A condition affecting nearly three in ten adults worldwide may be more complex than previously understood, with Mayo Clinic researchers identifying five distinct biological subtypes that carry different risks of complications.
The findings challenge the idea that metabolic dysfunction-associated steatotic liver disease (MASLD), commonly called fatty liver disease, follows one predictable pattern. They could help doctors identify patients at greater risk and eventually tailor care.
The study, conducted with Virginia Tech scientists and published in Nature Communications on September 2, analysed clinical and genetic information from more than 4,600 people with MASLD. The researchers found five subgroups with different clinical, genetic and risk profiles, also seen in independent patient groups.
“When clinical and genomic data are analysed together at this scale, you begin to see patterns of disease progression that would otherwise remain hidden,” said Shulan Tian, co-senior author and a bioinformatician at Mayo Clinic. “Once you separate these subtypes, you can start to match treatments to the biology that’s actually driving the disease.”
A disease with different pathways
MASLD develops when excess fat accumulates in the liver alongside metabolic risk factors such as overweight or obesity, type 2 diabetes, high blood pressure and unhealthy blood-fat levels. The condition was formerly known as non-alcoholic fatty liver disease, or NAFLD, before its name was updated to better reflect its relationship with metabolic health.
MASLD often causes no obvious symptoms. In some people, fat accumulation is accompanied by inflammation and liver-cell injury, a more serious condition called metabolic dysfunction-associated steatohepatitis (MASH). Ongoing injury can lead to fibrosis, or scarring, and eventually cirrhosis, in which the liver becomes permanently damaged. Advanced disease can also increase the risk of liver cancer and transplantation.
The study suggests that the route to these complications is not the same for everyone. Some subtypes were associated with familiar metabolic conditions, including obesity and diabetes. Others showed stronger genetic influences, suggesting inherited risk may be important even when a person does not have the usual metabolic warning signs.
The researchers also found differences in associated health conditions. One subgroup was predominantly male and had a cardiorenal profile, while another was predominantly female and associated with obesity and mood disorders. A genetically influenced subgroup had the highest rate of liver transplantation despite having comparatively fewer metabolic conditions and cases of ischaemic heart disease. Another genetic subtype was associated with a higher risk of advanced liver scarring and acute kidney failure.
The findings underline that MASLD can affect health beyond the liver.
Looking beyond weight and diabetes
The researchers combined genetic sequencing with medical records, including liver enzymes, body mass index, cholesterol, diabetes, depression and sleep apnoea. Computational modelling helped identify shared patterns.
Eric Klee, co-senior author and a Mayo Clinic research and innovation leader, said the work offered a way to recognise meaningful groups within a complex disease.
“What’s emerging here is a way to systematically identify meaningful subgroups within complex disease,” he said. “It helps us map complex disease with such precision that we can begin to anticipate its course and intervene before the most serious damage occurs.”
The analysis used Mayo Clinic’s Research Data Atlas, which links genetic information with patient records, and drew on the Tapestry Study’s exome data from more than 100,000 participants. Exome sequencing examines gene regions that provide instructions for making proteins.
Konstantinos Lazaridis, who led the Tapestry Study and is a co-author, said combining genetic information with detailed clinical records could reshape understanding of disease.
“When you connect genetic data with detailed clinical information across large populations, you can start to redefine diseases in ways that directly impact patient care,” he said.
What the findings mean for patients
The five subtypes are research categories, not diagnoses currently used in routine practice. Further studies must test the approach in broader populations and determine whether patients respond differently to treatments.
Mayo Clinic researchers plan to examine how the groups respond to therapies, including GLP-1 receptor agonists, medicines used in managing conditions such as type 2 diabetes and obesity.
People with metabolic risk factors should discuss liver health with a healthcare professional. MASLD may be detected through blood tests or imaging; further assessment can include blood-based risk scores or specialised scans that measure liver stiffness.
Lifestyle measures remain important. For people who are overweight, gradual weight loss, regular physical activity and a balanced diet can reduce liver fat and may improve inflammation. Managing diabetes, blood pressure and cholesterol is also central to reducing broader health risks. The absence of symptoms does not necessarily mean the liver is healthy. Physical activity can also benefit the liver even when it does not lead to substantial weight loss.
The aim is to identify why MASLD develops differently between people, helping clinicians recognise those most at risk and intervene earlier.
