Description
Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant genetic disorder leading to the decreased production of alpha-1 antitrypsin (AAT), a protein responsible for protecting the lungs from neutrophil elastase. The deficiency results in an increased risk of developing lung and liver diseases.
Pathogenesis
Alpha-1 antitrypsin is primarily produced in the liver and secreted into the bloodstream to reach the lungs where it inhibits the activity of neutrophil elastase. This enzyme, released by inflammatory cells, can damage lung tissues if not sufficiently regulated. In AATD, a genetic mutation of the SERPINA1 gene causes abnormal folding of the AAT protein, leading to its accumulation in the liver and a consequent lack in the lungs. This results in unopposed neutrophil elastase activity, leading to lung tissue destruction and development of emphysema, while the accumulation in the liver can lead to liver disease.
Subtypes
There are over 100 identified alleles of the SERPINA1 gene, which encodes AAT, but the most common severe deficiency alleles are:
- Z allele: The most common variant associated with severe AATD
- S allele: Associated with a milder deficiency.
Epidemiology, Risk Factors & Associations
- Autosomal co-dominant pattern of inheritance (one defective allele tends to result in milder disease than two defective alleles)
- Most common in individuals of Northern European descent (1 in 2000 to 1 in 5000 individuals)
- Onset of symptoms is typically between 20 and 50 years of age.
- Associated with early-onset panacinar emphysema, especially in smokers
- Associated with liver disease, particularly in children and older adults.
- AATD is considered to be the most common genetic cause of liver disease in children.
Clinical Features
- Shortness of breath and reduced exercise capacity
- Wheezing
- Chronic cough with sputum production
- Jaundice and signs of liver disease in a subset of patients
Complications
- Early-onset panacinar emphysema
- Cirrhosis and liver failure – due to the accumulation of abnormal AAT protein in the liver cells.
- Increased risk of hepatocellular carcinoma
Pathological Features
Histopathology
- Macroscopic: Liver can show signs of cirrhosis in advanced cases.
- Microscopic: Liver biopsy may reveal intracellular globules within hepatocytes (PAS-positive diastase-resistant globules) representing the accumulation of AAT.
Serology
- Reduced serum AAT levels
Biochemistry
- Liver function tests may show abnormalities in patients with liver disease.
Radiological Features
General Features
- Characteristically demonstrates panacinar emphysema which is typically basal predominant, opposite to the apical predominance seen in smoking-related emphysema.
CT
- Emphysema: areas of decreased attenuation and destruction of pulmonary architecture, typically in the lung bases
- Bullae may be present, particularly in lower lobes.
MRI
- No specific findings, not typically used in assessment of AATD.
PET FDG
- Not typically used in assessment of AATD.
Grading and Staging
Grading and staging usually apply to the resulting diseases (e.g., liver cirrhosis or COPD) rather than AATD itself.
Diagnosis
Diagnosis is typically made through serum testing of AAT levels and genotyping. Liver biopsy may be performed in some cases.
Differential Diagnosis
- COPD due to other causes: COPD due to smoking or occupational exposure also results in emphysema but usually shows upper lobe predominance on imaging.
- Other causes of liver disease: A number of conditions can cause liver cirrhosis and should be considered in differential diagnosis.
Management
Management involves treating the lung and liver diseases that result from AATD. This may include bronchodilators, inhaled corticosteroids, and oxygen therapy for lung disease. Liver transplantation may be necessary for severe liver disease. AAT augmentation therapy, involving intravenous infusion of AAT, may be considered in some patients.