Gyongyi Szabo, MD, PhD, FAASLD

Gyongyi Szabo, MD, PhD, FAASLD

Alcoholic liver disease is getting a new name, alcohol-associated liver disease, or AALD. The disease is also getting new treatment approaches and new attention from researchers, clinicians and industry.

“Alcohol use has been a concern for as long as we have had alcohol,” said Gyongyi Szabo, MD, PhD, FAASLD, Worcester Foundation for Biomedical Research Endowed Chair and professor of medicine at the University of Massachusetts Medical School and medical director at the Hepatology Center at UMass Memorial Medical Center, Worcester. “Renewed attention to alcohol and its effects on the liver and other organs has given us a new name for the disease, as well as new understanding and new approaches to treatment.”

Dr. Szabo provide an update on AALD during the AASLD State-of-the-Art Lecture Alcoholic Liver Disease: New Paradigms and Treatments on Tuesday, June 5, at DDW® in Washington, D.C.

About 35 percent of Americans do not drink and another 37 percent drink but are at low risk for AALD, Dr. Szabo said. The other 28 percent are heavy drinkers or at high risk for AALD for other reasons. Daily alcohol intake of 60 grams — a little more than four average drinks in the U.S. — seems to be the tipping point for developing AALD, Dr. Szabo said.

AALD affects multiple organs. In the brain, it can lead to inflammation, cognitive impairment and addiction.

In the liver, excessive alcohol leads to steatosis, inflammation and cellular damage.

In the gut, alcohol induces inflammation and decreases barrier function, allowing microbial translocation into the circulation.

Alcohol also has inflammatory and other effects on the immune system, pancreas, heart and muscle tissue.

In 2017, AASLD and the European Association for the Study of the Liver facilitated a meeting of international experts to explore alcohol-associated liver disease. And early this year, the Food and Drug Administration and the National Institute on Alcohol Abuse and Alcoholism held a consensus conference to better define AALD and clinical endpoints. The result was the transition from alcoholic liver disease to AALD and a new understanding of optimal clinical trials.

“We now have a roadmap for future studies,” Dr. Szabo said. “And we have new paradigms for the spectrum of the disease, better clinical definitions, emerging biomarkers, better management, new clinical study designs, new therapeutic targets and drug candidates, and growing interest in AALD by the pharmaceutical industry.”

One of the most important barriers to the study and treatment of alcohol-related diseases is the societal stigma surrounding alcoholism. It’s still widely seen as a personal failing, Dr. Szabo said. The new name, AALD, is intended to minimize that stigma and change perceptions.

“AALD or alcoholic hepatitis is not a personal choice,” Dr. Szabo emphasized. “These patients have a disease that drives them to alcohol use.”

Several genes have emerged as risk factors for AALD, including PNPLA3, the “steatosis gene,” and two “fibrosis genes,” TM6SF2 and MBOAT7.

Women are at increased risk for alcohol-related diseases. Alcoholic hepatitis develops at lower daily or cumulative alcohol intake compared to men. Women also have an increased risk for, and faster progression to, liver cirrhosis than men.

Obesity also plays a role. A body mass index greater than 25 in women and 27 in men carries a 2.5-fold risk for the development of cirrhosis. Obesity is also a risk factor for steatosis and alcoholic hepatitis.

Alcoholic hepatitis (AH) severity also has a new clinical definition, Dr. Szabo said. Moderate AH is defined as bilirubin greater than 3 mg/dL and mDF less than 32, or a MELD score of 11 to 20. Severe AH is bilirubin greater than 5 mg/dL and mDF of 32 or greater, or MELD greater than 20. The most recent data shows that MELD score is a better indicator than mDF, Dr. Szabo noted.

Current biomarkers, including AST, AST/ALT ratio, DF and others, are imprecise at best. Dr. Szabo said there’s an active search for more precise biomarkers in blood, serum, plasma, proteins, microRNAs, extracellular vesicles, urine, breath, saliva, stool and other sources.

“Stay tuned,” Dr. Szabo advised. “There should be new biomarkers available in a couple of years.”

The most important management change is to approach AALD as an addictive behavior that benefits from a combination of medical treatment, psychosocial support and psychiatric referral. A team approach with an addiction specialist, nutritional expert and social worker can improve outcomes for AALD.

Medical treatment for addiction can be problematic in AALD, Dr. Szabo cautioned. There are four FDA-approved medications for alcohol dependence: disulfiram, naltrexone, extended release naltrexone and acamprosate. Disulfiram causes hepatic toxicity and naltrexone is toxic in obesity and has limited used in advanced liver disease. Acamprosate is currently the most useful agent, but other candidates are in development.

Dr. Szabo suggested using two alcohol treatment locations. The NIAAA Alcohol Treatment Navigator is designed for families and patients looking for treatment options. The Substance Abuse and Mental Health Services Administration has a national helpline that offers free, 24-hour confidential treatment referral and information.

Clinical outcomes in alcoholic hepatitis have not improved in 50 years, Dr. Szabo noted. Corticosteroid therapy can improve survival, but adding pentoxifylline does not improve outcomes. Liver transplantation remains the best available treatment.

But that could change. The brain is the latest target to treat alcohol addiction. Hepatocytes, inflammation, stellate cells, gut mucosal barrier, activated macrophages and the microbiome are all emerging as new targets.

Several clinical trials using various agents — IL-1 receptor antagonists, probiotics, bovine colostrum, IL-22, obeticholic acid and granulocyte-colony stimulating factor among others — are under way. Early data could be reported later this year, Dr. Szabo said.