Prof Nedim Hadzic

2012 BSPGHAN/Guts UK Development Award Winner

Title: Genetic association studies in chronic liver disease and chronic obstructive pulmonary disease secondary to PiZ alpha-1-antitrypsin deficiency

Project Start Date: 1 January 2013

Completion Date: September 2015


Alpha-1-antitrypsin (A1AT) deficiency is a relatively common genetic disorder, with 1 in 2,000 people in Northern Europe carrying the genetic defect responsible for the disorder. The condition leads to chronic liver disease (CLD) in children and to chronic obstructive pulmonary disease (COPD) in young adults, particularly among smokers. However liver disease in people with A1AT deficiency presents in variable ways and with different outcomes, with some people affected showing no symptoms at all, some displaying intermediate stages of chronic liver disease, and some requiring a life-saving liver transplantation. The reasons why some people develop liver disease, some develop lung disease and some remain asymptomatic for life are unknown.

Additionally, at present it is not known whether children with liver disease due to A1AT deficiency will develop lung disease. This uncertainty represents one of the major problems in their long term management. Once patients who are at risk of developing lung disease in adulthood are identified, it will be possible to target them for early treatment. Currently this includes replacement therapy with the A1AT protein, in addition to lifestyle modifications such as avoidance of smoking and heavy alcohol use. In the future it may be possible to modify the condition by either changing the A1AT protein or giving medications before severe damage in the liver or lungs occurs. Furthermore, it is hoped that by analysing genetic markers in a minority of the children who required liver transplantation it would be possible to look for the same markers in adults and identify the ones who will need closer monitoring of liver function during their lifetime.

In this project Prof Hadzic and his colleagues tried to identify why individuals with seemingly identical defects in their gene responsible for A1AT deficiency develop liver or lung disease, by comparing genetic markers in large cohorts of children with chronic liver disease of different severity, and among adults with COPD from national referral centres. The researchers examined the full genetic material (DNA) of 384 patients with A1AT deficiency and lung disease but no obvious liver disease, and the genetic material of 132 children who presented with early onset liver disease. The primary aim was to find additional genetic differences between the children with liver disease and adult respiratory patients. They identified a number of genetic differences between the groups, which they plan to explore in future work.