Drug-Induced Liver Injury Guidelines Released by ACG

Medscape Medical News

Janis C. Kelly
June 18, 2014

Drug-induced liver injury is among the most challenging disorders for gastroenterologists to diagnose and treat, but the American College of Gastroenterology has issued new clinical guidelines to help physicians and other healthcare providers manage this disorder. The guidelines were published online June 17 in the American Journal of Gastroenterology.

Lead author Naga P. Chalasani, MD, writing on behalf of the ACG Practice Parameters Committee, presented an evidence-based approach to diagnosing and managing DILI, "with special emphasis on DILI due to herbal and dietary supplements and DILI occurring in individuals with underlying liver disease."

"[Herbal and dietary supplement] hepatotoxicity has received increasing attention over the past few years, in part owing to the recognition in the United States that among DILI cases HDS are the second most common cause," the authors write.

The authors stress that DILI is a diagnosis of exclusion and requires careful history-taking and workup for possible competing etiologies. "Accurate history of medication exposure and onset and course of liver biochemistry abnormalities is crucial," Dr. Chalasani, who is chief of the Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, said in a news release.

DILI is commonly categorized as intrinsic (because of drugs that predictably cause liver injury in humans or in animal models, such as acetaminophen) and idiosyncratic (affecting only susceptible individuals, having less-consistent dosage relationship, and more varied in presentation). "Despite its low incidence in the general population, gastroenterologists must always consider the possibility of DILI in patients with unexplained acute and chronic liver injury, as well as when prescribing certain gastrointestinal medications (e.g., azathioprine, anti-tumor necrosis factor agents, sulfonamides). Many herbal and dietary supplements...can cause DILI, and thus they must be considered as a cause for DILI," the authors write.

The clinical guideline provides an algorithm for evaluation of suspected DILI, which progresses from abnormal liver enzymes to thorough history and physical with complete review of medications and herbal and dietary supplements, to calculation of the R-value (serum alanine aminotransferase/upper limit of normal divided by serum alkaline phosphatase/upper limit of normal). The guidelines present separate diagnostic pathways for patients with hepatocellular (R ≤ 5), mixed (2 < R < 5), or cholestatic (R ≤ 2) types of liver damage.

According to the guidelines, liver biopsy can help confirm suspected DILI and should be considered if autoimmune hepatitis is a possible factor and if immunosuppressives are under consideration. Indications for biopsy include unrelenting risk in liver biochemistries or worsening liver function despite stopping the suspected drug; continued peak alanine aminotransferase elevation, if continued exposure or reexposure to the implicated agent is expected; and evaluating for chronic liver disease if liver biochemistry remains abnormal beyond 180 days.

Usual Clinical Tool May Underestimate Risk for Herbal/Diet Supplements

The Roussel Uclaf Causality Assessment Method (RUCAM) scale is widely used for assessing causality in suspected DILI, and the authors warn it might lead to underestimation of risks associated with herbal or dietary supplements. The authors write, "In the RUCAM, the presence of a labeled warning of hepatotoxicity increases the score; as warnings typically do not exist on [herbal or dietary supplement] labels, the highest score could rarely be awarded."

"A lot of consumers have a preconceived notion that if it's a natural product, it must be safe. But that is not necessarily the case," coauthor Herbert Bonkovsky, MD, said in the news release. "Most of these products are not well-regulated and have very little oversight. Traces of heavy metals and prescription drugs have even been found in some herbal and dietary supplements. We encourage patients to talk to their doctor about all medications they are taking, and herbal and dietary supplements should be no exception." Dr. Bonkovsky is professor of medicine and senior advisor for research, Carolinas HealthCare System, Charlotte, North Carolina.

The guidelines include a table of the most common over-the-counter and prescription drugs and supplements that cause DILI, and their usual patterns of liver injury. The table lists antibiotics (amoxicillin/clavulanate is the most commonly associated with DILI) and herbal and dietary supplements.

Green tea extract tops the list of herbal and dietary supplements associated with liver damage. According to Dr. Bonkovsky, the average cup of green tea has around 50 to 150 mg catechins, whereas some green tea extract pills (commonly used for weight loss) have catechin levels more than 700 mg and may be taken multiple times a day.

For more information, the National Institutes of Health has a free database of drugs associated with liver injury, available on their Web site.

Dr. Chalasani has served as a consultant to and received financial compensation from Boehringer Ingelheim, Abbvie, Aegerion, Salix, Bristol-Myers Squibb, and Lilly. He has research support from Cumberland Pharmaceuticals, Intercept Pharmaceuticals, Gilead, and Galectin Pharmaceuticals. Dr. Bonkovsky has served as a consultant and received financial compensation from Alnylam and Clinuvel. He has received research support from Clinuvel, Merck, the National Institutes of Health (National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases), and Vertex. One coauthor has served as a consultant to Glaxo-SmithKline. Another coauthor has served as a consultant to and received financial compensation from Lilly and Novartis and receives research support from Anadys, Bristol-Myers Squibb, Boehringer Ingelheim, Cumberland, Gilead, Vertex, Ocera, and Merck. Another coauthor has received grant support from Gilead and Vertex and served as a paid consultant to Tibotec, Merck, and GlaxoSmithKline.

Am J Gasterenterol. Published online June 17, 2014. Abstract

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Liver dangers from herbal supplements, OTC and RX drugs, new guidelines warn

Provided by ScienceDaily

Date: June 17, 2014

Source: American College of Gastroenterology (ACG)

Summary: New clinical guidelines on the diagnosis and management of idiosyncratic drug-induced liver injury (DILI) have now been released. DILI is a rare adverse drug reaction, challenging to diagnose, and can lead to jaundice, liver failure and even death. The frequency of DILI incidence is increasing, as the use of herbal and dietary supplements has drastically increased over the last 10 years.

New clinical guidelines on the diagnosis and management of idiosyncratic drug-induced liver injury (DILI) appear in the July issue of The American Journal of Gastroenterology. DILI is a rare adverse drug reaction, challenging to diagnose, and can lead to jaundice, liver failure and even death. The frequency of DILI incidence is increasing, as the use of herbal and dietary supplements has drastically increased over the last 10 years.

The new guidelines from the American College of Gastroenterology, intended for use by physician and other health-care providers, include an overview of risk factors, diagnosis evaluation and causality assessment, prognosis factors, and management of hepatotoxicity due to pre-existing chronic liver disease or herbal/dietary supplement intake. One of the key focuses of the guidelines is on herbal and dietary supplements, which many doctors warn should be used with caution.

"A lot of consumers have a preconceived notion that if it's a natural product, it must be safe. But that is not necessarily the case," said Herbert Bonkovsky, MD, FACG, co-author of the guidelines. "Most of these products are not well-regulated and have very little oversight. Traces of heavy metals and prescription drugs have even been found in some herbal and dietary supplements. We encourage patients to talk to their doctor about all medications they are taking, and herbal and dietary supplements should be no exception."

The guidelines include a table of the most common over-the-counter and prescription drugs and supplements that cause DILI, and their usual patterns of liver injury. The table lists antibiotics (amoxicillin/clavulanate is the most commonly associated with DILI) and herbal and dietary supplements.

Of the herbal and dietary supplements, green tea extract tops the list as one of the most common dietary supplements associate with DILI injury. To give context, Dr. Bonkovsky says that the average cup of green tea has around 50-150 mgs of catechins, a group of polyphenols that are the major active ingredients. In some green tea extract pills, known to help with weight loss and other factors, the levels of such catechins can be over 700 mg. This can be particularly dangerous when the pills are taken multiple times a day.

It is important to note that DILI remains a "diagnosis of exclusion," which underscores the importance of patients giving their doctors a full history of all medications and supplement use. "Accurate history of medication exposure and onset and course of liver biochemistry abnormalities is crucial," says lead guideline author Naga P. Chalasani, MD, FACG.

Story Source:

The above story is based on materials provided by American College of Gastroenterology (ACG). Note: Materials may be edited for content and length.

Journal Reference:

1. Naga P Chalasani, Paul H Hayashi, Herbert L Bonkovsky, Victor J Navarro, William M Lee, Robert J Fontana. ACG Clinical Guideline: The Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury. The American Journal of Gastroenterology, 2014; DOI: 10.1038/ajg.2014.131

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Also See: Drug-Induced Liver Injury Guidelines Released by ACG

Antidepressant-Induced Liver Injury Underestimated

Medscape Medical News > Psychiatry

Megan Brooks

December 31, 2013

All antidepressant drugs may potentially cause liver injury, even at recommended doses, and some groups are more vulnerable than others, French researchers report.

"Antidepressant liver toxicity has been underestimated in the scientific literature," say Gabriel Perlemuter, MD, PhD, from AP-HP Hôpital Bicêtre, Kremlin-Bicêtre, France, and colleagues.

In some cases, antidepressant-induced liver injury can be irreversible. Given that there currently is no strategy available to prevent antidepressant-induced liver injury, "early detection and prompt drug discontinuation remain critical," they say.

Their research was published online December 20 in theAmerican Journal of Psychiatry.

Liver Injury Unpredictable

The investigators reviewed clinical data on antidepressant-induced liver injury from 158 reports, including 88 case reports, 38 original articles, and 32 reviews.

They calculate that 0.5% to 3% of patients treated with antidepressants may develop asymptomatic mild elevation of serum alanine aminotransferase (ALT) levels.

In most cases, liver damage is "idiosyncratic and unpredictable, and it is generally unrelated to drug dosage," they say. Liver damage may occur between several days and 6 months after initiation of an antidepressant.

All antidepressants can induce hepatotoxicity, especially in elderly patients and those who take multiple pharmaceutical agents. However, there is not enough evidence to draw "rigorous conclusions" about the prevalence and severity of antidepressant-induced liver injury, the investigators say.

Based on the evidence, the antidepressants associated with highest risk for hepatotoxicity are monoamine oxidase (MAO) inhibitors, tricyclic/tetracyclic antidepressants, nefazodone, bupropion, duloxetine, and agomelatine. Those with seemingly lower risks are citalopram, escitalopram, paroxetine, and fluvoxamine.

Life-threatening or severe drug-induced liver injury has been reported for some antidepressants, including MAO inhibitors, tricyclic/tetracyclic antidepressants, venlafaxine, duloxetine, sertraline, bupropion, nefazodone, trazodone, and agomelatine, Dr. Perlemuter and colleagues report.

Although no dose-response relationship has been clearly demonstrated, it is best to stick to the minimum effective dosages of antidepressants to reduce the risk for liver injury, they advise.

Use With Caution

Dr. Perlemuter and colleagues say that antidepressants with a higher potential for hepatotoxicity "should be used with caution in elderly patients, in patients with coprescriptions, and in patients with substantial alcohol use, illicit substance use, or evidence of chronic liver disease."

"Systematic pretherapeutic screening and regular assessment of hepatic enzymes during treatment may be useful for antidepressants with a high potential for hepatotoxicity and for patients with known risk factors," they add.

It is also important to tell patients taking an antidepressant about the possibility of liver abnormalities, to encourage them to report any clinical symptoms suggestive of liver problems, and to stop treatment if jaundice develops, the researchers say.

Antidepressants "should be discontinued immediately" in any patient with suspected drug-induced liver injury, they write.

Dr. Perlemuter has received travel funds from Janssen, Gilead, and Roche, consulting fees from Bayer, Biocodex, Physiogenex, and Servier, and royalties from Elsevier-Masson. The original article contains a complete list of author disclosures.

Am J Psychiatry. Published online December 20, 2013. Abstract

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Drug-Induced Liver Injury Is On the Rise

Provided by the American Gastroenterological Association

Bethesda, MD (June 26, 2013) — More people are being affected by drug-induced liver injury (DILI) than ever before, according to a new study in Gastroenterology, the official journal of the American Gastroenterological Association. This type of liver injury results from the use of certain prescription and over-the-counter medications, as well as dietary supplements, and is among the more challenging forms of liver disease due to its difficulty to predict, diagnose and manage.

Investigators conducted a population-based study in Iceland uncovering 19.1 cases of drug-induced liver injury per 100,000 inhabitants, per year. These results are significantly higher than the last population-based study of this kind, conducted in France from 1997-2000, which reported 13.9 cases per 100,000 inhabitants, per year.

The most commonly implicated drugs were amoxicillin-clavulante (penicillin used to fight bacteria), azathioprine (an immunosuppressive drug used in organ transplantation and autoimmune diseases) and infliximab (also used to treat autoimmune disease).

“Drug-induced liver injury is not a single, uncommon disease of the general population, but rather a series of rare diseases that occur only in persons who take specific medications,” said Einar S. Björnsson, lead study author from the department of internal medicine, section of gastroenterology and hepatology, National University Hospital, Reykjavik, Iceland, and faculty of medicine at the University of Iceland. “Our study identified which medications put patients most at risk for developing liver diseases. With this information, physicians can better monitor and manage patients who are prescribed potentially liver-injuring drugs.”

The study also showed that drug-induced liver injury was caused by a single prescription medication in 75 percent of cases, by dietary supplements in 16 percent and by multiple agents in 9 percent. Further, the incidence was similar in women and men, but increased with age; not surprising since the need for medication also increases with age.

Jaundice and other symptoms highly suggestive of liver injury, such as itching, nausea, abdominal discomfort and lethargy, were present in the majority of patients. Most patients had a favorable outcome after receiving care.

For more, watch Dr. Björnsson discuss his research in a Gastroenterology video abstract.

About the AGA Institute

The American Gastroenterological Association is the trusted voice of the GI community. Founded in 1897, the AGA has grown to include 17,000 members from around the globe who are involved in all aspects of the science, practice and advancement of gastroenterology. The AGA Institute administers the practice, research and educational programs of the organization. www.gastro.org.

About Gastroenterology 

Gastroenterology, the official journal of the AGA Institute, is the most prominent scientific journal in the specialty and is in the top 1 percent of indexed medical journals internationally. The journal publishes clinical and basic science studies of all aspects of the digestive system, including the liver and pancreas, as well as nutrition. The journal is abstracted and indexed in Biological Abstracts, Current Awareness in Biological Sciences, Chemical Abstracts, Current Contents, Excerpta Medica, Index Medicus, Nutrition Abstracts and Science Citation Index. For more information, visit www.gastrojournal.org.

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