Study Assesses Who’s at Risk for Young-Onset MASLD Cirrhosis

A quarter of patients with cirrhosis from metabolic dysfunction-associated steatotic liver disease (MASLD) presented before the age of 50 and had distinct features, including inherited genetic risk factors and type 2 diabetes, according to data from a prospective multicenter study.

In multivariable models adjusting for demographic and metabolic factors, a high genetic risk score (OR 2.33, 95% CI 1.26-4.23, P=0.006) and type 2 diabetes (OR 3.74, 95% CI 2.08-6.82, P<0.001) were independently associated with cirrhosis in MASLD patients under the age of 50, reported Rohit Loomba, MD, of the University of California San Diego, and colleagues in Clinical Gastroenterology and Hepatology.

The prevalence of cirrhosis increased for patients with both low and high genetic risk scores if they also had type 2 diabetes: from 2.0% to 9.5% and from 6.2% to 10.7%, respectively.

“Our findings show that younger adults who develop cirrhosis from MASLD are not simply experiencing the same disease earlier,” said Loomba in a press release. “They appear to have a unique combination of genetic susceptibility and metabolic risk factors that accelerate progression to advanced liver disease.”

Loomba and team noted that while high genetic risk and type 2 diabetes independently identified younger adults at increased risk of MASLD cirrhosis, reliance on age-dependent first-line liver fibrosis tools like the Fibrosis-4 (FIB-4) index can miss cases.

A normal FIB-4 score is <1.3 for adults under age 65. However, about 30% of patients with early MASLD cirrhosis in this study had a FIB-4 score <1.3, “suggesting this population may be at higher risk of misclassification with current clinical care pathways,” the authors wrote.

“In our cohort, a FIB-4 cut-point of 1.0 identified 82.7% of cases … supporting direct referral for fibrosis assessment in these patients irrespective of FIB-4,” they added.

In the press release, co-author Veeral Ajmera, MD, also of the University of California San Diego, noted that since current screening tools like FIB-4 incorporate age, “they miss almost a third of patients with early-onset MASLD cirrhosis. This study helps us identify which patients are at greatest risk and need a more accurate assessment of their liver disease.”

The study included 2,395 patients with biopsy-confirmed MASLD enrolled in the national Nonalcoholic Steatohepatitis Clinical Research Network. Of these participants, 9.8% had cirrhosis. Median age was 58.4 years, 71.4% were women, 85% were white, 50% had a body mass index ≥30, and 66% had type 2 diabetes.

The cutoff for early MASLD cirrhosis (the lowest quartile of age) was less than 50 years, with 53 participants presenting with cirrhosis before age 50 and 181 presenting at 50 or older. Only 6% reported alcohol consumption two or more times per month, with no difference between early and non-early MASLD cirrhosis groups.

All study participants underwent a standardized clinical evaluation and biochemical testing. Genetic risk scores were calculated by adding up the number of alleles across three single-nucleotide polymorphisms — PNPLA3, HSD17B13, and TM6SF2 — which were selected based on their association with cirrhosis in multiple studies. Scores ranged from 0 to 6 (low 0 to 3, high 4 to 6).

Compared with non-cirrhotic MASLD participants under age 50, those with cirrhosis more often had a body mass index of at least 35, higher alkaline phosphatase levels, and lower alanine aminotransferase levels.

Loomba and colleagues said future work should validate age-aware screening thresholds, refine genetic risk, and evaluate targeted interventions in younger patients with genetically high-risk MASLD.