />
on patients who had experienced two or more episodes of HE in the last 6<br />
months and who were maintained on standard therapy (lactulose ± <br />
rifaximin). The GPB arm experienced fewer episodes of HE and <br />
hospitalizations as well as longer time to first event. More clinical <br />
studies on the same principle are under way and, if confirmed, may lead <br />
to clinical recommendations.</section><section id="hep27210-sec-0029"><h4>L-ornithine L-aspartate (LOLA)</h4>An<br />
RCT on patients with persistent HE demonstrated improvement by IV LOLA <br />
in psychometric testing and postprandial venous ammonia levels.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0105" target="_blank" title="Link to bibliographic citation">105</a>] Oral supplementation with LOLA is ineffective.</section><section id="hep27210-sec-0030"><h4>Probiotics</h4>A<br />
recent, open-label study of either lactulose, probiotics, or no therapy<br />
in patients with cirrhosis who recovered from HE found fewer episodes <br />
of HE in the lactulose or probiotic arms, compared to placebo, but were <br />
not different between either interventions. There was no difference in <br />
rates of readmission in any of the arms of the study.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0106" target="_blank" title="Link to bibliographic citation">106</a>]</section><section id="hep27210-sec-0031"><h4>Glutaminase Inhibitors</h4>Portosystemic<br />
shunting up-regulates the intestinal glutaminase gene so that <br />
intestinal glutaminase inhibitors may be useful by reducing the amounts <br />
of ammonia produced by the gut.</section><section id="hep27210-sec-0032"><h4>Neomycin</h4>This antibiotic still has its advocates and was widely used in the past for HE treatment; it is a known glutaminase inhibitor.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0107" target="_blank" title="Link to bibliographic citation">107</a>]</section><section id="hep27210-sec-0150"><h4>Metronidazole</h4>As short-term therapy,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0108" target="_blank" title="Link to bibliographic citation">108</a>]<br />
metronidazole also has advocates for its use. However, long-term <br />
ototoxicity, nephrotoxicity, and neurotoxicity make these agents <br />
unattractive for continuous long-term use.</section><section id="hep27210-sec-0033"><h4>Flumazenil</h4>This<br />
drug is not frequently used. It transiently improves mental status in <br />
OHE without improvement on recovery or survival. The effect may be of <br />
importance in marginal situations to avoid assisted ventilation. <br />
Likewise, the effect may be helpful in difficult differential diagnostic<br />
situations by confirming reversibility (e.g., when standard therapy <br />
unexpectedly fails or when benzodiazepine toxicity is suspected).</section><section id="hep27210-sec-0034"><h4>Laxatives</h4>Simple<br />
laxatives alone do not have the prebiotic properties of disaccharides, <br />
and no publications have been forthcoming on this issue.</section><section id="hep27210-sec-0035"><h4>Albumin</h4>A<br />
recent RCT on OHE patients on rifaximin given daily IV albumin or <br />
saline showed no effect on resolution of HE, but was related to better <br />
postdischarge survival.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0109" target="_blank" title="Link to bibliographic citation">109</a>]</section></section><section id="hep27210-sec-0036"><h3>Recommendations:</h3><b><i>18. Identify and treat precipitating factors for HE (GRADE II-2, A, 1)</i></b>.<br /><br />
<b><i>19. Lactulose is the first choice for treatment of episodic OHE (GRADE II-1, B, 1)</i></b>.<br /><br />
<b><i>20. Rifaximin is an effective add-on therapy to lactulose for prevention of OHE recurrence (GRADE I, A, 1)</i></b>.<br /><br />
<b><i>21.<br />
Oral BCAAs can be used as an alternative or additional agent to treat <br />
patients nonresponsive to conventional therapy (GRADE I, B, 2)</i></b>.<br /><br />
<b><i>22.<br />
IV LOLA can be used as an alternative or additional agent to treat <br />
patients nonresponsive to conventional therapy (GRADE I, B, 2)</i></b>.<br /><br />
<b><i>23. Neomycin is an alternative choice for treatment of OHE (GRADE II-1, B, 2)</i></b>.<br /><br />
<b><i>24. Metronidazole is an alternative choice for treatment of OHE (GRADE II-3, B, 2)</i></b>.</section><section id="hep27210-sec-0037"><h3>Prevention of Overt Hepatic Encephalopathy</h3><section id="hep27210-sec-0038"><h4>After an Episode of OHE</h4>There<br />
are no randomized, placebo-controlled trials of lactulose for <br />
maintenance of remission from OHE. However, it is still widely <br />
recommended and practiced. A single-center, open-label RCT of lactulose <br />
demonstrated less recurrence of HE in patients with cirrhosis.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0033" target="_blank" title="Link to bibliographic citation">33</a>] A recent RCT supports lactulose as prevention of HE subsequent to upper gastrointestinal (GI) bleeding.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0110" target="_blank" title="Link to bibliographic citation">110</a>]<br /><br />
Rifaximin<br />
added to lactulose is the best-documented agent to maintain remission <br />
in patients who have already experienced one or more bouts of OHE while <br />
on lactulose treatment after their initial episode of OHE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0101" target="_blank" title="Link to bibliographic citation">101</a>]</section><section id="hep27210-sec-0039"><h4>Hepatic Encephalopathy After TIPS</h4>Once<br />
TIPS was popularized to treat complications of PH, its tendency to <br />
cause the appearance of HE, or less commonly, intractable persistent HE,<br />
was noted. Faced with severe HE as a complication of a TIPS procedure, <br />
physicians had a major dilemma. Initially, it was routine to use <br />
standard HE treatment to prevent post-TIPS HE. However, one study <br />
illustrated that neither rifaximin nor lactulose prevented post-TIPS HE <br />
any better than placebo.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0111" target="_blank" title="Link to bibliographic citation">111</a>]<br />
Careful case selection has reduced the incidence of severe HE <br />
post-TIPS. If it occurs, shunt diameter reduction can reverse HE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0112" target="_blank" title="Link to bibliographic citation">112</a>] However, the original cause for placing TIPS may reappear.<br /><br />
Another<br />
important issue with TIPS relates to the desired portal pressure (PP) <br />
attained after placement of stents. Too low a pressure because of large <br />
stent diameter can lead to intractable HE, as noted above. There is a <br />
lack of consensus on whether to aim to reduce PP by 50% or below 12 <br />
mmHg. The latter is associated with more bouts of encephalopathy.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0113" target="_blank" title="Link to bibliographic citation">113</a>]<br />
It is widely used to treat post-TIPS recurrent HE as with other cases <br />
of recurrent HE, including the cases that cannot be managed by reduction<br />
of shunt diameter.</section><section id="hep27210-sec-0040"><h4>Hepatic Encephalopathy Secondary to Portosystemic Shunts (PSSs)</h4>Recurrent<br />
bouts of overt HE in patients with preserved liver function <br />
consideration should lead to a search for large spontaneous PSSs. <br />
Certain types of shunts, such as splenorenal shunts, can be successfully<br />
embolized with rapid clearance of overt HE in a fraction of patients in<br />
a good liver function status, despite the risk for subsequent VB.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0114" target="_blank" title="Link to bibliographic citation">114</a>]</section></section><section id="hep27210-sec-0041"><h3>Recommendations:</h3><b><i>25. Lactulose is recommended for prevention of recurrent episodes of HE after the initial episode (GRADE II-1, A, 1)</i></b>.<br /><br />
<b><i>26.<br />
Rifaximin as an add-on to lactulose is recommended for prevention of <br />
recurrent episodes of HE after the second episode (GRADE I, A, 1)</i></b>.<br /><br />
<b><i>27.<br />
Routine prophylactic therapy (lactulose or rifaximin) is not <br />
recommended for the prevention of post-TIPS HE (GRADE III, B, 1)</i></b>.<br /><br />
<section id="hep27210-sec-0042"><h4>Discontinuation of Prophylactic Therapy</h4>There<br />
is a nearly uniform policy to continue treatment indefinitely after it <br />
has successfully reversed a bout of OHE. The concept may be that once <br />
the thresholds for OHE is reached, then patients are at high risk for <br />
recurrent episodes. This risk appears to worsen as liver function <br />
deteriorates. However, what often occurs are recurrent bouts of OHE from<br />
a well-known list of precipitating factors. If a recurrent <br />
precipitating factor can be controlled, such as recurrent infections or <br />
variceal hemorrhages, then HE recurrence may not be a risk and HE <br />
therapy can be discontinued. Even more influential on the risk for <br />
further bouts of OHE is overall liver function and body habitus. If <br />
patients recover a significant amount of liver function and muscle mass <br />
from the time they had bouts of OHE, they may well be able to stop <br />
standard HE therapy. There are very little data on this issue, but tests<br />
positive for MHE or CHE before stopping HE drug therapy will predict <br />
patients at risk for recurrent HE.</section></section><section id="hep27210-sec-0043"><h3>Recommendation:</h3><b><i>28.<br />
Under circumstances where the precipitating factors have been well <br />
controlled (i.e., infections and VB) or liver function or nutritional <br />
status improved, prophylactic therapy may be discontinued (GRADE III, C,<br />
2)</i></b>.</section><section id="hep27210-sec-0044"><h3>Treatment of Minimal HE and Covert HE</h3>Although<br />
it is not standard to offer therapy for MHE and CHE, studies have been <br />
performed using several modes of therapy. The majority of studies have <br />
been for less than 6 months and do not reflect the overall course of the<br />
condition. Trials span the gamut from small open-label trials to <br />
larger, randomized, controlled studies using treatments varying from <br />
probiotics, lactulose, and rifaximin. Most studies have shown an <br />
improvement in the underlying cognitive status, but the mode of <br />
diagnosis has varied considerably among studies. A minority of studies <br />
used clinically relevant endpoints. It was shown, in an open-label <br />
study,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0115" target="_blank" title="Link to bibliographic citation">115</a>]<br />
that lactulose can prevent development of the first episode of OHE, but<br />
the study needs to be replicated in a larger study in a blinded fashion<br />
before firm recommendations can be made. Studies using lactulose and <br />
rifaximin have shown improvement in quality of life[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0034" target="_blank" title="Link to bibliographic citations">34, 116</a>] and also in driving simulator performance.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0117" target="_blank" title="Link to bibliographic citation">117</a>]<br />
Probiotics have also been used, but the open-label nature, varying <br />
amounts and types of organisms, and different outcomes make them <br />
difficult to recommend as therapeutic options at this time.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0118" target="_blank" title="Link to bibliographic citations">118-121</a>]<br /><br />
Because<br />
of the multiple methods used to define MHE and CHE, varying endpoints, <br />
short-term treatment trials, and differing agents used in trials to <br />
date, routine treatment for MHE is not recommended at this stage. <br />
Exceptions could be made on a case-by-case basis using treatments that <br />
are approved for OHE, particularly for patients with CHE and West Haven <br />
Grade I HE.</section><section id="hep27210-sec-0045"><h3>Recommendation:</h3><b><i>29. Treatment of MHE and CHE is not routinely recommended apart from a case-by-case basis (GRADE II-2, B, 1)</i></b>.</section><section id="hep27210-sec-0046"><h3>Nutrition</h3>Modulation<br />
of nitrogen metabolism is crucial to the management of all grades of <br />
HE, and nutritional options are relevant. Detailed recent guidelines for<br />
nutrition of patients with HE are given elsewhere.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0122" target="_blank" title="Link to bibliographic citation">122</a>]<br />
Malnutrition is often underdiagnosed, and approximately 75% of patients<br />
with HE suffer from moderate-to-severe protein-calorie malnutrition <br />
with loss of muscle mass and energy depots. Chronic protein restriction <br />
is detrimental because patients' protein requirements are relatively <br />
greater than that of healthy patients and they are at risk of <br />
accelerated fasting metabolism. Malnutrition and loss of muscle bulk is a<br />
risk factor for development of HE and other cirrhosis complications. <br />
Sarcopenia has been proven to be an important negative prognostic <br />
indicator in patients with cirrhosis.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0123" target="_blank" title="Link to bibliographic citations">123, 124</a>]<br />
All HE patients should undergo an assessment of nutritional status by <br />
taking a good dietary history, with anthropometric data and muscle <br />
strength measurement as practical, useful measures of nutritional <br />
status. In the undressed patient, particular attention is paid to the <br />
muscle structures around the shoulders and gluteal muscles. Pitfalls are<br />
water retention and obesity. Although body mass index is rarely <br />
helpful, the height-creatinine ratio may be useful, as well as the <br />
bioimpedance technique. More advanced techniques, such as dual-energy <br />
X-ray absorptiometry/CT/MR, are rarely useful for clinical purposes. The<br />
patient should undergo a structured dietary assessment, preferably by a<br />
dietician, or other specially trained staff. The majority of HE <br />
patients will fulfill criteria for nutritional therapy. The therapy is <br />
refeeding by moderate hyperalimentation, as indicated below. Small meals<br />
evenly distributed throughout the day and a late-night snack[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0125" target="_blank" title="Link to bibliographic citation">125</a>]<br />
should be encouraged, with avoidance of fasting. Glucose may be the <br />
most readily available calorie source, but should not be utilized as the<br />
only nutrition. Hyperalimentation should be given orally to patients <br />
that can cooperate, by gastric tube to patients who cannot take the <br />
required amount, and parenterally to other patients. The nutrition <br />
therapy should be initiated without delay and monitored during <br />
maintenance visits. The use of a multivitamin is generally recommended, <br />
although there are no firm data on the benefits of vitamin and mineral <br />
supplementation. Specific micronutrient replacement is given if there <br />
are confirmed measured losses, and zinc supplementation is considered <br />
when treating HE. If Wernicke's is suspected, large doses of thiamine <br />
should be given parenterally and before any glucose administration. <br />
Administration of large amounts of nonsaline fluids should be adjusted <br />
so as to avoid induction of hyponatremia, particularly in patients with <br />
advanced cirrhosis. If severe hyponatremia is corrected, this should be <br />
done slowly.<br /><br />
There is consensus that low-protein nutrition should <br />
be avoided for patients with HE. Some degree of protein restriction may <br />
be inevitable in the first few days of OHE treatment, but should not be <br />
prolonged. Substitution of milk-based or vegetable protein or <br />
supplementing with BCAAs is preferable to reduction of total protein <br />
intake. Oral BCAA-enriched nutritional formulation may be used to treat <br />
HE and generally improves the nutritional status of patients with <br />
cirrhosis,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0126" target="_blank" title="Link to bibliographic citation">126</a>] but IV BCAA for an episode of HE has no effect.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0127" target="_blank" title="Link to bibliographic citation">127</a>] The studies on the effect of oral BCAA have been more encouraging[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0128" target="_blank" title="Link to bibliographic citations">128, 129</a>] and confirmed by a recent meta-analysis of 11 trials.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0130" target="_blank" title="Link to bibliographic citation">130</a>]<br />
Ultimately, the effects of these amino acids may turn out to have more <br />
important effects on promotion of maintenance of lean body mass than a <br />
direct effect on HE.</section><section id="hep27210-sec-0047"><h3>Recommendations:</h3><b><i>30. Daily energy intakes should be 35-40 kcal/kg ideal body weight (GRADE I, A, 1)</i></b>.<br /><br />
<b><i>31. Daily protein intake should be 1.2-1.5 g/kg/day (GRADE I, A, 1)</i></b>.<br /><br />
<b><i>32.<br />
Small meals or liquid nutritional supplements evenly distributed <br />
throughout the day and a late-night snack should be offered (GRADE I, A,<br />
1)</i></b>.<br /><br />
<b><i>33. Oral BCAA supplementation may allow <br />
recommended nitrogen intake to be achieved and maintained in patients <br />
intolerant of dietary protein (GRADE II-2, B, 2)</i></b>.</section><section id="hep27210-sec-0048"><h3>Liver Transplantation (LT)</h3>Liver<br />
transplantation remains the only treatment option for HE that does not <br />
improve on any other treatment, but is not without its risks. The <br />
management of these potential transplant candidates as practiced in the <br />
United States has been published elsewhere,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0131" target="_blank" title="Link to bibliographic citations">131, 132</a>]<br />
and European guidelines are under way. Hepatic encephalopathy by itself<br />
is not considered an indication for LT unless associated with poor <br />
liver function. However, cases do occur where HE severely compromises <br />
the patient's quality of life and cannot be improved despite maximal <br />
medical therapy and who may be LT candidates despite otherwise good <br />
liver status. Large PSSs may cause neurological disturbances and <br />
persistent HE, even after LT. Therefore, shunts should be identified and<br />
embolization considered before or during transplantation.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0133" target="_blank" title="Link to bibliographic citation">133</a>] Also, during the transplant workup, severe hyponatremia should be corrected slowly.<br /><br />
Hepatic<br />
encephalopathy should improve after transplant, whereas <br />
neurodegenerative disorders will worsen. Therefore, it is important to <br />
distinguish HE from other causes of mental impairment, such as <br />
Alzheimer's disease and small-vessel cerebrovascular disease. Magnetic <br />
resonance imaging and spectroscopy of the brain should be conducted, and<br />
the patient should be evaluated by an expert in neuropsychology and <br />
neuro-degenerative diseases.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0134" target="_blank" title="Link to bibliographic citation">134</a>]<br />
The patient, caregivers, and health professionals should be aware that <br />
transplantation may induce brain function impairment and that not all <br />
manifestations of HE are fully reversible by transplantation.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0135" target="_blank" title="Link to bibliographic citation">135</a>]<br /><br />
One<br />
difficult and not uncommon problem is the development of a confusional <br />
syndrome in the postoperative period. The search of the cause is often <br />
difficult, and the problem may have multiple origins. Patients with <br />
alcoholic liver disease (ALD) and those with recurrent HE before <br />
transplantation are at higher risk. Toxic effects of immunosuppressant <br />
drugs are a frequent cause, usually associated with tremor and elevated <br />
levels in blood. Other adverse cerebral effects of drugs may be <br />
difficult to diagnose. Confusion associated with fever requires a <br />
diligent, systematic search for bacterial or viral causes (e.g., <br />
cytomegalovirus). Multiple causative factors are not unusual, and the <br />
patient's problem should be approached from a broad clinical view.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0136" target="_blank" title="Link to bibliographic citation">136</a>]</section><section id="hep27210-sec-0049"><h3>Economic/Cost Implications</h3>As<br />
outlined under epidemiology, the burden of HE is rapidly increasing and<br />
more cases of HE will be encountered, with substantial direct costs <br />
being attributed to hospitalizations for HE and to indirect costs. The <br />
patients with HE hospitalized in the United States in 2003 generated <br />
charges of approximately US$ 1 billion.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0040" target="_blank" title="Link to bibliographic citations">40, 137</a>]<br />
Resource utilization for this group of patients is also increasing as a<br />
result of longer lengths of stay and more complex and expensive <br />
hospital efforts, as well as a reported in-patient mortality of 15%. <br />
There are no directly comparable EU cost data, but by inference from <br />
epidemiological data, the event rate should be approximately the same <br />
and the costs comparable, differences between U.S. and EU hospital <br />
financing notwithstanding. These costs are an underestimate, because <br />
out-patient care, disability and lost productivity, and the negative <br />
effect on the patient's family or support network were not quantified.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0138" target="_blank" title="Link to bibliographic citation">138</a>]<br /><br />
The<br />
cost of medications is very variable to include in analyses because it <br />
varies widely from country to country and are usually determined by what<br />
the pharmaceutical companies believe the market can sustain. Regarding <br />
the beneficial effects of rifaximin, cost-effective analyses based on <br />
current drug prices favor treatments that are lactulose based,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0092" target="_blank" title="Link to bibliographic citations">92, 139</a>] as do analyses of accidents, deaths/morbidity, and time off from work[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0073" target="_blank" title="Link to bibliographic citation">73</a>]<br />
in patients with MHE or CHE. Therefore, until the costs of other <br />
medications fall, lactulose continues to be the least expensive, most <br />
cost-effective treatment.</section></section><section id="hep27210-sec-0050"><h2>Alternative Causes of Altered Mental Status</h2><section id="hep27210-sec-0051"><h3>Disorders to Be Considered</h3>The<br />
neurological manifestations of HE are nonspecific. Therefore, <br />
concomitant disorders have to be considered as an additional source of <br />
central nervous system dysfunction in any patient with CLD. Most <br />
important are renal dysfunction, hyponatremia, diabetes mellitus (DM), <br />
sepsis, and thiamine deficiency (Wernicke's encephalopathy); noteworthy <br />
also is intracranial bleeding (chronic subdural hematoma and parenchymal<br />
bleeding).</section><section id="hep27210-sec-0052"><h3>Interaction Between Concomitant Disorders and Liver Disease With Regard to Brain Function</h3>Hyponatremia is an independent risk factor for development of HE in patients with cirrhosis.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0140" target="_blank" title="Link to bibliographic citations">140, 141</a>] The incidence of HE increases[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0142" target="_blank" title="Link to bibliographic citation">142</a>] and the response rate to lactulose therapy decreases[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0143" target="_blank" title="Link to bibliographic citation">143</a>] with decreasing serum sodium concentrations.<br /><br />
Diabetes<br />
mellitus has been suggested as a risk factor for development of HE, <br />
especially in patients with hepatitis C virus (HCV) cirrhosis,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0144" target="_blank" title="Link to bibliographic citation">144</a>] but the relationship may also be observed in other cirrhosis etiologies.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0145" target="_blank" title="Link to bibliographic citation">145</a>]<br /><br />
An increased risk to develop HE has also been shown in patients with cirrhosis with renal dysfunction,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0146" target="_blank" title="Link to bibliographic citation">146</a>] independent of the severity of cirrhosis.<br /><br />
Neurological symptoms are observed in 21%-33% of patients with cirrhosis with sepsis and in 60%-68% of those with septic shock.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0147" target="_blank" title="Link to bibliographic citation">147</a>]<br />
Patients with cirrhosis do not differ from patients without cirrhosis <br />
regarding their risk to develop brain dysfunction with sepsis,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0148" target="_blank" title="Link to bibliographic citation">148</a>] although it is assumed that systemic inflammation and hyperammonemia act synergistically with regard to the development of HE.<br /><br />
Thiamine<br />
deficiency predominantly occurs in patients with ALD, but may also <br />
occur as a consequence of malnutrition in end-stage cirrhosis of any <br />
cause. The cerebral symptoms disorientation, alteration of <br />
consciousness, ataxia, and dysarthria cannot be differentiated as being <br />
the result of thiamine deficiency or hyperammonemia by clinical <br />
examination.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0149" target="_blank" title="Link to bibliographic citation">149</a>] In any case of doubt, thiamine should be given IV before glucose-containing solutions.</section><section id="hep27210-sec-0053"><h3>Effect of the Etiology of the Liver Disease Upon Brain Function</h3>Data<br />
upon the effect of the underlying liver disease on brain function are <br />
sparse, except for alcoholism and hepatitis C. Rare, but difficult, <br />
cases may be the result of Wilson's disease.<br /><br />
Even patients with alcohol disorder and no clinical disease have been shown to exhibit deficits in episodic memory,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0150" target="_blank" title="Link to bibliographic citation">150</a>] working memory and executive functions,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0151" target="_blank" title="Link to bibliographic citation">151</a>] visuoconstruction abilities,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0152" target="_blank" title="Link to bibliographic citation">152</a>] and upper- and lower-limb motor skills.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0153" target="_blank" title="Link to bibliographic citation">153</a>]<br />
The cognitive dysfunction is more pronounced in those patients with <br />
alcohol disorder who are at risk of Wernicke's encephalopathy as a <br />
result of malnutrition or already show signs of the problem.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0154" target="_blank" title="Link to bibliographic citation">154</a>]<br />
Thus, it remains unclear whether the disturbance of brain function in <br />
patients with ALD is the result of HE, alcohol toxicity, or thiamine <br />
deficiency.<br /><br />
There is mounting evidence that HCV is present and replicates within the brain.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0155" target="_blank" title="Link to bibliographic citations">155-158</a>] Approximately half of HCV patients suffer chronic fatigue irrespective of the grade of their liver disease,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0159" target="_blank" title="Link to bibliographic citations">159, 160</a>] and even patients with only mild liver disease display cognitive dysfunction,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0161" target="_blank" title="Link to bibliographic citations">161, 162</a>]<br />
involving verbal learning, attention, executive function, and memory. <br />
Likewise, patients with primary biliary cirrhosis and primary sclerosing<br />
cholangitis may have severe fatigue and impairment of attention, <br />
concentration, and psychomotor function irrespective of the grade of <br />
liver disease.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0163" target="_blank" title="Link to bibliographic citations">163-168</a>]</section><section id="hep27210-sec-0054"><h3>Diagnostic Measures to Differentiate Between HE and Cerebral Dysfunction Resulting From Other Causes</h3>Because<br />
HE shares symptoms with all concomitant disorders and underlying <br />
diseases, it is difficult in the individual case to differentiate <br />
between the effects of HE and those resulting from other causes. In some<br />
cases, the time course and response to therapy may be the best support <br />
of HE. As mentioned, a normal blood ammonia level in a patient suspected<br />
of HE calls for consideration. None of the diagnostic measures used at <br />
present has been evaluated for their ability to differentiate between HE<br />
and other causes of brain dysfunction. The EEG would not be altered by <br />
DM or alcohol disorders, but may show changes similar to those with HE <br />
in cases of renal dysfunction, hyponatremia, or septic encephalopathy. <br />
Psychometric tests are able to detect functional deficits, but are <br />
unable to differentiate between different causes for these deficits. <br />
Brain imaging methods have been evaluated for their use in diagnosing <br />
HE, but the results are disappointing. Nevertheless, brain imaging <br />
should be done in every patient with CLD and unexplained alteration of <br />
brain function to exclude structural lesions. In rare cases, <br />
reversibility by flumazenil may be useful.</section></section><section id="hep27210-sec-0055"><h2>Follow-up</h2>After a hospital admission for HE, the following issues should be addressed.<br /><br />
<section id="hep27210-sec-0056"><h3>Discharge From Hospital</h3><ol id="hep27210-list-0014"><li id="hep27210-li-0052">The<br />
medical team should confirm the neurological status before discharge <br />
and judge to what extent the patient's neurological deficits could be <br />
attributable to HE, or to other neurological comorbidities, for <br />
appropriate discharge planning. They should inform caregivers that the <br />
neurological status may change once the acute illness has settled and <br />
that requirement for medication could change.</li>
<li id="hep27210-li-0053">Precipitating<br />
and risk factors for development of HE should be recognized. Future <br />
clinical management should be planned according to (1) potential for <br />
improvement of liver function (e.g., acute alcoholic hepatitis, <br />
autoimmune hepatitis, and hepatitis B), (2) presence of large <br />
portosystemic shunts (which may be suitable for occlusion), and (3) <br />
characteristics of precipitating factors (e.g., prevention of infection,<br />
avoidance of recurrent GI bleeding, diuretics, or constipation).</li>
<li id="hep27210-li-0054">Out-patient<br />
postdischarge consultations should be planned to adjust treatment and <br />
prevent the reappearance of precipitating factors. Close liaison should <br />
be made with the patient's family, the general practitioner, and other <br />
caregivers in the primary health service, so that all parties involved <br />
understand how to manage HE in the specific patient and prevent repeated<br />
hospitalizations.</li>
</ol></section><section id="hep27210-sec-0057"><h3>Preventive Care After Discharge</h3><ol id="hep27210-list-0015"><li id="hep27210-li-0055">Education<br />
of patients and relatives should include (1) effects of medication <br />
(lactulose, rifaximin, and so on) and the potential side effects (e.g., <br />
diarrhea), (2) importance of adherence, (3) early signs of recurring HE,<br />
and (4) actions to be taken if recurrence (e.g., anticonstipation <br />
measures for mild recurrence and referral to general practitioner or <br />
hospital if HE with fever).</li>
<li id="hep27210-li-0056">Prevention of <br />
recurrence: the underlying liver pathology may improve with time, <br />
nutrition, or specific measures, but usually patients who have developed<br />
OHE have advanced liver failure without much hope for functional <br />
improvements and are often potential LT candidates. Managing the <br />
complications of cirrhosis (e.g., spontaneous bacterial peritonitis and <br />
GI bleeding) should be instituted according to available guidelines. <br />
Pharmacological secondary prevention is mentioned above.</li>
<li id="hep27210-li-0057">Monitoring<br />
neurological manifestations is necessary in patients with persisting HE<br />
to adjust treatment and in patients with previous HE to investigate the<br />
presence and degree of MHE or CHE or signs of recurring HE. The <br />
cognitive assessment depends on the available normative data and local <br />
resources. The motor assessment should include evaluation of gait and <br />
walking and consider the risk of falls.</li>
<li id="hep27210-li-0058">The<br />
socioeconomic implications of persisting HE or MHE or CHE may be very <br />
profound. They include a decline in work performance, impairment in <br />
quality of life, and increase in the risk of accidents. These patients <br />
often require economic support and extensive care from the public social<br />
support system and may include their relatives. All these issues should<br />
be incorporated into the follow-up plan.</li>
<li id="hep27210-li-0059">Treatment<br />
endpoints depend on the monitoring used and the specialist clinic, but <br />
at least they have to cover two aspects: (1) cognitive performance <br />
(improvement in one accepted test as a minimum) and (2) daily life <br />
autonomy (basic and operational abilities).</li>
<li id="hep27210-li-0060">Nutritional<br />
aspects: weight loss with sarcopenia may worsen HE, and, accordingly, <br />
the nutritional priority is to provide enough protein and energy to <br />
favor a positive nitrogen balance and increase in muscle mass, as <br />
recommended above.</li>
<li id="hep27210-li-0061">Portosystemic shunt: occlusion of a dominant shunt may improve HE in patients with recurring HE and good liver function.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0114" target="_blank" title="Link to bibliographic citation">114</a>] Because the current experience is limited, the risks and benefits must be weighed before employing this strategy.</li>
</ol></section></section><section id="hep27210-sec-0058"><h2>Suggestions for Future Research</h2>This<br />
section deals with research into the management of HE. However, such <br />
research should always be based on research into the pathophysiology of <br />
HE. It is necessary to gain more insight into which liver functions are <br />
responsible for maintenance of cerebral functions, which alterations in <br />
intestinal function and microbiota make failure of these liver functions<br />
critical, which brain functions are particularly vulnerable to the <br />
combined effects of the aforementioned events, and, finally, which <br />
factors outside this axis that result in the emergence of HE (e.g., <br />
inflammation, endocrine settings, or malnutrition). Therefore, the <br />
research fields into pathophysiology and clinical management should <br />
remain in close contact. Such collaboration should result in new causal <br />
and symptomatic treatment modalities that need and motivate clinical <br />
trials.<br /><br />
There is a severe and unmet need for controlled clinical <br />
trials on treatment effects on all the different forms of HE. Decisive <br />
clinical studies are few, although the number of patients and their <br />
resource utilization is high. There are no data on which factors and <br />
patients represent the higher costs, and research is needed to examine <br />
the effect of specific cirrhosis-related complications. At present, <br />
there is an insufficient basis for allocating resources and establishing<br />
priority policies regarding management of HE. Many drugs that were <br />
assessed for HE several decades ago were studied following a standard of<br />
care that, at present, is obsolete. Any study of treatment for HE <br />
should be reassessed or repeated using the current standard of care. It <br />
is critical to develop protocols to identify precipitating factors and <br />
ACLF. The benefit of recently assessed drugs is concentrated in the <br />
prevention of recurrence, and there is a large need for trials on <br />
episodic HE.<br /><br />
There is also an unmet need for research into <br />
diagnostic methods that is necessary to form a basis for clinical <br />
trials. The diagnosis of MHE and CHE has received enormous interest, but<br />
it is still not possible to compare results among studies and the <br />
precision should be improved. It may be useful to develop, validate, and<br />
implement HE scales that combine the degree of functional liver failure<br />
and PSS with more than one psychometric method.<br /><br />
One important <br />
area of uncertainty is whether the term CHE, which was introduced to <br />
expand MHE toward grade I of oriented patients, is informative and <br />
clinically valuable. This needs to be evaluated by a data-driven <br />
approach. Likewise, the distinction between isolated liver failure and <br />
ACLF-associated HE should be evaluated by independent data.<br /><br />
A <br />
closer scientific collaboration between clinical hepatologists and <br />
dedicated brain researchers, including functional brain imaging experts,<br />
is needed. Likewise, neuropsychologists and psychiatrists are needed to<br />
clarify the broad spectrum of neuropsychiatric symptoms that can be <br />
observed in patients with liver disease. Syndrome diagnoses should be <br />
more precisely classified and transformed into classifiable entities <br />
based on pathophysiology and responding to the requirements of clinical <br />
hepatology practice and research.<br /><br />
Future studies should fill our <br />
gaps in knowledge. They should be focused on assessing the effects of HE<br />
on individuals and society, how to use diagnostic tools appropriately, <br />
and define the therapeutic goals in each clinical scenario (Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0007" target="_blank" title="Link to table">7</a>).<br /><br />
<div><table id="hep27210-tbl-0007" style="margin-left: 0px; margin-right: 0px; text-align: left;"><caption>Table 7. Suggested Areas of Future Research in HE</caption><thead>
<tr><th>Aspect</th><th>Need</th><th>Suggestions</th></tr>
</thead><tbody>
<tr><td>Effect on individuals and society</td><td>Demonstrate the effects of HE on patients and society in order to encourage diagnosis and therapy</td><td>1. Studies on economic and social burden among different societies<br /><br />
2. Studies on cultural aspects on therapy and compliance with treatment<br /><br />
3. Long-term natural history studies</td></tr>
<tr><td>Diagnostic improvement</td><td>Enhance the diagnostic accuracy</td><td>1.<br />
Studies on clinically applicable high-sensitivity screening tests that <br />
can guide which patients may benefit from dedicated testing<br /><br />
2. Development of algorithms to decide when and how to apply the diagnostic process<br /><br />
3. Studies on competing factors (i.e., HCV, delirium, depression, and narcotic use on diagnosis)<br /><br />
4. Studies on biomarkers for presence and progression of neurological dysfunction</td></tr>
<tr><td>Treatment goals</td><td>Improve the appropriate use of therapeutic tools in different clinical scenarios</td><td>1. Studies on selecting who will benefit from preventing the first OHE episode<br /><br />
2. Studies for >6 months to evaluate compliance and continued effects on cognitive improvement<br /><br />
3. Develop protocols focused on how to diagnose and treat precipitating factors<br /><br />
4. Determine what should be the standard protocol to investigate new therapies<br /><br />
5. Decide which therapies have been adequately studied and are not a priority for additional studies</td></tr>
</tbody></table></div><section id="hep27210-sec-0059"><h3>Recommendations on Future Research in HE</h3>The<br />
existing literature suffers from a lack of standardization, and this <br />
heterogeneity makes pooling of data difficult or meaningless. <br />
Recommendations to promote consistency across the field have been <br />
published by ISHEN.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0066" target="_blank" title="Link to bibliographic citation">66</a>] Following is a synopsis of the recommendations.</section><section id="hep27210-sec-0060"><h3>Trials in Patients With Episodic OHE</h3><ol id="hep27210-list-0016"><li id="hep27210-li-0062">Patients who are not expected to survive the hospitalization, who are terminally ill or have ACLF should be excluded.</li>
<li id="hep27210-li-0063">A detailed standard-of-care algorithm must be agreed upon <i>a priori</i> and must be instituted and monitored diligently throughout the trial.</li>
<li id="hep27210-li-0064">Patients<br />
should not be entered into trials until after the institution of <br />
optimal standard-of-care therapy and only if their mental state <br />
abnormalities persist.</li>
<li id="hep27210-li-0065">Provided the <br />
optimal standard of care is instituted and maintained, the treatment <br />
trial can be initiated earlier if they include a placebo comparator; <br />
this would allow an evaluation of the trial treatment as an adjuvant to <br />
standard therapy.</li>
<li id="hep27210-li-0066">Large-scale, multicenter<br />
treatment trials should be evaluated using robust clinical outcomes, <br />
such as in-hospital and remote survival, liver-related and total deaths,<br />
completeness and speed of recovery from HE, number of days in intensive<br />
care, total length of hospital stay, quality-of-life measures, and <br />
associated costs. Markers for HE, such as psychometric testing, can be <br />
employed if standardized and validated tools are available in all <br />
centers. Individual centers can utilize additional, accessible, <br />
validated markers if they choose.</li>
<li id="hep27210-li-0067">Proof-of-concept<br />
trials will additionally be monitored using tools that best relate to <br />
the endpoints anticipated or expected; this may involve use of neural <br />
imaging or measurement of specific biomarkers.</li>
</ol></section><section id="hep27210-sec-0061"><h3>Trials in Patients With MHE or CHE</h3>Trials in this population should be randomized and placebo controlled. <br /><br />
<ol id="hep27210-list-0017"><li id="hep27210-li-0068">Patients receiving treatment for OHE or those with previous episodes of OHE should be excluded.</li>
<li id="hep27210-li-0069">In<br />
single-center or proof-of-concept studies, investigators may use tests <br />
for assessing the severity of HE with which they are familiar, provided <br />
that normative reference data are available and the tests have been <br />
validated for use in this patient population.</li>
<li id="hep27210-li-0070">Further<br />
information is needed on the interchangeability and standardization of <br />
tests to assess the severity of HE for use in multicenter trials. As an <br />
interim, two or more of the current validated tests should be used and <br />
applied uniformly across centers.</li>
</ol></section></section><footer><h2>Ancillary</h2><section id="footer-article-info"><h3>Article Information</h3></section><section id="footer-table-list"><h3>Tables </h3></section><section id="references-section"><h3>References</h3></section></footer></div><div class="pageSeparator" style="text-align: justify;"><div class="pageSeparatorLabel"><i>page 2</i></div></div><div style="text-align: justify;"><br /><br />
<nav> <div><a href="http://onlinelibrary.wiley.com/doi/10.1002/hep.v60.2/issuetoc" target="_blank"> Volume 60, Issue 2</a><br /><br />
August 2014 <br /><br />
Pages 715–735 </div></nav> </div><div style="text-align: justify;"><br /><br />
<header><div>AASLD<br />
Practice GuidelineHepatic encephalopathy in chronic liver disease: 2014<br />
Practice Guideline by the American Association for the Study Of Liver <br />
Diseases and the European Association for the Study of the Liver<br /><br />
<div><h2>Authors</h2><ul><li><h3>Hendrik Vilstrup,</h3></li>
<li><h3>Piero Amodio,</h3></li>
<li><h3>Jasmohan Bajaj,</h3></li>
<li><h3>Juan Cordoba,</h3></li>
<li><h3>Peter Ferenci,</h3></li>
<li><h3>Kevin D. Mullen,</h3></li>
<li><h3>Karin Weissenborn,</h3></li>
<li><h3>Philip Wong</h3></li>
</ul></div><div><ul id="header-meta-info-container"><li>First published: <time id="first-published-date">8 July 2014</time><a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#publication-history" target="_blank">Full publication history</a></li>
<li>10.1002/hep.27210</li>
<li><a href="http://onlinelibrary.wiley.com/doi/10.1002/hep.27210/citedby" target="_blank">Citing literature</a></li>
</ul></div></div><hr style="margin-left: 0px; margin-right: 0px;" /><div><ul><li id="hep27210-note-0002"> Potential<br />
conflict of interest: Dr. Wong consults, advises, and received grants <br />
from Gilead. He consults and advises Roche. He advises and received <br />
grants from Vertex. Dr. Ferenci advises Ocera and Salix. Dr. Bajaj <br />
consults and received grants from Otsuka and Grifols. He consults for <br />
Salix. Dr. Mullen is on the speakers' bureau for Salix and Abbott.</li>
<li id="hep27210-note-0003"> All<br />
AASLD Practice Guidelines are updated annually. If you are viewing a <br />
Practice Guideline that is more than 12 months old, please visit <a href="http://www.aasld.org/" target="_blank" title="Link to external resource: http://www.aasld.org">www.aasld.org</a> for an update in the material.</li>
<li id="hep27210-note-0021"> <i>This Practice Guideline is copublished in the</i> Journal of Hepatology.</li>
</ul></div></header><section id="pdf-section"><h4>Select a PDF to begin download</h4><ul><li><a href="http://onlinelibrary.wiley.com/doi/10.1002/hep.27210/pdf" target="_blank">Download PDF500.0 kB</a></li>
</ul></section></div><div style="text-align: justify;">Abbreviations<br />
<br /><br />
<dl id="hep27210-lp-0001"><dt>AASLD</dt>
<dd>American Association for the Study of Liver Diseases</dd>
<dt>ACLF</dt>
<dd>acute-on-chronic liver failure</dd>
<dt>ALD</dt>
<dd>alcoholic liver disease</dd>
<dt>ALF</dt>
<dd>acute liver failure</dd>
<dt>BCAAs</dt>
<dd>branced-chain amino acids</dd>
<dt>CFF</dt>
<dd>Critical Flicker Frequency</dd>
<dt>CHE</dt>
<dd>covert HE</dd>
<dt>CLD</dt>
<dd>chronic liver disease</dd>
<dt>CRT</dt>
<dd>Continuous Reaction Time</dd>
<dt>CT</dt>
<dd>computed tomography</dd>
<dt>DM</dt>
<dd>diabetes mellitus</dd>
<dt>EASL</dt>
<dd>European Association for the Study of the Liver</dd>
<dt>EEG</dt>
<dd>electroencephalography</dd>
<dt>GI</dt>
<dd>gastrointestinal</dd>
<dt>GRADE</dt>
<dd>the Grading of Recommendation Assessment, Development, and Evaluation</dd>
<dt>GCS</dt>
<dd>Glasgow Coma Scale</dd>
<dt>GPB</dt>
<dd>glyceryl phenylbutyrate</dd>
<dt>HCV</dt>
<dd>hepatitis C virus</dd>
<dt>HE</dt>
<dd>hepatic encephalopathy</dd>
<dt>HM</dt>
<dd>hepatic myelopathy</dd>
<dt>ICT</dt>
<dd>Inhibitory Control Test</dd>
<dt>ISHEN</dt>
<dd>International Society for Hepatic Encephalopathy and Nitrogen Metabolism</dd>
<dt>IV</dt>
<dd>intravenous</dd>
<dt>LOLA</dt>
<dd>L-ornithine L-aspartate</dd>
<dt>LT</dt>
<dd>Liver transplantation</dd>
<dt>MHE</dt>
<dd>minimal HE</dd>
<dt>MR</dt>
<dd>magnetic resonance</dd>
<dt>OHE</dt>
<dd>overt HE</dd>
<dt>PH</dt>
<dd>portal hypertension</dd>
<dt>PHES</dt>
<dd>Psychometric Hepatic Encephalopathy Score</dd>
<dt>PP</dt>
<dd>portal pressure</dd>
<dt>PSE</dt>
<dd>portosystemic encephalopathy</dd>
<dt>PSS</dt>
<dd>portosystemic shunting</dd>
<dt>RCT</dt>
<dd>randomized, controlled trial</dd>
<dt>TIPS</dt>
<dd>transjugular intrahepatic portosystemic shunt</dd>
<dt>VB</dt>
<dd>variceal bleeding</dd>
<dt>WHC</dt>
<dd>West Haven Criteria</dd>
<dt>WM</dt>
<dd>working memory</dd></dl></div><div style="text-align: justify;"><br /><br />
<section id="hep27210-sec-0080">The<br />
AASLD/EASL Practice Guideline Subcommittee on Hepatic Encephalopathy <br />
are: Jayant A. Talwalkar (Chair, AASLD), Hari S. Conjeevaram, Michael <br />
Porayko, Raphael B. Merriman, Peter L.M. Jansen, and Fabien Zoulim. This<br />
guideline has been approved by the American Association for the Study <br />
of Liver Diseases and the European Association for the Study of the <br />
Liver and represents the position of both associations.</section><section id="hep27210-sec-0001"><h2>Preamble</h2>These<br />
recommendations provide a data-supported approach. They are based on <br />
the following: (1) formal review and analysis of the recently published <br />
world literature on the topic; (2) guideline policies covered by the <br />
American Association for the Study of Liver Diseases/European <br />
Association for the Study of the Liver (AASLD/EASL) Policy on the Joint <br />
Development and Use of Practice Guidelines; and (3) the experience of <br />
the authors in the specified topic.<br /><br />
Intended for use by <br />
physicians, these recommendations suggest preferred approaches to the <br />
diagnostic, therapeutic, and preventive aspects of care. They are <br />
intended to be flexible, in contrast to standards of care, which are <br />
inflexible policies to be followed in every case. Specific <br />
recommendations are based on relevant published information.<br /><br />
To <br />
more fully characterize the available evidence supporting the <br />
recommendations, the AASLD/EASL Practice Guidelines Subcommittee has <br />
adopted the classification used by the Grading of Recommendation <br />
Assessment, Development, and Evaluation (GRADE) workgroup, with minor <br />
modifications (Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0001" target="_blank" title="Link to table">1</a>).<br />
The classifications and recommendations are based on three categories: <br />
the source of evidence in levels I through III; the quality of evidence <br />
designated by high (A), moderate (B), or low quality (C); and the <br />
strength of recommendations classified as strong (1) or weak (2).<br /><br />
<div><table id="hep27210-tbl-0001" style="margin-left: 0px; margin-right: 0px; text-align: left;"><caption>Table 1. GRADE System for Evidence</caption><thead>
<tr><th>Grade</th><th>Evidence</th></tr>
</thead><tbody>
<tr><td>I</td><td>Randomized, controlled trials</td></tr>
<tr><td>II-1</td><td>Controlled trials without randomization</td></tr>
<tr><td>II-2</td><td>Cohort or case-control analytic studies</td></tr>
<tr><td>II-3</td><td>Multiple time series, dramatic uncontrolled experiments</td></tr>
<tr><td>III</td><td>Opinions of respected authorities, descriptive epidemiology</td></tr>
</tbody></table><table id="hep27210-tbl-0001" style="margin-left: 0px; margin-right: 0px; text-align: left;"><thead>
<tr><th>Evidence</th><th>Description</th></tr>
</thead><tbody>
<tr><td>High quality</td><td>Further research is very unlikely to change our confidence in the estimated effect.</td><td>A</td></tr>
<tr><td>Moderate</td><td>Further research is likely to have an important impact on our confidence in the estimate effect and may change the estimate.</td><td>B</td></tr>
<tr><td>Low quality</td><td>Further<br />
research is likely to have an important impact on our confidence in the<br />
estimate effect and is likely to change the estimate. Any change of <br />
estimate is uncertain.</td><td>C</td></tr>
</tbody></table><table id="hep27210-tbl-0001" style="margin-left: 0px; margin-right: 0px; text-align: left;"><thead>
<tr><th colspan="3">Recommendation</th></tr>
</thead><tbody>
<tr><td>Strong</td><td>Factors<br />
influencing the strength of recommendation included the quality of <br />
evidence, presumed patient-important outcomes, and costs.</td><td>1</td></tr>
<tr><td>Weak</td><td>Variability<br />
in preferences and values, or more uncertainty. Recommendation is made <br />
with less certainty, higher costs, or resource consumption.</td><td>2</td></tr>
</tbody></table></div></section><section id="hep27210-sec-0002"><h2>Literature Review and Analysis</h2>The<br />
literature databases and search strategies are outlined below. The <br />
resulting literature database was available to all members of the <br />
writing group (i.e., the authors). They selected references within their<br />
field of expertise and experience and graded the references according <br />
to the GRADE system.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0001" target="_blank" title="Link to bibliographic citation">1</a>]<br />
The selection of references for the guideline was based on a validation<br />
of the appropriateness of the study design for the stated purpose, a <br />
relevant number of patients under study, and confidence in the <br />
participating centers and authors. References on original data were <br />
preferred and those that were found unsatisfactory in any of these <br />
respects were excluded from further evaluation. There may be limitations<br />
in this approach when recommendations are needed on rare problems or <br />
problems on which scant original data are available. In such cases, it <br />
may be necessary to rely on less-qualified references with a low <br />
grading. As a result of the important changes in the treatment of <br />
complications of cirrhosis (renal failure, infections, and variceal <br />
bleeding [VB]), studies performed more than 30 years ago have generally <br />
not been considered for these guidelines.</section><section id="hep27210-sec-0003"><h2>Introduction</h2>Hepatic<br />
encephalopathy (HE) is a frequent complication and one of the most <br />
debilitating manifestations of liver disease, severely affecting the <br />
lives of patients and their caregivers. Furthermore, cognitive <br />
impairment associated with cirrhosis results in utilization of more <br />
health care resources in adults than other manifestations of liver <br />
disease.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0002" target="_blank" title="Link to bibliographic citation">2</a>]<br />
Progress in the area has been hindered by the complex pathogenesis that<br />
is not yet fully elucidated. Apart from such biological factors, there <br />
remains the larger obstacle that there are no universally accepted <br />
standards for the definition, diagnosis, classification, or treatment of<br />
HE, mostly as a result of insufficient clinical studies and <br />
standardized definitions. Clinical management tends to be dependent on <br />
local standards and personal views. This is an unfavorable situation for<br />
patients and contrasts with the severity of the condition and the high <br />
level of standardization in other complications of cirrhosis. The lack <br />
of consistency in the nomenclature and general standards renders <br />
comparisons among studies and patient populations difficult, introduces <br />
bias, and hinders progress in clinical research for HE. The latest <br />
attempts to standardize the nomenclature were published in 2002 and <br />
suggestions for the design of HE trials in 2011. Because there is an <br />
unmet need for recommendations on the clinical management of HE, the <br />
EASL and the AASLD jointly agreed to create these practice guidelines. <br />
It is beyond the scope of these guidelines to elaborate on the theories <br />
of pathogenesis of HE, as well as the management of encephalopathy <br />
resulting from acute liver failure (ALF), which has been published as <br />
guidelines recently. Rather, its aim is to present standardized <br />
terminology and recommendations to all health care workers who have <br />
patients with HE, regardless of their medical discipline, and focus on <br />
adult patients with chronic liver disease (CLD), which is, by far, the <br />
most frequent scenario.<br /><br />
As these guidelines on HE were created, <br />
the authors found a limited amount of high-quality evidence to extract <br />
from the existing literature. There are many reasons for this; the <br />
elusive character of HE is among them, as well as the lack of generally <br />
accepted and utilized terms for description and categorization of HE. <br />
This makes a practice guideline all the more necessary for future <br />
improvement of clinical studies and, subsequently, the quality of <br />
management of patients with HE. With the existing body of evidence, <br />
these guidelines encompass the authors' best, carefully considered <br />
opinions. Although not all readers may necessarily agree with all <br />
aspects of the guidelines, their creation and adherence to them is the <br />
best way forward, with future adjustments when there is emergence of new<br />
evidence.</section><section id="hep27210-sec-0004"><h2>Definition of the Disease/Condition</h2><section id="hep27210-sec-0005"><h3>Overview</h3>Advanced<br />
liver disease and portosystemic shunting (PSS), far from being an <br />
isolated disorder of the liver, have well-known consequences on the body<br />
and, notably, on brain functioning. The alterations of brain <br />
functioning, which can produce behavioral, cognitive, and motor effects,<br />
were termed portosystemic encephalopathy (PSE)[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0003" target="_blank" title="Link to bibliographic citation">3</a>] and later included in the term HE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0004" target="_blank" title="Link to bibliographic citation">4</a>]<br /><br />
Unless the underlying liver disease is successfully treated, HE is associated with poor survival and a high risk of recurrence.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0005" target="_blank" title="Link to bibliographic citations">5, 6</a>] Even in its mildest form, HE reduces health-related quality of life and is a risk factor for bouts of severe HE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0007" target="_blank" title="Link to bibliographic citations">7-9</a>]</section><section id="hep27210-sec-0006"><h3>Definition of HE</h3><i>Hepatic<br />
encephalopathy is a brain dysfunction caused by liver insufficiency <br />
and/or PSS; it manifests as a wide spectrum of neurological or <br />
psychiatric abnormalities ranging from subclinical alterations to coma</i>.<br /><br />
This definition, in line with previous versions,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0010" target="_blank" title="Link to bibliographic citations">10, 11</a>] is based on the concept that encephalopathies are “diffuse disturbances of brain function”[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0005" target="_blank" title="Link to bibliographic citation">5</a>] and that the adjective “hepatic” implies a causal connection to liver insufficiency and/or perihepatic vascular shunting.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0006" target="_blank" title="Link to bibliographic citation">6</a>]</section><section id="hep27210-sec-0007"><h3>Epidemiology</h3>The incidence and prevalence of HE are related to the severity of the underlying liver insufficiency and PSS.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0012" target="_blank" title="Link to bibliographic citations">12-15</a>]<br />
In patients with cirrhosis, fully symptomatic overt HE (OHE) is an <br />
event that defines the decompensated phase of the disease, such as VB or<br />
ascites.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0007" target="_blank" title="Link to bibliographic citation">7</a>] Overt hepatic encephalopathy is also reported in subjects without cirrhosis with extensive PSS.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0008" target="_blank" title="Link to bibliographic citations">8, 9</a>]<br /><br />
The<br />
manifestation of HE may not be an obvious clinical finding and there <br />
are multiple tools used for its detection, which influences the <br />
variation in the reported incidence and prevalence rates.<br /><br />
The prevalence of OHE at the time of diagnosis of cirrhosis is 10%-14% in general,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0016" target="_blank" title="Link to bibliographic citations">16-18</a>] 16%-21% in those with decompensated cirrhosis,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0007" target="_blank" title="Link to bibliographic citations">7, 19</a>] and 10%-50% in patients with transjugular intrahepatic portosystemic shunt (TIPS).[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0020" target="_blank" title="Link to bibliographic citations">20, 21</a>]<br />
The cumulated numbers indicate that OHE will occur in 30%-40% of those <br />
with cirrhosis at some time during their clinical course and in the <br />
survivors in most cases repeatedly.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0022" target="_blank" title="Link to bibliographic citation">22</a>] Minimal HE (MHE) or covert HE (CHE) occurs in 20%-80% of patients with cirrhosis.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0023" target="_blank" title="Link to bibliographic citations">23-27, 81</a>] The prevalence of HE in prehepatic noncirrhotic portal hypertension (PH) is not well defined.<br /><br />
The<br />
risk for the first bout of OHE is 5%-25% within 5 years after cirrhosis<br />
diagnosis, depending on the presence of risk factors, such as other <br />
complications to cirrhosis (MHE or CHE, infections, VB, or ascites) and <br />
probably diabetes and hepatitis C.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0028" target="_blank" title="Link to bibliographic citations">28-32</a>] Subjects with a previous bout of OHE were found to have a 40% cumulative risk of recurring OHE at 1 year,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0033" target="_blank" title="Link to bibliographic citation">33</a>]<br />
and subjects with recurrent OHE have a 40% cumulative risk of another <br />
recurrence within 6 months, despite lactulose treatment. Even <br />
individuals with cirrhosis and only mild cognitive dysfunction or mild <br />
electroencephalography (EEG) slowing develop approximately one bout of <br />
OHE per 3 years of survival.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0034" target="_blank" title="Link to bibliographic citations">34, 35</a>]<br /><br />
After TIPS, the median cumulative 1-year incidence of OHE is 10%-50%[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0036" target="_blank" title="Link to bibliographic citations">36, 37</a>] and is greatly influenced by the patient selection criteria adopted.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0038" target="_blank" title="Link to bibliographic citation">38</a>] Comparable data were obtained by PSS surgery.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0039" target="_blank" title="Link to bibliographic citation">39</a>]<br /><br />
It<br />
gives an idea of the frequent confrontation of the health care system <br />
by patients with HE that they accounted for approximately 110,000 <br />
hospitalizations yearly (2005-2009)[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0040" target="_blank" title="Link to bibliographic citation">40</a>]<br />
in the United States. Though numbers in the European Union (EU) are not<br />
readily available, these predictions are expected to be similar. <br />
Furthermore, the burden of CLD and cirrhosis is rapidly increasing,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0041" target="_blank" title="Link to bibliographic citations">41, 42</a>] and more cases will likely be encountered to further define the epidemiology of HE.</section><section id="hep27210-sec-0008"><h3>Clinical Presentation</h3>Hepatic encephalopathy produces a wide spectrum of nonspecific neurological and psychiatric manifestations.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0010" target="_blank" title="Link to bibliographic citation">10</a>] In its lowest expression,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0043" target="_blank" title="Link to bibliographic citations">43, 44</a>]<br />
HE alters only psychometric tests oriented toward attention, working <br />
memory (WM), psychomotor speed, and visuospatial ability, as well as <br />
electrophysiological and other functional brain measures.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0045" target="_blank" title="Link to bibliographic citations">45, 46</a>]<br /><br />
As<br />
HE progresses, personality changes, such as apathy, irritability, and <br />
disinhibition, may be reported by the patient's relatives,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0047" target="_blank" title="Link to bibliographic citation">47</a>]<br />
and obvious alterations in consciousness and motor function occur. <br />
Disturbances of the sleep-wake cycle with excessive daytime sleepiness <br />
are frequent,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0048" target="_blank" title="Link to bibliographic citation">48</a>] whereas complete reversal of the sleep-wake cycle is less consistently observed.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0049" target="_blank" title="Link to bibliographic citations">49, 50</a>]<br />
Patients may develop progressive disorientation to time and space, <br />
inappropriate behavior, and acute confusional state with agitation or <br />
somnolence, stupor, and, finally, coma.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0051" target="_blank" title="Link to bibliographic citation">51</a>]<br />
The recent ISHEN (International Society for Hepatic Encephalopathy and <br />
Nitrogen Metabolism) consensus uses the onset of disorientation or <br />
asterixis as the onset of OHE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0065" target="_blank" title="Link to bibliographic citation">65</a>]<br /><br />
In<br />
noncomatose patients with HE, motor system abnormalities, such as <br />
hypertonia, hyper-reflexia, and a positive Babinski sign, can be <br />
observed. In contrast, deep tendon reflexes may diminish and even <br />
disappear in coma,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0052" target="_blank" title="Link to bibliographic citation">52</a>] although pyramidal signs can still be observed. Rarely, transient focal neurological deficits can occur.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0053" target="_blank" title="Link to bibliographic citation">53</a>] Seizures are very rarely reported in HE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0054" target="_blank" title="Link to bibliographic citations">54-56</a>]<br /><br />
Extrapyramidal<br />
dysfunction, such as hypomimia, muscular rigidity, bradykinesia, <br />
hypokinesia, monotony and slowness of speech, parkinsonian-like tremor, <br />
and dyskinesia with diminished voluntary movements, are common findings;<br />
in contrast, the presence of involuntary movements similar to tics or <br />
chorea occur rarely.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0052" target="_blank" title="Link to bibliographic citations">52, 57</a>]<br /><br />
Asterixis<br />
or “flapping tremor” is often present in the early to middle stages of <br />
HE that precede stupor or coma and is, in actuality, not a tremor, but a<br />
negative myoclonus consisting of loss of postural tone. It is easily <br />
elicited by actions that require postural tone, such as hyperextension <br />
of the wrists with separated fingers or the rhythmic squeezing of the <br />
examiner's fingers. However, asterixis can be observed in other areas, <br />
such as the feet, legs, arms, tongue, and eyelids. Asterixis is not <br />
pathognomonic of HE because it can be observed in other diseases[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0057" target="_blank" title="Link to bibliographic citation">57</a>] (e.g., uremia).<br /><br />
Notably,<br />
the mental (either cognitive or behavioral) and motor signs of HE may <br />
not be expressed, or do not progress in parallel, in each individual, <br />
therefore producing difficulties in staging the severity of HE.<br /><br />
Hepatic myelopathy (HM)[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0058" target="_blank" title="Link to bibliographic citation">58</a>]<br />
is a particular pattern of HE possibly related to marked, long-standing<br />
portocaval shunting, characterized by severe motor abnormalities <br />
exceeding the mental dysfunction. Cases of paraplegia with progressive <br />
spasticity and weakness of lower limbs with hyper-reflexia and <br />
relatively mild persistent or recurrent mental alterations have been <br />
reported and do not respond to standard therapy, including ammonia <br />
lowering, but may reverse with liver transplantation (LT).[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0059" target="_blank" title="Link to bibliographic citation">59</a>]<br /><br />
Persistent<br />
HE may present with prominent extrapyramidal and/or pyramidal signs, <br />
partially overlapping with HM, in which postmortem brain examination <br />
reveals brain atrophy.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0060" target="_blank" title="Link to bibliographic citation">60</a>]<br />
This condition was previously called acquired hepatolenticular <br />
degeneration, a term currently considered obsolete. However, this <br />
cirrhosis-associated parkinsonism is unresponsive to ammonia-lowering <br />
therapy and may be more common than originally thought in patients with <br />
advanced liver disease, presenting in approximately 4% of cases.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0061" target="_blank" title="Link to bibliographic citation">61</a>]<br /><br />
Apart<br />
from these less-usual manifestations of HE, it is widely accepted in <br />
clinical practice that all forms of HE and their manifestations are <br />
completely reversible, and this assumption still is a well-founded <br />
operational basis for treatment strategies. However, research on <br />
liver-transplanted HE patients and on patients after resolution of <br />
repeated bouts of OHE casts doubt on the full reversibility. Some mental<br />
deficits, apart from those ascribable to other transplantation-related <br />
causes, may persist and are mentioned later under transplantation.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0135" target="_blank" title="Link to bibliographic citation">135</a>] Likewise, episodes of OHE may be associated with persistent cumulative deficits in WM and learning.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0014" target="_blank" title="Link to bibliographic citation">14</a>]</section><section id="hep27210-sec-0009"><h3>Classification</h3>Hepatic encephalopathy should be classified according to all of the following four factors.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0010" target="_blank" title="Link to bibliographic citation">10</a>]<br /><br />
<ol id="hep27210-list-0001"><li id="hep27210-li-0001"> <b>According to the underlying disease,</b> HE is subdivided into <br /><br />
<ul id="hep27210-list-0002"><li id="hep27210-li-0002">Type A resulting from ALF</li>
<li id="hep27210-li-0003">Type B resulting predominantly from portosystemic bypass or shunting</li>
<li id="hep27210-li-0004">Type C resulting from cirrhosis</li>
</ul>The<br />
clinical manifestations of types B and C are similar, whereas type A <br />
has distinct features and, notably, may be associated with increased <br />
intracranial pressure and a risk of cerebral herniation. The management <br />
of HE type A is described in recent guidelines on ALF[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0062" target="_blank" title="Link to bibliographic citations">62, 63</a>] and is not included in this document.</li>
<li id="hep27210-li-0005"> <b>According to the severity of manifestations</b>.<br />
The continuum that is HE has been arbitrarily subdivided. For clinical <br />
and research purposes, a scheme of such grading is provided (Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0002" target="_blank" title="Link to table">2</a>).<br />
Operative classifications that refer to defined functional impairments <br />
aim at increasing intra- and inter-rater reliability and should be used <br />
whenever possible.</li>
<li id="hep27210-li-0006"> <b>According to its time course</b>, HE is subdivided into <br /><br />
<ul id="hep27210-list-0003"><li id="hep27210-li-0007"><b>Episodic HE</b></li>
<li id="hep27210-li-0008"><b>Recurrent HE</b> denotes bouts of HE that occur with a time interval of 6 months or less.</li>
<li id="hep27210-li-0009"><b>Persistent HE</b> denotes a pattern of behavioral alterations that are always present and interspersed with relapses of overt HE.</li>
</ul></li>
<li id="hep27210-li-0010"> <b>According to the existence of precipitating factors</b>, HE is subdivided into <br /><br />
<ul id="hep27210-list-0004"><li id="hep27210-li-0011"><b>Nonprecipitated</b> or</li>
<li id="hep27210-li-0012"><b>Precipitated</b>,<br />
and the precipitating factors should be specified. Precipitating <br />
factors can be identified in nearly all bouts of episodic HE type C and <br />
should be actively sought and treated when found (Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0003" target="_blank" title="Link to table">3</a>).</li>
</ul></li>
</ol><div><table id="hep27210-tbl-0002" style="margin-left: 0px; margin-right: 0px; text-align: left;"><caption>Table 2. WHC and Clinical Description</caption><thead>
<tr><th>WHC Including MHE</th><th>ISHEN</th><th>Description</th><th>Suggested Operative Criteria</th><th>Comment</th></tr>
</thead><tfoot>
<tr><td colspan="5"><ol><li id="hep27210-note-0004"> All conditions are required to be related to liver insufficiency and/or PSS.</li>
</ol></td></tr>
</tfoot><tbody>
<tr><td colspan="2">Unimpaired</td><td>No encephalopathy at all, no history of HE</td><td>Tested and proved to be normal</td><td></td></tr>
<tr><td>Minimal</td><td rowspan="2">Covert</td><td>Psychometric<br />
or neuropsychological alterations of tests exploring psychomotor <br />
speed/executive functions or neurophysiological alterations without <br />
clinical evidence of mental change</td><td>Abnormal results of established psychometric or neuropsychological tests without clinical manifestations</td><td>No universal criteria for diagnosis<br /><br />
Local standards and expertise required</td></tr>
<tr><td>Grade I</td><td>• Trivial lack of awareness<br /><br />
• Euphoria or anxiety<br /><br />
• Shortened attention span<br /><br />
• Impairment of addition or subtraction<br /><br />
• Altered sleep rhythm</td><td>Despite<br />
oriented in time and space (see below), the patient appears to have <br />
some cognitive/behavioral decay with respect to his or her standard on <br />
clinical examination or to the caregivers</td><td>Clinical findings usually not reproducible</td></tr>
<tr><td>Grade II</td><td rowspan="3">Overt</td><td>• Lethargy or apathy<br /><br />
• Disorientation for time<br /><br />
• Obvious personality change<br /><br />
• Inappropriate behavior<br /><br />
• Dyspraxia<br /><br />
• Asterixis</td><td>Disoriented<br />
for time (at least three of the followings are wrong: day of the month,<br />
day of the week, month, season, or year) ± the other mentioned symptoms</td><td>Clinical findings variable, but reproducible to some extent</td></tr>
<tr><td>Grade III</td><td>• Somnolence to semistupor<br /><br />
• Responsive to stimuli<br /><br />
• Confused<br /><br />
• Gross disorientation<br /><br />
• Bizarre behavior</td><td>Disoriented<br />
also for space (at least three of the following wrongly reported: <br />
country, state [or region], city, or place) ± the other mentioned <br />
symptoms</td><td>Clinical findings reproducible to some extent</td></tr>
<tr><td>Grade IV</td><td>Coma</td><td>Does not respond even to painful stimuli</td><td>Comatose state usually reproducible</td></tr>
</tbody></table></div><div><table id="hep27210-tbl-0003" style="margin-left: 0px; margin-right: 0px; text-align: left;"><caption>Table 3. Precipitating Factors for OHE by Decreasing Frequency</caption><thead>
<tr><th>Episodic</th><th>Recurrent</th></tr>
</thead><tfoot>
<tr><td colspan="2"><ol><li id="hep27210-note-0005"> Modified<br />
from Strauss E, da Costa MF. The importance of bacterial infections as <br />
precipitating factors of chronic hepatic encephalopathy in cirrhosis. <br />
Hepatogastroenterology 1998;45:900-904.</li>
<li id="hep27210-note-0006"><sup><i>a</i></sup> More recent unpublished case series confirm the dominant role of infections.</li>
</ol></td></tr>
</tfoot><tbody>
<tr><td>Infections<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-note-0006" target="_blank" title="Link to note">a</a></td><td>Electrolyte disorder</td></tr>
<tr><td>GI bleeding</td><td>Infections</td></tr>
<tr><td>Diuretic overdose</td><td>Unidentified</td></tr>
<tr><td>Electrolyte disorder</td><td>Constipation</td></tr>
<tr><td>Constipation</td><td>Diuretic overdose</td></tr>
<tr><td>Unidentified</td><td>GI bleeding</td></tr>
</tbody></table></div>A<br />
fifth classification, according to whether or not the patient has <br />
acute-on-chronic liver failure (ACLF), has recently been suggested.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0064" target="_blank" title="Link to bibliographic citation">64</a>] Although the management, mechanism, and prognostic impact differ, this classification is still a research area.</section><section id="hep27210-sec-0010"><h3>Differential Diagnoses</h3>The<br />
diagnosis requires the detection of signs suggestive of HE in a patient<br />
with severe liver insufficiency and/or PSS who does not have obvious <br />
alternative causes of brain dysfunction. The recognition of <br />
precipitating factors for HE (e.g., infection, bleeding, and <br />
constipation) supports the diagnosis of HE. The differential diagnosis <br />
should consider common disorders altering the level of consciousness <br />
(Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0004" target="_blank" title="Link to table">4</a>).<br /><br />
<div><table id="hep27210-tbl-0004" style="margin-left: 0px; margin-right: 0px; text-align: left;"><caption>Table 4. Differential Diagnosis of HE</caption><tfoot>
<tr><td colspan="1"><ol><li id="hep27210-note-0007"> Hyponatremia and sepsis can both produce encephalopathy <i>per se</i><br />
and precipitate HE by interactions with the pathophysiological <br />
mechanisms. In end-stage liver disease, uremic encephalopathy and HE may<br />
overlap.</li>
</ol></td></tr>
</tfoot><tbody>
<tr><td><i>Overt HE or acute confusional state</i></td></tr>
<tr><td>Diabetic (hypoglycemia, ketoacidosis, hyperosmolar, lactate acidosis)</td></tr>
<tr><td>Alcohol (intoxication, withdrawal, Wernicke)</td></tr>
<tr><td>Drugs (benzodiazepines, neuroleptics, opioids)</td></tr>
<tr><td>Neuroinfections</td></tr>
<tr><td>Electrolyte disorders (hyponatremia and hypercalcemia)</td></tr>
<tr><td>Nonconvulsive epilepsy</td></tr>
<tr><td>Psychiatric disorders</td></tr>
<tr><td>Intracranial bleeding and stroke</td></tr>
<tr><td>Severe medical stress (organ failure and inflammation)</td></tr>
<tr><td><i>Other presentations</i></td></tr>
<tr><td>Dementia (primary and secondary)</td></tr>
<tr><td>Brain lesions (traumatic, neoplasms, normal pressure hydrocephalus)</td></tr>
<tr><td>Obstructive sleep apnea</td></tr>
</tbody></table></div></section><section id="hep27210-sec-0011"><h3>Recommendations:</h3><b><i>1.<br />
Hepatic encephalopathy should be classified according to the type of <br />
underlying disease, severity of manifestations, time course, and <br />
precipitating factors (GRADE III, A, 1)</i></b>.<br /><br />
<b><i>2. A diagnostic workup is required, considering other disorders that can alter brain function and mimic HE (GRADE II-2, A, 1)</i></b>.<br /><br />
Every<br />
case and bout of HE should be described and classified according to all<br />
four factors, and this should be repeated at relevant intervals <br />
according to the clinical situation. The recommendations are summarized <br />
in Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0005" target="_blank" title="Link to table">5</a>.<br /><br />
<div><table id="hep27210-tbl-0005" style="margin-left: 0px; margin-right: 0px; text-align: left;"><caption>Table 5. HE Description and Clinical Example</caption><thead>
<tr><th>Type</th><th colspan="2">Grade</th><th>Time Course</th><th>Spontaneous or Precipitated</th></tr>
</thead><tfoot>
<tr><td colspan="5"><ol><li id="hep27210-note-0008"> The<br />
HE patient should be characterized by one component from each of the <br />
four columns. Example of a recommended description of a patient with HE:<br />
“The patient has HE, Type C, Grade 3, Recurrent, Precipitated (by <br />
urinary tract infection).” The description may be supplemented with <br />
operative classifications (e.g., the Glasgow Coma Score or psychometric <br />
performance).</li>
</ol></td></tr>
</tfoot><tbody>
<tr><td rowspan="2">A</td><td>MHE</td><td rowspan="2">Covert</td><td rowspan="2">Episodic</td><td rowspan="2">Spontaneous</td></tr>
<tr><td>B</td><td>2</td><td rowspan="3">Overt</td><td>Recurrent</td><td rowspan="3">Precipitated (specify)</td></tr>
<tr><td rowspan="2">C</td><td>3</td><td rowspan="2">Persistent</td></tr>
</tbody></table></div></section></section><section id="hep27210-sec-0012"><h2>Diagnosis and Testing</h2><section id="hep27210-sec-0013"><h3>Clinical Evaluation</h3>Judging and measuring the severity of HE is approached as a continuum.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0065" target="_blank" title="Link to bibliographic citation">65</a>]<br />
The testing strategies in place range from simple clinical scales to <br />
sophisticated psychometric and neurophysiological tools; however, none <br />
of the current tests are valid for the entire spectrum.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0011" target="_blank" title="Link to bibliographic citations">11, 66</a>]<br />
The appropriate testing and diagnostic options differ according to the <br />
acuity of the presentation and the degree of impairment.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0067" target="_blank" title="Link to bibliographic citation">67</a>]</section><section id="hep27210-sec-0014"><h3>Diagnosis and Testing for OHE</h3>The<br />
diagnosis of OHE is based on a clinical examination and a clinical <br />
decision. Clinical scales are used to analyze its severity. Specific <br />
quantitative tests are only needed in study settings. The gold standard <br />
is the West Haven criteria (WHC; Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0002" target="_blank" title="Link to table">2</a>,<br />
including clinical description). However, they are subjective tools <br />
with limited interobserver reliability, especially for grade I HE, <br />
because slight hypokinesia, psychomotor slowing, and a lack of attention<br />
can easily be overlooked in clinical examination. In contrast, the <br />
detection of disorientation and asterixis has good inter-rater <br />
reliability and thus are chosen as marker symptoms of OHE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0067" target="_blank" title="Link to bibliographic citation">67</a>] Orientation or mixed scales have been used to distinguish the severity of HE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0068" target="_blank" title="Link to bibliographic citations">68, 69</a>] In patients with significantly altered consciousness, the Glasgow Coma Scale (GCS; Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0006" target="_blank" title="Link to table">6</a>) is widely employed and supplies an operative, robust description.<br /><br />
<div><table id="hep27210-tbl-0006" style="margin-left: 0px; margin-right: 0px; text-align: left;"><caption>Table 6. GCS[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0169" target="_blank" title="Link to bibliographic citation">169</a>]</caption><thead>
<tr><th colspan="7">GCS</th></tr>
<tr><th>1</th><th>2</th><th>3</th><th>4</th><th>5</th><th>6</th></tr>
</thead><tfoot>
<tr><td colspan="7"><ol><li id="hep27210-note-0009"> The<br />
scale comprises three tests: eyes, verbal, and motor responses. The <br />
three values separately as well as their sum are considered. The lowest <br />
possible GCS (the sum) is 3 (deep coma or death), whereas the highest is<br />
15 (fully awake person).</li>
<li id="hep27210-note-0010"> Abbreviation: N/A, not applicable.</li>
</ol></td></tr>
</tfoot><tbody>
<tr><td>Eyes</td><td>Does not open eyes</td><td>Opens eyes in response to painful stimuli</td><td>Opens eyes in response to voice</td><td>Opens eyes spontaneously</td><td>N/A</td><td>N/A</td></tr>
<tr><td>Verbal</td><td>Makes no sounds</td><td>Incomprehensible sounds</td><td>Utters inappropriate words</td><td>Confused, disoriented</td><td>Oriented, converses normally</td><td>N/A</td></tr>
<tr><td>Motor</td><td>Makes no movements</td><td>Extension to painful stimuli (decerebrate response)</td><td>Abnormal flexion to painful stimuli (decorticate response)</td><td>Flexion/withdrawal to painful stimuli</td><td>Localizes painful stimuli</td><td>Obeys commands</td></tr>
</tbody></table></div>Diagnosing<br />
cognitive dysfunction is not difficult. It can be established from <br />
clinical observation as well as neuropsychological or neurophysiological<br />
tests. The difficulty is to assign them to HE. For this reason, OHE <br />
still remains a diagnosis of exclusion in this patient population that <br />
is often susceptible to mental status abnormalities resulting from <br />
medications, alcohol abuse, drug use, effects of hyponatremia, and <br />
psychiatric disease (Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0004" target="_blank" title="Link to table">4</a>).<br />
Therefore, as clinically indicated, exclusion of other etiologies by <br />
laboratory and radiological assessment for a patient with altered mental<br />
status in HE is warranted.</section><section id="hep27210-sec-0015"><h3>Testing for MHE and CHE</h3>Minimal<br />
hepatic encephalopathy and CHE is defined as the presence of <br />
test-dependent or clinical signs of brain dysfunction in patients with <br />
CLD who are not disoriented or display asterixis. The term “minimal” <br />
conveys that there is no clinical sign, cognitive or other, of HE. The <br />
term “covert” includes minimal and grade 1 HE. Testing strategies can be<br />
divided into two major types: psychometric and neurophysiological.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0070" target="_blank" title="Link to bibliographic citations">70, 71</a>]<br />
Because the condition affects several components of cognitive <br />
functioning, which may not be impaired to the same degree, the ISHEN <br />
suggests the use of at least two tests, depending on the local <br />
population norms and availability, and preferably with one of the tests <br />
being more widely accepted so as to serve as a comparator.<br /><br />
Testing<br />
for MHE and CHE is important because it can prognosticate OHE <br />
development, indicate poor quality of life and reduced socioeconomic <br />
potential, and help counsel patients and caregivers about the disease. <br />
The occurrence of MHE and CHE in patients with CLD seems to be as high <br />
as 50%,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0072" target="_blank" title="Link to bibliographic citation">72</a>] so, ideally, every patient at risk should be tested. However, this strategy may be costly,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0073" target="_blank" title="Link to bibliographic citation">73</a>]<br />
and the consequences of the screening procedure are not always clear <br />
and treatment is not always recommended. An operational approach may be <br />
to test patients who have problems with their quality of life or in whom<br />
there are complaints from the patients and their relatives.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0074" target="_blank" title="Link to bibliographic citation">74</a>] Tests positive for MHE or CHE before stopping HE drug therapy will identify patients at risk for recurrent HE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0033" target="_blank" title="Link to bibliographic citations">33, 75</a>] Furthermore, none of the available tests are specific for the condition,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0076" target="_blank" title="Link to bibliographic citation">76</a>]<br />
and it is important to test only patients who do not have confounding <br />
factors, such as neuropsychiatric disorders, psychoactive medication, or<br />
current alcohol use.<br /><br />
Testing should be done by a trained examiner<br />
adhering to scripts that accompany the testing tools. If the test <br />
result is normal (i.e., negative for MHE or CHE), repeat testing in 6 <br />
months has been recommended.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0077" target="_blank" title="Link to bibliographic citation">77</a>] A diagnosis of MHE or CHE does not automatically mean that the affected subject is a dangerous driver.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0078" target="_blank" title="Link to bibliographic citation">78</a>]<br />
Medical providers are not trained to formally evaluate fitness to drive<br />
and are also not legal representatives. Therefore, providers should act<br />
in the best interests of both the patient and society while following <br />
the applicable local laws.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0078" target="_blank" title="Link to bibliographic citation">78</a>]<br />
However, doctors cannot evade the responsibility of counseling patients<br />
with diagnosed HE on the possible dangerous consequences of their <br />
driving, and, often, the safest advice is to stop driving until the <br />
responsible driving authorities have formally cleared the patient for <br />
safe driving. In difficult cases, the doctor should consult with the <br />
authorities that have the expertise to test driving ability and the <br />
authority to revoke the license.<br /><br />
A listing of the most established<br />
testing strategies is given below. The test recommendation varies <br />
depending on the logistics, availability of tests, local norms, and <br />
cost.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0065" target="_blank" title="Link to bibliographic citations">65, 66, 71</a>] <br /><br />
<ol id="hep27210-list-0006"><li id="hep27210-li-0015">Portosystemic<br />
encephalopathy (PSE) syndrome test. This test battery consists of five <br />
paper-pencil tests that evaluate cognitive and psychomotor processing <br />
speed and visuomotor coordination. The tests are relatively easy to <br />
administer and have good external validity.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0076" target="_blank" title="Link to bibliographic citation">76</a>]<br />
The test is often referred to as the Psychometric Hepatic <br />
Encephalopathy Score (PHES), with the latter being the sum score from <br />
all subtests of the battery. It can be obtained from Hannover Medical <br />
School (Hannover, Germany), which holds the copyright <br />
(Weissenborn.karin@mh-hannover.de). The test was developed in Germany <br />
and has been translated for use in many other countries. For illiterate <br />
patients, the figure connection test has been used as a subtest instead <br />
of the number connection test.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0079" target="_blank" title="Link to bibliographic citation">79</a>]</li>
<li id="hep27210-li-0016">The<br />
Critical Flicker Frequency (CFF) test is a psychophysiological tool <br />
defined as the frequency at which a fused light (presented from 60 Hz <br />
downward) appears to be flickering to the observer. Studies have shown <br />
its reduction with worsening cognition and improvement after therapy. <br />
The CFF test requires several trials, intact binocular vision, absence <br />
of red-green blindness, and specialized equipment.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0080" target="_blank" title="Link to bibliographic citations">80, 81</a>]</li>
<li id="hep27210-li-0017">The<br />
Continuous Reaction Time (CRT) test. The CRT test relies on repeated <br />
registration of the motor reaction time (pressing a button) to auditory <br />
stimuli (through headphones). The most important test result is the CRT <br />
index, which measures the stability of the reaction times. The test <br />
result can differentiate between organic and metabolic brain impairment <br />
and is not influenced by the patient's age or gender, and there is no <br />
learning or tiring effect. Simple software and hardware are required.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0082" target="_blank" title="Link to bibliographic citation">82</a>]</li>
<li id="hep27210-li-0018">The Inhibitory Control Test (ICT) is a computerized test of response inhibition and working memory[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0083" target="_blank" title="Link to bibliographic citation">83</a>] and is freely downloadable at <a href="http://www.hecme.tv/" target="_blank" title="Link to external resource: http://www.hecme.tv">www.hecme.tv</a>.<br />
The ICT test has been judged to have good validity, but requires highly<br />
functional patients. The norms for the test have to be elaborated <br />
beyond the few centers that have used it.</li>
<li id="hep27210-li-0019">The<br />
Stroop test evaluates psychomotor speed and cognitive flexibility by <br />
the interference between recognition reaction time to a colored field <br />
and a written color name. Recently, mobile application software (“apps” <br />
for a smartphone or tablet computer) based on the test has been shown to<br />
identify cognitive dysfunction in cirrhosis compared to paper-pencil <br />
tests.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0084" target="_blank" title="Link to bibliographic citation">84</a>] Further studies are under way to evaluate its potential for screening for MHE and CHE.</li>
<li id="hep27210-li-0020">The<br />
SCAN Test is a computerized test that measures speed and accuracy to <br />
perform a digit recognition memory task of increasing complexity. The <br />
SCAN Test has been shown to be of prognostic value.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0085" target="_blank" title="Link to bibliographic citation">85</a>]</li>
<li id="hep27210-li-0021">Electroencephalography<br />
examination can detect changes in cortical cerebral activity across the<br />
spectrum of HE without patient cooperation or risk of a learning <br />
effect.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0070" target="_blank" title="Link to bibliographic citation">70</a>]<br />
However, it is nonspecific and may be influenced by accompanying <br />
metabolic disturbances, such as hyponatremia as well as drugs. Possibly,<br />
the reliability of EEG analysis can increase with quantitative <br />
analysis. This specifically should include the background frequency with<br />
mean dominant frequency or spectral band analysis.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0060" target="_blank" title="Link to bibliographic citation">60</a>]<br />
Also, in most situations, EEG requires an institutional setup and <br />
neurological expertise in evaluation, and the cost varies among <br />
hospitals.</li>
</ol>Although the above-described tests have been used<br />
to test for MHE and CHE, there is, most often, a poor correlation <br />
between them because HE is a multidimensional dysfunction.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0086" target="_blank" title="Link to bibliographic citation">86</a>]<br />
Learning effect is often observed with psychometric tests and it is <br />
unclear whether current HE therapy plays a role in the test performance.<br />
Therefore, interpretation of these tests and consideration of the <br />
results for further management need an understanding of the patient's <br />
history, current therapy, and effect on the patient's daily activities, <br />
if signs of HE are found. For multicenter studies, the diagnosis of MHE <br />
or CHE by consensus should utilize at least two of the current validated<br />
testing strategies: paper-pencil (PHES) and one of the following: <br />
computerized (CRT, ICT, SCAN, or Stroop) or neurophysiological (CFF or <br />
EEG).[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0066" target="_blank" title="Link to bibliographic citation">66</a>]<br />
In the clinical routine or single-center studies, investigators may use<br />
tests for assessing the severity of HE with which they are familiar, <br />
provided that normative reference data are available and the tests have <br />
been validated for use in this patient population.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0066" target="_blank" title="Link to bibliographic citation">66</a>]</section><section id="hep27210-sec-0016"><h3>Laboratory Testing</h3>High blood-ammonia levels alone do not add any diagnostic, staging, or prognostic value in HE patients with CLD.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0087" target="_blank" title="Link to bibliographic citation">87</a>]<br />
However, in case an ammonia level is checked in a patient with OHE and <br />
it is normal, the diagnosis of HE is in question. For ammonia-lowering <br />
drugs, repeated measurements of ammonia may be helpful to test the <br />
efficacy. There may be logistic challenges to accurately measure blood <br />
ammonia, which should be taken into consideration. Ammonia is reported <br />
either in venous, arterial blood, or plasma ammonia, so the relevant <br />
normal should be used. Multiple methods are available, but measurements <br />
should only be employed when laboratory standards allow for reliable <br />
analyses.</section><section id="hep27210-sec-0017"><h3>Brain Scans</h3>Computed<br />
tomography (CT) or magnetic resonance (MR) or other image modality <br />
scans do not contribute diagnostic or grading information. However, the <br />
risk of intracerebral hemorrhage is at least 5-fold increased in this <br />
patient group,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0088" target="_blank" title="Link to bibliographic citation">88</a>]<br />
and the symptoms may be indistinguishable, so a brain scan is usually <br />
part of the diagnostic workup of first-time HE and on clinical suspicion<br />
of other pathology.</section><section id="hep27210-sec-0018"><h3>Recommendations:</h3><b><i>3.<br />
Hepatic encephalopathy should be treated as a continuum ranging from <br />
unimpaired cognitive function with intact consciousness through coma <br />
(GRADE III, A, 1)</i></b>.<br /><br />
<b><i>4. The diagnosis of HE is through exclusion of other causes of brain dysfunction (GRADE II-2, A, 1)</i></b>.<br /><br />
<b><i>5.<br />
Hepatic encephalopathy should be divided into various stages of <br />
severity, reflecting the degree of self-sufficiency and the need for <br />
care (GRADE III, B, 1)</i></b>.<br /><br />
<b><i>6. Overt hepatic <br />
encephalopathy is diagnosed by clinical criteria and can be graded <br />
according the WHC and the GCS (GRADE II-2, B, 1)</i></b>.<br /><br />
<b><i>7.<br />
The diagnosis and grading of MHE and CHE can be made using several <br />
neurophysiological and psychometric tests that should be performed by <br />
experienced examiners (GRADE II-2, B, 1)</i></b>.<br /><br />
<b><i>8. <br />
Testing for MHE and CHE could be used in patients who would most benefit<br />
from testing, such as those with impaired quality of life or <br />
implication on employment or public safety (GRADE III, B, 2)</i></b>.<br /><br />
<b><i>9.<br />
Increased blood ammonia alone does not add any diagnostic, staging, or <br />
prognostic value for HE in patients with CLD. A normal value calls for <br />
diagnostic reevaluation (GRADE II-3, A, 1)</i></b>.</section></section><section id="hep27210-sec-0019"><h2>Treatment</h2><section id="hep27210-sec-0020"><h3>General Principles</h3>At this time, only OHE is routinely treated.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0010" target="_blank" title="Link to bibliographic citation">10</a>]<br />
Minimal hepatic encephalopathy and CHE, as its title implies, is not <br />
obvious on routine clinical examination and is predominantly diagnosed <br />
by techniques outlined in the previous section. Despite its subtle <br />
nature, MHE and CHE can have a significant effect on a patient's daily <br />
living. Special circumstances can prevail where there may be an <br />
indication to treat such a patient (e.g., impairment in driving skills, <br />
work performance, quality of life, or cognitive complaints). Liver <br />
transplantation is mentioned under the treatment recommendations.</section><section id="hep27210-sec-0140"><h3>Recommendations:</h3><b><i>General recommendations for treatment of episodic OHE type C include the following:</i></b><br /><br />
<b><i>10. An episode of OHE (whether spontaneous or precipitated) should be actively treated (GRADE II-2, A, 1)</i></b>.<br /><br />
<b><i>11. Secondary prophylaxis after an episode for overt HE is recommended (GRADE I, A, 1)</i></b>.<br /><br />
<b><i>12.<br />
Primary prophylaxis for prevention of episodes of OHE is not required, <br />
except in patients with cirrhosis with a known high risk to develop HE <br />
(GRADE II-3, C, 2)</i></b>.<br /><br />
<b><i>13. Recurrent intractable OHE, together with liver failure, is an indication for LT (GRADE I)</i></b>.</section><section id="hep27210-sec-0021"><h3>Specific Approach to OHE Treatment</h3><b><i>A four-pronged approach to management of HE is recommended (GRADE II-2, A, 1):</i></b><br /><br />
<b><i>14. Initiation of care for patients with altered consciousness</i></b><br /><br />
<b><i>15. Alternative causes of altered mental status should be sought and treated</i></b>.<br /><br />
<b><i>16. Identification of precipitating factors and their correction</i></b><br /><br />
<b><i>17. Commencement of empirical HE treatment</i></b></section><section id="hep27210-sec-0022"><h3>Comments on Management Strategy</h3>Patients<br />
with higher grades of HE who are at risk or unable to protect their <br />
airway need more intensive monitoring and are ideally managed in an <br />
intensive care setting. Alternative causes of encephalopathy are not <br />
infrequent in patients with advanced cirrhosis. Technically, if other <br />
causes of encephalopathy are present, then the episode of encephalopathy<br />
may not be termed HE. In the clinical setting, what transpires is <br />
treatment of both HE and non-HE.<br /><br />
Controlling precipitating factors<br />
in the management of OHE is of paramount importance, because nearly 90%<br />
of patients can be treated with just correction of the precipitating <br />
factor.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0089" target="_blank" title="Link to bibliographic citation">89</a>] Careful attention to this issue is still the cornerstone of HE management.</section><section id="hep27210-sec-0023"><h3>Therapy for Episodes of OHE</h3>In<br />
addition to the other elements of the four-pronged approach to <br />
treatment of HE, specific drug treatment is part of the management. Most<br />
drugs have not been tested by rigorous randomized, controlled studies <br />
and are utilized based on circumstantial observations. These agents <br />
include nonabsorbable disaccharides, such as lactulose, and antibiotics,<br />
such as rifaximin. Other therapies, such as oral branched-chain amino <br />
acids (BCAAs), intravenous (IV) L-ornithine L-aspartate (LOLA), <br />
probiotics, and other antibiotics, have also been used. In the hospital,<br />
a nasogastric tube can be used to administer oral therapies in patients<br />
who are unable to swallow or have an aspiration risk.<br /><br />
<section id="hep27210-sec-0024"><h4>Nonabsorbable Disaccharides</h4>Lactulose<br />
is generally used as initial treatment for OHE. A large meta-analysis <br />
of trial data did not completely support lactulose as a therapeutic <br />
agent for treatment of OHE, but for technical reasons, it did not <br />
include the largest trials, and these agents continue to be used <br />
widely.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0090" target="_blank" title="Link to bibliographic citation">90</a>]<br />
Lack of effect of lactulose should prompt a clinical search for <br />
unrecognized precipitating factors and competing causes for the brain <br />
impairment. Though it is assumed that the prebiotic effects (the drug <br />
being a nondigestible substance that promotes the growth of beneficial <br />
microorganisms in the intestines) and acidifying nature of lactulose <br />
have an additional benefit beyond the laxative effect, <br />
culture-independent studies have not borne those out.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0075" target="_blank" title="Link to bibliographic citations">75, 91</a>]<br />
In addition, most recent trials on lactulose have been open label in <br />
nature. Cost considerations alone add to the argument in support of <br />
lactulose.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0092" target="_blank" title="Link to bibliographic citation">92</a>] In some centers, lactitol is preferred to lactulose, based on small meta-analyses of even smaller trials.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0093" target="_blank" title="Link to bibliographic citations">93, 94</a>]<br /><br />
In populations with a high prevalence of lactose intolerance, the use of lactose has been suggested.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0095" target="_blank" title="Link to bibliographic citation">95</a>]<br />
However, the only trial to show that stool-acidifying enemas (lactose <br />
and lactulose) were superior to tap-water enemas was underpowered.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0096" target="_blank" title="Link to bibliographic citation">96</a>] The use of polyethylene glycol preparation[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0097" target="_blank" title="Link to bibliographic citation">97</a>] needs further validation.<br /><br />
The dosing of lactulose should be initiated[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0098" target="_blank" title="Link to bibliographic citation">98</a>]<br />
when the three first elements of the four-pronged approach are <br />
completed, with 25 mL of lactulose syrup every 1-2 hours until at least <br />
two soft or loose bowel movements per day are produced. Subsequently, <br />
the dosing is titrated to maintain two to three bowel movements per day.<br />
This dose reduction should be implemented. It is a misconception that <br />
lack of effect of smaller amounts of lactulose is remedied by much <br />
larger doses. There is a danger for overuse of lactulose leading to <br />
complications, such as aspiration, dehydration, hypernatremia, and <br />
severe perianal skin irritation, and overuse can even precipitate HE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0099" target="_blank" title="Link to bibliographic citation">99</a>]</section><section id="hep27210-sec-0025"><h4>Rifaximin</h4>Rifaximin has been used for the therapy of HE in a number of trials[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0100" target="_blank" title="Link to bibliographic citation">100</a>]<br />
comparing it with placebo, other antibiotics, nonabsorbable <br />
disaccharides, and in dose-ranging studies. These trials showed effect <br />
of rifaximin that was equivalent or superior to the compared agents with<br />
good tolerability. Long-term cyclical therapy over 3-6 months with <br />
rifaximin for patients with OHE has also been studied in three trials <br />
(two compared to nonabsorbable disaccharides and one against neomycin) <br />
showing equivalence in cognitive improvement and ammonia lowering. A <br />
multinational study[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0101" target="_blank" title="Link to bibliographic citation">101</a>]<br />
with patients having two earlier OHE bouts to maintain remission showed<br />
the superiority of rifaximin versus placebo (in the background of 91% <br />
lactulose use). No solid data support the use of rifaximin alone.</section><section id="hep27210-sec-0026"><h4>Other Therapies</h4>Many<br />
drugs have been used for treatment of HE, but data to support their use<br />
are limited, preliminary, or lacking. However, most of these drugs can <br />
safely be used despite their limited proven efficacy.</section><section id="hep27210-sec-0027"><h4>BCAAs</h4>An<br />
updated meta-analysis of eight randomized, controlled trials (RCTs) <br />
indicated that oral BCAA-enriched formulations improve the <br />
manifestations of episodic HE whether OHE or MHE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0102" target="_blank" title="Link to bibliographic citations">102, 130</a>] There is no effect of IV BCAA on the episodic bout of HE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0127" target="_blank" title="Link to bibliographic citation">127</a>]</section><section id="hep27210-sec-0028"><h4>Metabolic Ammonia Scavengers</h4>These<br />
agents, through their metabolism, act as urea surrogates excreted in <br />
urine. Such drugs have been used for treatment of inborn errors of the <br />
urea cycle for many years. Different forms are available and currently <br />
present as promising investigational agents. Ornithine phenylacetate has<br />
been studied for HE, but further clinical reports are awaited.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0103" target="_blank" title="Link to bibliographic citation">103</a>] Glyceryl phenylbutyrate (GPB) was tested in a recent RCT[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0104" target="_blank" title="Link to bibliographic citation">104</a>]<br />
on patients who had experienced two or more episodes of HE in the last 6<br />
months and who were maintained on standard therapy (lactulose ± <br />
rifaximin). The GPB arm experienced fewer episodes of HE and <br />
hospitalizations as well as longer time to first event. More clinical <br />
studies on the same principle are under way and, if confirmed, may lead <br />
to clinical recommendations.</section><section id="hep27210-sec-0029"><h4>L-ornithine L-aspartate (LOLA)</h4>An<br />
RCT on patients with persistent HE demonstrated improvement by IV LOLA <br />
in psychometric testing and postprandial venous ammonia levels.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0105" target="_blank" title="Link to bibliographic citation">105</a>] Oral supplementation with LOLA is ineffective.</section><section id="hep27210-sec-0030"><h4>Probiotics</h4>A<br />
recent, open-label study of either lactulose, probiotics, or no therapy<br />
in patients with cirrhosis who recovered from HE found fewer episodes <br />
of HE in the lactulose or probiotic arms, compared to placebo, but were <br />
not different between either interventions. There was no difference in <br />
rates of readmission in any of the arms of the study.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0106" target="_blank" title="Link to bibliographic citation">106</a>]</section><section id="hep27210-sec-0031"><h4>Glutaminase Inhibitors</h4>Portosystemic<br />
shunting up-regulates the intestinal glutaminase gene so that <br />
intestinal glutaminase inhibitors may be useful by reducing the amounts <br />
of ammonia produced by the gut.</section><section id="hep27210-sec-0032"><h4>Neomycin</h4>This antibiotic still has its advocates and was widely used in the past for HE treatment; it is a known glutaminase inhibitor.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0107" target="_blank" title="Link to bibliographic citation">107</a>]</section><section id="hep27210-sec-0150"><h4>Metronidazole</h4>As short-term therapy,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0108" target="_blank" title="Link to bibliographic citation">108</a>]<br />
metronidazole also has advocates for its use. However, long-term <br />
ototoxicity, nephrotoxicity, and neurotoxicity make these agents <br />
unattractive for continuous long-term use.</section><section id="hep27210-sec-0033"><h4>Flumazenil</h4>This<br />
drug is not frequently used. It transiently improves mental status in <br />
OHE without improvement on recovery or survival. The effect may be of <br />
importance in marginal situations to avoid assisted ventilation. <br />
Likewise, the effect may be helpful in difficult differential diagnostic<br />
situations by confirming reversibility (e.g., when standard therapy <br />
unexpectedly fails or when benzodiazepine toxicity is suspected).</section><section id="hep27210-sec-0034"><h4>Laxatives</h4>Simple<br />
laxatives alone do not have the prebiotic properties of disaccharides, <br />
and no publications have been forthcoming on this issue.</section><section id="hep27210-sec-0035"><h4>Albumin</h4>A<br />
recent RCT on OHE patients on rifaximin given daily IV albumin or <br />
saline showed no effect on resolution of HE, but was related to better <br />
postdischarge survival.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0109" target="_blank" title="Link to bibliographic citation">109</a>]</section></section><section id="hep27210-sec-0036"><h3>Recommendations:</h3><b><i>18. Identify and treat precipitating factors for HE (GRADE II-2, A, 1)</i></b>.<br /><br />
<b><i>19. Lactulose is the first choice for treatment of episodic OHE (GRADE II-1, B, 1)</i></b>.<br /><br />
<b><i>20. Rifaximin is an effective add-on therapy to lactulose for prevention of OHE recurrence (GRADE I, A, 1)</i></b>.<br /><br />
<b><i>21.<br />
Oral BCAAs can be used as an alternative or additional agent to treat <br />
patients nonresponsive to conventional therapy (GRADE I, B, 2)</i></b>.<br /><br />
<b><i>22.<br />
IV LOLA can be used as an alternative or additional agent to treat <br />
patients nonresponsive to conventional therapy (GRADE I, B, 2)</i></b>.<br /><br />
<b><i>23. Neomycin is an alternative choice for treatment of OHE (GRADE II-1, B, 2)</i></b>.<br /><br />
<b><i>24. Metronidazole is an alternative choice for treatment of OHE (GRADE II-3, B, 2)</i></b>.</section><section id="hep27210-sec-0037"><h3>Prevention of Overt Hepatic Encephalopathy</h3><section id="hep27210-sec-0038"><h4>After an Episode of OHE</h4>There<br />
are no randomized, placebo-controlled trials of lactulose for <br />
maintenance of remission from OHE. However, it is still widely <br />
recommended and practiced. A single-center, open-label RCT of lactulose <br />
demonstrated less recurrence of HE in patients with cirrhosis.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0033" target="_blank" title="Link to bibliographic citation">33</a>] A recent RCT supports lactulose as prevention of HE subsequent to upper gastrointestinal (GI) bleeding.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0110" target="_blank" title="Link to bibliographic citation">110</a>]<br /><br />
Rifaximin<br />
added to lactulose is the best-documented agent to maintain remission <br />
in patients who have already experienced one or more bouts of OHE while <br />
on lactulose treatment after their initial episode of OHE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0101" target="_blank" title="Link to bibliographic citation">101</a>]</section><section id="hep27210-sec-0039"><h4>Hepatic Encephalopathy After TIPS</h4>Once<br />
TIPS was popularized to treat complications of PH, its tendency to <br />
cause the appearance of HE, or less commonly, intractable persistent HE,<br />
was noted. Faced with severe HE as a complication of a TIPS procedure, <br />
physicians had a major dilemma. Initially, it was routine to use <br />
standard HE treatment to prevent post-TIPS HE. However, one study <br />
illustrated that neither rifaximin nor lactulose prevented post-TIPS HE <br />
any better than placebo.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0111" target="_blank" title="Link to bibliographic citation">111</a>]<br />
Careful case selection has reduced the incidence of severe HE <br />
post-TIPS. If it occurs, shunt diameter reduction can reverse HE.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0112" target="_blank" title="Link to bibliographic citation">112</a>] However, the original cause for placing TIPS may reappear.<br /><br />
Another<br />
important issue with TIPS relates to the desired portal pressure (PP) <br />
attained after placement of stents. Too low a pressure because of large <br />
stent diameter can lead to intractable HE, as noted above. There is a <br />
lack of consensus on whether to aim to reduce PP by 50% or below 12 <br />
mmHg. The latter is associated with more bouts of encephalopathy.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0113" target="_blank" title="Link to bibliographic citation">113</a>]<br />
It is widely used to treat post-TIPS recurrent HE as with other cases <br />
of recurrent HE, including the cases that cannot be managed by reduction<br />
of shunt diameter.</section><section id="hep27210-sec-0040"><h4>Hepatic Encephalopathy Secondary to Portosystemic Shunts (PSSs)</h4>Recurrent<br />
bouts of overt HE in patients with preserved liver function <br />
consideration should lead to a search for large spontaneous PSSs. <br />
Certain types of shunts, such as splenorenal shunts, can be successfully<br />
embolized with rapid clearance of overt HE in a fraction of patients in<br />
a good liver function status, despite the risk for subsequent VB.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0114" target="_blank" title="Link to bibliographic citation">114</a>]</section></section><section id="hep27210-sec-0041"><h3>Recommendations:</h3><b><i>25. Lactulose is recommended for prevention of recurrent episodes of HE after the initial episode (GRADE II-1, A, 1)</i></b>.<br /><br />
<b><i>26.<br />
Rifaximin as an add-on to lactulose is recommended for prevention of <br />
recurrent episodes of HE after the second episode (GRADE I, A, 1)</i></b>.<br /><br />
<b><i>27.<br />
Routine prophylactic therapy (lactulose or rifaximin) is not <br />
recommended for the prevention of post-TIPS HE (GRADE III, B, 1)</i></b>.<br /><br />
<section id="hep27210-sec-0042"><h4>Discontinuation of Prophylactic Therapy</h4>There<br />
is a nearly uniform policy to continue treatment indefinitely after it <br />
has successfully reversed a bout of OHE. The concept may be that once <br />
the thresholds for OHE is reached, then patients are at high risk for <br />
recurrent episodes. This risk appears to worsen as liver function <br />
deteriorates. However, what often occurs are recurrent bouts of OHE from<br />
a well-known list of precipitating factors. If a recurrent <br />
precipitating factor can be controlled, such as recurrent infections or <br />
variceal hemorrhages, then HE recurrence may not be a risk and HE <br />
therapy can be discontinued. Even more influential on the risk for <br />
further bouts of OHE is overall liver function and body habitus. If <br />
patients recover a significant amount of liver function and muscle mass <br />
from the time they had bouts of OHE, they may well be able to stop <br />
standard HE therapy. There are very little data on this issue, but tests<br />
positive for MHE or CHE before stopping HE drug therapy will predict <br />
patients at risk for recurrent HE.</section></section><section id="hep27210-sec-0043"><h3>Recommendation:</h3><b><i>28.<br />
Under circumstances where the precipitating factors have been well <br />
controlled (i.e., infections and VB) or liver function or nutritional <br />
status improved, prophylactic therapy may be discontinued (GRADE III, C,<br />
2)</i></b>.</section><section id="hep27210-sec-0044"><h3>Treatment of Minimal HE and Covert HE</h3>Although<br />
it is not standard to offer therapy for MHE and CHE, studies have been <br />
performed using several modes of therapy. The majority of studies have <br />
been for less than 6 months and do not reflect the overall course of the<br />
condition. Trials span the gamut from small open-label trials to <br />
larger, randomized, controlled studies using treatments varying from <br />
probiotics, lactulose, and rifaximin. Most studies have shown an <br />
improvement in the underlying cognitive status, but the mode of <br />
diagnosis has varied considerably among studies. A minority of studies <br />
used clinically relevant endpoints. It was shown, in an open-label <br />
study,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0115" target="_blank" title="Link to bibliographic citation">115</a>]<br />
that lactulose can prevent development of the first episode of OHE, but<br />
the study needs to be replicated in a larger study in a blinded fashion<br />
before firm recommendations can be made. Studies using lactulose and <br />
rifaximin have shown improvement in quality of life[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0034" target="_blank" title="Link to bibliographic citations">34, 116</a>] and also in driving simulator performance.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0117" target="_blank" title="Link to bibliographic citation">117</a>]<br />
Probiotics have also been used, but the open-label nature, varying <br />
amounts and types of organisms, and different outcomes make them <br />
difficult to recommend as therapeutic options at this time.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0118" target="_blank" title="Link to bibliographic citations">118-121</a>]<br /><br />
Because<br />
of the multiple methods used to define MHE and CHE, varying endpoints, <br />
short-term treatment trials, and differing agents used in trials to <br />
date, routine treatment for MHE is not recommended at this stage. <br />
Exceptions could be made on a case-by-case basis using treatments that <br />
are approved for OHE, particularly for patients with CHE and West Haven <br />
Grade I HE.</section><section id="hep27210-sec-0045"><h3>Recommendation:</h3><b><i>29. Treatment of MHE and CHE is not routinely recommended apart from a case-by-case basis (GRADE II-2, B, 1)</i></b>.</section><section id="hep27210-sec-0046"><h3>Nutrition</h3>Modulation<br />
of nitrogen metabolism is crucial to the management of all grades of <br />
HE, and nutritional options are relevant. Detailed recent guidelines for<br />
nutrition of patients with HE are given elsewhere.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0122" target="_blank" title="Link to bibliographic citation">122</a>]<br />
Malnutrition is often underdiagnosed, and approximately 75% of patients<br />
with HE suffer from moderate-to-severe protein-calorie malnutrition <br />
with loss of muscle mass and energy depots. Chronic protein restriction <br />
is detrimental because patients' protein requirements are relatively <br />
greater than that of healthy patients and they are at risk of <br />
accelerated fasting metabolism. Malnutrition and loss of muscle bulk is a<br />
risk factor for development of HE and other cirrhosis complications. <br />
Sarcopenia has been proven to be an important negative prognostic <br />
indicator in patients with cirrhosis.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0123" target="_blank" title="Link to bibliographic citations">123, 124</a>]<br />
All HE patients should undergo an assessment of nutritional status by <br />
taking a good dietary history, with anthropometric data and muscle <br />
strength measurement as practical, useful measures of nutritional <br />
status. In the undressed patient, particular attention is paid to the <br />
muscle structures around the shoulders and gluteal muscles. Pitfalls are<br />
water retention and obesity. Although body mass index is rarely <br />
helpful, the height-creatinine ratio may be useful, as well as the <br />
bioimpedance technique. More advanced techniques, such as dual-energy <br />
X-ray absorptiometry/CT/MR, are rarely useful for clinical purposes. The<br />
patient should undergo a structured dietary assessment, preferably by a<br />
dietician, or other specially trained staff. The majority of HE <br />
patients will fulfill criteria for nutritional therapy. The therapy is <br />
refeeding by moderate hyperalimentation, as indicated below. Small meals<br />
evenly distributed throughout the day and a late-night snack[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0125" target="_blank" title="Link to bibliographic citation">125</a>]<br />
should be encouraged, with avoidance of fasting. Glucose may be the <br />
most readily available calorie source, but should not be utilized as the<br />
only nutrition. Hyperalimentation should be given orally to patients <br />
that can cooperate, by gastric tube to patients who cannot take the <br />
required amount, and parenterally to other patients. The nutrition <br />
therapy should be initiated without delay and monitored during <br />
maintenance visits. The use of a multivitamin is generally recommended, <br />
although there are no firm data on the benefits of vitamin and mineral <br />
supplementation. Specific micronutrient replacement is given if there <br />
are confirmed measured losses, and zinc supplementation is considered <br />
when treating HE. If Wernicke's is suspected, large doses of thiamine <br />
should be given parenterally and before any glucose administration. <br />
Administration of large amounts of nonsaline fluids should be adjusted <br />
so as to avoid induction of hyponatremia, particularly in patients with <br />
advanced cirrhosis. If severe hyponatremia is corrected, this should be <br />
done slowly.<br /><br />
There is consensus that low-protein nutrition should <br />
be avoided for patients with HE. Some degree of protein restriction may <br />
be inevitable in the first few days of OHE treatment, but should not be <br />
prolonged. Substitution of milk-based or vegetable protein or <br />
supplementing with BCAAs is preferable to reduction of total protein <br />
intake. Oral BCAA-enriched nutritional formulation may be used to treat <br />
HE and generally improves the nutritional status of patients with <br />
cirrhosis,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0126" target="_blank" title="Link to bibliographic citation">126</a>] but IV BCAA for an episode of HE has no effect.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0127" target="_blank" title="Link to bibliographic citation">127</a>] The studies on the effect of oral BCAA have been more encouraging[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0128" target="_blank" title="Link to bibliographic citations">128, 129</a>] and confirmed by a recent meta-analysis of 11 trials.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0130" target="_blank" title="Link to bibliographic citation">130</a>]<br />
Ultimately, the effects of these amino acids may turn out to have more <br />
important effects on promotion of maintenance of lean body mass than a <br />
direct effect on HE.</section><section id="hep27210-sec-0047"><h3>Recommendations:</h3><b><i>30. Daily energy intakes should be 35-40 kcal/kg ideal body weight (GRADE I, A, 1)</i></b>.<br /><br />
<b><i>31. Daily protein intake should be 1.2-1.5 g/kg/day (GRADE I, A, 1)</i></b>.<br /><br />
<b><i>32.<br />
Small meals or liquid nutritional supplements evenly distributed <br />
throughout the day and a late-night snack should be offered (GRADE I, A,<br />
1)</i></b>.<br /><br />
<b><i>33. Oral BCAA supplementation may allow <br />
recommended nitrogen intake to be achieved and maintained in patients <br />
intolerant of dietary protein (GRADE II-2, B, 2)</i></b>.</section><section id="hep27210-sec-0048"><h3>Liver Transplantation (LT)</h3>Liver<br />
transplantation remains the only treatment option for HE that does not <br />
improve on any other treatment, but is not without its risks. The <br />
management of these potential transplant candidates as practiced in the <br />
United States has been published elsewhere,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0131" target="_blank" title="Link to bibliographic citations">131, 132</a>]<br />
and European guidelines are under way. Hepatic encephalopathy by itself<br />
is not considered an indication for LT unless associated with poor <br />
liver function. However, cases do occur where HE severely compromises <br />
the patient's quality of life and cannot be improved despite maximal <br />
medical therapy and who may be LT candidates despite otherwise good <br />
liver status. Large PSSs may cause neurological disturbances and <br />
persistent HE, even after LT. Therefore, shunts should be identified and<br />
embolization considered before or during transplantation.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0133" target="_blank" title="Link to bibliographic citation">133</a>] Also, during the transplant workup, severe hyponatremia should be corrected slowly.<br /><br />
Hepatic<br />
encephalopathy should improve after transplant, whereas <br />
neurodegenerative disorders will worsen. Therefore, it is important to <br />
distinguish HE from other causes of mental impairment, such as <br />
Alzheimer's disease and small-vessel cerebrovascular disease. Magnetic <br />
resonance imaging and spectroscopy of the brain should be conducted, and<br />
the patient should be evaluated by an expert in neuropsychology and <br />
neuro-degenerative diseases.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0134" target="_blank" title="Link to bibliographic citation">134</a>]<br />
The patient, caregivers, and health professionals should be aware that <br />
transplantation may induce brain function impairment and that not all <br />
manifestations of HE are fully reversible by transplantation.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0135" target="_blank" title="Link to bibliographic citation">135</a>]<br /><br />
One<br />
difficult and not uncommon problem is the development of a confusional <br />
syndrome in the postoperative period. The search of the cause is often <br />
difficult, and the problem may have multiple origins. Patients with <br />
alcoholic liver disease (ALD) and those with recurrent HE before <br />
transplantation are at higher risk. Toxic effects of immunosuppressant <br />
drugs are a frequent cause, usually associated with tremor and elevated <br />
levels in blood. Other adverse cerebral effects of drugs may be <br />
difficult to diagnose. Confusion associated with fever requires a <br />
diligent, systematic search for bacterial or viral causes (e.g., <br />
cytomegalovirus). Multiple causative factors are not unusual, and the <br />
patient's problem should be approached from a broad clinical view.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0136" target="_blank" title="Link to bibliographic citation">136</a>]</section><section id="hep27210-sec-0049"><h3>Economic/Cost Implications</h3>As<br />
outlined under epidemiology, the burden of HE is rapidly increasing and<br />
more cases of HE will be encountered, with substantial direct costs <br />
being attributed to hospitalizations for HE and to indirect costs. The <br />
patients with HE hospitalized in the United States in 2003 generated <br />
charges of approximately US$ 1 billion.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0040" target="_blank" title="Link to bibliographic citations">40, 137</a>]<br />
Resource utilization for this group of patients is also increasing as a<br />
result of longer lengths of stay and more complex and expensive <br />
hospital efforts, as well as a reported in-patient mortality of 15%. <br />
There are no directly comparable EU cost data, but by inference from <br />
epidemiological data, the event rate should be approximately the same <br />
and the costs comparable, differences between U.S. and EU hospital <br />
financing notwithstanding. These costs are an underestimate, because <br />
out-patient care, disability and lost productivity, and the negative <br />
effect on the patient's family or support network were not quantified.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0138" target="_blank" title="Link to bibliographic citation">138</a>]<br /><br />
The<br />
cost of medications is very variable to include in analyses because it <br />
varies widely from country to country and are usually determined by what<br />
the pharmaceutical companies believe the market can sustain. Regarding <br />
the beneficial effects of rifaximin, cost-effective analyses based on <br />
current drug prices favor treatments that are lactulose based,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0092" target="_blank" title="Link to bibliographic citations">92, 139</a>] as do analyses of accidents, deaths/morbidity, and time off from work[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0073" target="_blank" title="Link to bibliographic citation">73</a>]<br />
in patients with MHE or CHE. Therefore, until the costs of other <br />
medications fall, lactulose continues to be the least expensive, most <br />
cost-effective treatment.</section></section><section id="hep27210-sec-0050"><h2>Alternative Causes of Altered Mental Status</h2><section id="hep27210-sec-0051"><h3>Disorders to Be Considered</h3>The<br />
neurological manifestations of HE are nonspecific. Therefore, <br />
concomitant disorders have to be considered as an additional source of <br />
central nervous system dysfunction in any patient with CLD. Most <br />
important are renal dysfunction, hyponatremia, diabetes mellitus (DM), <br />
sepsis, and thiamine deficiency (Wernicke's encephalopathy); noteworthy <br />
also is intracranial bleeding (chronic subdural hematoma and parenchymal<br />
bleeding).</section><section id="hep27210-sec-0052"><h3>Interaction Between Concomitant Disorders and Liver Disease With Regard to Brain Function</h3>Hyponatremia is an independent risk factor for development of HE in patients with cirrhosis.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0140" target="_blank" title="Link to bibliographic citations">140, 141</a>] The incidence of HE increases[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0142" target="_blank" title="Link to bibliographic citation">142</a>] and the response rate to lactulose therapy decreases[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0143" target="_blank" title="Link to bibliographic citation">143</a>] with decreasing serum sodium concentrations.<br /><br />
Diabetes<br />
mellitus has been suggested as a risk factor for development of HE, <br />
especially in patients with hepatitis C virus (HCV) cirrhosis,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0144" target="_blank" title="Link to bibliographic citation">144</a>] but the relationship may also be observed in other cirrhosis etiologies.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0145" target="_blank" title="Link to bibliographic citation">145</a>]<br /><br />
An increased risk to develop HE has also been shown in patients with cirrhosis with renal dysfunction,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0146" target="_blank" title="Link to bibliographic citation">146</a>] independent of the severity of cirrhosis.<br /><br />
Neurological symptoms are observed in 21%-33% of patients with cirrhosis with sepsis and in 60%-68% of those with septic shock.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0147" target="_blank" title="Link to bibliographic citation">147</a>]<br />
Patients with cirrhosis do not differ from patients without cirrhosis <br />
regarding their risk to develop brain dysfunction with sepsis,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0148" target="_blank" title="Link to bibliographic citation">148</a>] although it is assumed that systemic inflammation and hyperammonemia act synergistically with regard to the development of HE.<br /><br />
Thiamine<br />
deficiency predominantly occurs in patients with ALD, but may also <br />
occur as a consequence of malnutrition in end-stage cirrhosis of any <br />
cause. The cerebral symptoms disorientation, alteration of <br />
consciousness, ataxia, and dysarthria cannot be differentiated as being <br />
the result of thiamine deficiency or hyperammonemia by clinical <br />
examination.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0149" target="_blank" title="Link to bibliographic citation">149</a>] In any case of doubt, thiamine should be given IV before glucose-containing solutions.</section><section id="hep27210-sec-0053"><h3>Effect of the Etiology of the Liver Disease Upon Brain Function</h3>Data<br />
upon the effect of the underlying liver disease on brain function are <br />
sparse, except for alcoholism and hepatitis C. Rare, but difficult, <br />
cases may be the result of Wilson's disease.<br /><br />
Even patients with alcohol disorder and no clinical disease have been shown to exhibit deficits in episodic memory,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0150" target="_blank" title="Link to bibliographic citation">150</a>] working memory and executive functions,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0151" target="_blank" title="Link to bibliographic citation">151</a>] visuoconstruction abilities,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0152" target="_blank" title="Link to bibliographic citation">152</a>] and upper- and lower-limb motor skills.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0153" target="_blank" title="Link to bibliographic citation">153</a>]<br />
The cognitive dysfunction is more pronounced in those patients with <br />
alcohol disorder who are at risk of Wernicke's encephalopathy as a <br />
result of malnutrition or already show signs of the problem.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0154" target="_blank" title="Link to bibliographic citation">154</a>]<br />
Thus, it remains unclear whether the disturbance of brain function in <br />
patients with ALD is the result of HE, alcohol toxicity, or thiamine <br />
deficiency.<br /><br />
There is mounting evidence that HCV is present and replicates within the brain.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0155" target="_blank" title="Link to bibliographic citations">155-158</a>] Approximately half of HCV patients suffer chronic fatigue irrespective of the grade of their liver disease,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0159" target="_blank" title="Link to bibliographic citations">159, 160</a>] and even patients with only mild liver disease display cognitive dysfunction,[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0161" target="_blank" title="Link to bibliographic citations">161, 162</a>]<br />
involving verbal learning, attention, executive function, and memory. <br />
Likewise, patients with primary biliary cirrhosis and primary sclerosing<br />
cholangitis may have severe fatigue and impairment of attention, <br />
concentration, and psychomotor function irrespective of the grade of <br />
liver disease.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0163" target="_blank" title="Link to bibliographic citations">163-168</a>]</section><section id="hep27210-sec-0054"><h3>Diagnostic Measures to Differentiate Between HE and Cerebral Dysfunction Resulting From Other Causes</h3>Because<br />
HE shares symptoms with all concomitant disorders and underlying <br />
diseases, it is difficult in the individual case to differentiate <br />
between the effects of HE and those resulting from other causes. In some<br />
cases, the time course and response to therapy may be the best support <br />
of HE. As mentioned, a normal blood ammonia level in a patient suspected<br />
of HE calls for consideration. None of the diagnostic measures used at <br />
present has been evaluated for their ability to differentiate between HE<br />
and other causes of brain dysfunction. The EEG would not be altered by <br />
DM or alcohol disorders, but may show changes similar to those with HE <br />
in cases of renal dysfunction, hyponatremia, or septic encephalopathy. <br />
Psychometric tests are able to detect functional deficits, but are <br />
unable to differentiate between different causes for these deficits. <br />
Brain imaging methods have been evaluated for their use in diagnosing <br />
HE, but the results are disappointing. Nevertheless, brain imaging <br />
should be done in every patient with CLD and unexplained alteration of <br />
brain function to exclude structural lesions. In rare cases, <br />
reversibility by flumazenil may be useful.</section></section><section id="hep27210-sec-0055"><h2>Follow-up</h2>After a hospital admission for HE, the following issues should be addressed.<br /><br />
<section id="hep27210-sec-0056"><h3>Discharge From Hospital</h3><ol id="hep27210-list-0014"><li id="hep27210-li-0052">The<br />
medical team should confirm the neurological status before discharge <br />
and judge to what extent the patient's neurological deficits could be <br />
attributable to HE, or to other neurological comorbidities, for <br />
appropriate discharge planning. They should inform caregivers that the <br />
neurological status may change once the acute illness has settled and <br />
that requirement for medication could change.</li>
<li id="hep27210-li-0053">Precipitating<br />
and risk factors for development of HE should be recognized. Future <br />
clinical management should be planned according to (1) potential for <br />
improvement of liver function (e.g., acute alcoholic hepatitis, <br />
autoimmune hepatitis, and hepatitis B), (2) presence of large <br />
portosystemic shunts (which may be suitable for occlusion), and (3) <br />
characteristics of precipitating factors (e.g., prevention of infection,<br />
avoidance of recurrent GI bleeding, diuretics, or constipation).</li>
<li id="hep27210-li-0054">Out-patient<br />
postdischarge consultations should be planned to adjust treatment and <br />
prevent the reappearance of precipitating factors. Close liaison should <br />
be made with the patient's family, the general practitioner, and other <br />
caregivers in the primary health service, so that all parties involved <br />
understand how to manage HE in the specific patient and prevent repeated<br />
hospitalizations.</li>
</ol></section><section id="hep27210-sec-0057"><h3>Preventive Care After Discharge</h3><ol id="hep27210-list-0015"><li id="hep27210-li-0055">Education<br />
of patients and relatives should include (1) effects of medication <br />
(lactulose, rifaximin, and so on) and the potential side effects (e.g., <br />
diarrhea), (2) importance of adherence, (3) early signs of recurring HE,<br />
and (4) actions to be taken if recurrence (e.g., anticonstipation <br />
measures for mild recurrence and referral to general practitioner or <br />
hospital if HE with fever).</li>
<li id="hep27210-li-0056">Prevention of <br />
recurrence: the underlying liver pathology may improve with time, <br />
nutrition, or specific measures, but usually patients who have developed<br />
OHE have advanced liver failure without much hope for functional <br />
improvements and are often potential LT candidates. Managing the <br />
complications of cirrhosis (e.g., spontaneous bacterial peritonitis and <br />
GI bleeding) should be instituted according to available guidelines. <br />
Pharmacological secondary prevention is mentioned above.</li>
<li id="hep27210-li-0057">Monitoring<br />
neurological manifestations is necessary in patients with persisting HE<br />
to adjust treatment and in patients with previous HE to investigate the<br />
presence and degree of MHE or CHE or signs of recurring HE. The <br />
cognitive assessment depends on the available normative data and local <br />
resources. The motor assessment should include evaluation of gait and <br />
walking and consider the risk of falls.</li>
<li id="hep27210-li-0058">The<br />
socioeconomic implications of persisting HE or MHE or CHE may be very <br />
profound. They include a decline in work performance, impairment in <br />
quality of life, and increase in the risk of accidents. These patients <br />
often require economic support and extensive care from the public social<br />
support system and may include their relatives. All these issues should<br />
be incorporated into the follow-up plan.</li>
<li id="hep27210-li-0059">Treatment<br />
endpoints depend on the monitoring used and the specialist clinic, but <br />
at least they have to cover two aspects: (1) cognitive performance <br />
(improvement in one accepted test as a minimum) and (2) daily life <br />
autonomy (basic and operational abilities).</li>
<li id="hep27210-li-0060">Nutritional<br />
aspects: weight loss with sarcopenia may worsen HE, and, accordingly, <br />
the nutritional priority is to provide enough protein and energy to <br />
favor a positive nitrogen balance and increase in muscle mass, as <br />
recommended above.</li>
<li id="hep27210-li-0061">Portosystemic shunt: occlusion of a dominant shunt may improve HE in patients with recurring HE and good liver function.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0114" target="_blank" title="Link to bibliographic citation">114</a>] Because the current experience is limited, the risks and benefits must be weighed before employing this strategy.</li>
</ol></section></section><section id="hep27210-sec-0058"><h2>Suggestions for Future Research</h2>This<br />
section deals with research into the management of HE. However, such <br />
research should always be based on research into the pathophysiology of <br />
HE. It is necessary to gain more insight into which liver functions are <br />
responsible for maintenance of cerebral functions, which alterations in <br />
intestinal function and microbiota make failure of these liver functions<br />
critical, which brain functions are particularly vulnerable to the <br />
combined effects of the aforementioned events, and, finally, which <br />
factors outside this axis that result in the emergence of HE (e.g., <br />
inflammation, endocrine settings, or malnutrition). Therefore, the <br />
research fields into pathophysiology and clinical management should <br />
remain in close contact. Such collaboration should result in new causal <br />
and symptomatic treatment modalities that need and motivate clinical <br />
trials.<br /><br />
There is a severe and unmet need for controlled clinical <br />
trials on treatment effects on all the different forms of HE. Decisive <br />
clinical studies are few, although the number of patients and their <br />
resource utilization is high. There are no data on which factors and <br />
patients represent the higher costs, and research is needed to examine <br />
the effect of specific cirrhosis-related complications. At present, <br />
there is an insufficient basis for allocating resources and establishing<br />
priority policies regarding management of HE. Many drugs that were <br />
assessed for HE several decades ago were studied following a standard of<br />
care that, at present, is obsolete. Any study of treatment for HE <br />
should be reassessed or repeated using the current standard of care. It <br />
is critical to develop protocols to identify precipitating factors and <br />
ACLF. The benefit of recently assessed drugs is concentrated in the <br />
prevention of recurrence, and there is a large need for trials on <br />
episodic HE.<br /><br />
There is also an unmet need for research into <br />
diagnostic methods that is necessary to form a basis for clinical <br />
trials. The diagnosis of MHE and CHE has received enormous interest, but<br />
it is still not possible to compare results among studies and the <br />
precision should be improved. It may be useful to develop, validate, and<br />
implement HE scales that combine the degree of functional liver failure<br />
and PSS with more than one psychometric method.<br /><br />
One important <br />
area of uncertainty is whether the term CHE, which was introduced to <br />
expand MHE toward grade I of oriented patients, is informative and <br />
clinically valuable. This needs to be evaluated by a data-driven <br />
approach. Likewise, the distinction between isolated liver failure and <br />
ACLF-associated HE should be evaluated by independent data.<br /><br />
A <br />
closer scientific collaboration between clinical hepatologists and <br />
dedicated brain researchers, including functional brain imaging experts,<br />
is needed. Likewise, neuropsychologists and psychiatrists are needed to<br />
clarify the broad spectrum of neuropsychiatric symptoms that can be <br />
observed in patients with liver disease. Syndrome diagnoses should be <br />
more precisely classified and transformed into classifiable entities <br />
based on pathophysiology and responding to the requirements of clinical <br />
hepatology practice and research.<br /><br />
Future studies should fill our <br />
gaps in knowledge. They should be focused on assessing the effects of HE<br />
on individuals and society, how to use diagnostic tools appropriately, <br />
and define the therapeutic goals in each clinical scenario (Table <a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-tbl-0007" target="_blank" title="Link to table">7</a>).<br /><br />
<div><table id="hep27210-tbl-0007" style="margin-left: 0px; margin-right: 0px; text-align: left;"><caption>Table 7. Suggested Areas of Future Research in HE</caption><thead>
<tr><th>Aspect</th><th>Need</th><th>Suggestions</th></tr>
</thead><tbody>
<tr><td>Effect on individuals and society</td><td>Demonstrate the effects of HE on patients and society in order to encourage diagnosis and therapy</td><td>1. Studies on economic and social burden among different societies<br /><br />
2. Studies on cultural aspects on therapy and compliance with treatment<br /><br />
3. Long-term natural history studies</td></tr>
<tr><td>Diagnostic improvement</td><td>Enhance the diagnostic accuracy</td><td>1.<br />
Studies on clinically applicable high-sensitivity screening tests that <br />
can guide which patients may benefit from dedicated testing<br /><br />
2. Development of algorithms to decide when and how to apply the diagnostic process<br /><br />
3. Studies on competing factors (i.e., HCV, delirium, depression, and narcotic use on diagnosis)<br /><br />
4. Studies on biomarkers for presence and progression of neurological dysfunction</td></tr>
<tr><td>Treatment goals</td><td>Improve the appropriate use of therapeutic tools in different clinical scenarios</td><td>1. Studies on selecting who will benefit from preventing the first OHE episode<br /><br />
2. Studies for >6 months to evaluate compliance and continued effects on cognitive improvement<br /><br />
3. Develop protocols focused on how to diagnose and treat precipitating factors<br /><br />
4. Determine what should be the standard protocol to investigate new therapies<br /><br />
5. Decide which therapies have been adequately studied and are not a priority for additional studies</td></tr>
</tbody></table></div><section id="hep27210-sec-0059"><h3>Recommendations on Future Research in HE</h3>The<br />
existing literature suffers from a lack of standardization, and this <br />
heterogeneity makes pooling of data difficult or meaningless. <br />
Recommendations to promote consistency across the field have been <br />
published by ISHEN.[<a href="http://onlinelibrary.wiley.com/enhanced/doi/10.1002/hep.27210/#hep27210-bib-0066" target="_blank" title="Link to bibliographic citation">66</a>] Following is a synopsis of the recommendations.</section><section id="hep27210-sec-0060"><h3>Trials in Patients With Episodic OHE</h3><ol id="hep27210-list-0016"><li id="hep27210-li-0062">Patients who are not expected to survive the hospitalization, who are terminally ill or have ACLF should be excluded.</li>
<li id="hep27210-li-0063">A detailed standard-of-care algorithm must be agreed upon <i>a priori</i> and must be instituted and monitored diligently throughout the trial.</li>
<li id="hep27210-li-0064">Patients<br />
should not be entered into trials until after the institution of <br />
optimal standard-of-care therapy and only if their mental state <br />
abnormalities persist.</li>
<li id="hep27210-li-0065">Provided the <br />
optimal standard of care is instituted and maintained, the treatment <br />
trial can be initiated earlier if they include a placebo comparator; <br />
this would allow an evaluation of the trial treatment as an adjuvant to <br />
standard therapy.</li>
<li id="hep27210-li-0066">Large-scale, multicenter<br />
treatment trials should be evaluated using robust clinical outcomes, <br />
such as in-hospital and remote survival, liver-related and total deaths,<br />
completeness and speed of recovery from HE, number of days in intensive<br />
care, total length of hospital stay, quality-of-life measures, and <br />
associated costs. Markers for HE, such as psychometric testing, can be <br />
employed if standardized and validated tools are available in all <br />
centers. Individual centers can utilize additional, accessible, <br />
validated markers if they choose.</li>
<li id="hep27210-li-0067">Proof-of-concept<br />
trials will additionally be monitored using tools that best relate to <br />
the endpoints anticipated or expected; this may involve use of neural <br />
imaging or measurement of specific biomarkers.</li>
</ol></section><section id="hep27210-sec-0061"><h3>Trials in Patients With MHE or CHE</h3>Trials in this population should be randomized and placebo controlled. <br /><br />
<ol id="hep27210-list-0017"><li id="hep27210-li-0068">Patients receiving treatment for OHE or those with previous episodes of OHE should be excluded.</li>
<li id="hep27210-li-0069">In<br />
single-center or proof-of-concept studies, investigators may use tests <br />
for assessing the severity of HE with which they are familiar, provided <br />
that normative reference data are available and the tests have been <br />
validated for use in this patient population.</li>
<li id="hep27210-li-0070">Further<br />
information is needed on the interchangeability and standardization of <br />
tests to assess the severity of HE for use in multicenter trials. As an <br />
interim, two or more of the current validated tests should be used and <br />
applied uniformly across centers.</li>
</ol></section></section></div>xar126http://www.blogger.com/profile/18156479389972587139noreply@blogger.com1tag:blogger.com,1999:blog-4276174933280603731.post-39456326026880484482014-07-31T09:49:00.001-07:002014-07-31T09:49:39.383-07:00Resuscitation in the ED: Beyond the ABCs<div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;"><em style="border: 0px; font-family: inherit; font-size: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;"><a href="http://www.mountsinai.org/profiles/reuben-strayer" style="border: 0px; color: #1f0909; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank"><br class="Apple-interchange-newline" />Reuben Strayer, MD</a>, assistant clinical professor of emergency medicine at Mount Sinai Hospital in New York City, shares his expanded resuscitation mnemonic for the critical first 5 minutes. This talk originally appeared on </em><a href="http://emupdates.com/2014/07/03/the-first-five-minutes-of-resuscitation/" style="border: 0px; color: #1f0909; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">EMupdates.com</a><em style="border: 0px; font-family: inherit; font-size: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;"> and is lightly edited here.</em><em style="border: 0px; font-family: inherit; font-size: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;"> We last featured a talk by Strayer from AAEM 2014 about <a href="http://www.medpagetoday.com/EmergencyMedicine/EmergencyMedicine/44833" style="border: 0px; color: #1f0909; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">10 ways to safely push ketamine in the ED</a>.</em></div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Approaching a critically ill patient can be nerve-racking, and when your nerves are racked it can be hard to remember what to do. However, when you remember what to do, your nerves get less racked. So, I'm going to present a top-down approach to resuscitation that uses an expanded ABC's mnemonic to jog your memory and unrack your nerves:</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;"><strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">DC3, A through J</strong></div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">For many years now, I go through this sequence in my head every time I'm confronted with a critically ill patent, and it makes me calm and organized, and a better doctor.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;"><strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">D for Danger</strong></div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Danger to you the provider. Is it safe to approach the patient? In the emergency department this usually means protecting yourself from body fluid or airborne infectious diseases. Occasionally, there may be other concerns like the patient having something dangerous on their clothes or skin requiring decontamination. We deal with agitated or potentially violent patients all the time.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Like many of these bullet points, this is a talk unto itself, but from the perspective of resuscitation, if a critically ill patient is too agitated to be properly assessed, it is an absolutely crucial lifesaving maneuver to immediately and aggressively sedate.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">There are a variety of effective agents I recommend: Droperidol, midazolam, and ketamine. If an IV is not yet available the agents should be given IM or IO.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;"><strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">C3</strong></div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">The first C in C3 is "<strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Call for help</strong>," move the patient to resus, call for your defibrillator, crash cart, airway cart, or whatever else is indicated. In big centers, you generally want more nurses and tech than usually show up and fewer doctors than usually show up.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Now that everyone is in the room you have to get them to be quiet. The second C is "<strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Calm</strong>." Noise and shouting raise the ambient catecholamine level which makes it harder to take care of the patient. A forceful "Quiet please!" is usually all that's necessary to take everyone down a few notches. In big centers, there are usually too many people in the resus room when the patient arrives. Big resus cases are good for learning and occasionally someone in the peanut gallery has a good idea -- occasionally -- so I don't like to ask folks to leave the room.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Get them away from the action by announcing something like, "If you are not directly taking care of the patient please move to the perimeter of the room." If there is an orthopedist hanging out, he won't know the word "perimeter," so try "Please move away from the bed."</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">This is the time to determine who the resus leader is; if you're not sure, maybe it's you. All right, now that we've established the conditions in which the patient can be properly resuscitated, it's time to resuscitate the patient.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">The third C in C3 stands for "<strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Cardiac Arrest.</strong>" Cardiac arrest has to be recognized straight away and is surprisingly easy to miss especially in a patient who arrives intubated by EMS. The first two priorities in cardiac arrest are<a href="http://www.ncbi.nlm.nih.gov/pubmed/20956217" style="border: 0px; color: #1f0909; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">immediate uninterrupted high-quality chest compressions</a> and defibrillation of v-fib and pulseless v-tach.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;"><strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Cardinal ABCs</strong></div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Now, we start in with the cardinal ABCs and A is of course "<strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Airway</strong>." Our question is whether the patient needs an airway intervention. To answer this question, start with the patient's voice. The patient speaking comfortably with a normal voice is very unlikely to require an airway maneuver in the immediate term. Patients who are not speaking, demonstrate a patent and defended airway by handling their secretions.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Drooling and gurgling, coughing and gagging, are your clue that you may have an airway problem. But do not elicit a gag reflex as a way to test airway integrity. It's inaccurate and may induce vomiting and is exactly the person you do not want to vomit. Stridor is another sign and patients with a good level of consciousness and an airway obstruction may assume an airway posture, which is sniffing position.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Sometimes, the patient just needs repositioning of the head<strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">,</strong> but this is also the time to suction out the oropharynx, place oral or nasal airways or even an LMA if indicated, and determine if intubation is required or soon will be. If so, call for medications if needed and prepare for definitive airway management.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Move on to "<strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Breathing</strong>," which is oxygenation and ventilation. Do yourself and patients a favor and put a nasal cannula on every critically ill patient from the start and then any additional oxygen or ventilation on top of that. Unless the patient is truly crashing, I apply the nasal cannula and keep the wall-oxygen off until I get a room air oxygen saturation, which provides much more information about oxygenation and ventilation than a saturation with supplemental oxygen.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Ventilate the patient if needed. Your initial exam maneuvers are pulse oximetry, respiratory rate, effort, and then breath sounds. Auscultating the lungs is a reflex action taken by many junior clinicians as a response to a distressed patient. I think that's because it makes it seem like you're doing something when you don't know what to do. In most cases, listening to the lungs is not helpful and is always less important than evaluating oxygenation and ventilation using respiratory effort and saturation. What you're listening for is air entering both sides, and the presence of wheezes or crackles. This should take no longer than seven second -- 3.5 seconds per lung.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Therapies to consider in the first five minutes relevant to breathing include needle finger or tube or ostomy, albuterol, epinephrine, or nitro. Call for a portable chest x-ray if indicated.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">The initial <strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">"Circulation"</strong> priorities include immediate establishment of either intravenous or intraosseous access, measurement of heart rate and blood pressure, which is usually accomplished by putting a patient on a monitor, and the assessment of the adequacy of perfusion, feel for pulses, and assess the skin at the hands and feet. Immediate therapies to support circulation include IV fluids and uncrossed matched blood products and call for EKG when indicated.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;"><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126683/" style="border: 0px; color: #1f0909; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">Hyperkalemia is so common</a> and <a href="http://www.ncbi.nlm.nih.gov/pubmed/18936701" style="border: 0px; color: #1f0909; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">so dangerous</a> it should specifically be considered in a primary survey. C can also stand for "<strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Calcium</strong>" in a critically ill dialysis patient with bradycardia or a wide complex rhythm.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;"><strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">D for Neurologic Disability</strong></div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">In the first phase of resuscitation, this calls for four maneuvers. Assessment of level of consciousness, usually using a responsiveness scale like GCS as well as the quality of the patient's mentation. Agitation or confusion are as important as decreased consciousness. Measure the pupils and their response to light. Determine movement at four extremities and rule out or treat hyperglycemia.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">We don't have a problem with getting to do head CTs, but to be complete I must mention that this is the time to consider a STAT brain scan.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;"><strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">E for Exposure</strong></div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Remove all clothing. And visualize every inch of skin. It is ideal if you can get this done at the initial assessment. It really sucks when the ICU team comes down and pulls the nitro patch off your hypotensive patient. Have someone check the pocket for pill bottles, the pacemaker wallet card, or a summary of their medical history. Use the opportunity to do a rectal temp if needed, and initiate active cooling or warming if indicated.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;"><strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">F Stands for Family and friends</strong></div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">If the history isn't clear, get a better story. Ask about goals of care, if appropriate. Give the patient's family an update on a patient's status within a cautious prognosis. If you say, "I'm very concerned about grandma," and she does well that's not a big problem. In fact, it makes you look like a very skillful doctor. If you say, "Grandma is doing great," and the next time the family sees her they have to unzip a body bag, you're not going to get a rave review on Healthgrades.com. If the family is outside the resus area, ask them if they wish to be <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1203366" style="border: 0px; color: #1f0909; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">present during the resuscitation</a>.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;"><strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">G Is for Analgesia</strong></div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Do not forget to treat your patient's pain. I have looked back at many resuscitations and realized the only thing I did that actually helped the patient was morphine. Give it early and in appropriate doses: IV, IM or IO. If hypertension is a concern use fentanyl. If you don't have a line in a child, intranasal fentanyl is very effective. And for the patient in severe pain, adding an analgesic dose of ketamine is magic.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;"><strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">H Is for HCG</strong></div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">This is easy to forget and <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3730371/" style="border: 0px; color: #1f0909; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">pregnancy changes everything</a>. The bedside urine HCG assay works just as well with two drops of whole blood or capillary blood from a finger stick. In the clearly gravid female who is hypotensive, push the uterus to the left, And if she is dying or dead, consider a perimortem C-section. Don't worry about how many weeks or how many minutes mom has been arrested -- perimortem cesarean section is for mom more than for baby.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;"><strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">I Is for Infection</strong></div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Consider whether the patient should be isolated, and do not delay the administration of broad spectrum antibiotics in a patient thought to be critically ill from an infection. If source control is required, this needs to be done expeditiously.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;"><strong style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">J Is for Ultrasound Jel</strong></div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">The last part of the first 5 minutes is ultrasound. Let me know if you have a better way of getting the word ultrasound to work with the letter J. All patients with hypotension of unclear etiology should have a comprehensive point of care ultrasound for shock. There is an ever expanding list of indications of point of care ultrasound. Get the <a href="http://www.ncbi.nlm.nih.gov/pubmed/20825919" style="border: 0px; color: #1f0909; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">probe on the chest early in a critically ill patient</a>.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">There is another C I left out: If you are using a mnemonic to study for oral board exams, add one more C after Cardiac Arrest -- as in C for spine immobilization collars. These have <a href="http://www.ncbi.nlm.nih.gov/pubmed/22962052" style="border: 0px; color: #1f0909; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">minimal if any utility in few, if any patients, and certainly cause harm</a>, but we're probably a long way away from standard of care catching up to science in this domain. So if you're resuscitating a patient while wearing your best suit seated uncomfortably in a hotel across from somebody with gray hair who doesn't want to be there any more than you, add a C for C spine precautions.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">In real life for the first 5 minutes of resuscitation: DC3, A through J.</div><div><br /></div>Le Chathttp://www.blogger.com/profile/16652437603050138213noreply@blogger.com0tag:blogger.com,1999:blog-4276174933280603731.post-89511694892083732342014-07-31T09:47:00.001-07:002014-07-31T09:47:24.601-07:00Vitamin D Blog: Nutrient or Hormone?<div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Few people view their vitamin D supplement as hormone replacement therapy, but that's exactly what it is, experts told <em style="border: 0px; font-family: inherit; font-size: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">MedPage Today</em>.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">The weight of the literature suggests that vitamin D is indeed a hormone, not a nutrient, said <a href="http://www.bumc.bu.edu/endo/faculty/holick/" style="border: 0px; color: #1f0909; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">Michael Holick, MD, PhD</a>, of Boston University.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">"By definition, vitamin D is a hormone," Holick told <em style="border: 0px; font-family: inherit; font-size: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">MedPage Today</em>. "The body synthesizes it after sun exposure, and it's activated by the liver and kidneys. That activated form again acts like a hormone to regulate calcium metabolism."</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">No other vitamin goes through the process of activation that D does before it can be used by the body, Holick said. First, the skin must synthesize vitamin D3, or cholecalciferol, after exposure to UVB radiation. D3 is then metabolized by the liver into 25-hydroxyvitamin D, or 25(OH)D, and then moves on to the kidney where it is converted to the biologically active form 1,25-dihydroxyvitamin D, or 1,25(OH)<span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">2</span>D.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">"D3 is the prohormone, 25(OH)D is the major circulating form, and 1,25(OH)<span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">2</span>D is the hormonally active form," Holick said, adding that vitamins A and C do get metabolized, but they don't need to be activated the way D does.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">But vitamin D's status as a hormone rather than a nutrient raises questions about the way companies use it to fortify foods, said <a href="http://steinhardt.nyu.edu/faculty_bios/view/Marion_Nestle" style="border: 0px; color: #1f0909; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">Marion Nestle, PhD, MPH</a>, a food policy expert from New York University.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Nestle recently submitted comments to the FDA on its <a href="http://www.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinformation/labelingnutrition/ucm385663.htm#Summary" style="border: 0px; color: #1f0909; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">proposed changes to the Nutrition Facts</a> panel on foods, arguing that companies shouldn't be permitted to tout vitamin D fortification without more context or details.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">"Vitamin D fortification must be understood as a form of hormone replacement therapy," <a href="http://www.foodpolitics.com/2014/07/fdas-food-label-proposals-comments-on-vitamin-d/" style="border: 0px; color: #1f0909; font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">Nestle wrote on her blog</a>. "As such, it raises questions about efficacy, dose, and side effects that should be asked about all such therapies."</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">She notes that D is found naturally in very few foods -- fish is one exception -- and even then it only exists in small quantities.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">"It is present in most foods as a result of fortification," she said.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">Holick disagreed that its status as a hormone should give people pause over vitamin D supplementation, because D deficiency affects such a large proportion of the population. Thus, a national hormone replacement therapy program would only provide benefit, he said.</div><div style="border: 0px; color: #1f0909; font-family: 'PT Serif'; font-size: 16px; line-height: 24px; margin-bottom: 1.5em; padding: 0px; vertical-align: baseline;">"It's reasonable to have on the label," Holick said, "because everyone should be taking steps to increase their vitamin D intake." Though Holick's prescription is simpler -- 15 minutes a day in the sun should do the trick for sufficiency.</div><div><br /></div>Le Chathttp://www.blogger.com/profile/16652437603050138213noreply@blogger.com0