Type 2 Diabetes, Genetic Risk Linked to MASLD Cirrhosis Before Age 50

Type 2 diabetes (T2D) and elevated genetic risk were independently associated with metabolic dysfunction-associated steatotic liver disease (MASLD)-related cirrhosis before age 50 years, according to a new study of 2395 adults with biopsy-confirmed MASLD.¹

A high genetic risk score was associated with more than doubled the odds of cirrhosis before age 50 (odds ratio [OR], 2.33; 95% CI, 1.26-4.23; P = .006), while T2D was associated with nearly 4-fold higher odds of cirrhosis (OR, 3.74; 95% CI, 2.08-6.82; P < .001).¹

The findings, published online in Clinical Gastroenterology and Hepatology, suggest that younger adults who develop MASLD-related cirrhosis have a distinct combination of inherited and metabolic risk factors. They also raise concerns about reliance on age-dependent fibrosis scores, which may underestimate advanced liver disease in younger patients.

One-Quarter of Cirrhosis Cases Occurred Before Age 50

Investigators analyzed adults with biopsy-confirmed MASLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases-sponsored NASH Clinical Research Network. Among 2395 participants, 234, or 9.8%, had cirrhosis. Their median age was 58.4 years, median body mass index (BMI) was 34.9 kg/m², and 66% had T2D.¹

Researchers defined younger-onset cirrhosis as the youngest quartile of participants with MASLD-related cirrhosis, establishing a threshold of younger than 50 years. Approximately one-quarter of all cirrhosis cases occurred before that age.¹

Compared with 999 participants younger than 50 years who had MASLD without cirrhosis, those with cirrhosis were more likely to have T2D, a BMI of at least 35 kg/m², higher alkaline phosphatase levels, and lower alanine aminotransferase levels.¹

The lower alanine aminotransferase finding is clinically notable because normal or modestly elevated aminotransferase levels do not exclude advanced MASLD. However, the observational analysis does not establish that any individual laboratory value causes or independently predicts accelerated progression.

Genetic Susceptibility May Accelerate Progression

Investigators calculated a genetic risk score based on risk alleles in PNPLA3 and TM6SF2 and the absence of the protective HSD17B13 variant. Participants were classified as having high or low genetic risk according to the median score.¹

The protective HSD17B13 variant was present in 24% of participants with younger-onset cirrhosis compared with 34% of participants without younger-onset disease (P=.004). High genetic risk remained independently associated with cirrhosis before age 50 after adjustment for demographic and metabolic factors.

“Our findings show that younger adults who develop cirrhosis from MASLD are not simply experiencing the same disease earlier,” senior author Rohit Loomba, MD, said in a UC San Diego Health statement.² He added that genetic susceptibility and metabolic risk may combine to accelerate progression to advanced liver disease.

The findings do not establish a role for routine genetic testing in primary care. The genetic score was developed for the study, and prospective validation would be required before it could be incorporated into standard MASLD risk-stratification pathways.

Age-Based Fibrosis Scores May Miss Younger Patients

Nearly one-third of participants with younger-onset cirrhosis had fibrosis scores that would not ordinarily prompt further assessment under standard thresholds, according to the UC San Diego release.²

“As current screening tools incorporate age, they miss almost a third of patients with early-onset MASLD cirrhosis,” first author Veeral Ajmera, MD, said in the statement.²

This limitation is particularly relevant to the Fibrosis-4 Index and other noninvasive tools that include age in their calculations. A low score in a younger adult can partly reflect age rather than an absence of clinically important fibrosis.

For primary care clinicians, the results support closer attention to cumulative metabolic risk when assessing younger adults with MASLD, particularly those with T2D or severe obesity. The findings do not establish a new screening algorithm, but they suggest that age-dependent scores should be interpreted cautiously when substantial metabolic risk or other evidence of liver disease is present.

Earlier identification of cirrhosis is clinically important because it affects management, specialist referral, monitoring for portal hypertension, and eligibility for hepatocellular carcinoma surveillance. Still, the study population was drawn from a research network of patients with biopsy-confirmed MASLD and may not reflect the broader primary care population. Its observational design also prevents conclusions about causality or the rate at which individual patients progressed to cirrhosis.

References:

1. Ajmera V, Schwantes-An L, Díaz LA, et al. Risk factors and definition of younger-onset metabolic dysfunction-associated steatotic liver disease (MASLD) cirrhosis. Clin Gastroenterol Hepatol. Published online September 16, 2026. doi:10.1016/j.cgh.2026.08.033
2. UC San Diego Health. Study finds why young adults may develop early fatty liver disease. Published September 16, 2026. Accessed September 23, 2026. https://health.ucsd.edu/news/press-releases/2026-09-16-study-finds-why-young-adults-may-develop-early-fatty-liver-disease/