22nd July 2023

Alpha-1 antitrypsin deficiency

Background

Alpha-1 antitrypsin (AAT) deficiency is a genetic condition which can affect the lungs and the liver. This section will focus on the hepatic manifestations.

The inheritance is autosomal codominant, meaning that one or two defective alleles can be inherited, and both can cause disease. However, the inheritance of only one allele tends to result in milder disease. There are numerous causative mutations affecting the ​​SERPINA1 gene on chromosome 14. These mutations lead to a deficiency of effective circulating AAT; the exact pathophysiology depends on the type of mutation.

A normal phenotype is denoted as PI*MM. Z denotes the most common mutation in AAT deficiency, and so a carrier would be PI*MZ, and a person with the disease would have the phenotype PI*ZZ. S is another common mutation, which is associated with decreased function of AAT and is often associated with a less severe form of the disease.

Liver involvement may be seen as early as the neonatal period. In adults, clinical features include fatigue, jaundice, abdominal distension, bruising and abdominal pain. There may be signs of chronic liver disease on examination, such as asterixis, hepatomegaly or ascites.

Assessment and diagnosis 

The key investigation is serum AAT levels. However, these must be interpreted with caution as AAT is an acute phase reactant and, therefore, may be falsely normal. For some, it may be beneficial to test for the underlying phenotype. Genotyping may also be done.

Additional investigations relating to hepatic disease may include liver ultrasound. AAT level testing is part of a non-invasive liver screen to investigate for the cause of undiagnosed liver disease.

Management

Management focuses on monitoring and managing complications of chronic liver disease. Ultimately, liver transplantation may be required. Patients with AAT deficiency should be advised to avoid or limit their alcohol intake.