Alpha-1-antitrypsin deficiency

Alpha-1-Antitrypsin Deficiency

Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder that can result in serious lung disease in adults and/or liver disease at any age. It is caused by mutations in the SERPINA1 gene, which encodes the protein alpha-1-antitrypsin (AAT). AAT is primarily produced in the liver and functions to protect the lungs from neutrophil elastase, an enzyme that can degrade connective tissue.

Pathophysiology

Alpha-1-antitrypsin is a serine protease inhibitor (serpin) that protects tissues from enzymes of inflammatory cells, especially neutrophil elastase. In individuals with AATD, the deficiency or dysfunction of AAT leads to unopposed activity of neutrophil elastase, resulting in the degradation of elastin in the alveoli, which can cause emphysema and chronic obstructive pulmonary disease (COPD).

The most common mutation associated with AATD is the Z allele (Glu342Lys), which results in the production of an abnormal protein that accumulates in the liver, leading to liver disease. Other alleles, such as the S allele (Glu264Val), also contribute to the disease but to a lesser extent.

Clinical Manifestations

The clinical manifestations of AATD can vary widely among individuals. Common symptoms include:

• Pulmonary symptoms: Shortness of breath, wheezing, chronic cough, and recurrent respiratory infections. These symptoms are often misdiagnosed as asthma or smoking-related COPD.
• Liver symptoms: Jaundice, fatigue, and cirrhosis. In infants, AATD can cause neonatal cholestasis.

Diagnosis

Diagnosis of AATD involves measuring serum levels of alpha-1-antitrypsin and identifying the specific genetic mutations. The following tests are commonly used:

• Serum AAT level: Low levels suggest AATD.
• Phenotyping: Identifies the specific protein variant present.
• Genotyping: Detects specific mutations in the SERPINA1 gene.

Management

Management of AATD focuses on reducing symptoms and preventing complications. Key strategies include:

• Augmentation therapy: Intravenous infusion of purified AAT to increase serum levels and protect lung tissue.
• Lifestyle modifications: Smoking cessation and avoidance of lung irritants.
• Liver transplantation: Considered in cases of severe liver disease.

Epidemiology

AATD is one of the most common genetic disorders among Caucasians, with an estimated prevalence of 1 in 2,500 individuals. However, it is often underdiagnosed due to its variable presentation and overlap with other respiratory diseases.

Also see

• Chronic obstructive pulmonary disease
• Emphysema
• Liver cirrhosis
• Genetic disorders