Prognostic value of liver histology in steatotic liver disease: a systematic literature review and meta-analysis
Publication: Journal of Comparative Effectiveness Research
Abstract
Aim: Metabolic dysfunction-associated steatohepatitis (MASH) and steatotic liver disease (MASLD) are progressive liver conditions that can lead to serious long-term outcomes and adverse clinical events. Histologic liver fibrosis is an accepted short-term surrogate end point used in pivotal clinical trials supporting conditionally approved MASH therapies. This study aimed to synthesize up-to-date published associations between histologic liver fibrosis and clinical outcomes, including several novel syntheses. Materials & methods: A systematic literature review identified studies of MASH ± MASLD patients published January 2014 to November 2024 from Ovid MEDLINE®, Embase and grey literature. Studies reporting hazard ratios (HRs) comparing the risk of relevant major adverse liver outcomes (MALO; e.g., cirrhosis, hepatic decompensation, hepatocellular carcinoma) and mortality by histologic liver fibrosis stage were included in meta-analysis. Pooled estimates were reported as HRs and 95% CIs. Results: Of 2810 returned records, there were 32 eligible studies from 39 articles. Higher fibrosis stage was associated with increased risk of clinical outcomes. Risk of progression to cirrhosis was twofold higher in F3 versus F2 (2.05 [1.45, 2.90]). Risk of hepatic decompensation was >ten-times higher in F3–4 versus F0–2 (10.93 [6.31, 18.92]). Risk of MALO and all-cause mortality were also significantly higher in F4 versus F3 and versus F2, and in F3–4 versus F0–2. Results were directionally consistent among studies of MASH-majority (≥80% MASH) populations and individually reported HRs. Conclusion: Increased clinical risk with more advanced fibrosis and/or cirrhosis among patients with significant liver disease supports the value of histologic liver fibrosis as a short-term surrogate for long-term clinical outcomes.
Plain language summary: Using long-term studies to connect changes in liver tissue to risk of serious consequences for patients with metabolic dysfunction-associated steatohepatitis
What is this article about?
In chronic liver diseases such as metabolic dysfunction-associated steatohepatitis (MASH), symptoms may not be visible until they have progressed to serious consequences such as liver failure or liver cancer, which may be life-threatening. A challenge of testing new medications for MASH is the length of time it can take for these serious consequences to occur, which can be longer than the 1–2 years of most clinical trials. In such cases, a clinical trial may use a ‘proxy’ test that is known to be connected to serious long-term consequences, but shows improvements in a shorter timeframe. Previous research has found that a potentially useful proxy in MASH is liver scarring (‘fibrosis’), and many studies have individually found a connection between severity of liver fibrosis and risk of serious long-term consequences. This article aimed to combine the data from these studies to determine how consistent and strong this connection is across studies.
How was the research carried out?
The authors reviewed previously published studies measuring both liver fibrosis and later occurrence of serious consequences, including liver swelling, bleeding, failure, transplant and death. Then the individual results of each study were pooled together in a combined analysis.
What were the results?
Both individual study results and the combined analysis showed that increased severity of liver fibrosis was associated with increased risk of cirrhosis and other liver problems leading to hospitalization, as well as death, indicating that liver fibrosis is likely a useful proxy test for clinical trials.
Supplementary Material
File (supplementary data.docx)
References
Papers of special note have been highlighted as: • of interest
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Received: 8 July 2026
Accepted: 17 August 2026
Published online: 3 September 2026
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Prognostic value of liver histology in steatotic liver disease: a systematic literature review and meta-analysis. (2026) Journal of Comparative Effectiveness Research. DOI: 10.57264/cer-2026-0148
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