Scientists solve puzzle of why some children with cystic fibrosis sustain liver damage

Scientists have for the first time discovered the mechanism that causes severe liver disease in some children with cystic fibrosis.

The discovery could pave the way forward for the development of a targeted treatment.

The study was led by the head of the Hepatic Fibrosis laboratory at QIMR Berghofer Medical Research Institute, Professor Grant Ramm.

He and his collaborators have identified how and why a build-up of bile in the liver occurs and causes irreversible scarring, known as fibrosis.

Professor Ramm said it was a vital first step to finding a treatment.

“If we understand how scarring and liver disease occurs in these children with cystic fibrosis, we can identify for the first time what we need to target in order to treat it,” he said.

“This is an important first step because finding a treatment could transform the lives of around 10 to 15 per cent of children with cystic fibrosis who develop quite severe liver disease.

“Liver disease caused by cystic fibrosis has no known treatment and can cause irreversible damage, cirrhosis and, ultimately, liver failure.”

Professor Ramm said people with cystic fibrosis lived to an average of 38 years thanks to improvements in treatment for lung disease.

However, he said the development of liver disease in 10 to 15 per cent of children with cystic fibrosis could tragically shorten their lifespan even further.

He said that in the lungs, cystic fibrosis caused a build-up of mucous.

When this occurred in the bile ducts of the liver, the gene defect slowed the efficient removal of toxin-filled bile from the liver into the intestine and out of the body.

“In children with cystic fibrosis who develop liver disease, the usual pathways to remove toxin-filled bile from the liver don’t work as efficiently as they should,” Professor Ramm said.

He said a build-up of bile increased the presence of a toxic bile acid, known as taurocholic acid, in the liver.

The study showed higher levels of taurocholic acid in the bile caused liver progenitor (stem) cells to transform into large numbers of new bile duct cells, he said.

Professor Ramm said the new bile duct cells secreted chemicals that ultimately caused excessive scarring in the liver.

“That scarring – or fibrosis – can lead to cirrhosis and liver failure,” he said.

“The study found it was this mechanism – combined with the liver’s unique ability to continually attempt to regenerate itself after injury – that causes fibrosis, or the hardening of the liver induced by scar tissue.”

Professor Ramm said the study, which was published in The American Journal of Pathology, was a collaboration with Professor Peter Lewindon from the Lady Cilento Children’s Hospital in Brisbane.

He said the next step was to identify why some children with cystic fibrosis developed liver disease, when others did not.

“Increasing our understanding of the role of bile acids and their impact on liver progenitor cells, as well as the unique relationship between different cell populations in the liver, will help in the development of targeted therapies to reduce scarring in the livers of children with cystic fibrosis,” Professor Ramm said.

The study was supported by a National Health and Medical Research Council research grant and made possible through collaboration with researchers from the Lady Cilento Children’s Hospital and Curtin University.