Liver disease (fibrosis)
Dr Varinder Athwal

Institution: University of Manchester
Title: Investigating fibrosis pathobiology in cystic fibrosis related liver disease to improve clinical detection and management
Project Start Date:  2 January 2019
Completion Date: 1 January 2022

Summary:

Cystic Fibrosis (CF) is a genetic condition which affects 1 in 2500 newborn infants and is the commonest genetic condition in the UK. 1 in 25 of the white population carry the mutation. The genetic defect prevents the movement of fluids from cells, leading to thickened secretions and injury. With improvements in treatments from the commonest organ affected, the lungs, patients born with CF now can expect to live into the 40s with more than 60% living past 16. Though better, more can be done. As treatments from lung complications have improved, the management of liver disease (second commonest organ involved) remains unchanged for a considerable time. The only treatment option remains a liver transplant for those with the severest disease. Though it can be life changing, it has multiple risks and an organ shortage means alternative treatment options are desperately needed.

Identifying those with or at risk of Cystic Fibrosis related liver disease is difficult due to inadequate diagnostic tools. Routine blood tests are unreliable. Therefore, specific blood tests to identify scarring of the liver (biomarkers) are urgently needed. Ultrasound scan, the recommended diagnostic investigation, is only accurate in identifying the late stages of liver disease. For new therapies to be most effective we need to be able to identify patients at a much earlier stage.

It is thought that the genetic defect in the cells responsible for the movement of bile causes injury to the liver and other cells become activated that are responsible for producing scar tissue. These cells are normally in a resting state but once ‘activated’ they produce the components of scar tissue and are more mobile. They move through the liver, depositing scar tissue as they go. Several cell types are thought to play a role in this, but myofibroblasts have received attention as playing significant role. Contact with scar tissue leads to further activation of cells and the process of scarring becomes a vicious cycle. Consequently, breaking this cycle will provide insight into novel therapies for the disease. Interestingly, not all patients get liver problems and it is not clear why some do and others do not.

Understanding how this genetic defect leads to these cells becoming activated and producing the scar is critically important to find strategies to prevent or minimise damage. We have exciting data suggesting that the defect may not only cause problems in the bile duct cells but in the actual scar forming cells themselves. It may be this change that causes the liver scar forming cells to continue the spiral of fibrosis. My research will investigate these cells to see if this defect does have direct effects on their scar-forming ability. I will also look to find better methods to diagnose those with liver scarring and use this as a way to find why some get scarring whilst others don’t.