Showing posts with label toxicity. Show all posts
Showing posts with label toxicity. Show all posts

Wednesday, October 17, 2018

Combination immunotherapy may increase liver injury risk

Combination immunotherapy may increase liver injury risk
October 17, 2018
PHILADELPHIA – Patients who received treatment with multiple immunotherapy drugs had increased risks for drug-induced liver injury compared with single therapy courses, as presented at the American College of Gastroenterology Annual Meeting.

“This is a rather new subsection of drug-induced liver injury that has come to our attention since the advent of immunotherapy drugs in the treatment of various different cancers, ranging from metastatic melanoma ... to colorectal cancer and renal cell carcinoma,” Vivek Bose, MD, from the Rutgers Robert Wood Johnson Medical Group in New Jersey, said during his presentation. 

Healio Meeting Coverage
See more from American College of Gastroenterology Annual Meeting

Tuesday, January 9, 2018

Healio - Herbal, dietary supplement-induced liver injury more common in young women

Herbal, dietary supplement-induced liver injury more common in young women
Medina-Cáliz I, et al. Clin Gastroenterol Hepatol. 2017;doi:10.1016/j.cgh.2017.12.051.
January 9, 2018

Analysis of the Spanish Drug-Induced Liver Injury registry showed that cases of herbal and dietary supplement-induced liver injury were more common in young women than older patients or men and correlated with hepatocellular injury and high levels of transaminases.

“Herbal and dietary supplement-induced liver injury is an increasing healthcare problem,” Inmaculada Medina-Cáliz, PhD, from the University of Málaga, Spain, and colleagues wrote. “In contrast to medicinal products including Traditional Herbal Medicinal Products which are regulated in the European Union with regard to efficacy, safety and quality standards, the lack of regulation of ‘natural’ dietary supplemental products, together with the limited awareness of physicians and consumers about possible harmful effects of these supplements, reflect the need for research and reporting in this field.”

Saturday, November 11, 2017

Psoriasis tied to higher risk of serious liver disease

Psoriasis tied to higher risk of serious liver disease
Last Updated: 2017-11-10
By Lisa Rapaport

(Reuters Health) - People with chronic inflammatory disorders like psoriasis and rheumatoid arthritis may have an increased risk of developing serious liver damage, a recent study suggests.

These inflammatory disorders are often treated with methotrexate, a medication linked to an increased risk of liver disease. For the current study, researchers followed more than 1 million people for an average of six years to see how having conditions like psoriasis or rheumatoid arthritis - and taking methotrexate - influenced the odds of developing serious liver disorders.

Compared to people without chronic inflammatory diseases, people with psoriasis were 37% more likely to develop liver disorders. When psoriasis patients took methotrexate, they had roughly twice the odds of liver damage.

With psoriatic arthritis, the increased risk of liver disease was 38% without drug therapy and 67% with methotrexate. For rheumatoid arthritis, there was no increased risk of liver disease when people took methotrexate, but when they didn't they had 49% higher odds of liver damage.


J Invest Dermatol 2017.

Sunday, August 27, 2017

Easy Learning With Yogi - 2017 Drug-Induced Liver Injury Conference For Patients

2017 Drug-Induced Liver Injury Conference
June 6-7, 2017
Hi folks, recently a very nice person on Twitter asked if I will be attending the AASLD 2017 meeting, I smiled when I read the message, thinking they would never let me in. I'm just a woman who had HCV, always a patient first, with a passion to pass on information to my readers. However, for a moment I envisioned myself meeting the ever so handsome Ira M. Jacobson. The good doctor is my hero! But how might it all end? Badly. In my state of excitement, I'll attempt to say something clever, I am clever by the way, but under pressure, not so much.

Anyhoo, after coming down to earth, a tweet from @AASLD came through announcing content from the 2017 Drug-Induced Liver Injury Conference is ready to read over at the AASLD website. Off I went to see what I could see - for you and me.

What About The Conference?
In June, experts in clinical hepatology and toxicology gathered to share current information about drug-induced liver injury (DILI). For people outside the medical profession, navigating around this incredible information is time consuming, maybe even boring, unless you know where to look . So with that said, for those of you living with liver disease or viral hepatitis, I have highlighted a few points of interest to share with you.

Learning With Yogi

Well, on second thought, all the great information coming out of the conference isn't boring, some information is even pretty entertaining, for instance this presentation:
Diagnosing DILI in Patients with Active or Advanced Underlying  Liver Disease (with a little help from Yogi)

Download PDF

So What About HBV Reactivation Associated with HCV Therapy? 
Yep, the conference covered that too. After PDF download, scroll down to the following topics: Reactivation of Hepatitis B in Trials with Immune Suppressive Drug and Detecting, and Evaluating Drug-Induced Liver Injury DILI with Active or Advanced Liver Disease; here is a quick summary.

Opening First Session - Tuesday 6 June 2017

Download PDF
Reactivation of Hepatitis B in Trials with Immune Suppressive Drug
Rajender Reddy
Lastly, I want to talk briefly about what's been going on in the hepatitis C field where there's been hepatitis B reactivation reported in the context of DAA therapy.

Detecting, Evaluating Drug-Induced Liver Injury DILI with Active or Advanced Liver Disease
Jim Lewis
Just to finish up.  The non-DILI causes of jaundice and other events are more common than we think.  Remember, DILI is uncommon.  It's a rare event, but so many other things are more common. People get viral hepatitis, they have gallstone diseases, they have all of the other things that are listed here, all of which confuse someone who's looking at abnormal liver tests.

Of Interest
12 Detection and Management of DILI in NASH/NAFLD
Subjects – Naga Chalasani
As the NAFLD field has heated up, it has come up quite frequently that DILI is more common in patients with NAFLD. How do you monitor for it, given that there are baseline fluctuations in liver chemistries?
LINK - Begin here......

Easy Reading
Abstract I-6_2017: Detection and Evaluation of DILI in Patients with Chronic Liver Disease.
Download Abstract
The specific issue of detecting acute liver injury in patients with underlying chronic liver disease (CLD)  and assigning causality to diagnose DILI remains challenging. The 2009 FDA Guidance FDA detecting and managing hepatotoxicity in patients in clinical trials did not provide any specifics in terms of dealing with patients with CLD. Recent clinical trials evaluating various therapies in patients with chronic hepatitis B, hepatitis C, NAFLD, PBC, malignancy  (with hepatic metastases), among other disorders face the very real issue of assessing hepatic events in the setting of underlying liver disease, which brings with it a potentially different set of rules. As a result, clinicians and drug manufacturers have had to utilize what Dr Senior refers to as “medical reasoning” in order to determine if DILI has occurred, and how usual stopping rules should be modified using the currently available causality assessment methods. The topic at hand can be divided into the historical past, the present and the future.
LINK - Continue reading....

More Easy Reading
Session IV - Consortia for Best Practices to Reduce DILI
General Discussion of Issues [PDF]
4.1 The IQ Initiative
 # 8. And we're all familiar with those areas.  Patients with pre-existing liver diseases are very poorly covered by existing guidelines, and there are many questions regarding how to address drug-induced liver injury in these patients.  It includes Hepatitis C, B, and NASH, and so on. Specific populations such as pediatric populations, geriatric population, oncology patients are, again, not well covered by existing guidelines or guidance or position papers.  Non-hepatocellular DILI is a big topic.  We are almost entirely focused on hepatocellular DILI, but there are 15 other types of drug-induced liver injury that we are not addressing. Specific drug groups are a big issue, such as immunosuppressant drugs, the group of chemotherapy-related immunotherapy.  The question of drug re-challenge that is repeatedly being addressed, but there's no strong, clear guidelines for drug developers. And finally, the huge question of biomarkers is an ongoing question.

We All Know About This Website
4.4 LiverTox update and prospects
Okay, I was asked to give an update on LiverTox, which is an online website dedicated to drug-induced liver disease.  It's been a collaborative effort between NIDDK and the National Library of Medicine, and is meant to be a source of reliable information on the clinical features, courses, and outcomes, and perhaps management of drug-induced liver disease due to both prescription and non-prescription medications, to herbal and dietary supplements. And its aims are to advance knowledge and support research.

 # 8. So how did we come up with a list of drugs to be included in this?  There's no one place that I know that you can go to that lists all the drugs that are available in the United States.  We began with a list provided by the, ah, it's not a pointer, provided by the National Library of Medicine, a computerized list of 28,000 drugs, which was a little bit frightening at the time. But actually, most of them were multiples, like acetaminophen, there were over 1,000 drugs that include acetaminophen.  There were unfortunately 700 varieties of OxyContin that you can purchase in America.  So we took out all the duplicates, and we got down to a total of about 2,800 different compounds, chemical compounds.

And then going through those one at a time, we excluded those that were topical agents only.  We excluded those that were very special.  There were some like vaccines, plasma products, drugs that are not prescribed but are given in very rare situations.  And also we took out veterinary medications and took out drugs that were not approved in the United States. 

We came down with an initial master list of 900 different drugs, which was seen to be achievable.  But in the interim, we've added more, we've added some HDS products, and we've added new agents as they're approved by the FDA each year, # 9. We currently have on my master list about 1236 agents.  And as I said before, 1124 are on the website as of last week. 

So here it is again, 1124 agents, about 91% of those on my list, master list.  And if we take out the herbals and the nutritional supplements, the metals and so forth, we end up with around 1,000 different prescribed drugs.  And looking those, there are some that are really similar, and you can group them together. For instance, all the estrogens we group as estrogens.  All the anabolic steroids.  Some drugs are actually just isomers of each other, like esomeprazole and omeprazole.  We come down to what I think is about 941 different drugs.
LINK - Check Out LIVERTOX Website

4.7 Chinese DILIN experience
# 2. And as we all know, the incidence of DILI in the general population is not very high.  The data from the United States suggests it's less 20 in 100 individuals.  The data suggests the older the age, the higher the incidence.  But one of the most important reasons behind this is the more prescriptions in older people.

# 3. Also, it is not so frequent in the general population.  But in clinical practice, DILI is one of the most common reasons for no-cause liver injury or for a no-cause liver disease because the drug can cause all kinds of liver injury we have ever known. # 4. Some countries have reported their data.  For example, the data from the United States and the European countries,
the most frequent agent to cause DILI is antibiotics.  However, in the Asia region, like Korea or Singapore, the most frequent agent is herbals or the traditional Chinese medicines, TCMs.
LINK - Review above topics, download general discussion here....

Better yet, jump over the AASLD website and sift through vast amounts of information.

Enjoy the rest of your weekend! Bye Ira.

Monday, May 15, 2017

Which Patients Are at Greatest Risk From Mushroom Poisoning?

Which Patients Are at Greatest Risk From Mushroom Poisoning?
Kristine Novak

Almost 20% of patients with liver damage from mushroom (Amanita) poisoning and peak levels of total bilirubin greater than 2 mg/dL require liver transplantation or die, researchers report in the May issue of Clinical Gastroenterology and Hepatology.

The authors show that peak level of aspartate aminotransferase (AST) below 4000 IU/L identifies patients who can be safely monitored in a local hospital, whereas patients with levels of bilirubin >2 mg/dL or AST >4000 IU/L should be transferred to a liver transplant center. Women and older patients were more likely to have a poor outcome than men and younger patients.

Acute liver failure after toxic mushroom ingestion is a significant problem worldwide and in the United States. The genus Amanita accounts for more than 90% of fatal mushroom poisonings. Although exposures to toxic mushrooms often cause no or only mild symptoms, some patients develop severe hepatic necrosis and fulminant hepatic failure.

There has been no reliable system to differentiate between patients who can be safely treated at a local hospital vs those that require transfer to a transplant center.

Friday, August 8, 2014

Watch: Drug-Induced Liver Injury

Drug-Induced Liver Injury

As summer heats up, so do I. Now, where did I put that trashy romance novel? You too?

In any event, whatever your pleasure, check out ....

Clinical Liver Disease Special Summer Issue: Drug-Induced Liver Injury

Clinical Liver Disease (CLD) is a great starting point for anyone interested in learning more about hepatitis C and liver disease. The journal is a product of the AASLD and published every two months. Topics in the July issue include; liver injury caused by dietary supplements, acetaminophen overdose, and drug-induced liver injury in Chinese herbal medicine, to name a few.

The reader will find articles with full-text audio, and other interactive content for a pleasant viewing and listening experience.

Although, unlike my novel "Valley Of Love Under The Bridge To Nowhere" the journal is void of any real romance, no heart-pounding sizzle or fantasy, only facts, not even a swoon.

I did however have a romantic moment with Dr. Maddukuri, after viewing his video with Dr. Bonkovsky. The good doctors summarize their May 2014 publication; Herbal and dietary supplement hepatotoxicity.

After finishing the video, I was rather surprised at myself. In the end, a very distinguished Dr. Bonkovsky won my heart, I was moved when he inquired about liver injury, and green tea extracts. Its the little things that matter.

Tonight, while drinking iced coffee, and reading Fifty Shades of Grey, I will let myself fondly remember Dr. Bonkovsky.

Herbal and dietary supplements (HDS) include vitamins, minerals, herbs or other plant materials, and some can cause hepatotoxicity. HDS hepatotoxicity has risen almost threefold over the past decade, read more to learn what to look for....

Clinical Liver Disease
Special Issue: Drug-Induced Liver Injury (DILI)
Volume 4, Issue 1, pages 1–3, July 2014
Begin here....

Until next time, stay healthy.

Thursday, June 26, 2014

Linking Herbal Supplements with Liver Injury

Linking Herbal Supplements with Liver Injury

Despite the perceived safety of herbal and dietary supplements, they can cause serious liver injury. In the July issue of Clinical Gastroenterology and Hepatology, Simona Rossi and Victor J. Navarro discuss the scope, use, and regulation of herbal and dietary supplements, as well as the diagnosis of herbal and dietary supplement-induced liver injury.

Patients take dietary supplements for many reasons, including anxiety, obesity, diabetes, rheumatoid arthritis, cancer, cardiovascular disease, and pain.

Almost a quarter of patients enrolled in a long-term hepatitis C treatment trial reported using herbal and dietary supplements.

Rossi and Navarro explain that the ease of access to these supplements allows consumers to assume that they are safe and can be used without consequences. Most patients do not divulge use of dietary supplements to health care providers.

However, in the US National Health and Nutrition Examination Survey, 52% of respondents reported using a dietary supplement, and other surveys have reported even higher use. In some Asian and African countries, up to 80% of the population use herbal supplements as their primary means of medical care.

Rossi and Navarro discuss the incidences of injury caused by different supplements in different countries. These range from 1%–2% of cases of liver injury in Spain (with antibiotics being among the most common class implicated) to Singapore, where 71% of cases of drug-related liver injury have been attributed to medicinal herbs—many adulterated with active drugs.

The authors discuss preliminary findings from the US Drug-Induced Liver Injury Network (DILIN) showing that herbal and dietary supplements are responsible for an increasing proportion of hepatotoxicity cases.

Rossi and Navarro discuss the US Dietary Supplement Health and Education Act of 1994, in which manufacturers are required to attest to a product’s safety, but give no authority to the Food and Drug Administration (FDA) to approve the supplements before marketing. Routine analysis of products’ contents by the FDA is performed on only a random basis.

They present strategies for diagnosis of herbal and dietary supplement–induced liver injury, and the process for linking a drug or dietary supplement to liver injury. Products and ingredients associated with hepatotoxicity include weight loss supplements (Hydroxycut, Herbalife/green tea, and usnic acid), joint health supplements (flavocoxid- and glucosamine-based supplements), and bodybuilding supplements.

Attributing liver injury to any specific ingredient in herbal and dietary supplements is the single greatest challenge to clinicians and researchers interested in liver injury. Rossi and Navarro explain that even detailed chemical analyses of products, which are expensive and complex, do not always identify the agents responsible for injury. The authors propose using chemical analyses to identify ingredients common to products implicated in injury; proposed culprits could then be tested in formal toxicologic analyses.

Nonetheless, Rossi and Navarro state that a better understanding of the epidemiology of supplement-induced liver injury is needed, to identify the scope of the problem and the groups most affected, as well as to develop management and prevention strategies. Without more accurate estimates of the overall use of herbal and dietary supplements and more complete reporting of adverse events, it is impossible to determine disease prevalence and incidence.


Thursday, May 29, 2014

FDA UPDATE - Sometimes Drugs and the Liver Don't Mix

Sometimes Drugs and the Liver Don't Mix

The liver is a remarkable, if underappreciated, organ. It turns the nutrients in our diets to substances the body can use and converts toxins into harmless substances or makes sure they are removed from the body

When the liver is working well, our metabolism hums along in equilibrium. But drugs and dietary supplements can sometimes wreak havoc with that system, leading to dangerous liver problems. The Food and Drug Administration (FDA) is working to prevent drug-induced liver injuries.

“Any drug may cause dangerous liver problems but, fortunately, such problems only occur rarely,” says John R. Senior, M.D., an FDA gastrointestinal medical reviewer and consultant in hepatology, which includes study of the liver. “It is challenging to predict how drugs will affect the liver because each patient is different in how they respond to a given drug. Our goal is to prevent the toxicity of drugs.”

Acute liver failure is a rapid deterioration of the organ’s ability to function. Data suggest that prescription and over-the-counter drugs (OTC) and dietary supplements cause more acute liver failure cases than all other reasons combined.

FDA has identified several instances of liver damage caused by dietary supplements. For example, the agency has issued public health warnings and sent warning letters to companies marketing supplements for weight loss and muscle building. In one instance, a Texas-based company agreed to recall and destroy certain dietary supplement products after discovering a link between the supplement and cases of liver failure and non-viral hepatitis.

No Easy Way to Identify the Vulnerable
Finding even a few cases of serious liver toxicity in clinical trial subjects exposed to a drug can be a reason for discontinuing the trial. Also, cases of serious liver toxicity have prompted FDA to request sponsors to withdraw their approved drugs from the market.
Senior explains there’s no easy way to identify the people who might be vulnerable. “The drug-disease relationship is not so simple,” he says. “Identifying drugs that may cause liver injury only solves half the problem. The other half: Drugs that appear to be safe in pre-clinical studies still may be harmful to some patients.”

Meanwhile, we have an aging population that is more dependent on drugs. “The more medications you take, the more likely you are to have trouble,” Senior says.

A few drugs are toxic to the liver only when used in excess. One example is acetaminophen.
“Acetaminophen when used as labeled is generally considered to be safe. But overdoses of acetaminophen are the most common cause of drug-related liver injury, whether these occur accidentally or otherwise,” says Mark Avigan, M.D., a medical reviewer at FDA with a background in gastroenterology and hepatology. “With acetaminophen overdoses, some people get a more severe reaction than others.”

Acetaminophen is an active ingredient in hundreds of OTC and prescription medicines commonly used to treat musculoskeletal pain and fever, allergies, coughing, colds, flu, and even sleeplessness. Overdoses leading to serious liver injury have resulted from consumers inadvertently taking both OTC and prescription drugs containing acetaminophen.

Inadvertent overdoses with prescription drugs that contain acetaminophen and a narcotic have been responsible for a significant proportion of all the cases of acetaminophen-related liver failure in the United States, some of which have resulted in liver transplant or death.FDA has taken steps to keep consumers safe. In early 2014, FDA requested withdrawal of over 120 applications for combination prescription acetaminophen drug products containing more than 325 mg acetaminophen per dosage unit. The agency also has reminded pharmacists and physicians to stop prescribing and dispensing combination prescription acetaminophen products containing more than 325 mg. It is FDA’s understanding that as a result, all manufacturers have discontinued marketing combination prescription drug products that contain more than 325 mg of acetaminophen.

Some antibiotics and nonsteroidal anti-inflammatory medications also have been tied to liver damage.
Hepatitis, a liver inflammation, can have several potential causes. Drugs may induce a form of hepatitis that closely resembles viral hepatitis (liver inflammation caused by viral infection). 

Signs and Symptoms
How can you recognize the signs of liver problems?
Avigan says you might feel tired and have a poor appetite. In more extreme cases, your eyes and skin become yellowish (jaundice) and your skin becomes very itchy. “Your skin itches because the liver is not properly clearing toxins from the body,” he says.

When patients taking a drug they have not used before get those symptoms, they should seek immediate medical attention and stop using that drug if it is identified as the cause, Avigan cautions.
If the symptoms surface and the patient has been taking a medication for a long time, there could be another cause. Senior says it’s difficult to be certain that the symptoms were caused by a drug and not something else. Obesity and excessive consumption of alcohol also can damage the liver.

Considering Risks and Benefits
Patients should discuss the risks and benefits of any drug with their doctors when they start treatment, Avigan says. They should also discuss dietary supplements with their clinician before taking them.
Some life-saving drugs are the only options for very sick patients.

“Before approving or denying approval of a drug, we evaluate its risks and work to identify its liver injury potential, even if only one in 10,000 people will be badly affected,” Avigan says. “With some drugs, for example for cancer patients, the benefits of treatment might far outweigh the risks.”

The liver can regenerate even when 65% of it is destroyed or surgically removed, as in a cancer treatment. This versatile organ is often capable of adapting and becoming tolerant of various foreign agents, including drug products. But if the liver isn’t healthy, complications from drug interactions can be even worse.

This article appears on FDA's Consumer Updates page, which features the latest on all FDA-regulated products.
May 28, 2014

Thursday, February 20, 2014

Lessening liver damage - Possible improved treatment for acetaminophen poisoning

Lessening liver damage

Scientists believe they’ve found improved treatment for acetaminophen poisoning

February 19, 2014

By Joseph Caputo, Harvard Correspondent

B. D. Colen/Harvard Staff

The human liver can safely process up to 4 grams (8 pills) of acetaminophen, best known as Tylenol, over 24 hours. Surpassing that amount risks poisoning or killing liver cells.

Harvard stem cell scientists studying the effect of nitric oxide on liver growth and regeneration appear to have serendipitously discovered a markedly improved treatment for liver damage caused by acetaminophen toxicity, the root of half of the hospital visits involving acute liver failure in the United States.

The human liver can safely process up to 4 grams (8 pills) of acetaminophen, best known as Tylenol, over 24 hours. Surpassing that amount risks poisoning or killing liver cells. Accidental acetaminophen overdoses commonly occur when people who feel sick but don’t know the dangers posed by the over-the-counter pain and fever reducer exceed the safe dosage. Such poisoning kills hundreds of people each year.

Writing in the journal Cell Reports, the researchers described how nitric oxide, which is commonly used to relax cardiac blood vessels in patients with heart disease, enhances liver growth and regeneration, independent of its effect on blood vessels. Using zebrafish and mice, the research team also showed how manipulating these pathways with drugs could improve treatment of toxic liver injury caused by acetaminophen overdose.

The only federally approved treatment for acetaminophen toxicity, N-acetylcysteine (NAC), is most effective if a patient seeks medical help within 8 to 12 hours of overdose. Unfortunately, most overdose-specific symptoms, such as confusion and intestinal bleeding, don’t occur until the liver injury is critical.

“We tried to model that in our studies where we gave fish Tylenol first, waited 18 hours, and gave them a new nitric oxide-based drug combined with the clinically approved drug,” said study co-senior author Wolfram Goessling of the Harvard Stem Cell Institute. “These drugs worked together to improve liver injury even when out of the previously established therapeutic window, and so we think there’s significant potential for clinical application.”

Goessling and his research associates happened upon the nitric oxide-liver injury connection while investigating the signaling pathways that are important for liver development. Goessling’s lab, which he shares with study co-senior author Trista North, screened thousands of known drugs on zebrafish embryos to see which produced a bigger or smaller liver. The compounds with the most dramatic effect were a family of drugs that affect nitric oxide and nitric oxide signaling.

Andrew Cox, a postdoctoral fellow in Goessling’s lab, conducted a series of experiments to show that nitric oxide enhanced liver formation during organ development in zebrafish and that blocking nitric oxide led to smaller, less-developed livers. Further investigation found that nitric oxide worked through different pathways in the liver than it did in the blood vessels, where its ability to regulate blood flow has been well established.

“During these experiments, we found a recently recognized pathway, called protein nitrosylation, where the activity of proteins gets changed by nitric oxide,” Goessling said. “We think that’s the basic principle behind how it works in liver development.”

The members of Goessling and North’s lab found it was possible to enhance liver growth and regeneration by disrupting the nitrosylation pathway so that nitric oxide could better change proteins in the liver. They found a nitrosylation enhancer currently used in clinical trials for other purposes and began testing it in clinical models of illnesses such as Tylenol overdose, where it proved successful.

“This potential drug doesn’t only work in fish,” Goessling said. “We did use mouse models to show that this might have relevance to human disease.”

If the nitrosylation drug for liver toxicity reaches clinical trials, it would join a handful of other drugs developed from zebrafish research that originated from Harvard Stem Cell Institute labs.

Last year, a compound discovered by North and Goessling while they were working as postdoctoral fellows in the lab of Leonard Zon was found to expand cord blood during hematopoietic stem cell transplants in a Phase 1b clinical trial. Another drug for melanoma, also discovered in the Zon lab, reached the federal Food and Drug Administration approval process in 2011.

The research was funded by a Harvard Stem Cell Institute junior faculty grant, a Public Health Service grant, the Pew Charitable Trusts, and an American Liver Foundation Postdoctoral Research Fellowship award

Friday, January 3, 2014

In Most Cases Antidepressant-Induced Liver Injury Is Unpredictable

"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."
Antidepressant-Induced Liver Injury Underestimated
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 the American 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

Sunday, September 8, 2013

Better tests for liver toxicity would mean more medicines -- and safer medicines -- for patients

American Chemical Society

Better tests for liver toxicity would mean more medicines -- and safer medicines -- for patients

INDIANAPOLIS, Sept. 8, 2013 — How many breakthrough new drugs never reach patients because tests in clinical trials suggested a high risk of liver damage when the drug actually was quite safe?

That question underpins major international research efforts to modernize tests for drug-induced liver injury, mentioned here today at the 246th National Meeting & Exposition of the American Chemical Society (ACS), the world's largest scientific society. The meeting, which features almost 7,000 reports on new discoveries in science and other topics, continues through Thursday in the Indiana Convention Center and downtown hotels.

Paul B. Watkins, M.D., who made the presentation, explained that drug-induced liver damage is a rare drug side effect, but so serious — the No. 1 cause of sudden liver failure — that it has a disproportionate impact on a drug's fate. Liver toxicity is also the No. 1 safety concern causing pharmaceutical companies to halt development of new medicines — sometimes after spending hundreds of millions of dollars on clinical trials to establish the drug's safety and effectiveness. Likewise, it is the leading reason why drugs already on the market must be restricted or banned.

"Blood tests used today in clinical trials for assessing liver safety are the same ones we've used for at least 40 years," said Watkins, referring to tests that measure substances released into the blood when liver cells die. "The tests do indicate damage to liver cells, and everyone assumed over the years that a positive result raised a red flag about a drug's safety. We now know, however, you can have abnormalities in these tests — even pretty remarkable ones — with drugs that pose no serious threat of damaging the liver."

Watkins described research, done with colleagues at the Hamner-University of North Carolina Institute for Drug Safety Sciences, in which healthy volunteers took prescription and non-prescription medicines that have been in use for decades and have an established safety record. The volunteers then got the standard blood tests for liver damage. Those tests measure levels of two enzymes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are released into the blood when liver cells die. The results showed alarmingly high AST/ALT levels, which the scientists first thought were false-positive results, meaning that liver cells weren't really dying. Follow-up tests, however, verified that liver cells were dying.

Those experiments led to a realization that drugs can cause liver cells to die, produce elevated AST/ALT levels in patients, but not cause the kind of permanent liver damage that can mean a liver transplant or death. In most cases, the liver recovers and adjusts, and patients actually can continue taking the medication without risking permanent damage, Watkins explained.

In other patients, Watkins suspects, the immune system goes into overdrive in response to the initial damage and mistakenly begins to attack and kill liver cells. If that's the case, a test that accurately predicts the risk of permanent liver damage would detect the proteins and genes associated with activation of the immune system.

Watkins' group and other research teams in the Drug-Induced Liver Injury Network (DILIN), which he leads, are now on the hunt to find markers that could be better indicators of liver safety. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) established DILIN to collect and analyze cases of severe liver injury caused by prescription drugs, over-the-counter drugs and alternative medicines, such as herbal products and supplements.

DILIN is among major international efforts to develop better tests for predicting serious side effects of medicines. The European Union, for instance, is seeking better tests for liver, kidney and heart damage with its SAFE-T consortium. And the Predictive Safety Testing Consortium (PSTC) helps drug companies come together to validate safety testing methods. The U.S. Food and Drug Administration and its European and Japanese counterparts — the European Medicines Agency and the Japanese Pharmaceutical and Medical Devices Agency — advise the PSTC.

Better tests would help save some drugs from being abandoned during development and might mean new life for medicines dropped on the basis of AST/ALT tests during the last 40 years, Watkins said. Dozens or more such drugs could find a new life in medicine, he said.

Improved liver toxicity tests may be a long way off. Watkins explained that development of such tests is just the first step. Then the tests must be validated on thousands of blood samples from patients with different diseases taking different drugs. Watkins is currently working to set up a liver safety consortium to get drug companies to work together and collect these samples to evaluate new tests.


A press conference on this topic will be held Sunday, Sept. 8, at 11 a.m., in the ACS Press Center, Room 211, in the Indiana Convention Center. Reporters can attend in person or access live audio and video of the event and ask questions at

Watkins acknowledged funding from the National Institute of Diabetes and Digestive and Kidney Diseases, which is part of the National Institutes of Health.

The American Chemical Society is a nonprofit organization chartered by the U.S. Congress. With more than 163,000 members, ACS is the world's largest scientific society and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.

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Biomarkers for the diagnosis and management of drug-induced liver injury

Genome-wide association studies (GWAS) have linked specific HLA alleles to the risk for developing DILI due to several drugs. These insights have not yet led to personalized medicine approaches to risk management of DILI because the associations lack specificity. That is, although prospective genetic testing would identify most patients susceptible to DILI, it would deny treatment to many more patients who could be safely be treated with the drug. For this and other reasons, there is intense interest in developing non-genetic biomarkers that could be useful in DILI risk management. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been used for over 40 years to monitor the liver safety of drugs and are sensitive measures of liver injury. However, there are drugs that, when administered at recommended doses, are quite safe for the liver yet cause marked elevations in serum ALT and AST. We have been exploring whether current mechanistic biomarkers can distinguish benign enzyme elevations from those that may lead to clinically important liver injury. We have analyzed serial serum samples obtained from cohorts of healthy adult volunteers treated with different therapeutic drug regimens that can cause marked elevations in serum ALT and AST but have low or no risk for serious hepatotoxicity (acetaminophen, various heparins, and cholestyramine). We and our collaborators have employed a variety of techniques, including transcriptomics, metabolomics and proteomics to identify biomarkers that may provide insight into the mechanisms underlying these benign and self-limited laboratory abnormalities. These studies indicate that recurrent therapeutic doses of acetaminophen, heparins and cholestyramine cause hepatocyte death, but the mechanisms involved in cell death differ between these treatments. The reason why these treatments are safe for the liver remains unclear but several theories will be discussed.

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Wednesday, June 26, 2013

Drug-Induced Liver Injury Is On the Rise

Drug-Induced Liver Injury Is On the Rise

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.

Thursday, June 20, 2013

Healio-SVR more dependent on adherence to treatment duration than dosing interval

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Nearly all patients with chronic hepatitis C who achieved sustained virologic response to therapy with pegylated interferon, ribavirin and direct-acting...More »

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Patients with chronic hepatitis C genotype 1 had higher sustained virologic response rates with better treatment duration adherence, while adherence to...More »

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A drug with a dose of 100 mg or greater and high lipophilicity is significantly more likely to lead to drug-induced liver injury, according to a recent...More »

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Patients coinfected with chronic hepatitis C and occult hepatitis B were more likely to develop cirrhosis or hepatocellular carcinoma and had poorer...More »

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Outcomes of partial liver transplantation from deceased donors for very young recipients are comparable to those from whole liver transplantation,...More »

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Monday, April 29, 2013

Frequently used biologic agents might cause acute liver injury

Frequently used biologic agents might cause acute liver injury

Bethesda, MD (April 29, 2013) — A commonly used class of biologic response modifying drugs can cause acute liver injury with elevated liver enzymes, according to a new study in Clinical Gastroenterology and Hepatology, the official clinical practice journal of the American Gastroenterological Association. Patients with inflammatory diseases such as Chron's disease or ulcerative colitis often are prescribed tumor necrosis factor-alpha (TNF-α) antagonists, which modify the body's response to infection. Patients with inflammatory arthropathies and selected dermatological diseases are also candidates to receive such compounds.

"TNF-α antagonists are extremely beneficial as therapies for several bowel, joint and skin inflammatory conditions," said Maurizio Bonacini, MD, AGAF, study author and associate clinical professor, University of California, San Francisco. "However, gastroenterologists, internists, rheumatologists and dermatologists all need to be aware of this potential complication and know how to diagnose it. They should conduct tests for autoimmunity early upon diagnosis of abnormalities to determine the proper path of care."

Researchers searched the U.S. Drug-Induced Liver Injury Network database and identified six well-characterized cases of drug-induced liver injury (DILI) in the setting of TNF-α antagonist therapy. Additionally, they reviewed 28 additional cases identified in PubMed. The researchers found acute liver injury in all cases, most frequently autoimmunity and hepatocellular injury, but mixed non-autoimmune patterns and cholestasis (blocked flow of bile from the liver) also occurred. No deaths were attributed to the liver injury; one patient required a liver transplant, which was attributed to pre-existing cirrhosis with superimposed DILI.

Of the TNF-α antagonists, infliximab-associated liver injury has been the best documented, most likely because of its earlier approval and more wide-spread clinical use. Etanercept and adalimumab have also been linked to drug-induced liver injury. So far, there are no published cases found to be linked to natalizumab, golimumab or certolizumab.

The researchers found that liver damage was typically resolved following drug discontinuation, although some patients did benefit from a course of corticosteroids. Importantly, patients treated with an alternative TNF-α after resolution of their liver injury appeared to tolerate the drugs without recurrence.

"If patients who are taking these biologic agents experience symptoms such as abdominal pain, nausea and fatigue, physicians should check liver enzyme levels to determine if the symptoms are a result of these drugs," added Dr. Bonacini.


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.

About Clinical Gastroenterology and Hepatology
The mission of Clinical Gastroenterology and Hepatology is to provide readers with a broad spectrum of themes in clinical gastroenterology and hepatology. This monthly peer-reviewed journal includes original articles as well as scholarly reviews, with the goal that all articles published will be immediately relevant to the practice of gastroenterology and hepatology. For more information, visit

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Thursday, November 8, 2012

Review article: herbal and dietary supplement hepatotoxicity

Review article: herbal and dietary supplement hepatotoxicity
  1. C. Bunchorntavakul1,2,
  2. K. R. Reddy2,*
Article first published online: 5 NOV 2012
DOI: 10.1111/apt.12109

Alimentary Pharmacology & Therapeutics
Herbal and dietary supplements are commonly used throughout the World. There is a tendency for underreporting their ingestion by patients and the magnitude of their use is underrecognised by Physicians. Herbal hepatotoxicity is not uncommonly encountered, but the precise incidence and manifestations have not been well characterised.

To review the epidemiology, presentation and diagnosis of herbal hepatotoxicity. This review will mainly discuss single ingredients and complex mixtures of herbs marketed under a single label.

A Medline search was undertaken to identify relevant literature using search terms including ‘herbal’, ‘herbs’, ‘dietary supplement’, ‘liver injury’, ‘hepatitis’ and ‘hepatotoxicity’. Furthermore, we scanned the reference lists of the primary and review articles to identify publications not retrieved by electronic searches.

The incidence rates of herbal hepatotoxicity are largely unknown. The clinical presentation and severity can be highly variable, ranging from mild hepatitis to acute hepatic failure requiring transplantation. Scoring systems for the causality assessment of drug-induced liver injury may be helpful, but have not been validated for herbal hepatotoxicity. Hepatotoxicity features of commonly used herbal products, such as Ayurvedic and Chinese herbs, black cohosh, chaparral, germander, greater celandine, green tea, Herbalife, Hydroxycut, kava, pennyroyal, pyrrolizidine alkaloids, skullcap, and usnic acid, have been individually reviewed. Furthermore, clinically significant herb–drug interactions are also discussed.

A number of herbal medicinal products are associated with a spectrum of hepatotoxicity events. Advances in the understanding of the pathogenesis and the risks involved are needed to improve herbal medicine safety.

With historical background on use, the use of herbal medicine can be traced back as far as 2100 BC in ancient China and India.[1] Despite their largely unproven therapeutic potential through systematic and rigorous investigations, herbal therapy has been increasingly used for the treatment of various diseases, not only in the Eastern World but also in the Western World. In the US, herbal and dietary supplements (HDS) represent a $180 billion market and their use was reported by 18.9% individuals in 2004, and this had doubled from the previous decade.[2, 3] Interestingly, 30–40% of patients admitted that they did not disclose the use of HDS to their Physicians.[3] The list of the ten most commonly used herbal preparations for various conditions, included echinacea, garlic, ginko biloba, saw palmetto, ginseng, grape seed extract, green tea, St. John's wort, bilberry and aloe.[4] Notably, the use of HDS is particularly common in individuals with chronic liver disease, as was reported by 30–62% of patients who ingested silymarin (milk thistle).[3] This population is theoretically more susceptible for hepatotoxicity as well as more likely to develop severe hepatic adverse consequences.

Herbal Products and Their Regulations
Herbal products used for treating disease exist as both crude and commercial preparations. Crude herbal products (come as roots, leaves, seeds or teas) are more often used in less developed countries. They are sometimes formulated as a mixture (i.e. Chinese and Thai herbal medicine, and Indian ayurvedic medicine), where often all constituents are not known and may contain harmful contaminants, such as heavy metals (i.e. lead, mercury and arsenic), corticosteroids nonsteroidal anti-inflammatory drugs and benzodiazepines.[5] Commercial herbal products (as tablets or capsules) are more commonly used in developed countries. They often vary in content and concentration of chemical constituents from batch-to-batch and also come from different manufacturers. Even with standardisation for the known active compounds, there may be variation in other constituents, resulting in differences in bioavailability and pharmacological activity in humans.[2, 5, 6] In the US, these commercial herbal products are expected to adhere to the regulations of the Dietary Supplement and Health Education Act (DSHEA), issued in 1994, and the Final Rule for Current Good Manufacturing Practices for Dietary Supplements, issued in 2007. These regulations require for the manufacturers to determine the safety of herbal products before marketing, to define dietary ingredients as vitamins, minerals, herbs, amino acids (and any concentrate, metabolite, extract thereof), to provide standards in identification and purity and as well as to ensure that claims made regarding the product are accurate and not misleading.[2, 5] However, this does not always guarantee good manufacturing practices and the manufacturers are not bound to register their products before distribution.[2, 5] Thus, there is no aspect of the law to give the US Food and Drug Administration (FDA) authority to review and approve herbal products for safety and effectiveness.[2]

The true prevalence of herbal product use and incidence of herbal hepatotoxicity are unknown. Unlike modern prescription medications, current regulations for herbal products do not mandate systematic surveillance or reporting of adverse events by the manufacturer to the FDA. Therefore, the data regarding herbal hepatotoxicity are derived largely from anecdotal case reports, case series, retrospective databases and, more recently, from prospective registries of drug-induced liver injury (DILI), such as the US DILI Network and the Spanish DILI Registry. Notably, some of these DILI reports have excluded patients with herbal hepatotoxicity. Based on available data of DILI cohorts from the US and Europe, herbal products are implicated as a cause of hepatotoxicity in 2–11% of patients with DILI,[7-9] and in 5–10% of patients with drug-induced acute liver failure (ALF),[10, 11] although a single-centre experience has implicated HDS in up to 70% of patients with ALF.[12] These numbers reflect the magnitude of herbal hepatotoxicity in clinical practice, and it should again be emphasised that this prevalence is likely to be underestimated. As traditional herbal medications are widely used in China and India, as well as in many other countries in Southeast Asia, Africa and Central America, one can speculate that herbal hepatotoxicity is encountered commonly in these parts of the World. While the data from such areas are scant, prospective DILI studies from Korea and Singapore do support this assumption by reporting a high prevalence of herbal hepatotoxicity, among all cases of DILI, of 73% and 71% respectively.[13, 14] Surprisingly, a low prevalence of herbal hepatotoxicity (1.3%) was reported from India, where the use of herbal remedies and ayurvedic compounds are quite common.[15] Although the exact reasons remain unclear, the authors speculated that ayurvedic compounds in India are often taken after the development of a hepatitis like illness and the high rate of heavy metal contamination in the remedies result in a more dominant nonhepatic organ involvement that may overshadow hepatitis, which may be insignificant and overlooked and thus, underreported.[15] (Table 1)
Table 1. Herbal and dietary supplement hepatotoxicity: Prevalence and clinical features among drug-induced liver injury in different reports
ReferenceCountries and patient characteristicsPrevalence of HDS hepatotoxicityClinical features and prognosis of cases identified as HDS hepatotoxicity
  1. ALF, acute liver failure; DILI, drug-induced liver injury; HDS, herbal and dietary supplement; LT, liver transplantation; UNOS, United Network for Organ Sharing.
Ibunez et al.[9]
Spain (1993–1998)
N = 103; DILI
Population-based, prospective
64% hepatocellular injury
18% mixed injury
18% cholestasis injury
Andrade et al.[7]
Spain (1994–2004)
N = 446; DILI
Multi-centre, prospective
89% hepatocellular
11% cholestasis
56% needed hospitalisation
11% death
Chalasani et al.[8]
USA (2003–2008)
N = 300; DILI
Multi-centre, prospective
63% hepatocellular
17% cholestasis
21% mixed injury
41% needed hospitalisation
6% ALF
9% chronic DILI
Suk et al.[13]
Korea (2005–2007)
N = 371; DILI
Multi-centre, prospective
73% (40% herbs, 14% dietary supplement, 19% folk remedies)
~78% hepatocellular
~10% cholestasis
~12% mixed injury
1.5% death or LT
Wai et al.[14]
Singapore (2004–2006)
N = 31; DILI
Multi-centre, prospective
74% hepatocellular
19% cholestasis
7% mixed injury
Devarbhavi et al.[15]
India (1997–2008)
N = 313; DILI
Single-centre, retrospective
1.3%50% mortality
Estes et al.[12]
USA (2001–2002)
N = 20, ALF
Single-centre, retrospective
50%60% underwent LT
Russo et al.[11]
USA (1990–2002)
N = 270; ALF from drug
Retrospective, UNOS data
5.1%All underwent LT
Reuben et al.[10]
USA (1998–2007)
N = 133; ALF from drug
Multi-centre, prospective
>90% hepatocellular injury
21% spontaneous recovery
50% underwent LT
29% death
The incidence of idiosyncratic liver injury among persons who use HDS is variable. Based on limited data, the incidence of hepatotoxicity from Chinese herbs appears to be low (less than 1%).[16, 17] Melchart et al. reported a study of 1507 consecutive inpatients treated with traditional Chinese medicine wherein 1% developed more than 2-fold elevation of serum alanine aminotransferase (ALT), and only 2 patients were symptomatic.[16] Furthermore, a prospective, observational study from Korea reported that significant changes in hepatic biochemical tests were not observed among 122 patients who took herbal medicine.[17] However, relatively high incidence of hepatotoxicity has been reported in a randomised controlled trial of Tinospora crispa as an adjunctive therapy for diabetes mellitus (N = 40), wherein significant ALT elevations (>200 IU/L) occurred in 10% of patients.[18] Although it is difficult to quantitate the exact amount of active herbal ingredients ingested, dose-dependent pattern of hepatotoxicity can be seen with several herbs, such as pyrrolizidine alkaloids (PA), greater celandine and Atractylis gummifera.

The clinical presentation of herbal hepatotoxicity varies from asymptomatic abnormal hepatic biochemical test abnormalities indicating mild self-limiting liver injury, to severe ALF requiring LT. In symptomatic individuals, the manifestation often begins with nonspecific constitutional symptoms, followed by jaundice.[19] Due to the variety and complexity of herbal regimens, it is difficult to summarise the clinical manifestations of herbal hepatotoxicity in general. In 28 patients with DILI from herbs and dietary supplements in the US DILI Network, the median duration from exposure to DILI recognition was 54 days (IQR 36–109); 50% were female and the mean age was 45 (±12) years. Pattern of liver injury was hepatocellular in 63%, cholestatic in 17% and 21% were mixed, with a mean bilirubin of 14.7 (±13.0) mg/dL. The severity was mild–moderate in 88% of patients, whereas 12% have severe–fatal DILI; 3.5% of patients underwent LT and chronic DILI developed in 9%.[8] A prospective nationwide study of DILI in Korea reported 270 patients with HDS-related hepatotoxicity; most patients were female with median age of 48–53 years.[13] Hepatocellular pattern of injury was noted in the majority of cases (~78%) with a median ALT of 566–796 IU/L and a median bilirubin of 5.4–7.0 mg/dL. Median hospital stay was 7–9 days; most patients spontaneously recovered with 2 deaths and 2 requiring LT.[13]

Diagnosis and Causality Assessment
As with DILI, an early and high-index of suspicion of herbal hepatotoxicity is paramount. The use of herbal products should always be a part of history taking in patients presenting with any form of acute liver injury or in those with acute on chronic liver disease. Further details on all herbal preparations used, dose and duration and concomitant medications are essential. In some instances, it can be helpful to examine the label of the herbal products, which sometimes contains a long list of ingredients mixed in the preparation. Prompt recognition of common culprit herbs and their hepatotoxicity patterns (some of them may have a ‘signature’) reported previously in the literature (see below) is very important. Currently, there is no gold standard, even with a liver biopsy, for the diagnosis of herbal hepatotoxicity. The diagnosis, therefore, depends greatly on the exclusion of other causes of liver disease by a thorough clinical assessment, as well as laboratory testing. A list of essential diagnostic elements for the exclusion of other causes of hepatic dysfunction and to increase the reliability of the diagnosis of DILI has been suggested and this could increase the quality and clinical utility of the publications on drug toxicity.[20] Acute hepatitis E has accounted for some cases of suspected DILI (up to 13% in developed countries, and possibly much higher in developing countries),[21, 22] and therefore testing for hepatitis E antibody should be performed, particularity if clinical features resemble acute viral hepatitis.[22] The possibility of herbal hepatotoxicity superimposed on pre-existing liver disease should also be considered, especially because many herbal remedies are used by patients with chronic liver diseases, and in this situation, it is more challenging to make a clear-cut diagnosis. Liver histology often is nonspecific, but may be helpful in some cases. Uncommon histological patterns of liver injury should trigger the suspicion of herbal hepatotoxicity, and these include zonal necrosis, necrotic lesions with steatosis or bile duct injury, and vascular injury, particularly veno-occlusive disease (VOD).[19]
Several scoring systems have been proposed for aiding in the causality assessment of DILI, such as the Roussel Uclaf Causality Assessment Method (RUCAM) by the Council for the International Organization of Medical Sciences (CIOMS)[23] and the clinical scale by Maria and Victorino.[24] Among these scoring systems, the CIOMS scale is perhaps the most widely used in the literature.[8, 23] This scale applies numerical weighting to key features in 7 different domains: chronology (latency and dechallenge), risk factors, concomitant drug use, exclusion of other causes, previous information on drug's hepatotoxicity potential and response to rechallenge. The score given to each domain is summed up to generate a total score that reflects the causality probability of DILI; definite, very likely, probable, possible, unlikely or excluded.[23] The CIOMS scale, when initially validated, demonstrated acceptable reproducibility and performance, with 93% positive predictive value and 78% negative predictive value.[25] However, subsequent validations have questioned the reliability of this method, and there have been several pitfalls in applying the score in clinical practice.[26, 27]
Although the CIOMS scale has been utilised as a diagnostic tool in most of the literature pertaining to herbal hepatotoxicity, the performance of this method in causality assessment of herbal hepatotoxicity remains undefined. Herbals and dietary supplements are less likely to be well characterised with regard to hepatotoxicity information of the active ingredients. This may compromise the CIOMS score for herbal products as no points are given for agents without existing information on hepatotoxicity. A recent study from Hong Kong Herb-induced Liver Injury Network evaluated the performance of CIOMS scale and a multidisciplinary approach (consisting of expert opinion by a hepatologist, clinical toxicologist, analytic toxicologist and Chinese medicine pharmacist) in 27 patients with suspected herbal hepatotoxicity. The concordance for causality assessment was moderate, either between the hepatologist and clinical toxicologist (weight k = 0.48), or between the multidisciplinary team and the CIOMS scale (weight k = 0.51).[28] The diagnostic algorithm for the causality assessment of drugs and dietary supplements, consisting of a pretest (qualitatively oriented for hepatocellular injury and/or cholestasis), a main-test (CIOMS scale) and a posttest (exclusion of other liver diseases not considered in the CIOMS) procedure, has also been proposed by Teschke.[29] More recently, a group of experts from the US DILI Network has developed a novel causality assessment tool specifically for HDS (HDS-CAT), which needs further investigation and validation.[30]

Herbal Products that have been linked to Hepatotoxicity
Ayurvedic herbal products 
Ayurvedic medicine is the science of a plant-based system of healing applicable to a spectrum of disorders that originated is ancient India. It generally consists of numerous plants, but metals may also be present due to the practice of ‘Rasa shastra’ (combining herbs with metals, minerals and gems).[31] Notably, 20–22% of both US- and Indian-manufactured Ayurvedic medicines randomly purchased via the Internet in 2005 contain detectable lead, mercury or arsenic.[31] Although cases of heavy metal poisoning associated with Ayurvedic medicine have been continuously reported, this form of treatment is still utilised by the majority in rural India (1.1 billion people) and worldwide by the South Asian diaspora and others.[31, 32] Interestingly, despite being widely used, hepatotoxicity from Ayurvedic medicine has been rarely reported in the literature. Severe hepatitis has been documented in a woman who had treated herself for 9 months with various Indian Ayurvedic herbal products for her vitiligo, in which the key implicated ingredient was believed to be Psoralea corylifolia.[33] Centella asiatica (Gotu kola, Mandukaparni, Kannada), an ayurvedic medicine used mainly for leprosy, has been reported to be associated with granulomatous hepatitis and cirrhosis.[34, 35] Additionally, in the European RCT of Ayurvedic herbal combination, Liv.52 which contains capers, wild chicory, arjuna, black nightshade, yarrow, and others, for the treatment of alcoholic cirrhosis (N = 188), no effect on survival was seen in Child class A/B patients, but substantially increased liver-related mortality was observed in those with Child class C (2-year survival: 40% vs. 81% in those who adhered to treatment, P = 0.02), suggesting a potential detrimental effect of this Ayurvedic preparation.[36]

Atractylis gummifera and Callilepsis laureola (Impila)
Atractylis gummifera is a thistle located in the Mediterranean regions, where more than 26 species have been identified. These plants secrete a whitish glue-like substance often used by children as chewing gum, and also used as an antipyretic, antiemetic, abortifacient and a diuretic.[5] Ingestion of A. gummifera continues despite its well-known toxicity attributed to atractyloside and carboxyatractyloside, which are concentrated in the root of the plant.[5, 37] These two diterpenoid glucosides are capable of inhibiting mitochondrial oxidative phosphorylation by interaction with a mitochondrial protein, the adenine nucleotide translocator.[37] More than hundred cases of liver and renal injury associated with A. gummifera ingestion have been reported, and they frequently involved children.[38, 39] In addition, toxicity is reported with the cutaneous application.[40] The onset of toxicity usually begins within few hours after ingestion, and is characterised by headache, anxiety, vomiting, abdominal pain, diarrhoea, and convulsion, which then often leads to acute liver and renal failure, neurovegetative state and death.[38-41] There is no specific pharmacological treatment for A. gummifera intoxication available and all the current therapeutic approaches are only symptomatic, with LT being an option. In vitro experiments noted that some compounds such as verapamil, or dithiothreitol could protect against the toxic effects of atractyloside by blocking ADP-ATP conversion through inhibition of P450 cytochrome, but only if administered before atractyloside exposure.[37, 41] New therapeutic approaches could come from immunotherapy research; efforts to develop polyclonal antibodies against the toxic components of A. gummifera are in progress.[37, 41]
Callilepsis laureola (Impila), is a plant indigenous to the Natal region of South Africa, and has been used as a traditional remedy, mainly by the Zulu Tribe. Similar to A. gummifera, C. laureola also contains the toxic atractyloside.[42] Several cases of acute liver and renal failure have been reported with a mortality rate greater than 90% by 5 days.[43, 44] Interestingly, C. laureola-induced cytotoxicity in Hep G2 cells involves depletion of cellular glutathione and preventing glutathione depletion by supplementing cells with N-acetylcysteine to reduce its cytotoxicity potential has been demonstrated.[45]

Chaparral (Larrea tridentate) is made from the leaves of a desert shrub, known as the creosote bush or greasewood, found in Southwestern United States and Mexico.[5] It has been used for the treatment of various conditions, such as pain, bronchitis, skin conditions, cancer, and also as an alternative medicine for AIDS.[52, 53] Currently, chaparral comes in the form of a tea, and as capsules, tablets and salves.[5, 53] It is perceived to have antimicrobial and antioxidant activities and its active ingredient is nordihydroguiaretic acid, a potent inhibitor of lipoxygenase and cyclooxygenase pathways.[5, 19]
Several reports on hepatotoxicity associated with ingestion of chaparral leaf, including acute and subacute hepatocellular injury, and cholestatic hepatitis, have been published.[54-57] Sheikh et al. reviewed 13 cases of chaparral-induced hepatotoxicity in 1997.[53] Most patients presented with jaundice with a marked increase in ALT within 3–52 weeks after ingestion, which often resolved 1–17 weeks after discontinuing the product. However, 2 patients developed ALF requiring LT, and 4 patients eventually evolved onto cirrhosis.[53] Histological findings ranged from biliary changes and cholestasis to massive hepatic necrosis, particularly in zone 3.[19, 53-57]

Chinese herbal medicines
Numerous herbs from China have been used for centuries as traditional medicine. Chinese herbal medicines, while being quite popular in the East, have also become highly popular among Western countries as a form of ‘natural’ alternative medicine; they are perceived to be free of side effects. Most traditional Chinese medicines are blends of 4–6 different herbs, but there is typically a primary pharmacologically active component referred to as the ‘King herb’. The remaining constituents are believed to function as modifiers of toxicity, act synergistically with the King herb, improve the immune function or strengthen certain aspects of actions, and such conglomeration of constituents makes the identification and assignment of causative hepatotoxic compounds extremely difficult.[6] In addition, adulteration by synthetic drugs and heavy metals has also been reported.[58-60]
Jin Bu Huan (Lypocodium serratum) has been widely used as a sedative and analgesic, as it contains levo-tetrahydropalmatine, a potent neuroactive substance. In North America, it was marketed as ‘anodyne tablets’ in the 1990s, and subsequently was banned due to convincing reports of toxicity (i.e. central nervous system and respiratory depression, cardiovascular collapse, and hepatotoxicity) after both acute and chronic use.[61-64] In a series of 7 cases of Jin Bu Huan-associated liver injury, acute hepatitis occurred after 7–52 weeks (mean 20 weeks) of ingestion and usually resolved within 2–30 weeks (mean 8 weeks).[64] Liver biopsy specimens noted mild hepatitis, moderate fibrosis and micro vesicular steatosis, with or without eosinophilic infiltrates.[64] In addition, chronic hepatitis with bridging fibrosis has also been described.[63] The mechanism of hepatotoxicity is unclear, but an immune-mediating process might play a role based on the development of fever, rash and eosinophilia in many individuals.[5, 64]
Ma huang (Ephedra sinica) is used as a nasal decongestant and bronchodilator, as well as to aid weight loss. In a meta-analysis, it was noted to promote modest short-term weight loss (not sufficient data regarding long-term weight loss and the contribution from athletic performance), but was associated with increased rate of psychiatric and autonomic system issues, gastrointestinal symptoms and heart palpitations.[65] Liver injury, including severe hepatitis, ALF, and as fulminant exacerbation of AIH, has been described in association with ma huang ingestion,[66, 67] as well as with the use of multiple different commercial weight-loss herbal products containing ma huang.[68, 69]
Dai-saiko-to (Sho-saiko-to, TJ-19, Da-chai-hu-tang, Xiao-chai-hu-tang) is a Chinese herbal medicine that has been used widely in Japan for the treatment of liver diseases and is part of the Japanese Kampo medical system.[5, 38] Dai-saiko-to differs from Sho-saiko-to only in the proportion of herbal constituents and which contains bupleuri, pinelliae, scutellaria, ginseng, ginger, glycyrrhiza and jujube fruits.[5, 38] Several in vitro and in vivo studies suggested that this product may be effective in preventing hepatic inflammation, fibrosis and hepatocellular carcinoma.[3] There have been, however, reports of liver injury attributed to these products.[70-72] Itoh et al. reported 4 cases of acute hepatitis following a latency period of 1.5–3 months after ingestion of Sho-saiko-to, which improved with cessation and recurred with rechallenge.[71] The liver histology revealed centrilobular confluent necrosis or spotty necrosis, micro vesicular fatty change, acidophilic degeneration, and a granuloma.[71] Kamiyama et al. reported a case of AIH, which possibly was triggered by Dai-saiko-to and this was based on the development of fatigue, fever, ALT elevation,, and ANA titre of 1:2560 after 2 weeks of treatment. Alanine aminotransferase returned to normal after treatment with prednisolone.[72]
Geniposide is one of the major iridoid glycosides in Gardenia fruit (Gardenia jasminoides) and is used in several Chinese and Kampo herbal medicines (i.e. Shui-Zhi-Zi, Sansisi) to treat various conditions, such as febrile conditions, liver diseases and cancers. In rat livers, acute hepatotoxicity of geniposide at high doses was predictable and likely to be linked to oxidative stress.[73] Interestingly, a case series and review of case reports from Japan suggested that long-term use of geniposide-containing herbal medicines appears to be associated with mesenteric phlebosclerosis.[74] The mechanism is not well understood, but possibly is due to biotransformation of geniposide by intestinal microflora into more toxic metabolite, genipin, that is cytotoxic and can induce cross-link formation in collagen.[74]
Sporadic cases of liver toxicity attributed to other Chinese herbs containing Paeonia spp. (commonly used for eczema)[6, 75] and Polygonum multiflorum (Shou-wu-pian)[76-78] have also been described.

The blossoms of Germander (Teucrium chamaedrys), a plant found in Europe and the Middle East, have been used for thousands of years for a variety of conditions, such as dyspepsia, hypertension, gout, diabetes and obesity.[5, 6] It is available as tea, capsules and as an addition to liquor.[6] Many reports (mostly from France) of liver injury have been documented, and these include presentations as acute, chronic hepatitis and as ALF.[79-83] Most cases of hepatotoxicity occurred after 2 months of intake at the manufacturer's recommended doses (600–1600 mg/day).[79-83] Symptoms were nonspecific (anorexia, nausea, abdominal pain and jaundice) and were accompanied by a marked elevation of ALT. After withdrawal, jaundice generally disappeared within 8 weeks; however, the development of cirrhosis and relapse following accidental exposure have also been anecdotally reported.[80] Germander contains saponins, glycosides, flavonoids and furan-containing diterpenoids. Furan-containing diterpenoids are well-known to be cytotoxic and carcinogenic.[84-86] In rat studies, these constituents are oxidised by cytochrome P450 3A4 to reactive metabolites that bind to proteins, deplete cellular glutathione and protein thiols, and ultimately induce membrane disruption and hepatocyte apoptosis.[84-86]
Apart from the instances of hepatitis from T. chamaedrys, there have been anecdotal case reports involving other herbs in the same genus (Teucrium), including T. polium,[87-89] T. capitatum[90] and T. viscidum.[91] These herbal products are often used as hypoglycaemic agents to aid in treatment of diabetes. Notably, acute severe cholestasis, cholestatic hepatitis and ALF requiring LT can be associated with T. polium ingestion.[87, 92-94] Based on chemical analysis, hepatotoxic neo-clerodane diterpenoids have also been isolated from other species of Teucrium, including T.alpestre, T. cuneifolium, T. divarication subsp. villosum and T. flavum subsp. hellenicum.[95]

Greater celandine
Greater celandine (Chelidonium majus) is a plant found mainly in Europe and contains at least 20 different alkaloids, such as berberine, coptisine, chelerythrine and chelidonine. Its extracts have been used for the treatment of biliary disorders and irritable bowel syndrome.[5, 6] Several reports, mostly from Germany, where commercial drug preparations containing Greater celandine are widely available, described liver injury associated with this herb.[96-99] In the largest case series of 10 patients, all were women presenting with moderate elevation of ALT and ALP, which began often around 3 months after ingestion.[96] Marked cholestasis was observed in 5 patients, but liver failure did not occur. Most of the liver biopsies showed portal inflammation and eosinophilic infiltrates, and in all patients, discontinuation of greater celandine treatment led to normalisation of hepatic biochemical tests in 2–6 months. Interestingly, low titre of antinuclear and smooth muscle autoantibodies were noted in 8 cases, which may indicate low-grade autoimmunity.[96] Additional 40 cases of hepatic injury from C. majus have been reported to the German regulatory authorities. Based on these data, C. majus has been banned from oral use in Germany and other European countries, while the Australian Complementary Medicines Evaluation Committee has recently recommended that all oral products containing C. majus have a warning label and be used under professional healthcare supervision.[100]

Green tea (Camellia sinensis)
Green tea is very popular worldwide and is also a frequent ingredient in various dietary supplements used predominantly for weight loss.[2] Several reports of hepatotoxicity, including ALF, following the ingestion of numerous and different green tea preparations have been published since 1999.[101-106] A review of 34 published case reports and 2 unpublished cases suggests a causal association between green tea and liver damage. Majority of cases were judged as ‘possible’ according to the CIOMS score and a positive rechallenge occurred in 7 cases.[106] Patterns of liver injury were hepatocellular in most cases, but cholestasis and a mixed pattern were also observed. Liver histology examination revealed inflammatory reactions, cholestasis, occasional steatosis and necrosis.[106-108] In addition, a case with features mimicking AIH (elevation of ALT, hyperglobulinemia, transient presence of antismooth-muscle antibodies and necroinflammation with interface hepatitis on liver histology) following green tea infusion has also been described.[109] The mechanism of hepatotoxicity is incompletely understood, but components responsible are probably catechins and their gallic acid esters, particularly epigallocatechin-3-gallate, which, under certain conditions such as fasting, can induce reactive oxygen species formation, and affect mitochondrial membrane potential. Although there is reason to be concerned regarding green tea-induced liver injury, a systematic review of 34 such cases (27 were categorised as possible causality and 7 as probable causality) performed by the US Pharmacopoeia has not uncovered a major safety issue and therefore a warning on the label of the product has not been implemented.[104]
While there is concern of hepatotoxicity, significant amount of data from both experimental and clinical studies have suggested the role of green tea in hepatoprotection and cancer prevention, as well as in ‘optimizing’ general health.[107, 108, 110, 111] Although heterogeneity among studies exists, a systematic review of 10 studies, including 4 RCTs, showed a significant protective role of green tea against various liver diseases.[110] Whether the potential risk of hepatotoxicity from green tea outweighs their benefits remains unclear.

Herbalife products
Herbalife products (Los Angeles, CA, USA) are distributed as herbal and dietary supplements in the form of drinks, tablets, capsules and energy bars for weight control, cosmetics, nutritional support and improvement in well-being, via online marketing and through independent sale agents. It is one of the largest weight management and nutritional supplement companies in the World, with activity in almost 60 countries, and sales of over 3 billion US dollars.[108] Since 2007, there have been several published reports of Herbalife hepatotoxicity from different countries (i.e. Argentina, Iceland, Israel, Spain and Switzerland) describing more than 34 cases.[108, 112-116] Pattern of liver injury was hepatocellular in the majority of cases, but mixed and cholestatic patterns were also observed. Severity ranged from mild-to-severe liver damage and included cases that developed cirrhosis and ALF requiring LT.[108, 115, 116] Causality relationship was assessed by various widely used scores, and it was considered ‘probable’ in most cases, although ‘certain’ (with positive rechallenge) cases were also reported.[108, 113, 115] The exact mechanism of liver injury has not been established, but Elinav et al. hypothesised that immune-mediated injury could be a possible explanation, based on their observation of plasma cell infiltrates and occasional transient presence of autoantibodies in some cases.[113] More recently, Stickel et al. reported on 2 cases of severe hepatotoxicity associated with consumption of Herbalife products contaminated with Bacillus subtilis. Causality according to CIOMS was scored as ‘probable’ in both cases, and histology showed cholestatic and lobular/portal hepatitis with cirrhosis in one patient, and biliary fibrosis with ductopenia in the other. The authors further demonstrated that culture supernatants of the Bacillus subtilis isolated from the products induced dose-dependent leakage of LDH from HepaG2 cells, which they interpreted as the basis for the liver injury, thus raising concern for the possibility of adulteration of Herbalife products with hepatotoxin-producing bacterial strains. Therefore, it seems quite likely that hepatotoxicity does occur among some people who receive these products, but the precise mechanism or the responsible agent in the products is uncertain, in part because, to date, the complete listing of the ingredients of these products is not known and the manufacturer apparently is unwilling to provide the needed information.[117] Besides, Herbalife representatives have so far challenged the causal relationship between consumption of their products and DILI, as well as confirming good quality control for ingredients and contaminants in their production lines.[118, 119]

Hydroxycut is a popular dietary supplement consisting of a variety of herbal mixtures that claim to enhance the ability to lose weight. Several cases of hepatotoxicity associated with Hydroxycut have been reported.[120-122] Most patients exhibited a hepatocellular pattern of injury with marked elevation of ALT, but some patients had a more insidious and usually cholestatic course.[120-122] Notably, cases of AIH-like features and ALF requiring liver transplantation have also been described.[120, 121] The responsible toxic ingredient is not entirely certain, but may be the consequence of Camellia sinensis present in the product.[121] In May 2009, the FDA issued a warning to stop using Hydroxycut products, which was followed by a voluntary recall of all its products by the manufacturer.[108, 121] Subsequently, a new formulation of Hydroxycut has been developed and is being sold.[108]

Kava (Piper methysticum) is a plant indigenous to the South Pacific Islands, including Hawaii, Vanuatu, Polynesia, Melanesia and some parts of Micronesia, where an extract from its rhizome is commonly used to prepare a traditional beverage for social and recreational purposes.[123, 124] In Western countries, dietary supplements containing kava are promoted as an agent to relieve stress, anxiety, and tension, as well as for sleeplessness and menopausal symptoms.[123, 124] Its efficacy for the treatment of anxiety is supported by a Cochrane meta-analysis.[125] Numerous reports of severe hepatotoxicity have been described in the US and Europe, and some of which have been confirmed by structured, quantitative and liver-specific causality assessment methods.[5, 6, 29, 38, 126-128] In an analysis of 36 cases of kava hepatotoxicity, the pattern of injury was both hepatocellular and cholestasis; majority of the patients were women, the cumulative dose and latency were highly variable, and ALF developed in 9 patients and 8 of whom underwent LT.[126] The US-FDA began advising consumers on the potential risk of severe liver injury associated with the use of kava-containing dietary supplements in the year 2002 and the products have been banned from the markets of some countries in Europe, although they are still available in the US, Canada, Australia, New Zealand and South Pacific Islands, as well as via the Internet.[124]
The mechanism of hepatotoxicity has not been clearly elucidated; however, several potential hepatotoxic constituents (i.e. pipermethystine, flavokavain B and mould hepatotoxins) and co-factors (i.e. alterations in hepatic microsomal cytochrome P450, cyclooxygenase inhibition, P-glycoprotein and glutathione) have been extensively reviewed by Teschke.[123, 129] The author suggested that kava hepatotoxicity is partly preventable by quality control, prescription adherence and avoidance of co-medications, since it occurs primarily due to daily overdose (exceeding 250 mg of kava lactones), prolonged treatment and the use of the kava plant's aerial parts, which may contain the hepatotoxic alkaloid pipermethysticin, and contaminated kava raw material.[123, 124, 129]

Pennyroyal (squawmint oil) is an herb containing pulegone and a smaller amount of other monoterpenes, which often is in a form of oil.[5, 19] It has long been used as an abortifacient despite its potentially lethal hepatotoxic and neurotoxic effects.[130] Pennyroyal's toxicity is believed to be mainly from menthofuran, a metabolite of pulegone, which is oxidised by cytochrome P450. In addition, pulegone markedly depletes glutathione as measured in both liver tissue and plasma.[131] Therefore, drugs inhibiting cytochrome P450 (i.e. cimetidine and disulfuram) and/or replacement of glutathione with N-acetylcysteine may theoretically alleviate or prevent pennyroyal hepatotoxicity.[19, 131, 132] Anderson et al. published a report with a literature review of 22 cases of hepatotoxicity associated with pennyroyal oil.[130] Patients often developed severe gastrointestinal upset and central nervous system effects within 1–2 h following ingestion of the oil. Severe/fatal hepatic necrosis and multiorgan failure seemed to occur when more than 15 mL was ingested.[130] One patient was successfully treated by N-acetylcysteine.[130]

Pyrrolizidine alkaloids
Pyrrolizidine alkaloids (PA) are found in more than 350 plant species worldwide. These alkaloids have been well-recognised in causing hepatotoxicity for over 70 years, particularly with Senecio, Heliotropium, Crotalaria, and Symphytium (Comfrey) species.[19, 133-137] The key pattern of liver injury is VOD, newly termed sinusoidal obstruction syndrome (SOS), which was first reported in Jamaican children who drank bush tea for their illness.[133] Subsequently, several cases of VOD associated with an ingestion of PA-containing plants (most often as herbal tea) have been reported mainly from the Southern US, Africa, and Asia, as well as sporadically from Western Countries.[19, 134-138]
PA-associated VOD typically presents with ascites, oedema and hepatomegaly. The clinical onset and severity are variable. In the acute form, abdominal pain develops suddenly, often with jaundice and markedly elevated ALT levels, and with rapid deterioration ending in death.[19, 133-138] The pathogenic process begins with damage to sinusoid endothelial cells that leads to partial obstruction of the sinusoidal lumens, thereby causing obstruction to the sinusoidal blood flow.[38] Liver histology is characterised by nonthrombotic occlusion of small terminal hepatic venules, leading to sinusoidal dilatation and, eventually, haemorrhagical centrilobular necrosis.[19, 133-138] Acute VOD is fatal in 15–20% of patients, with it being worse in adults as compared with children.[133] Complete recovery has been observed in about half of the patients, whereas approximately 15% of patients may have a protracted course of liver injury, characterised by perivenular and bridging fibrosis, and some may die from decompensated liver disease several years later.[19, 133-138] A smaller proportion of patients may have subacute or chronic onset of illness, which may insidiously progress to cirrhosis and portal hypertension.[19] In animal models, the hepatotoxicity of PA seems to be related to the biotransformation by cytochrome P450 3A4 into unstable toxic metabolites (pyrrole derivatives) that may act as alkylating agents and this depends on the type and total dose of PA ingested, along with susceptibility to the alkaloids.[139-141] Notably, herb–drug or herb–herb interactions involving cytochrome P450 are likely to affect PA-associated VOD susceptibility and severity, as toxicity can be amplified by concomitant use of phenobarbital via the induction of cytochrome P450.[6, 141] Acute VOD may result from a short time exposure to high doses, whereas chronic liver injury may be caused by prolonged exposure to even small doses of PA.[139-141]
The management of PA-associated VOD is mainly supportive. Defibrotide, a polydisperse oligonucleotide with local antithrombotic, anti-ischaemic and anti-inflammatory activity, appears to be effective for severe VOD following haematopoietic stem cell transplant;[142] however, its role in the treatment of PA-associated VOD is unknown. As soon as acute or chronic liver failure appears imminent, LT may be the only effective therapy.[6]

Other herbal and dietary supplements
Numerous other herbal products, including camphor oil (Cinnamomum camphora, Vicks VapoRub),[38, 143] black cohosh,[46-51] saw palmetto (Serrenoa repens),[144]Noni juice (Morinda citrifolia),[145-148] Cascara (Cascara sagrada),[38, 149] mistletoe (Viscus album),[150-152] skullcap (Scutellaria),[153, 154] valerian (Valeriana officinalis),[155] senna (Cassia angustifolia and C. acutifolia),[156-158] usnic acid,[159-161] Margosa oil (Antelaea azadirachta, Azadirachta indica)[6, 38] and Aloe vera,[162, 163] as well as dietary supplements, including vitamin A have been described to cause hepatotoxicity.[108, 164-166] Furthermore, preparations containing anabolic steroids[108, 167, 168] have also been linked to liver injury and are summarised in Table S1.

Herb–Drug Interactions 
In addition to the potential for direct hepatotoxicity, some of these herbs may have interactions with certain prescription medications by various mechanisms leading to adverse events, including potentiation of risk for hepatotoxicity, renal toxicity, abnormal bleeding, graft rejection and cardiovascular collapse.[169-171] Many herbs have been identified as substrates, inhibitors, and/or inducers of various cytochrome P450 enzymes, such as St. John's wort, garlic, pepper, licorice, flavonoids, triterpenoids and anthraquinones.[172] For example, St. John's wort is a potent inducer of CYP3A4, mediated by activation of the pregnane X receptor, which can then potentiate the intrinsic hepatotoxicity of other substances, such as germander and acetaminophen, by way of an increased conversion to toxic metabolites.[19, 172] It also enhances plasma clearance of a number of drugs, such as cyclosporine and protease inhibitors, which can complicate the management of posttransplant immunosuppression, as well as HIV and hepatitis C therapy.[169, 170, 172, 173] In addition, coadministration of St. John's wort significantly increased the systemic exposure and toxicity of methotrexate in a rat model.[174] Several herbs, including Danshen, Dong quai, garlic, papaya, tamarind, feverfew, and Gingko biloba, have been associated with an increased risk of bleeding in patients who are on warfarin and/or aspirin. Other herb–drug interactions that may result in hepatotoxicity or significantly affect practice are summarised in Table 2.
Table 2. Herb–drug interactions relevant to hepatology
[Adapted from Ref. (38)]
MedicationsHerbsInteractions and potential consequences
  1. CYP, cytochrome P450; INR, international ratio.
Warfarin and aspirinDanshen (S. miltiorrhiza)Increased INR → bleeding risk
Dong quai (A. sinensis)Increased INR → bleeding risk
GarlicIncreased INR → bleeding risk
PapayaIncreased INR → bleeding risk
TamarindIncreased aspirin level → bleeding risk
FeverfewPlatelet dysfunction → bleeding risk
Gingko bilobaPlatelet dysfunction → bleeding risk
GinsengDecreased INR → clotting risk
St. John's wortDecreased INR → clotting risk
Devil's claw (H. cumbens)Purpura
CYP34A drugsPyrrolizidinesCYP3A4 induction → hepatotoxicity
GermanderCYP3A4 induction → hepatotoxicity
CyclosporineSt. John's wortCYP3A4 induction → rejection risk
Grape fruit juiceCYP3A4 induction → rejection risk
MethotrexateSt. John's wortIncreased methotrexate level and toxicity
EchinaceaIncreased hepatotoxicity ?
PrednisoloneGinsengPossible additive effect
Glycyrrhizin (licorice root)Reduced clearance → hypokalemia
Sho-saiko-toAltered clearance → low prednisolone level
Protease inhibitorsSt. John's wortCYP3A4 induction → suboptimal antiviral activity
GarlicCYP3A4 induction → suboptimal antiviral activity
SpironolactoneGlycyrrhizin (licorice root)Mineralocorticoid → low spironolactone level
BenzodiazepinesKavaIncreased sedative effects
As herbal products continue to be used widely around the World, herbal hepatotoxicity will continue to be observed. Such events are not necessarily unique to herbal medications as they can be seen with prescription medications such as antibiotics, anticonvulsants, etc. It is therefore imperative that the recognition and reporting of herbal hepatotoxicity be held to the same standards as prescription medications. Liver injury is mostly hepatocellular, but mixed and cholestatic patterns can also occur, and the severity ranges from mild injury to ALF, as well as with evolution to chronicity. The diagnosis of herbal hepatotoxicity depends on a proper knowledge of the available literature on hepatotoxicity with the spectrum of herbal preparations ingested and also on a heightened awareness for such hepatotoxic events. Advances in the understanding of the frequency, the pathogenesis, the clinical manifestations and outcomes are needed to be able to improve herbal medicine safety.

Guarantor of the article: K. R. Reddy.
Author contributions: C. Bunchorntavakul conceptualized, searched and reviewed the literature, and drafted the manuscript. K. R. Reddy conceptualized and critically reviewed the manuscript. All authors approved the final version of the manuscript.

Declaration of personal and funding interests: None.

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