Study finds anti-inflammatory drugs increase liver damage

Using an experimental mouse model of the disorder, the researchers investigated the effects of a non-steroidal anti-inflammatory drug (NSAID) on liver injury. The findings show that the NSAID indomethacin, administered at doses typically nontoxic to mice, significantly increased liver damage. The mice carried a mutated form of the human alpha-1-AT gene, the most common form of the gene associated with the development of liver disease in people with alpha-1-AT deficiency.

“These data demonstrate that environmental factors such as drug administration can affect the development of liver injury in this animal model,” said lead author David Rudnick, assistant professor of pediatrics. “And they raise the possibility that NSAIDs could have similar effects on gene and protein expression and perhaps on liver injury in people with alpha-1-AT deficiency.”

Normally, the liver secretes alpha-1-AT protein into the bloodstream, but the abnormal protein, alpha-1-ATZ, can get “stuck” in liver cells. The defective alpha-1-ATZ doesn’t reach the lungs, where alpha-1-AT normally regulates enzymes that digest protein. Loss of alpha-1-AT’s regulation of protein-digesting enzymes in the lungs can result in tissue damage and emphysema.

In the mice carrying the human alpha-1-ATZ gene, the NSAID indomethacin not only caused liver cells to accumulate even more of the abnormal alpha-1-ATZ protein but also to proliferate or multiply faster than usual – a hallmark of liver response to injury.

“We don’t yet know the mechanism accounting for such wide variability in this disorder, but other genetic and environmental factors must contribute,” noted David Rudnick.