Factors associated with histologic response in adult patients with nonalcoholic steatohepatitis
Open accessAbstract
Background & aims Nonalcoholic steatohepatitis (NASH) is a leading cause of liver transplantation, and many trials are underway to evaluate potential therapies. The farnesoid X receptor ligand obeticholic acid in the NASH treatment trial evaluated the effects of obeticholic acid vs placebo on histologic response (defined as decrease in nonalcoholic fatty liver disease activity score [NAS] by ≥2, with no worsening of fibrosis); 45% of patients had a histologic response to obeticholic acid (25 mg), and 21% had a response to placebo (P < .01). We performed a secondary analysis of data from this trial to identify clinical parameters associated with a histologic response.Methods We used a logistic regression model with a stepwise selection procedure to identify baseline and early on-treatment factors associated with a histologic response at 72 weeks. Baseline demographics, liver histology, medical history, concomitant medications, cardiometabolic parameters, and serum biochemistry, as well as the changes over the course of the trial (at weeks 12 and 24), were evaluated as potential predictors of a histologic response. The model was cross-validated by a jackknife method, and performance was evaluated with the area under the receiver operating characteristic curve.Results The logistic regression model found that obeticholic acid treatment, baseline NAS > 5, baseline triglyceride level ≤ 154 mg/dL, baseline international normalized ratio ≤ 1, baseline aspartate aminotransferase level ≤ 49 U/L, and a decrease in alanine aminotransferase level at week 24 by 17 U/L or more, to be significantly associated with histologic response (area under the receiver operating characteristic curve, 0.83; 95% confidence interval, 0.77-0.89; P < .0001).Conclusions In a secondary analysis of data from a clinical trial of obeticholic acid in patients with NASH, we identified routine clinical and laboratory parameters during the first 24 weeks of treatment (such as baseline NAS, triglyceride levels, and a decrease in alanine aminotransferase level) to significantly associate with histologic markers of response.
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A secondary analysis of the NASH CRN FLINT trial identified a decrease in ALT at week 24 as a predictor of response (namely a decrease in NAS of > -2 and no worsening of fibrosis).
“A secondary analysis of the NASH CRN FLINT trial identi fi ed a decrease in ALT at week 24 as a predictor of response (namely a decrease in NAS of > -2 and no worsening of fi brosis). 271”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [271]
The Methods identify this as an analysis of the NASH CRN FLINT trial, and the Discussion identifies a decrease in ALT at week 24 as a predictor of histologic response. The Introduction defines that response as a NAS improvement of at least 2 points without worsening of fibrosis; the citing sentence’s “> -2” does not accurately express that threshold. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAn ALT decrease of > -17 U/L yielded the highest accuracy to separate responders from nonresponders (OR > 10).
“An ALT decrease of > -17 U/L yielded the highest accuracy to separate responders from nonresponders (OR > 10).”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [271]
The Abstract Results and Results > Univariate Analysis report that an ALT decrease of at least 17 U/L at week 24 was associated with histologic response and differed significantly between responders and nonresponders. Our copy does not establish that ALT alone had the highest classification accuracy or an odds ratio greater than 10; the reported accuracy is for the multivariable model. The paper specifies a decrease of 17 U/L or more, rather than the claim’s ambiguous “> -17 U/L.” (LLM, conf=0.85)
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References 20 · Cited by 124
- Authors
- Loomba, R., Sanyal, A. J., Kowdley, K. V., Terrault, N., Chalasani, N. P., Abdelmalek, M. F., McCullough, A. J., Shringarpure, R., Ferguson, B., Lee, L., Chen, J., Liberman, A., Shapiro, D., & Neuschwander-Tetri, B. A.
- Affiliations
- University of California San Diego (US)
- Virginia Commonwealth University (US)
- Swedish Medical Center (US)
- University of California, San Francisco (US)
- Indiana University Indianapolis (US)
- Duke University (US)
- Cleveland Clinic (US)
- Intercept Pharmaceuticals (United States) (US)
- Corresponding author
- Loomba, Rohit
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 156
- Issue
- 1
- Pages
- 88-95.e5
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC6696948
- OpenAlex
- W2891159865
- Cited by
- 124
- References
- 20
- Citations by year
- 2026: 9 · 2025: 20 · 2024: 20 · 2023: 21 · 2022: 13 · 2021: 22 · 2020: 13 · 2019: 5 · 2018: 1
- FWCI
- 8.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Intercept Pharmaceuticals, Inc
- National Institute of Diabetes and Digestive and Kidney Diseases
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- nonalcoholic steatohepatitis, obeticholic acid, histological response, predictors of treatment response, triglyceride levels, aspartate aminotransferase, international normalized ratio, farnesoid X receptor agonist, liver fibrosis
- MeSH terms
- Receptor, Farnesoid X-Activated, Adult, Biopsy, Chenodeoxycholic Acid, Decision Support Techniques, Clinical Enzyme Tests, Female, Gastrointestinal Agents, Humans, Ligands, Liver, Liver Cirrhosis, Male, Middle Aged, Predictive Value of Tests, Time Factors, United States, Biomarkers, Treatment Outcome, Receptors, Cytoplasmic and Nuclear, Non-alcoholic Fatty Liver Disease
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