Cholesterol crystals in the liver may play a role in making the organ stiffer early in people with metabolic dysfunction-associated steatotic liver disease (MASLD), according to new research from the Perelman School of Medicine at the University of Pennsylvania. The study, published in Proceedings of the National Academy of Sciences, suggests that these crystals could be an early warning sign for more serious liver problems.
Rebecca G. Wells, MD, professor of Gastroenterology and Hepatology at Penn and senior author of the study, said, “Predicting liver health, particularly among those who have MASLD, has been a major challenge for clinicians because about a third of the world’s population has significant amounts of fat in the liver, but only a small percentage go on to have more serious disease. Our findings suggest that detecting cholesterol crystals in the liver, and creating an easy way to do so, could help identify those patients at highest risk for severe liver disease. That would allow clinicians to intervene earlier by encouraging healthy eating habits or monitoring them more closely and providing treatment before serious damage occurs.”
MASLD develops when excess fat accumulates in the liver. Projections indicate that by 2050, up to 122 million adults in the United States may have MASLD. In advanced cases, patients can require liver transplants or develop cancer.
Fat buildup is often linked to obesity, insulin resistance, type-2 diabetes, and poor diet. Some individuals may also have a genetic tendency toward developing this condition.
In laboratory experiments led by Wells’s team, rats were fed either high-fat or high-fat plus high-cholesterol diets. Both groups developed fat deposits in their livers; however, only those given extra cholesterol formed cholesterol crystals. These livers were also stiffer than those without crystals. Currently, detecting these crystals requires an invasive biopsy.
Earlier studies had shown that high cholesterol levels are associated with fibrosis—scarring—in MASLD patients’ livers. The new research demonstrates that cholesterol crystals themselves can stiffen tissue even before scarring begins and may set conditions for further damage. The researchers managed to reverse this stiffening by removing cholesterol crystals from rat livers using methods not suitable for humans yet.
One limitation is that measuring crystal accumulation still requires biopsy; developing non-invasive tests would help doctors better identify which MASLD patients face higher risks.
The study notes that statins are known to lower blood cholesterol levels and researchers are interested in whether such medications might also help reduce or prevent cholesterol crystal formation within the liver itself.
Other contributors from Penn include David Li, Abigail E. Loneker, Jamie Ford, Elaine Mihelc, and Paul A. Janmey.
