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New Research in Alcoholic Hepatitis and Liver Disease

March 18, 2019

Section Chief of Hepatology, Ramon Bataller, MD, PhD, studies the epidemiological, clinical, and molecular aspects of alcoholic fatty liver disease and alcoholic hepatitis. As a member of the American Association for the Study of Liver Diseases (AASLD), Dr. Bataller sits on the Alcoholic Liver Disease Special Interest Group (ALD SIG). Dr. Bataller is a co-editor of The Journal of Hepatology, and in 2018 he was named as a permanent member to the Hepatobiliary Pathophysiology Study Section at the National Institutes of Health (NIH).

Dr. Bataller is a primary investigator in one of four NIH-funded consortia seeking to identify the molecular targets responsible for disease pathogenesis and novel treat - ments for alcoholic hepatitis — the most severe form of alcoholic liver disease (ALD).

Dr. Bataller’s research has identified that a systemic inflammatory response as part of the alcoholic hepatitis disease course is likely driving the induction of renal failure and other complications. Identifying which molecular signatures emanate from the liver and cause the inflammatory response may lead to more effective, targeted therapies. Further research by Dr. Bataller seeks to better understand the regenerative mechanisms of the liver in relation to alcoholic hepatitis — when, how, and why the regeneration process fails, leading to acute and dramatic decompensation and liver failure. Previous work also has shown that a decrease in persistent alcohol intake is the primary determinant of long-term survival in patients with alcoholic hepatitis.

“Alcoholic liver diseases and associated patient morbidity and mortality have been steadily increasing over the last two decades, particularly in the United States, with troubling increases in younger patients and also in females who in the past have had a lower incidence of disease. The recent large epidemiological studies highlight these trends and the new challenges we are facing with preventable liver disease. Layer into these findings the rising rates of obesity in the general population, and the rampaging national opioid abuse problem, and it should come as little surprise that liver disease associated with alcohol consumption is affecting more and younger people,” says Dr. Bataller.

Severe Consequences — Alcoholic Hepatitis

The most severe form of alcoholic liver disease is alcoholic hepatitis (AH). It is a condition Dr. Bataller has spent many years studying, and one he sees all too frequently in the clinic. “Incidence of the condition is increasing, and we still have few effective treatments outside of prevention. Once it manifests, decompensation can be rapid and irreversible. There is a 30 percent chance of death within three months. We see AH in younger and younger patients. Of course, not everyone who abuses or uses alcohol excessively ends up with AH, and this conundrum is the focus of one of our recently received grants,” says Dr. Bataller.

Dr. Bataller has three current, active research grants funded by the NIH to investigate various aspects of alcoholic hepatitis. One study examines the potential genetic factors that may predispose an individual to the condition. This study is a collaborative effort with Dr. Laura Nagy at the Cleveland Clinic, the NIH, and other institutions to pinpoint genetic determinants predisposing individuals to AH.

A second project, an NIH-funded U01 grant, is a basic science study designed to further Dr. Bataller’s research into why hepatocytes in the liver fail during alcoholic hepatitis. This research will explore the main transcription factors that regulate gene expression in hepatocytes.

“From previous studies, we determined that in alcoholic hepatitis the hepatocytes that regenerate revert to a fetal-like state. New hepatocytes form in response to the liver injury. They grow, sometimes with massive hepatomegaly, but they do not function properly. As a consequence of this improper functioning, the liver fails. These hepatocytes grow massively in a dedifferentiated fashion but cannot synthesize albumin or clotting factors. There are many of these new hepatocytes, but they are metaplastic and dysfunctional. We hope, with our new research over the next five to six years, to identify a way to modulate or inactivate this fetal transcription factor,” says Dr. Bataller.

Lastly, Dr. Bataller is leading a multicenter, multiarmed clinical trial with the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and nine centers across the United States to examine new and promising thera -  peutics to combat alcohol-caused liver disease and damage. One of the first trials in this new effort will compare the use and effectiveness of the growth factor known 
as granulocyte colony-stimulating factor (G-CSF) versus the use of anakinra, an interleukin-1 antagonist. Both agents are being compared against the current standard- of-care treatment — prednisone — in cases of alcoholic hepatitis.

“G-CSF is a colony growth factor that can mobilize the glomerular cells to repopulate the liver and regenerate it. Anakinra, also known as Kineret®, is a biologic agent that works to decrease inflammation and is currently used in the treatment of rheumatoid arthritis and other inflammatory conditions. We are completing the study design and IRB reviews for this trial now. This is but one of a number of new clinical investigations to examine new and novel therapeutic targets for treating AH. We are tremendously excited to see where the science leads us,” says Dr. Bataller.

References and Further Reading

Moon A, Barritt AS, Bataller RB, Peery AF. Alcohol Associated Liver Disease Mortality Rates in the United States, 1999-2016. Pending publication.

Tapper EB, Parikh ND. Mortality Due to Cirrhosis and Liver Cancer in the United States, 1999-2016: Observational Study. BMJ. 2018; 362: k2817. Alcoholic Hepatitis Consortia: An Intramural/Extramural Collaboration to Unravel Genetic Determinants. NIH Project Number: U01aa026264-02.

Liver-Enriched Transcription Factors as Prognostic Markers and Therapeutic Targets in Alcoholic Hepatitis. NIH Project Number: UO1AA026972-01.

Alcoholic Hepatitis Clinical and Translational Network Late Phase Clinical Trials and Observational Studies 7/9. NIH Project Number: UO1AA02697801.