Genetic and Metabolic Risks Linked to Young-Onset MASLD Cirrhosis: Study
USA: About one-quarter of patients with MASLD-related cirrhosis developed the disease before age 50, according to a prospective multicenter study. Early-onset cases were independently associated with higher genetic risk and type 2 diabetes, suggesting a combination of inherited susceptibility and metabolic factors. The researchers also cautioned that age-dependent liver fibrosis assessment tools may miss younger at-risk patients.
The study, published in Clinical Gastroenterology and Hepatology, was conducted by Veeral Ajmera of the MASLD Research Center, Division of Gastroenterology, University of California at San Diego, La Jolla, California, USA, and colleagues. The researchers investigated genetic and metabolic characteristics associated with cirrhosis developing at a younger age among individuals with metabolic dysfunction-associated steatotic liver disease (MASLD).
Although MASLD-related cirrhosis generally develops with advancing age, some patients progress to advanced liver disease much earlier. Identifying factors associated with this younger-onset disease could help improve risk assessment and enable earlier intervention.
The study included 2,395 adults with biopsy-proven MASLD enrolled in the NASH Clinical Research Network. Among them, 234 patients (9.8%) had cirrhosis, with a median age of 58.4 years and median body mass index (BMI) of 34.9 kg/m². Approximately 66% had type 2 diabetes mellitus (T2DM).
Researchers defined younger-onset cirrhosis as cirrhosis occurring within the youngest quartile of affected participants, corresponding to an age of less than 50 years. Genetic susceptibility was assessed using a genetic risk score incorporating variants in PNPLA3 and TM6SF2, along with the wild-type HSD17B13 allele.
Key findings:
- Of the 234 participants with MASLD cirrhosis, approximately one-quarter developed cirrhosis before age 50.
- Younger-onset cirrhosis was associated with a lower prevalence of the protective HSD17B13 variant compared with non-younger-onset cases (24% versus 34%).
- Among participants younger than 50, those with cirrhosis were more likely to have T2DM and BMI of at least 35 kg/m², along with higher alkaline phosphatase and lower alanine aminotransferase levels.
- After adjustment for demographic and metabolic factors, a high genetic risk score was independently associated with younger-onset cirrhosis (OR, 2.33).
- T2DM showed an even stronger independent association with cirrhosis before age 50 (OR, 3.74).
The findings indicate that younger-onset MASLD cirrhosis may have a distinct risk profile characterized by greater genetic susceptibility and a higher prevalence of diabetes. The lower frequency of the protective HSD17B13 variant among younger patients further supports a potential genetic contribution to earlier disease progression.
The researchers noted that conventional fibrosis risk assessment may be less reliable in younger adults because some commonly used tools incorporate age into their calculations. Consequently, younger patients with significant metabolic or genetic risk factors could potentially remain under-recognized despite having advanced liver disease.
The authors concluded that approximately one in four patients with MASLD cirrhosis may develop the condition before age 50, emphasizing the importance of recognizing metabolic and genetic risk factors early in the disease course.
Reference:
Ajmera, V., Schwantes-An, L., Díaz, L. A., Zaborenko, C., Yates, K. P., Chalasani, N. P., & Loomba, R. (2026). Risk Factors and Definition of Younger-Onset Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Cirrhosis. Clinical Gastroenterology and Hepatology. https://doi.org/10.1016/j.cgh.2026.08.033
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