Options for Alcohol-Associated Liver Disease Therapies Should Include Metabolic Risk

Hepatologists managing alcohol-associated liver disease (ALD) must consider all aspects of the disease, including both addiction and metabolic risk factors, according to Po-Hung (Victor) Chen, MD, PhD, assistant professor of medicine at Johns Hopkins University School of Medicine who is speaking on medical therapies for ALD during Digestive Disease Week® (DDW) 2024.

“ALD is only one-half of the condition,” says Dr. Chen in an interview. “Alcohol use disorder is the other. To have long-lasting impacts, we need to improve our approaches toward both facets of the condition, starting as early as possible with screening and detection.”

DDW News spoke with Dr. Chen about the challenges to developing medical therapies for ALD:

DDW: What is the current state of medical treatment for ALD?

Chen: Currently, we don’t have many effective, proven therapies. Corticosteroids with or without intravenous N-acetylcysteine are the only evidence-based treatment for acute alcohol-associated hepatitis. These therapies only impact short-term mortality and are ineffective for up to 35–40%  of patients.

DDW: What are some of the challenges to managing ALD?

Chen: In addition to a lack of therapies, a new category of ALD, MetALD, was recently recognized by professional liver societies worldwide. This new category acknowledges the synergy between unhealthy alcohol use and metabolic risks on liver disease progression.

In the short term, this new category presents challenges because we haven’t established best practices for managing ALD in the presence of multiple metabolic risk factors. In the long term, I am hopeful that this will open an avenue for new treatment strategies.

In addition, we don’t have enough physicians who are comfortable managing all aspects of ALD, namely alcohol use disorder. Up to 80% of individuals with advanced ALD also have moderate-to-severe alcohol use disorder as defined by DSM-5 criteria. We need more primary care providers, gastroenterologists and hepatologists familiar with the fundamental principles of addiction care.

DDW: Why has it been difficult to develop new medical therapies for ALD?

Chen: The ALD field has seen decades of disappointing trial results for studies on candidate pharmacotherapies to reduce inflammation, which would likely improve outcomes. Several medications are currently being studied for ALD, including glucagon-like peptide 1 agonists in the setting of MetALD, and granulocyte colony-stimulating factor, but we don’t have robust data yet.

It’s challenging to study new candidate agents for several reasons. On the preclinical side, we don’t have animal models yet that mimic the human phenotype of alcohol-associated hepatitis with organ failure and a high risk for short-term mortality.

On the clinical side, we need biomarkers that can show treatment response. In addition, recruiting and retaining patients in clinical trials involving alcohol or substance use is a challenge. Participants may not be interested in research, experience socioeconomic barriers that limit access to transportation, feel stigma or guilt at having resumed substance use, or be too ill to follow up.

DDW: How might new medications for ALD impact how it is managed?

Chen: New, efficacious medications for decompensated ALD or acute alcohol-associated hepatitis may:

• Reduce the need for rescue liver transplants for patients with severe ALD.
• Increase the availability of liver transplants for those in need, including patients with severe ALD who do not improve with even the new efficacious medications.
• Provide extra time for patients to engage with alcohol use disorder treatment services.
• Shift overall healthcare utilization for ALD earlier in the care cascade to emphasize prevention, early detection and timely outpatient treatment.

Dr. Chen’s oral presentation, “Meds for ALD — ready for primetime?” on Monday, May 20, at 2 p.m. EDT is part of the session “Pharmacotherapies For Alcohol-Associated Liver Disease  — Ready For Primetime?”