Distinct subtypes of MASLD discovered independently
Types differ largely in risk of diabetes, cardiovascular complications
An international team of researchers using different experimental approaches identified two distinct types of metabolic dysfunction-associated steatotic liver disease (MASLD), a form of fatty liver disease, with markedly different clinical outcomes.
In one type, elevated liver fat is genetically driven and marked by a rapid progression of liver disease, but a low risk of cardiovascular disease. The second type had comparable liver disease progression, but high liver fat is more body-wide and associated with a high risk of type 2 diabetes and cardiovascular complications.
“This research marks a turning point,” François Pattou, MD, a co-leader of the research and a professor at the University of Lille, in France, said in a university news story. “We now have a clear path to develop subtype-specific treatments that can improve patient outcomes.”
“This discovery sheds light on why current treatments often yield inconsistent results,” said Stefano Romeo, MD, PhD, the research’s other co-leader and a professor at the University of Gothenburg, in Sweden. “It was a true ‘eureka’ moment for our team.”
The findings were described in two studies published back to back in Nature Medicine.
In MASLD, which was formerly called nonalcoholic fatty liver disease, fat accumulates in the liver. Its development is associated with cardiometabolic risk factors, including being overweight or obese, having high blood pressure, high blood sugar or type 2 diabetes, or elevated blood levels of fatty molecules (triglycerides or cholesterol).
Over time, fat buildup causes inflammation that can damage the liver, resulting in a more severe condition called metabolic dysfunction-associated steatohepatitis, or MASH (formerly nonalcoholic steatohepatitis). MASH can lead to permanent scarring (cirrhosis) and liver cancer.
Also, “MASLD harbors an increased risk of cardiovascular disease and type 2 diabetes,” the researchers wrote.
But not every MASLD patient will progress to MASH or develop cardiovascular disease or type 2 diabetes. Moreover, current treatment approaches often fail to account for these variations.
Identifying two types of MASLD
Pattou’s team collaborated mainly with Romeo’s group to investigate that variability and each group independently applied different experimental techniques and reported their findings in two back-to-back studies.
In the first study, “Data-driven cluster analysis identifies distinct types of metabolic dysfunction-associated steatotic liver disease,” researchers identified six groups of patients, or clusters, with distinctive patterns of clinical variables collected from 1,389 obese people.
The variables included age, body mass index (a ratio of height and weight), and blood levels of low-density lipoprotein (LDL), which is known as bad cholesterol, alanine aminotransferase (ALT; a liver damage marker), triglycerides, and HbA1c, a blood sugar marker.
Identified clusters were then replicated in three independent groups of people with obesity who underwent a liver biopsy, totaling 1,099 participants, and confirmed with liver MRI data from more than 6,700 UK Biobank participants.
Two distinct MASLD subtypes were identified. The liver-specific cluster, marked by the highest ALT levels, was found to have a strong genetic component along with rapid liver disease progression, but a low risk of cardiovascular disease.
The cardiometabolic cluster contained patients with the highest HbA1c, altered blood fat levels, and high blood pressure. While this group showed a similar frequency of chronic liver disease, it was characterized by a higher risk of type 2 diabetes and cardiovascular disease.
“This work on clustering using simple clinical variables is of utmost importance because it allows us to differentiate at an individual level who has MASLD and will develop cardiovascular disease and who will not,” Romeo said in a separate university news story. “We discovered that there are at least two types of steatotic liver disease with different clinical trajectories. One is more aggressive and mainly affects the liver, while the other is entwined in the [cardio-kidney-metabolic] syndrome.”
The clustering prediction tool was made available online.
Further experiments showed that while these two MASLD types showed similar liver features under the microscope or on MRI at first evaluation, they were associated with distinct gene activity patterns in the liver, unique metabolic signatures in the blood, and different clinical trajectories.
Different types confirmed
In the second study, “Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease,” researchers identified 27 previously unknown genetic variants linked to liver triglyceride content in more than 36,000 people. Six of these variants were confirmed in four independent groups of nearly 4,000 obese people.
The researchers then generated two polygenic risk scores, or the cumulative risk derived from aggregating contributions of genetic variants associated with a complex trait or disease, based on the retention of triglycerides in the liver.
Consistent with the first study, the polygenic risk scores suggested two distinct types of MASLD — one associated with fat retention within the liver and marked by more aggressive liver disease, but carrying a low risk of cardiovascular complications, the other a body-wide form due to other mechanisms, including an increased uptake from the blood or production of fatty energy molecules. The second type is associated with a higher risk of diabetes, high blood pressure, cardiovascular disease, and heart failure.
“This discovery is important because it helps us understand why some individuals develop more severe liver diseases while others suffer from cardio-[kidney] diseases,” Romeo added. “This will allow us to better predict the progression of these diseases and tailor the treatment to the specific needs of the patient.”
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