High prevalence of clonal hematopoiesis in biopsy-proven MASH and implications for cancer care

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is a systemic disease increasingly recognized for its oncologic relevance. Patients with MASH face elevated risks of visceral malignancies, including hepatocellular, colorectal, and endometrial cancers. Age-related clonal hematopoiesis (CH)-defined by somatic mutations in peripheral blood cells-is associated with inflammation, cardiovascular disease, malignancy, and therapy-related myeloid neoplasms. Recent studies suggest CH contributes to MASH pathogenesis, yet its prevalence and clinical impact remain unclear. We evaluated the prevalence of CH in biopsy-proven MASH patients within a community hepatology cohort. Methods: We conducted a cross-sectional study of 20 patients with biopsy-confirmed MASH who underwent next-generation sequencing using a commercial hematologic malignancy panel. CH was defined as the presence of somatic mutations with variant allele frequency (VAF) ≥2.5%. Demographic, metabolic, and hepatic (including transient elastography with FibroScan® and histologic characteristics) parameters were analyzed for association with CH. Results: Among 20 patients (13 female, 7 male; mean BMI 29; mean age 57.0 ± 15.5 years, range 25-84), CH was detected in 5 (25%; mean age 59.4 ± 12.4 years, range 45-75). Compared with the expected population prevalence of 10% at age 70, the relative risk of CH was 2.5, with an indirect age-adjusted relative risk of 3.07. Detected driver mutations (VAF%) included ASXL1 (8.2), ATRX (3.6), CBL (2.7), DNMT3A (3.7), and KMT2C (4.1). All CH-positive patients were low risk by clonal hematopoiesis risk score (CHRS) and none reported tobacco use. ALT was significantly lower in CH-positive vs CH-negative patients (median 36.5 vs 70 U/L; p = 0.048). No significant differences were observed in age, BMI, AST, NAFLD activity score, fibrosis stage, liver stiffness measurement, or peripheral blood counts. Conclusions: CH is enriched in biopsy-proven MASH, independent of fibrosis or disease severity. Given its oncologic implications, CH testing may help identify MASH patients at increased risk for cancer and therapy-related complications. Integration of CH screening into hepatology-oncology workflows could enhance risk stratification and inform treatment planning for this high-risk population.