MASLD fibrosis significantly drives HCC risk, study finds

Advanced liver scarring sharply increases the risk of liver cancer in people with metabolic dysfunction–associated steatotic liver disease (MASLD), new research shows. The finding comes from a large meta-analysis that reconstructed data from nearly 4 million people and provides updated estimates of how cancer risk changes over time.

The study, published in Clinical Gastroenterology and Hepatology, pooled data from 26 cohort studies involving 3,995,728 individuals and found that cumulative hepatocellular carcinoma (HCC ) incidence rises steadily over time among patients with MASLD and advanced fibrosis, reaching 8.8% at 10 years in population-based administrative database cohorts and as high as 48.5% in hospital- or clinic-based cohorts.

For the analysis, senior author Daniel Q. Huang, MBBS, MCI, FRCP — of the Division of Gastroenterology and Hepatology in the Department of Medicine at National University Hospital, Singapore — and colleagues conducted a systematic review of Medline and Embase from inception through Nov. 21, 2024, identifying 4,951 articles.

After duplicate removal and screening, 26 studies met eligibility criteria and were included in the quantitative analysis. The researchers reconstructed individual patient time-to-event data from Kaplan–Meier curves reported in each study. They used a validated method that digitizes the survival curves and estimates when events occurred based on the number of patients at risk and the events reported in the study tables.

Across database studies, patients with MASLD and advanced fibrosis experienced a cumulative HCC incidence of 0.8% at 1 year, 2.4% at 3 years, 3.9% at 5 years, and 8.8% at 10 years. In contrast, patients without advanced fibrosis had substantially lower cumulative incidence estimates of 0.1%, 0.5%, 0.7%, and 1.3% at the same time points.

Multilevel Cox regression analysis confirmed the strength of this association. The presence of advanced fibrosis was linked to an approximately elevenfold higher risk of developing HCC compared with MASLD without advanced fibrosis in administrative database cohorts.

The pattern was similar but more pronounced in hospital- or clinic-based studies. In these cohorts, cumulative HCC incidence among patients with advanced fibrosis reached 3.9% at 1 year, 11.7% at 3 years, 21% at 5 years, and 48.5% at 10 years. Patients without advanced fibrosis had lower but still notable risks of 1.6%, 4.7%, 8.2%, and 18.3% over the same intervals. Advanced fibrosis in these cohorts was associated with a tenfold increase in HCC risk.

Subgroup analyses also highlighted the influence of cirrhosis. In administrative database studies, cumulative HCC incidence among patients with MASLD and cirrhosis reached 1.4% at 1 year, 4.1% at 3 years, 6.7% at 5 years, and 15.3% at 10 years, compared with 0.1%, 0.3%, 0.4%, and 1.1% among patients without cirrhosis. Cirrhosis increased the risk of HCC more than eightfold in these datasets.

Hospital-based cohorts again showed higher incidence overall. Patients with cirrhosis had cumulative HCC rates of 3.8% at 1 year, 10.3% at 3 years, and 20.5% at 5 years, compared with 0.9%, 2.8%, and 4.6% among those without cirrhosis. Cirrhosis increased the likelihood of HCC development more than twentyfold in these studies.

Researchers analyzed administrative database and hospital-based studies separately because of differences in patient selection and surveillance practices. Patients treated in specialty clinics may have more severe metabolic conditions and may receive cancer screening more often. This could lead to higher reported rates of HCC compared with rates seen in broader population-based datasets.

Sensitivity analyses also examined the effect of MASLD diagnostic methods. Studies that relied on histologic confirmation tended to report higher HCC incidence than those using imaging or administrative coding, which investigators attributed partly to selection bias because patients undergoing biopsy often have more severe disease.

MASLD has become the fastest-growing cause of HCC worldwide, according to the study authors. However, current European Association for the Study of the Liver guidelines say there is not enough evidence to recommend routine HCC screening for patients with MASLD and advanced fibrosis.

“These data help to supplement the knowledge gap, and further prospective studies will be helpful to discern if HCC surveillance is cost-effective for people with MASLD and advanced fibrosis,” the authors concluded.

Dr. Huang disclosed that he receives funding support from the Singapore Ministry of Health’s National Medical Research Council and the NUH Clinician Scientist Program.

____________________________________________________________________________________

GI & Hepatology News invited Maya Balakrishnan, MD, MPH, of the Section of Gastroenterology & Hepatology at Baylor College of Medicine, Houston, to weigh in on the study.

Why is this study important?

Dr. Balakrishnan: This study is important because MASLD is extremely common, and it is one of the fastest-rising causes of HCC. To figure out which patients with MASLD are at most at risk for HCC, we need precise, time-based estimates of risk. This study helps address this important public health question. It shows that HCC risk is not uniform across people with MASLD, and that HCC risk in MASLD is concentrated much more heavily in patients with advanced fibrosis and cirrhosis.

What are the potential clinical implications?

Dr. Balakrishnan: The biggest clinical implication is risk stratification. The study supports the idea that fibrosis stage is central when thinking about HCC risk in MASLD. They found that the risk of HCC over 10 years was substantially higher in MASLD with cirrhosis versus without cirrhosis: 8-fold higher in the database studies and 20 times higher in clinic/hospital samples. The analyses also showed that HCC hazard was higher in MASLD with advanced fibrosis versus without.

These findings provide continued evidence that patients with MASLD and cirrhosis need close surveillance. Whether surveillance is needed in people with advanced cirrhosis but without cirrhosis though is still an open question and requires further prospective studies to determine whether surveillance is beneficial and cost-effective in that subgroup.

What are the study’s key strengths?

Dr. Balakrishnan: First, the study includes a very large sample size, incorporating 26 studies and nearly 4 million individuals. Second, the authors used a rigorous analytic approach by reconstructing individual time-to-event data from Kaplan–Meier curves, which allows for a more accurate estimation of cumulative cancer incidence over time. This matters because surveillance decisions depend on how risk accumulates over years, not just whether cancer occurs at any point.

Third, the authors performed a stratified analysis in which administrative database studies were analyzed separately from hospital- or clinic-based cohorts rather than being pooled together. This is important because these populations differ substantially. Clinic-based cohorts often represent sicker or more selected patients who are more likely to undergo surveillance, which can inflate observed cancer incidence. By separating these groups, the authors provide more clinically interpretable estimates.

What are the biggest limitations of this research?

The main limitation is that this study reports pooled incidence drawn from observational cohort studies, not from prospective studies specifically designed to answer a uniform HCC risk question. The findings are therefore informative but cannot by themselves establish surveillance thresholds or prove surveillance benefit.

Other study limitations are standard limitations of most MASLD meta-analyses. For example, heterogeneity in how MASLD and fibrosis were defined across studies —histology, imaging, non-invasive tests, and/or administrative codes. Also, the authors couldn’t assess covariates that were not reported in the original studies. Consequently, they could not perform detailed multivariable analyses for additional risk factors that could refine how we think about HCC risk. They also could not conduct competing-risk analyses.

Is there anything else you’d like to say about this work?

As MASLD becomes a more common driver of HCC, we need better ways to identify which patients are at truly meaningful risk. This study is an important step toward more precise, fibrosis-based surveillance strategies. This study is further evidence that HCC risk is not uniform in MASLD. Fibrosis continues to be centrally important when we think of clinical HCC risk factors in MASLD. The study’s findings continue to support surveillance in MASLD cirrhosis, though the jury is still out on whether earlier stages of advanced fibrosis should or should not undergo screening.

Dr. Balakrishnan reported having no disclosures.