CNIO scientists decipher how the immune system induces liver damage during hepatitis

PUBLIC RELEASE DATE: 8-Nov-2013

Contact: Nuria Noriega

comunicacion@cnio.es

Centro Nacional de Investigaciones Oncologicas (CNIO)

The immune system causes liver damage when the organ becomes inflamed by the JunB gene, a member of the AP-1 complex

This is an inflamed liver containing immune cells expressing AP-1 protein (brown).

Viral infections are the primary cause of liver inflammation or hepatitis, affecting hundreds of millions of people all over the world, and they represent a public health problem worldwide. The acute condition can cause irreversible damage to the liver, and if not cured can become chronic, leading to serious diseases such as cirrhosis or cancer.

A study published today in the online edition of The Journal of Clinical Investigation, and carried out by Erwin Wagner's team, Director of the BBVA Foundation-CNIO Cancer Cell Biology Programme and holder of an ERC Advanced Grant, shows how the immune system 'attacks' liver cells during hepatitis by using the AP-1 gene JunB.

Latifa Bakiri, one of the study's authors and a researcher in Wagner's laboratory details: "The activation of the JunB/AP-1 gene in a subset of immune cells, called NK cells, increases the production of interferon-gamma that attacks liver cells while the organ is suffering from hepatitis".

With this discovery, the study's authors propose a new mechanism by which AP-1 acts as a double-edged sword in the liver: it's a first line of defence against viruses that cause the disease, but also encourages liver damage depending on the diet or genetics of the patient.

"The balance of these signals is fundamental to the understanding of the pathogenesis of inflammatory liver disease and to design new therapeutic approaches to reverse this disease", says Wagner.

NK-type immune cells are also part of the micro-environment surrounding tumours. Researchers point out in the discussion of the article that a better knowledge of these cells may be vital for designing immune-therapies that specifically target tumour cells.

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The study has been supported by the BBVA Foundation, the European Research Council, Boehringer Ingelheim and the Ministry of Economy and Competitiveness.

Reference article:

JUNB/AP-1 controls IFN-γ during inflammatory liver disease. Martin K. Thomsen, Latifa Bakiri, Sebastian C. Hasenfuss, Rainer Hamacher, Lola Martinez, Erwin F. Wagner. The Journal of Clinical Investigation (2013). DOI: 10.1172/JCI70405

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Herbal and Weight Loss Supplements, Energy Drink Associated with Liver Damage and Liver Failure: Four Case Reports

EMBARGOED FOR RELEASE
Monday, October 14, 2013
8:00 a.m. EDT

San Diego, CA (October 14, 2013)– Severe liver damage, and even failure, has been associated with the consumption of weight loss supplements, an herbal supplement and an energy drink, according to four separate case reports presented at the American College of Gastroenterology’s 78th Annual Scientific Meeting in San Diego, CA. Use of herbal and dietary supplements is widespread for a variety of health problems. Because many patients do not disclose supplement use to their physicians, important drug side effects can be missed.

Case Report 1: SlimQuick™- Associated Hepatotoxicity Resulting in Fulminant Liver Failure

There have been many reports of toxicity associated with dietary supplement use over the years, some with severe and even fatal outcomes. Lead investigator Dina Halegoua-De Marzio, M.D., reported a rare case of fulminant liver failure associated with the ingestion of SlimQuick™, a weight loss supplement containing green tea extract.

A 52-year old female patient was admitted to the emergency room after one week of vomiting and progressive jaundice. The patient reported she had ingested SlimQuick™ for two days, while fasting three weeks prior to intake. Past medical and family histories of the patient were normal. According to Dr. Halegoua-De Marzio, the patient’s physical examination showed normal mental status, icteric sclera, mild abdominal distension and lower extremity edema. Her liver biopsy was consistent with confluent hepatic necrosis with collapse. The steroid prednisone was started but discontinued after two days, as liver function worsened and mental status deteriorated. After being evaluated and listed for liver transplant, the patient underwent transplantation two days later.

“There is a lack of knowledge about the status of Food and Drug Administration regulation of dietary supplements,” said Dr. Halegoua-De Marzio. “Currently, dietary supplements are not required to have safety or efficacy studies before they are marketed to the public, and they remain popular among consumers despite reports of hepatotoxicity. This case report is an example of how even minimal use of these unregulated dietary supplements can lead to fulminant liver failure requiring liver transplant. It is important that patients talk with their doctors before starting any new dietary supplements.”

Dr. Halegoua-De Marzio believes this is the first reported case of fulminant liver failure due to the consumption of SlimQuick™. The main ingredient in SlimQuick™ is green tea extract, a common ingredient in several dietary supplements, some of which have been withdrawn from the market due to safety concerns.

Case Report 2: Black Cohosh-induced Hepatotoxicity Leading to Early Cirrhosis

Lead investigator Khadija Haroon Chaudrey, M.D., presented a rare case of black cohosh-induced hepatotoxicity leading to early cirrhosis. A 44-year-old female had developed jaundice for one month,

and initial lab work revealed elevated liver function tests (LFTs). The patient had no history of alcohol intake, IV drug use, unprotected sex, recent travel outside the United States, NSAID ingestion or blood transfusions. After unsuccessful outpatient improvement on steroids, she was referred to inpatient evaluation because of gradual progression of her symptoms, marked scleral icterus and jaundiced skin.

The patient then reported she had started taking black cohosh about one month prior, to help with her menstrual symptoms. “Her ultrasound abdomen showed nodular contour of liver consistent with cirrhosis,” said Dr. Chaudrey. “Her liver biopsy showed histologic pattern consistent with cholestasis, hepatocellular injury and early cirrhosis. Given patient’s history of black cohosh use and the timing of her abnormal liver chemistries, it was clinically evident the culprit agent was black cohosh.”

Once the patient stopped taking black cohosh, her symptoms improved and her LFTs normalized. Dr. Chaudrey adds that clinician awareness can be the key to early diagnosis, therapeutic intervention, and even prevention of drug-induced liver injury (DILI). DILI is a common problem associated with herbal supplements and over the counter medications. Although drug-induced hepatitis with most herbal supplements is considered rare, significant outcomes can occur.

Case Report 3: Acute Liver Failure Following Consumption of a Popular Sugar-free Energy Drink for a Year

Lead author Brian Huang M.D., Chief Resident of the Internal Medicine Residency Program at Cedars Sinai Medical Center, presented a case which is one of only a few known reports that directly link energy drink consumption with liver failure. A 36-year-old male without prior medical history sought medical attention after symptoms of right upper quadrant abdominal pain, jaundice and fatigue. After abnormal lab work, he was brought to the hospital. The patient admitted to binge drinking (10 beers in a three-hour period) prior to symptom onset. He denied consuming herbal supplements, but admitted to having three energy drinks, specifically Rockstar® Sugar Free, on a daily basis for the past year.

According to Dr. Huang, “The patients’ pathology reports showed massive hepatocellular necrosis and parenchymal collapse consistent with drug-induced liver injury. We believe his prior history of binge drinking may have provided initial damage on his liver, making him more susceptible to develop liver failure. Although the patient had a history of weekend binge drinking, his liver biopsy was not consistent with alcoholic hepatitis. Thus, we believe the liver failure was linked to the long-term energy drink consumption.”

According to the authors, the patient’s liver biopsy showed severe active hepatitis with bridging necrosis consistent with an herbal/drug-toxicity pattern. Upon worsening LFTs, the patient was placed on a donor waiting list and within a couple days found a suitable donor and underwent a successful liver transplantation.

“As energy drinks have become increasingly popular over the years, their ingredients are being looked at more closely, many which do not have a well-established safety profile. Some of these products have even been banned in other countries. While drinking modest amounts of energy drinks may be relatively safe, frequent consumption over an extended period of time has been linked with liver injury,” said Dr. Huang. More studies are needed to look at the relationships between energy drinks and liver damage.

Case Report 4: A Case of Drug-induced Liver Injury Arising from Ripped Fuel®

Another case of drug-induced liver injury was found in the advanced weight loss supplement, Ripped Fuel®. The supplement contains herbal extract with 60 percent flavoids, caffeine and cacao. The following case report illustrates drug-induced liver injury secondary to its use.

A 36-year old female with history of depression and no prior liver disease was seen after having one week of abdominal pain, anorexia and nausea. On physical examination, she had scleral icterus and mild jaundice. The patient had started to take Ripped Fuel® three weeks prior to developing these symptoms, to lose weight. She denied use of other herbal medicine, supplements or acetaminophen. There had been no recent changes in her depression medication.

“Initial laboratory findings suggested fulminant hepatic failure,” said lead author Hye Yeon Jhun, M.D. “Findings of the liver biopsy was consistent with marked portal inflammation, with circumferential interface activity and bridging hepatocyte necrosis consistent with DILI.” With treatment, the patient continued to improve clinically, with no evidence of hepatic failure during hospitalization, and was safely discharged.

Flavonoids have been thought to cause significant liver injury in several case reports. Treatment after development of drug-induced liver injury has been poorly defined, besides discontinuing the triggering substance. Previously, steroids have been studied to prevent tissue damage from inflammatory response, which failed to show beneficial effects. Dr. Jhun adds, “The usage of ursodeoxycholic acid (UDCA) has been shown to be favorable, due to protection of hepatocytes against cytotoxic effects of bile acids and stimulating hepatobiliary secretion. Recently, the combination of steroids and UDCA proved to benefit the outcome of patients with severe drug-induced liver injury.”

View the abstracts.

About the American College of Gastroenterology
Founded in 1932, the American College of Gastroenterology (ACG) is an organization with an international membership of more than 12,000 individuals from 80 countries. The College's vision is to be the pre-eminent professional organization that champions the evolving needs of clinicians in the delivery of high quality, evidence-based, and compassionate health care to gastroenterology patients. The mission of the College is to advance world-class care for patients with gastrointestinal disorders through excellence, innovation and advocacy in the areas of scientific investigation, education, prevention and treatment. www.gi.org. View releases on research breaking at the ACG meeting and follow ACG on Twitter and share your live updates #acg2013.

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Obesity Trumps Alcohol in Liver Damage

Daniel M. Keller, PhD

May 13, 2013

AMSTERDAM, the Netherlands — In terms of liver-related morbidity and mortality, obesity is even more dangerous than alcohol consumption, a study of more than 100,000 women has shown.

"For both overweight and obese women in this study, heavy drinking increased the absolute risk of liver events." The effect was additive if the women were overweight and super additive if they were obese, said lead author Paul Trembling, BM, MRCP, clinical research fellow at the Institute for Liver and Digestive Health, University College London, the United Kingdom.

Dr. Trembling presented the results here at the International Liver Congress 2013.

Dr. Trembling and his team examined the effect of the interaction between body mass index and alcohol consumption on liver-related events in the general population of women middle-aged and older.

The researchers obtained data on 107,742 women who participated in the UK Collaborative Trial of Ovarian Cancer Screening. They obtained follow-up data from routine healthcare databases and death certificates.

BMIs were calculated from self-reported height and weight at recruitment, and subjects reported their alcohol consumption 3.5 years after recruitment.

Median age at baseline was 61 years, 35% of the participants were smokers, 32% had hypertension, 24% had hypercholesterolemia, 6% had heart disease, and 5% had diabetes.

For alcohol intake, 62% of participants consumed 0 to 3 units per week (23% drank 0), 3% drank 16 to 20 units per week, and 2% drank more than 20 units per week.

For BMI, 44% of participants were in the normal range (18.50 - 24.99 kg/m²), 37% were overweight (25.00 - 29.99 kg/m²), and 19% were obese (≥30.00 kg/m²).

Investigators used hospital inpatient data and death certificates with any mention of alcoholic liver disease or fatty liver to determine the outcome measure of the incidence of a first event related to chronic liver disease, cirrhosis, or decompensation of cirrhosis.

During follow-up, there were 616 first events, including 110 deaths, 74 of which were from a liver-related cause. The standardized event rate was 0.06 per 100 participant-years.

For women who drank 20 units per week or less, being overweight was a risk-factor equivalent to drinking more than 21 units of alcohol per week, Dr. Trembling reported (adjusted hazard ratio, 1.7 vs 1.8). "For those who drink heavily, the risk of an event increases whether or not you are overweight and whether or not you are obese."

Table. Influence of Weight and Alcohol on Risk for Liver Outcomes

BMI (kg/m²)	Alcohol (Units/Week)	Adjusted Hazard Ratio (95% Confidence Interval)*
<30	<21	1.0
≥30	<21	1.7 (1.4–2.0)
<30	≥21	1.8 (1.0–3.4)
≥30	≥21	2.4 (0.8–7.6)

*After adjustment for metabolic factors.

Dr. Trembling reported that the event rate was higher in heavy drinkers who are overweight than in heavy drinkers who are not. It was also higher in people who are overweight but do not drink heavily. "The combined risk here is additive," he pointed out.

The risk is even higher in those who drink heavily and are obese. "The combined risk here is super additive," he said. The risk for an event is higher in those who are overweight than in those who drink heavily, and higher in those who are obese than those who drink heavily, he noted.

After adjustment for factors other than metabolic risk, the hazard ratios increase, indicating that features of metabolic syndrome contribute to the risk associated with weight.

Dr. Trembling concluded that the absolute risk for liver events increases with increasing alcohol consumption and weight gain, but BMI appears to be the greater risk. The absolute risk for events attributable to high alcohol intake is similar to that attributable to being overweight, and obesity results in a higher risk than heavy alcohol consumption.

"If you're obese, the damage that you do to yourself by drinking is much greater than if you're just overweight, explained senior researcher William Rosenberg, MBBS, DPhil, professor of hepatology at University College London.

"This is the first study really to demonstrate this in a large population of women," he said. "People are not aware that they are putting themselves at this risk."

During a news conference, moderator Daniele Prati, MD, from the Ospedale Alessandro Manzoni in Lecco, Italy, pointed out that Europe has the heaviest alcohol consumption in the world, and that alcohol consumption is the third leading cause of early death and illness, after tobacco and hypertension.

"From the early 1970s to 2000 in England, there was a 10-fold increase in women aged 35 to 44 dying from liver cirrhosis," he said.

He praised the study for its large size and for its assessment of the influence of alcohol and weight on liver-related morbidity and mortality. "There is a need to better set the proper thresholds, alone and in combination, to be able to prevent liver disease," Dr. Prati explained.

Solutions do not lie with hepatologists, he told Medscape Medical News. "Most of the work should be done with education and by the government in terms of...sensitizing the population to the risk. That's probably the only way, because both obesity and alcohol, despite the relevance for public health (not only in terms of liver disease), are conditions for which we have no really effective treatments," he concluded.

Dr. Trembling and Dr. Rosenberg have disclosed no relevant financial relationships. Dr. Prati reports consulting for Roche, Bristol-Myers Squibb, Novartis, and AbbVie.

International Liver Congress 2013: 48th Annual Meeting of the European Association for the Study of the Liver (EASL). Abstract 115. Presented April 27, 2013.

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Herbal, Body Building, Diet Supplements Linked To Severe Liver Damage, Study

Even though supplements account for 18 percent of all liver injuries in the U.S. and their potential side effects and hepatotoxicity of supplements are still not well defined, nearly 4 out of 10 Americans take them. (David Gray/Reuters)

People taking body-building, weight-loss pills and other types of dietary and herbal supplements may be at risk for liver injury severe enough to warrant an organ transplant, experts warned.

By Christine Hsu | May 22, 2012

People taking body-building, weight-loss pills and other types of dietary and herbal supplements may be at risk for liver injury severe enough to warrant an organ transplant, experts warned at a press briefing at Digestive Disease Week in San Diego.

Even though supplements account for 18 percent of all liver injuries in the U.S. and their potential side effects and hepatotoxicity of supplements are still not well defined, nearly 4 out of 10 Americans take them.

"The number of cases in our network has increased over the years," Serrano said during the briefing. "There were no deaths, but 7% of patients needed a liver transplant. These are not trivial consequences," Dr. Jose Serrano of the National Institutes of Health said at the conference, according to Medpage Today.

According to the latest research from the U.S. Drug Induced Liver Injury Network, which evaluated patient information from eight locations across the U.S. from 2003 to 2011, dietary supplements used for body building and weight loss are the most common of any supplements to cause liver injury.

Serrano said that out of the 679 liver injury cases analyzed, 93 of the cases were caused by patients taking herbal or dietary supplements, adding that many of these patients were often younger than those who have similar liver injuries caused by other medications.

Among patients who had liver damage caused by supplements, 33 percent of them used them for body building, 26 percent for weight loss, and the remaining 31 percent used a variety of other supplements.

While the symptoms of liver injury caused by dietary or herbal supplements weren’t much different from injuries caused by other medications, researchers noted that one factor that distinguished liver injury from body building and supplements over drugs were itching, which occurred in more than 80 percent of the patients.

Around 66 percent of the patients in the study had to be hospitalized and 11 percent had developed abnormal liver function that lasted for more than 6 months.

While more than half of patients were only taking one type of supplement, 23 percent of patients used two or more supplements and 16 percent of patients look at least one supplement along with prescription drugs.

"There is so little regulation of the many products on the market," lead researcher Dr. Victor Navarro, professor at Thomas Jefferson University in Philadelphia, said in a meeting news release. "We couldn't possibly begin to figure out which products to target first without doing this research."

Dr. Donald Jensen of the University of Chicago warned that the biggest risk to patients that use supplements is not reporting it to a healthcare professional.

"Patients need to be label readers," Jensen told MedPage Today. "They can't just assume that everything out there is safe. There are things out there that can be potentially damaging."

He added that most patients may think that supplements "are food or that they're very safe. And there are some herbal medicines that probably are safe and may even do some benefit for people. I don't want to throw everything in the trash can. But, on the other hand, there are enough [supplements] that are damaging."

While not all people react negatively to supplements, Jensen said that there needs to be more research on potential patient interactions with herbal supplements.

"I don't think we're going to stop people from taking herbal medicines," he said. "I'd like to see the FDA regulate the toxic ones better, but otherwise I think the important next step is some scientific understanding of why some people get damaged and others don't."

Published by Medicaldaily.com

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Also See: Herbal, Dietary Supplements Take Toll on Liver

Hepatitis C Causing Liver Damage in Greater Numbers: Study

Last Updated: May 22, 2012.

An additional 300,000 Americans could develop advanced liver disease from the virus by 2015.

TUESDAY, May 22 (HealthDay News) -- Hundreds of thousands of Americans infected with chronic hepatitis C virus could develop potentially life-threatening liver complications over the next few years, according to a new study.

Researchers evaluated medical insurance claims data and found that more than 200,000 hepatitis C patients had advanced liver disease in 2008, and estimated that another 300,000 patients could have advanced liver disease by 2015.

The risk of developing advanced liver disease is especially high among baby boomers, who account for 82 percent of hepatitis C patients in the United States, according to the findings, which are scheduled to be presented Tuesday at the Digestive Disease Week meeting in San Diego.

The study was funded by Vertex Pharmaceuticals, makers of the hepatitis C drug Incivek (telaprevir).

"This alarming finding places additional stress on an already overburdened health care system, which will need to prepare for an increase in patients suffering from advanced liver disease," Ann Kwong, vice president and hepatitis C virus franchise lead at Vertex, said in a meeting news release. "It is critical to treat [hepatitis C] patients before they develop costly and irreversible liver complications."

Screening patients for hepatitis C infection can help doctors identify and potentially cure infection before liver complications occur. Available hepatitis C treatments are most effective in patients without advanced liver disease, so early diagnosis offers patients the best chance to be cured, Kwong said.

Up to 5 million U.S. adults have chronic hepatitis C, and as many as 75 percent of them don't know they have the infection. Chronic hepatitis C is the leading cause of liver cancer and the most common reason for liver transplant in the United States.

Last week the U.S. Centers for Disease Control and Prevention recommended that all Americans born between 1945 and 1965 -- the baby boom generation -- be tested for hepatitis C.

Because this study was presented at a medical meeting, the data and conclusions should be viewed as preliminary until published in a peer-reviewed journal.

More information

The American Academy of Family Physicians has more about hepatitis C.

SOURCE: Digestive Disease Week, news release, May 22, 2012

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Some liver damage can be reversed through exercise

Updated: 2012-03-05 16:42:38 CST

Most people associate liver problems like cirrhosis with years of heavy drinking. However, people who have never touched a drop of liquor in their lives are increasingly receiving unhealthy liver panel test results. The cause is obesity.

Excess body fat is a risk factor for a condition known as non-alcoholic fatty liver disease. It occurs when the liver is unable to clear the excess fat from the blood and instead stores it. This can cause scarring and loss of healthy function, according to the Mayo Clinic. However, it is possible to reverse the condition.

Experts from the Baylor College of Medicine recently told the school's news source that every pound a person loses gets them one step closer to healthy liver function. This can be accomplished through a healthy diet and exercise.

"Losing 10 percent body weight primarily reduces fat inside the abdomen, which triggers a significant amount of liver healing," Dr. John Vierling told the news source. "It's easy for people to get discouraged when it comes to weight loss, but understanding that every pound lost is helping your liver heal is motivating."

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Serum Levels of Alanine Aminotransferase Decrease With Age in Longitudinal Analysis

Clinical Gastroenterology and Hepatology
Volume 10, Issue 3 , Pages 285-290.e1, March 2012

Mamie H. Dong, Ricki Bettencour, David A. Brenner, Elizabeth Barrett–Connor, Rohit Loomba

published online 24 October 2011.

Abstract

Background & Aims

An increased level of alanine aminotransferase (ALT) is a marker of liver injury. The mean ALT level has been reported to decrease with age; we performed a longitudinal analysis to determine whether serum levels of ALT changes with age among community-dwelling, older adults in the US.

Methods

We analyzed clinical data from 2 cohorts of individuals who participated in the Rancho Bernardo Study, in Southern CA. The first cohort comprised 1073 community-dwelling participants (59% women); clinical data was collected from 1984–1987 and 1992–1997. The second cohort comprised 416 participants (64% women); data was collected from 1984–1987, 1992–1997, and 1997–1999. Demographic, metabolic covariates, ALT, bilirubin, and albumin were measured. Changes in individual ALT over time were examined in unadjusted and multivariable-adjusted linear and logistic regression analyses.

Results

At the baseline visit, the patients' mean age was 65.7 years and body mass index was 24.9 kg/m². In cohort 1, the mean levels of ALT decreased with age by 10% (from 21 to 19 IU/L) between the time periods of 1984–1987 and 1992–1997 (P < .0001). In cohort 2, they decreased by 20% (from 20 to 16 IU/L) between the time periods of 1984–1987 and 1997–1999 (P < .0001). Categorically-defined increases in ALT also decreased with age (P < .0001). Results remained consistent in sex-specific analyses and after adjusting for metabolic syndrome components, alcohol use, bilirubin, and serum levels of albumin (P < .0001).

Conclusions

In a longitudinal analysis, we observed that levels of ALT decrease with age, independent of sex, metabolic factors, alcohol use, and results from commonly used liver function tests (bilirubin and albumin). When interpreting serum levels of ALT, physicians should consider patients’ age especially in the elderly.

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