Why people under 50 may develop fatty liver disease

People under the age of 50 who develop fatty liver disease have a distinct risk profile shaped by both inherited genetic factors and metabolic conditions, specifically Type 2 diabetes, according to new research from the University of California San Diego School of Medicine that was recently published online at Clinical Gastroenterology and Hepatology.

Metabolic dysfunction-associated steatotic liver disease (MASLD), or fatty liver, is a disease that causes the liver to swell and can lead to cirrhosis, liver cancer and liver failure. In children and young adults, cirrhosis due to MASLD is linked to liver-related mortality and cardiovascular disease.

“Our findings show that younger adults who develop cirrhosis from MASLD are not simply experiencing the same disease earlier,” Rohit Loomba, M.D., senior author of the study, gastroenterologist and hepatologist at UC San Diego Health and chief of the Division of Gastroenterology and Hepatology at UC San Diego School of Medicine, said in a news release. “They appear to have a unique combination of genetic susceptibility and metabolic risk factors that accelerate progression to advanced liver disease.”

Loomba and his colleagues wanted to determine who those patients are who develop MASLD as a younger adult and whether there were genetic or clinical factors that were associated with the disease.

Researchers used data from almost 2,400 adults enrolled in the National NASH Clinical Research Network, which was established by the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases. The NASH Clinical Research Network is a multicenter study of people 18 years of age and older who do not have an alcohol-related liver disease.

What researchers found was that approximately 25% of cirrhosis cases occurred before the age of 50. Additionally, one-quarter of participants with cirrhosis before age 50 have a higher genetic risk and a greater prevalence of Type 2 diabetes.

They also found that early cirrhosis was associated with a lower risk of hypertension and hyperlipidemia, but younger patients had a higher liver of LDL cholesterol. This may indicate a metabolic basis for fatty liver disease rather than an age-related basis.

A distinct genetic risk

Younger patients, researchers noted, had a lower prevalence of a variant of the HSD17B13 gene that can protect against liver disease. They also found that younger MASLD patients had higher prevalence of two other genes, TM6SF2 T/T and PNPLA3, that can amplify the effects of obesity, insulin resistance and alcohol use, but researchers said this was not statistically significant.

“These data support a gene-metabolic interaction in the pathogenesis of early cirrhosis and provide an actionable framework for risk stratification in younger adults,” researchers wrote.

Current guidelines, researchers said, prioritize screening for liver disease in people older than 50, but younger people with obesity or who have Type 2 diabetes would benefit from genetic testing.

“As current screening tools incorporate age, they miss almost a third of patients with early-onset MASLD cirrhosis,” Veral Ajmera, M.D., first author of the study, hepatologist at UC San Diego Health, and associate professor of medicine at UC San Diego School of Medicine, said in a news release.

One limitation of the study, researchers noted, is that the number of younger patients (53) with MASLD was small, which may have limited the power of the genetic analyses. The study also evaluated population risk, rather than family or genetic segregation. Additionally, the population in the NASH Clinical Research Network was predominantly white.