Scientists have discovered a new clue about why some people with fatty liver disease develop serious liver problems while others do not.
A study from researchers at the Perelman School of Medicine at the University of Pennsylvania suggests that tiny cholesterol crystals forming inside the liver may stiffen the organ early in the disease process, even before permanent scarring appears.
The condition, now called metabolic dysfunction-associated steatotic liver disease (MASLD), happens when too much fat builds up in the liver.
It is extremely common and is linked to obesity, insulin resistance, type 2 diabetes, and unhealthy diets.
Although many people have fatty liver, only a smaller number develop severe complications such as liver failure, cancer, or the need for a transplant. Doctors have long struggled to predict who will worsen.
The new research, published in the journal Proceedings of the National Academy of Sciences, offers a possible explanation.
The scientists found that cholesterol crystals can form in the liver and make the tissue stiffer, which may set the stage for future damage. This stiffening happened before the usual signs of scarring, suggesting that the crystals themselves may trigger disease progression.
To investigate, researchers fed laboratory rats either a high-fat diet or a high-fat diet combined with high cholesterol.
Both groups developed fatty liver, but only the animals eating the high-fat, high-cholesterol diet formed cholesterol crystals.
Their livers were also noticeably stiffer. This suggests that cholesterol, not just fat alone, may play a key role in making the disease more dangerous.
Liver stiffness matters because it can encourage fibrosis, the process in which healthy tissue is replaced by scar tissue.
Over time, fibrosis can lead to cirrhosis, a severe form of liver damage. The study showed that cholesterol crystals could physically stiffen liver tissue and create conditions that promote this scarring, even before fibrosis begins.
Encouragingly, the researchers were able to reduce the stiffness in the animals by removing the cholesterol crystals, although the method used cannot yet be applied to people. They hope future treatments, possibly including medications that lower cholesterol such as statins, might help prevent or reduce crystal formation in the liver.
Another challenge is detection. Currently, the only way to confirm the presence of cholesterol crystals in the liver is through a biopsy, an invasive procedure that involves removing a small piece of tissue. Scientists say developing a reliable, non-invasive test would help doctors identify patients at highest risk much earlier.
Experts believe the findings could lead to better ways to monitor and treat MASLD, especially as the condition becomes more widespread worldwide. By identifying high-risk patients sooner, doctors may be able to recommend lifestyle changes, medications, and closer monitoring before serious damage occurs.
The study highlights that high cholesterol may harm more than the heart. It could also quietly affect the liver, reinforcing the importance of healthy eating, weight management, and regular medical care to protect long-term health.
