Cholesterol crystals may be hidden trigger for some liver disease

Cholesterol crystals in the liver may stiffen the organ early in those with metabolic dysfunction-associated steatotic liver disease (MASLD)—well before scarring develops—according to new research from a team in the Perelman School of Medicine at the University of Pennsylvania. The findings, published in Proceedings of the National Academy of Sciences, may help explain why high cholesterol worsens this type of liver disease and point to new opportunities for earlier diagnosis and treatment in people.

“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,” said senior study author Rebecca G. Wells, MD, a professor of Gastroenterology and Hepatology at Penn. “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.”

The threat of fat in the liver

MASLD occurs when excess fat builds up in the liver. By 2050, estimates suggest 122 million US adults could have MASLD. In some cases, people with the disease require liver transplants or develop liver cancer.

Fat buildup in the liver can be the result of obesity, insulin resistance, and type-2 diabetes, often combined with a poor diet. Some individuals may be genetically predisposed to the condition.

In Wells’s lab, rats were given high-fat, high-cholesterol diets or just high-fat diets. Both diets led to steatosis, or fat buildup in liver cells. But rats on high-fat, high-cholesterol diets developed crystals in their livers compared to rats just on high-fat diets. And livers with crystals were stiffer than livers without crystals. Crystals could only be measured through an invasive biopsy.

A readily-available drug might inform future treatment

Previous research has demonstrated that high cholesterol levels in the livers of people with MASLD were linked to fibrosis, or liver scarring. Now, the Penn team‘s research shows that cholesterol crystals physically, and independently of previous scarring, stiffen the liver tissue and create an environment that encourages more scarring. Researchers were also able to reverse liver stiffening by removing cholesterol crystals, though their method is not applicable to people. Another barrier to clinical application is that cholesterol crystals can only be measured through biopsy; an accurate, non-invasive approach to measure crystal accumulation in the liver would allow clinicians to know which patients with MASLD are at risk of severe liver damage.

While it’s widely known that statins reduce cholesterol in the blood, researchers hope to learn if these and other readily accessible medications and other interventions have potential to help treat cholesterol crystals in the liver.

Other Penn authors of this study include David Li, Abigail E. Loneker, Jamie Ford, Elaine Mihelc, and Paul A. Janmey.