Abstract:
Mayo Clinic and Virginia Tech researchers have found that metabolic dysfunction-associated fatty liver disease (MASLD, formerly known as non-alcoholic fatty liver disease) is not a single pathological process, but consists of five subtypes with different clinical characteristics, genetic backgrounds and disease risks. About 30% of adults worldwide are affected by MASLD; this disease often has no obvious symptoms in the early stages, but may gradually develop into liver inflammation, fibrosis, cirrhosis and even liver cancer.
The research team combined the patient's genetic data with clinical indicators in medical records, analyzed more than 4,600 MASLD patients, and used latent class analysis to summarize five groups based on 13 clinical and demographic indicators. The five groups were replicated in independent cohorts, and the researchers further compared disease progression across groups using follow-up records for up to ten years.
The first group, which accounts for the largest proportion, accounts for about 30.5%. Most of the patients are older, not obese, and have normal liver enzyme levels, but heart disease and metabolic syndrome are more common; this shows that normal liver enzymes or low weight do not necessarily mean a low risk of liver disease. The second group accounts for about 26.8%, mainly men, with high blood sugar and triglycerides, and more heart and kidney diseases and sleep apnea. The third group accounts for about 24.1%, and is mainly female. Mood disorders such as obesity and depression are more prominent, and problems such as migraines are also more common.
The fourth group accounts for about 9.1%. The patients are relatively young, have fewer common metabolic abnormalities, and have low liver enzymes. However, the study found that this group has an increased risk of liver fibrosis and cirrhosis, and the proportion of liver transplants is the highest among all groups. The researchers call this polygenic MASLD and believe that genetic factors may drive liver disease even when traditional metabolic risks are not apparent. The fifth group accounts for about 9.5%. It has the highest liver enzyme and MASLD genetic risk scores and more prominent liver fibrosis. The research team calls it the polygenic metabolic dysfunction-associated steatohepatitis (MASH) type.
Ten-year follow-up showed that the complications faced by each group were not the same. Compared with the first group, the risk of subsequent sleep apnea in the second group was about 2.58 times; the risk of depression in the third group was about 1.88 times and the risk of sleep apnea was about 2.49 times, but the risk of liver cancer was lower. The fourth group has the highest risk of liver cirrhosis; the fifth group has a risk of MASH of about 2.22 times, and the risks of liver fibrosis and acute renal failure are also about 2.13 times and 2.10 times, respectively. These hazard ratios are statistical associations within the study cohort and do not mean that every patient will have the same outcome.
The development cohort of the study came from the Mayo Clinic Biobank, and the institution's Tapestry Genome Study cohort was used for independent verification; however, the analysis relied on complete clinical variables in the medical records, some indicators may be missing, and patients were classified into a single subtype, which could not fully express the uncertainty of those at the group boundaries. Therefore, these five groups are currently a risk stratification framework proposed by the study and are not established clinical diagnostic criteria or personal diagnostic tools. The team plans to continue validation in a broader patient population and study the response of different subtypes to treatments including GLP-1 receptor agonists.
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