Researchers discover new risk factor for liver disease

More than 10 percent of people over 70 have clonal hematopoiesis of indeterminate potential, or CHIP, which is caused by blood stem cells that carry cancer-causing mutations and proliferate. Scientists have linked CHIP to increased risk of leukemia and heart disease, and now a new study adds chronic liver disease to the list of disorders strongly associated with CHIP.

The findings, which appear today in Nature, also suggest a biochemical pathway in cells that could be targeted by drugs to treat liver disease in patients with CHIP.

“We’ve identified a very potent risk factor for chronic liver disease,” said co-senior author Pradeep Natarajan, an associate member at the Broad, director of preventive cardiology at Massachusetts General Hospital, and assistant professor of medicine at Harvard Medical School. Benjamin Ebert, an institute member at the Broad, a professor at Harvard Medical School, and the chair of medical oncology at the Dana-Farber Cancer Institute, is a co-senior author. Waihay Wong, a postdoctoral researcher in Ebert’s lab, and Connor Emdin, a visiting researcher in Natarajan’s lab, are co-first authors.

“We are excited about this because chronic liver disease has few treatment options and we identified a new potentially modifiable molecularly-defined risk factor,” Natarajan said. 

Both CHIP and liver disease are marked by dysregulation of white blood cells and inflammation, so Natarajan wondered if CHIP causes liver disease. He, Ebert, and colleagues studied clinical data from more than 200,000 individuals collected by the Framingham Heart Study, the Atherosclerosis Risk in Communities study, and the UK Biobank. They found that people with CHIP were twice as likely to have chronic liver disease as those without. Individuals with CHIP also showed signs of liver inflammation in MRI images. 

Using an approach called Mendelian randomization, which uses genetic variation to untangle cause and effect relationships, the researchers determined that CHIP likely causes, and is not simply associated with, chronic liver disease in humans. Mice with blood stem cells that were deficient in Tet2, one of the most frequently mutated genes in CHIP, mirrored features seen in MRIs from liver disease patients: the lab animals had high inflammation and developed liver scarring and more severe disease without accumulating much fat in the liver. Natarajan says that together, these findings are compelling evidence that CHIP likely causes liver disease.

In Mendelian analyses and gene expression studies, the researchers found that NLRP3, an inflammatory protein, mediated these effects. They add that drugs that inhibit this “inflammasome” protein — which clinical trials are testing for a variety of diseases — could help reduce liver inflammation and scarring for patients with CHIP. 

Natarajan hopes that physicians could one day use inflammasome inhibitors or other drugs to treat and prevent liver disease in patients with CHIP. In the meantime, he and his team plan to continue studying the genes, pathways, and mechanisms underlying the association between CHIP and liver disease.