Alpha-1-antitrypsin: Deficiency, Symptoms & Treatment
Alpha-1-antitrypsin is a protective protein produced by the liver. A deficiency can lead to serious lung and liver disease.
Things worth knowing about "Alpha-1-antitrypsin"
Alpha-1-antitrypsin is a protective protein produced by the liver. A deficiency can lead to serious lung and liver disease.
What is Alpha-1-antitrypsin?
Alpha-1-antitrypsin (A1AT) is a protein primarily produced in the liver and released into the bloodstream. It belongs to the family of serine protease inhibitors (serpins) and its main role is to inhibit aggressive enzymes – in particular neutrophil elastase – that are released by the immune system to fight pathogens. Without adequate A1AT, these enzymes can attack and destroy the body's own tissues, especially in the lungs. Alpha-1-antitrypsin therefore serves as a critical protective shield for lung tissue.
Alpha-1-antitrypsin deficiency: Causes
Alpha-1-antitrypsin deficiency (A1ATD) is one of the most common inherited metabolic disorders. It follows an autosomal codominant inheritance pattern and is caused by mutations in the SERPINA1 gene on chromosome 14. The most clinically significant variants include:
- PiZZ genotype: Both gene copies carry the Z mutation; leads to severely reduced A1AT blood levels and accumulation of misfolded protein within liver cells.
- PiSZ genotype: Combined S and Z mutations; moderate deficiency.
- PiMZ genotype: One normal (M) and one Z copy; mild deficiency, but increased risk when combined with additional risk factors such as smoking.
Worldwide, an estimated 3.4 million people are affected by severe A1AT deficiency. The condition is particularly prevalent in Europe.
Symptoms and affected organs
Lungs
In the lungs, insufficient alpha-1-antitrypsin allows elastase to act unchecked, progressively destroying the delicate lung tissue. This leads to:
- Pulmonary emphysema: Destruction of the air sacs (alveoli), often occurring as early as the age of 30–50 years
- Chronic obstructive pulmonary disease (COPD): Shortness of breath, chronic cough, increased mucus production
- Bronchiectasis: Permanent widening and scarring of the airways
Smoking dramatically accelerates lung destruction and is the most important modifiable risk factor for people with A1ATD.
Liver
In individuals with the ZZ genotype, misfolded A1AT protein accumulates within liver cells rather than being secreted into the bloodstream. This can cause:
- Neonatal hepatitis (jaundice in newborns)
- Liver fibrosis and cirrhosis
- Increased risk of hepatocellular carcinoma (liver cancer)
Other organs
Rarer manifestations include panniculitis (inflammation of the subcutaneous fat tissue) and certain vascular conditions such as granulomatosis with polyangiitis.
Diagnosis
Diagnosis of A1AT deficiency involves several steps:
- Blood test: Measurement of serum alpha-1-antitrypsin levels (normal range: 0.9–2.0 g/L)
- Phenotyping (isoelectric focusing): Identification of protein variants
- Genotyping / DNA analysis: Detection of specific mutations in the SERPINA1 gene
- Lung function tests: Spirometry to assess airflow limitation
- Imaging: Chest CT scan to detect emphysema
- Liver biopsy: If liver involvement is suspected
Diagnosis is frequently delayed because symptoms resemble those of other conditions such as asthma or common COPD.
Treatment
General measures
- Complete smoking cessation – the single most important step to slow lung deterioration
- Avoidance of air pollution and occupational dust exposure
- Vaccinations against influenza, pneumococcal disease, and hepatitis A/B
- Pulmonary rehabilitation and exercise
Augmentation therapy
The only specific treatment available for the lung manifestation is intravenous augmentation therapy: purified alpha-1-antitrypsin concentrate derived from human donor plasma is administered on a regular basis (typically weekly) to raise blood levels and protect lung tissue. Clinical evidence shows that this therapy slows the progression of emphysema.
Symptomatic lung treatment
- Bronchodilators (e.g., beta-2 agonists, anticholinergics)
- Inhaled corticosteroids when indicated
- Supplemental oxygen for advanced COPD
- In end-stage disease: lung transplantation
Treatment of liver disease
Currently, no approved specific therapy exists for the liver manifestation. In end-stage liver cirrhosis, liver transplantation may be necessary and effectively cures the genetic defect, as the new liver produces normal A1AT. Novel approaches such as RNA interference (RNAi) and gene therapy are under active clinical investigation.
References
- Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. The Lancet. 2005;365(9478):2225–2236. doi:10.1016/S0140-6736(05)66781-5
- American Thoracic Society / European Respiratory Society. Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency. American Journal of Respiratory and Critical Care Medicine. 2003;168(7):818–900.
- Strnad P et al. Alpha1-Antitrypsin Deficiency. New England Journal of Medicine. 2020;382(15):1443–1455. doi:10.1056/NEJMra1910234
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