Spontaneous Fluctuations in Liver Biochemistries in Patients with Compensated NASH Cirrhosis: Implications for Drug Hepatotoxicity Monitoring
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Introduction Patients with cirrhosis may have spontaneous fluctuations in liver enzymes, which may confound detection of drug-induced liver injury (DILI), but these fluctuations have not been described.Objective We sought to quantify spontaneous liver enzyme abnormalities in patients with cirrhosis due to nonalcoholic steatohepatitis (NASH) enrolled in clinical trials.Methods We examined the laboratory values of patients with compensated cirrhosis randomized to placebo in two clinical trials for NASH. Patients in one study were followed every 13 weeks up to week 57; patients in the other study were followed every 4 weeks up to week 120.Results In total, 53 and 85 patients were randomized to placebo in the trials. Baseline alanine aminotransferase (ALT) was greater than the laboratory upper limit of normal (ULN) in 53% and 49% of participants, aspartate aminotransferase (AST) was > ULN in 49% and 59%, alkaline phosphatase was > ULN in 36% and 27%, and bilirubin was >ULN in 13% and 19%. During follow-up, ALT increased to 2× baseline in 8% and 15%, AST increased to 2× baseline in 6% and 21%, and bilirubin increased to 2× baseline in 9% and 18%. Alkaline phosphatase did not increase to 2× baseline for any patient. The maximum ALT was 3× ULN in 9% and 12%. ALT increased to 3× baseline in three patients and to 5× ULN in two patients. No patients had elevations consistent with Hy's law. The maximum ALT for patients with abnormal baseline values was higher [median 48 U/L (range 34-299) and 56 U/L (47-85)] than for those with normal baseline values [median 26.5 U/L (range 18-33) and 29 U/L (25.5-30.5)] in both studies, respectively, with p < 0.001.Conclusion Spontaneous liver enzyme abnormalities are common in patients with NASH cirrhosis in clinical trials, and these abnormalities rarely met criteria for DILI suspicion. Further work to better define these abnormalities and continued vigilance to detect DILI in this population is needed.
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Patients with MASLD may have spontaneous improvement without intervention, which could contribute to high placebo response rates in clinical trials.
“Additionally patients may have spontaneous improvement without intervention, a feature that could contribute to the surprisingly high rates of response among placebo patients in clinical trials (250-252).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [250]
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References 29 · Cited by 6
- Authors
- Shamseddeen, H., Vilar-Gomez, E., Chalasani, N., Myers, R. P., Subramanian, G. M., Shlevin, H. H., Allgood, A. E., & Orman, E. S.
- Affiliations
- Indiana University School of Medicine (US)
- Gilead Sciences (United States) (US)
- Galectin Therapeutics (United States) (US)
- Corresponding author
- Orman, Eric S.
- Venue
- Drug Safety
- Published
- 2020-01-06
- Volume
- 43
- Issue
- 3
- Pages
- 281-290
- ISSN
- 0114-5916 (ISSN-L)
- 1179-1942
- PMC
- PMC7050367
- OpenAlex
- W2996905269
- Cited by
- 6
- References
- 29
- Citations by year
- 2025: 1 · 2023: 3 · 2021: 1 · 2019: 1
- FWCI
- 0.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Drug Safety (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (K23DK109202)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Keywords
- NASH cirrhosis, nonalcoholic steatohepatitis, drug-induced liver injury, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, Hy's law, compensated cirrhosis, clinical trial safety monitoring
- MeSH terms
- Alanine Transaminase, Alkaline Phosphatase, Aspartate Aminotransferases, Bilirubin, Female, Humans, Liver, Liver Cirrhosis, Male, Middle Aged, Pectins, Risk Factors, Chemical and Drug Induced Liver Injury, Antibodies, Monoclonal, Humanized, Non-alcoholic Fatty Liver Disease
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