Through the Lens of CK18:  Reflections on the AASLD ETC 2025: metALD and ALD

Posted on: March 31, 2025

— Contributed by Olivia Stricker, PhD and Jessica Tuohy, PhD

The 2025 AASLD Emerging Topics Conference in Las Vegas delivered an invigorating discussion on one of the most pressing challenges in hepatology today—metabolic dysfunction-associated alcohol-related liver disease (metALD) and the evolving landscape of ALD clinical trials. As research advances, our understanding of these diseases continues to shift, with new therapeutic strategies emerging that could reshape patient outcomes.

The Rising Complexity of metALD

  1. metALD actually covers three diseases in many instances (metabolic, liver, and AUD-mental health), making classification and treatment complex.
  2. metALD and ALD as disease categories are likely much larger problems in the real world than depicted in the literature due to stigma, underreporting of alcohol use, and lack of alcohol-related data.
  3. Alcohol seems to be a more severe risk factor than metabolic dysfunction, but aging could be the highest.
  4. Time and pattern of alcohol use are major challenges for clinical trials. Alcohol consumption patterns can change significantly over a trial’s course, potentially altering patient categorization and confounding drug efficacy evaluations.
  5. GLP1 drugs are now a first-line therapy for diabetes and obesity, potentially confounding trials and shrinking treatable trial populations.

The Complex Role of Alcohol in Liver Disease

There is a consensus that any amount of alcohol is detrimental to liver health, but much remains unknown about the nuances of alcohol consumption patterns and their impact on liver disease.

Key Unanswered Questions:

  • What are the most harmful drinking patterns? While consistently high intake is clearly damaging, where do low daily consumption and periodic binge drinking fall on the risk spectrum?
  • What are the most harmful drinking levels? Is two drinks per day low or medium risk? Is binge drinking on weekends a high-risk factor?
  • How does time impact liver damage? Since the liver regenerates, does heavy drinking 10 years ago have the same long-term impact as a recent 6-month period of heavy drinking?

Metabolic Considerations in Trial Design

Certain metabolic risk factors should be prioritized when designing trials for metALD and ALD:

  • BMI and Type 2 Diabetes should be required as at least one of the two cardiometabolic risk factors for trial inclusion.
    • Not all cardiometabolic risk factors (CMRFs) contribute equally to fibrosis, suggesting they should be weighted differently in disease classification.
  • Fluctuations in alcohol consumption and weight can cause major shifts in patients between categories, complicating long-term trial results.
  • GLP1s are here to stay, but they are expensive and not universally effective, making their role in liver disease management uncertain.
  •  Rezdiffra™ trials show that high drinkers (per PEth tests) still benefit from the drug, suggesting metALD-specific trials may not always be necessary.

Challenges in Trial Design

Alcohol consumption must be carefully accounted for in clinical trial design, but it is not ethical to require consistent alcohol use as a control factor. This makes the evaluation of drug efficacy difficult. PEth testing is widely agreed to be the most accurate short-term (weeks) measure of drinking levels but does not yet fully capture drinking patterns.

Other trial design challenges include:

  • Transient elastography (FibroScan) is unreliable in active drinkers, as alcohol-induced inflammation can skew liver stiffness readings.
  • Alcohol affects metabolic markers, such as blood pressure and lipid synthesis, potentially confounding the evaluation of drug efficacy.
  • Grouping metALD with ALD for trial design and stratifying by alcohol consumption levels could improve comparisons within clinical trials.
  • AUD is an underappreciated third disease influencing alcohol-related liver damage, yet exclusion of high-AUD risk patients could bias trial results.
  • Endpoints?…. FDA approval of potential metALD therapies will be based on monitoring of clinical events, however, improvements in histology evidenced by liver biopsies won’t be required for Subpart H approval. Which NITs can predict outcomes in MetALD and could serve as surrogate endpoints instead?

The Potential Role as a Problem Solver:  CK18 as a metALD Biomarker

  1. In ALD research, CK18 shows an association with disease severity and has been shown to characterize subject populations more effectively than ALT or transient elastography (TE). These research findings suggest potential areas for further investigation and validation.
  2. Dr. McClain suggested that CK18 levels may help investigate where on the MASLD-metALD-ALD spectrum a subject falls.
  3. CK18 is widely used in MASH trials as a treatment response marker. In ALD studies, it correlates with disease severity and changes rapidly with alcohol abstinence, making it a strong candidate for metALD and ALD trials.

Conclusion

The AASLD 2025 conference highlighted the increasing complexity of metALD and ALD, underscoring the urgent need for refined biomarkers, robust trial designs, and interdisciplinary approaches. As clinical trials adapt to new therapies like GLP1s and emerging biomarkers like PEth and CK18, the hepatology community must navigate the evolving landscape of alcohol-related and metabolic liver disease to improve patient outcomes.

Don’t be like Heppy Liver, be a Happy Liver!