Researchers Identify the Risk Factors for MASLD Cirrhosis Under Age

A US COHORT study has identified distinct genetic and metabolic risk factors for MASLD cirrhosis presenting before age 50, with a high genetic risk score and type 2 diabetes each independently linked to younger-onset disease.

Risk Factors at Younger Ages Have Remained Unclear

Cirrhosis from metabolic dysfunction-associated steatotic liver disease (MASLD) has usually developed with advancing age, yet a subset of patients has continued to present younger. The genetic and metabolic risk factors distinguishing this younger-onset group from typical MASLD cirrhosis have remained poorly defined.

Researchers included adults with biopsy-proven MASLD enrolled in the NASH Clinical Research Network. Participants were genotyped, and a genetic risk score (GRS) was calculated from risk alleles in PNPLA3 and TM6SF2 plus the wild-type HSD17B13 allele, dichotomised at the median into low and high categories; previously published weighted GRSs were also evaluated. Younger-onset cirrhosis was defined as the youngest quartile among participants with cirrhosis. Multivariable logistic regression assessed factors associated with younger-onset cirrhosis, adjusting for demographic and metabolic variables.

Genetics and Diabetes Independently Linked to Early Cirrhosis

Among 2,395 participants, 234 (9.8%) had MASLD cirrhosis, with a median age of 58.4 years, median BMI of 34.9 kg/m², and 66% having type 2 diabetes mellitus (T2DM). Younger-onset cirrhosis, defined as under 50 years, was associated with a lower prevalence of the protective HSD17B13 variant (24% vs 34%, p = 0.004). Compared with non-cirrhotic MASLD participants under 50 (n = 999), those with cirrhosis more often had T2DM, a BMI of 35 kg/m² or higher, higher alkaline phosphatase, and lower ALT. In multivariable models, high GRS (p = 0.006) and T2DM (p < 0.001) remained independently associated with cirrhosis under age 50.

Implications for Early Risk Stratification

These findings indicate that one-quarter of patients with MASLD cirrhosis present before age 50 and have distinguishing features, including elevated genetic risk and a higher burden of T2DM. Identifying risk factors for MASLD cirrhosis at younger ages may support earlier genetic and metabolic risk stratification, helping clinicians recognise patients who warrant closer surveillance well before the age at which cirrhosis is typically expected.

Reference

Ajmera V et al. Risk Factors and definition of younger-onset metabolic dysfunction-associated steatotic liver disease (MASLD) Cirrhosis. Clinical Gastroenterology and Hepatology. 2026;DOI:10.1016/j.cgh.2026.08.033.

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