Alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin (AAT) deficiency is a common and underdiagnosed genetic condition that most commonly occurs in individuals of European descent. AAT is a protease inhibitor, and deficiency results in a lack of neutrophil elastase inhibition in the alveoli and potential polymerization of mutant AAT in hepatocytes. AAT deficiency is caused by mutations in the SERPINA1 gene, and severity varies by genotype. The effect is either reduced AAT levels or reduced AAT activity. Homozygosity for the Z allele causes severe deficiency. AAT deficiency clinically manifests in the lungs (e.g., with COPD, panacinar emphysema) and, in some cases, the liver (e.g., with hepatitis, cirrhosis, neonatal jaundice). Measurement of serum AAT levels is recommended for individuals with associated conditions (e.g., COPD, liver disease, adult-onset asthma). Phenotyping and/or genotyping should be performed in individuals with decreased AAT levels to confirm the diagnosis; if results are inconclusive, gene sequencing should be performed. Management includes supportive measures (e.g., smoking cessation, vaccinations), monitoring, and, in some cases, IV augmentation therapy. Treatment for lung disease may include bronchodilators and, in advanced cases, lung transplantation; liver transplantation may be required in end-stage liver disease.

AAT deficiency most commonly occurs in individuals of European descent.

• 1 in 25 individuals of European descent is a carrier of the Z allele. ^[1]
• 1 in 2000 individuals of European descent is homozygous for the Z allele, resulting in severe AAT deficiency. ^[1]

Epidemiological data refers to the US, unless otherwise specified.

AAT deficiency is a genetic disorder with autosomal codominant inheritance.

• Mutations in the SERPINA1 gene include: ^[1]
  • S mutation: moderate decrease in AAT production and polymerization of mutant AAT in hepatocytes
  • F mutation: reduced elastase inhibition despite normal AAT production
  • Z mutation: significant decrease in AAT production and polymerization of mutant AAT in hepatocytes
  • Null alleles (rare): no AAT production, severely affecting the lungs but not the liver ^[1]
• Disease severity ^[1][2][3]
  • PiMM: 100% expression of normal protein and therefore normal serum AAT levels
  • PiFF: 100% of normal serum AAT levels but possible reduced AAT activity ^[4]
  • PiMS: 80% of normal serum AAT levels
  • PiSS, PiMZ, PiSZ: 40–60% of normal serum AAT levels and polymerization of mutant AAT in hepatocytes
  • PiZZ: 10–15% of normal serum AAT levels (severe AAT deficiency) and polymerization of mutant AAT in hepatocytes ^[5]

Disease severity depends on the genotype, which determines how much AAT is produced and whether the mutant protein polymerizes in hepatocytes.

• Alpha-1 antitrypsin: a protease inhibitor that is synthesized in the liver and protects cells from breakdown by neutrophil elastase
• Gene mutation induces a conformational change in the structure of AAT protein → dysfunctional (or absent) AAT
  • Effect on the liver: accumulation of AAT in hepatocellular endoplasmic reticulum → hepatocyte destruction → hepatitis and liver cirrhosis
  • Effect on the lungs: deficient AAT → uninhibited neutrophil elastase activity → destruction of the pulmonary parenchyma → panacinar emphysema

The age of onset and the severity of symptoms depend on the type of mutation.

• Pulmonary manifestations ^[6]
  • Clinical features of COPD, e.g.:
    • Cough, wheezing
    • Dyspnea
    • Diminished breath sounds
    • Barrel chest
  • Onset may be earlier than in patients with COPD without AAT deficiency.
• Hepatic manifestations ^[6]
  • Prolonged neonatal jaundice
  • Hepatitis
  • Clinical features of cirrhosis

AAT deficiency should be considered in all patients < 50 years of age with emphysema, COPD, and/or liver dysfunction.

Approach

• Obtain serum AAT levels in individuals with indications for testing.
• If AAT levels are decreased, refer to a center specializing in AAT deficiency for genetic testing and management.
• Manifestation-specific diagnostics (e.g., chest CT) may be helpful to assess organ involvement and disease severity.

Indications for testing ^[1]

• First-degree relatives of individuals with AAT deficiency
• Patients with any of the following pulmonary conditions:
  • COPD
  • Asthma that does not respond to therapy or adult-onset asthma ^[7]
  • Bronchiectasis of uncertain etiology
• Patients with any of the following extrapulmonary conditions:
  • Liver disease
  • c-ANCA vasculitis (e.g., granulomatosis with polyangiitis)
  • Panniculitis

Laboratory studies ^[1][7]

• Initial testing
  • ↓ Serum AAT level (< 1.1 g/L): indicates potential deficiency ^[1][7]
  • Normal CRP: If elevated, AAT levels may be increased due to infection or inflammation, and testing should be repeated.
• Genetic testing: performed in a specialized laboratory
  • Phenotyping
    • Uses isoelectric focusing to determine the protein phenotype (e.g., MM, MZ, MS, ZZ)
    • May incorrectly label certain rare variants (e.g., M_Malton labeled as M)
  • Genotyping: can detect common mutations (e.g., Z or S) and certain less common mutations using specific DNA primers
  • Gene sequencing
    • Can detect unknown or rare mutations
    • Performed if phenotyping and/or genotyping is inconclusive

Decreased serum AAT levels and confirmation of a deficient phenotype or genotype are diagnostic for AAT deficiency.

Manifestation-specific diagnostics

Lung disease ^[6][8]

• Diagnostics for COPD (e.g., spirometry)
• Chest x-ray findings in COPD, including:
  • Low and flat diaphragm
  • Widened intercostal spaces
  • Hyperinflation
  • Possible increased basilar radiolucency of both lungs ^[9]
• Chest CT
  • Panacinar emphysema (in contrast to centriacinar emphysema in smoking-related emphysema) is a characteristic finding.
  • Bronchiectasis
  • Bullae

All patients with COPD should be tested for AAT deficiency. ^[8]

Liver disease ^[1]

• Perform diagnostics for cirrhosis or diagnostics for elevated transaminases depending on the patient's symptoms and/or laboratory findings.
• If performed, liver biopsy may show:
  • Diastase-resistant, PAS-positive, spherical inclusion bodies in periportal hepatocytes
  • Signs of cirrhosis; see “Pathology of cirrhosis.”

• Pulmonary diseases
  • Asthma
  • Emphysema secondary to smoking (centriacinar)
  • COPD without AAT deficiency
  • Cystic fibrosis
• Liver diseases
  • Autoimmune hepatitis
  • Alcohol-associated liver disease
  • Wilson disease
  • Hemochromatosis
  • Drug-induced liver injury
  • MASLD

The differential diagnoses listed here are not exhaustive.

Refer all patients to a center specializing in AAT deficiency for management.

Supportive care ^[1][7][8]

• Avoid active and passive cigarette smoking. ^[7]
• Preventive vaccination (e.g., recommended immunizations in COPD)
• Pulmonary rehabilitation
• Nutritional support if necessary
• Supportive care for cirrhosis

Treatment of lung and liver disease ^[1][7][8]

• IV augmentation therapy: antitrypsin replacement for patients with lung disease
  • Indication: nonsmoking individuals with severe AAT deficiency and evidence of decreased airflow
  • Reduces lung density loss but has no effect on quality of life, AECOPD, FEV₁, or liver disease ^[1]
• COPD treatment
  • Pharmacological treatment for stable COPD (e.g., bronchodilators)
  • Symptomatic treatment (e.g., pharmacotherapy for AECOPD)
  • Management of advanced COPD (e.g., long-term oxygen therapy, lung transplantation)
• Liver transplantation
  • Results in correction of AAT deficiency
  • Consider in end-stage liver disease. ^[10]

IV augmentation therapy is the only disease-specific therapy for AAT deficiency but does not treat liver disease.

Monitoring ^[1]

• Monitoring for lung disease progression
  • Severe AAT deficiency: every 6 months for the first few years after diagnosis, then annually
  • Studies include spirometry (e.g., FEV₁), DL_CO, 6MWT, and quality of life questionnaires. ^[7]
• Monitoring for liver disease progression
  • Noninvasive testing to monitor for fibrosis (e.g., liver elastography, FIB-4 score)
  • Liver ultrasound
    • Patients with cirrhosis, portal hypertension, or elevated transaminases: every 6 months
    • All other patients: Consider annually.

Patients with AAT deficiency have an increased risk of hepatocellular carcinoma.