Alpha-1 Antitrypsin Deficiency-associated Liver Disease
Alpha-1 antitrypsin (A1AT) deficiency is an inherited disorder that can cause liver disease in children and adults, leading to complications such as fatigue, jaundice or unintended weight loss. Patients with A1AT deficiency are also at risk of serious or life-threatening conditions such as cirrhosis, liver failure and hepatocellular carcinoma, and may develop lung disease. There are currently no approved therapies specifically designed to treat the liver manifestations of this condition.
The disorder is caused by mutations in a gene called SERPINA1. This gene provides instructions for making a protein called A1AT, which normally protects the body from an enzyme called neutrophil elastase. This enzyme is released from white blood cells to fight infection, but it can attack normal tissues if not tightly controlled by A1AT. Mutations in the SERPINA1 gene can result in a deficiency, or shortage, of functional A1AT and an abnormal form of the protein that cannot control neutrophil elastase. Uncontrolled neutrophil elastase can destroy alveoli (small air sacs in the lungs) and cause lung disease. In the liver, the accumulation of abnormal A1AT can trigger an injury cascade, which can lead to liver injury.
About 10% of adults with A1AT deficiency develop cirrhosis, or liver damage, due to formation of scar tissue in the liver. Individuals affected by A1AT deficiency are also at risk of developing hepatocellular carcinoma, a type of liver cancer. People with A1AT deficiency may develop the first symptoms of lung disease between the ages of 20 and 50 years. Symptoms can include shortness of breath following mild activity, reduced ability to exercise, wheezing, unintended weight loss, recurring respiratory infections, fatigue and rapid heartbeat upon standing. Some individuals with A1AT deficiency develop emphysema, a lung disease caused by damage to the alveoli.
A1AT deficiency occurs all over the world, though its prevalence varies by population. The disorder affects roughly one in 1,500 to 3,500 individuals with European ancestry and is uncommon in people of Asian descent. Congenital A1AT deficiency is estimated to affect 2.4 people out of every 10,000 in the EU. Many individuals with A1AT deficiency are thought to be undiagnosed, particularly those who also have chronic obstructive pulmonary disease (COPD). Some people with A1AT deficiency are misdiagnosed with asthma.
References:
- Genetics Home Reference. Alpha-1 antitrypsin deficiency. Bethesda, Md.: U.S. Department of Health and Human Services, National Institutes of Health, National Library of Medicine; 2013. Available at: https://ghr.nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency#genes. Accessed Dec. 16, 2019.
- Townsend SA, Edgar RG, Ellis PR, et al. Systematic review: the natural history of alpha-1 antitrypsin deficiency, and associated liver disease. Aliment Pharmacol Ther. 2018; 1–9.
- Tanash H, Piitulainen E. Liver disease in adults with severe alpha-1-antitrypsin deficiency. Alpha-1-antitrypsin deficiency liver disease. J Gastroenterol 2019; 54:541–548.
- EU congenital A1AT deficiency based on Dicerna internal estimates.
Resources for patients with A1AT deficiency
The following organizations provide educational resources and support research to help people living with A1AT deficiency.