Alpha-1-Antitrypsin Deficiency

Alpha-1-antitrypsin (AAT, alpha-1-protease inhibitor) is the chief protease inhibitor in human serum. The loss of this protease inhibitor results in the degradation of the connective protein elastin in lung alveoli and increases the risk for developing severe lung disease during early adulthood.

Epidemiology

Prevalence
- AAT deficiency is estimated to affect 2-3% of the 2-3 million patients with chronic obstructive pulmonary disease (COPD) in the U.S.
- Severe deficiency – 1/6,000 in Caucasian populations; less frequent in other ethnicities
Incidence – 1/3,000-5,000
Age
- 50s for early-onset COPD (nonsmokers)
- Tobacco smokers usually become symptomatic in their 40s
Ethnicity – highest prevalence in Caucasians of North American and European descent

Risk Factors

Genetics – SERPINA1
- Autosomal recessive
- Isoelectric focusing (PI typing) has identified >100 AAT allelic variants classified according to electrophoretic mobility; most variants have no clinical significance
  - Mutations in the AAT glycoprotein gene on chromosome 14q31-32.3; homozygosity for the Z allele is most common cause
- Most common normal phenotype is PI MM (100% AAT activity)
  - PI MM is found in 95% of Caucasians
- Other common phenotypes and percentage of AAT activity include PI MS (80%), PI SS (60%), PI MZ (57.5%) and PI ZZ (15%)
- S and Z alleles represent 95% of the deficiency phenotypes in the general population
  - PI ZZ is associated with severe liver and lung disease
  - PI SS is associated with milder lung disease
- Heterozygotes (PI MS and PI MZ) are at slightly increased risk for AAT deficiency-related disorders
Tobacco use
- Tobacco smoke contains oxidants capable of inactivating AAT protein, further impairing reduced AAT function
- Increases risk of developing severe lung disease with symptoms beginning ≥10 years earlier than nonsmokers

Pathophysiology

AAT is an acute phase reactant synthesized by the liver
- Most important role is inhibition of protease neutrophil elastase
Inherited deficiency is associated with liver and lung disease
- Decreased quantities of AAT allow elastase to degrade lung parenchyma
- Hepatic disease is secondary to accumulation of unsecreted AAT in hepatocytes

Clinical Presentation

Adults
- Pulmonary – early onset emphysema (panacinar)
- Hepatic – liver disfunction, cirrhosis
  - Occurs more often in individuals with Z allele
  - Hepatitis with jaundice
  - Chronic liver disease
- Skin – panniculitis
  - Necrotic areas with spontaneous suppuration
Neonates
- 10% of affected newborns have hepatitis with cholestatic jaundice (prolonged jaundice with conjugated hyperbilirubinemia)
- Low AAT levels are also found in neonatal respiratory distress syndrome and severe protein-losing disorders
Rare associated diseases
- Wegener granulomatosis, necrotizing panniculitis, aneurysms of aortic and brain arteries
Complications
- Hepatocellular carcinoma and cholangiocarcinoma

Treatment

Early diagnosis is crucial in order to begin enzyme-replacement therapy

Indications for Testing

American Thoracic Society/European Respiratory Society statement, 2003
- Adult with early-onset COPD or emphysema without recognized risk factors
- Necrotizing panniculitis (unexplained)
- Family history of emphysema, AAT, bronchiectasis, liver disease, panniculitis
- Bronchiectasis with no known etiology
- Unexplained liver disease
- ANCA vasculitis (anti-PR3 type)
Other
- Newborns with bleeding disorder or prolonged jaundice

Laboratory Testing

Initial testing
- Serum AAT – concentrations usually low in symptomatic disease
  - AAT is also an acute phase reactant and may be elevated by other disease processes
    - Up to fourfold increase observed in inflammatory conditions, cancer, and liver disease
    - Plasma concentration can be elevated into the normal range in PI MZ heterozygotes
Phenotyping and genotyping
- Phenotype testing to identify AAT protein variants if AAT concentration is <100 mg/dL
- Molecular testing of SERPINA1 gene for S and Z alleles if phenotype is abnormal

Histology

Immunohistochemistry – alpha-1-antitrypsin (AAT)

Differential Diagnosis

Adults
- Non-AAT COPD
- Cirrhosis from other etiologies
Pediatric
- Viral infection
- Hemochromatosis
- Wilson disease
- Autoimmune hepatitis
- Inborn errors of metabolism

Screening tests available prior to testing for AAT levels
- Pulmonary function studies (irreversible airflow obstruction)
- Chest x-ray/CT scan
Population-based screening not recommended even though disease recognized as being underdiagnosed

Tests generally appear in the order most useful for common clinical situations

Test name: Alpha-1-Antitrypsin (SERPINA1) Enzyme Concentration and 2 Mutations with Reflex to Alpha-1-Antitrypsin Phenotype

ARUP #: 0051256

Methodology: Immunoturbidimetric/Polymerase Chain Reaction/Fluorescent Resonance Energy Transfer/Isoelectric Focusing

Use:

Detects presence of S and Z deficiency alleles and identifies AAT deficiency; includes reflex to phenotyping if AAT concentration is inconsistent with genotype

95% clinical sensitivity

Limitations:

AAT is an acute phase reactant; acutely ill, AAT-deficient patients may have falsely normal AAT concentrations

95% clinical sensitivity

Mutations other than those targeted in S allele (c.791A>T) and Z allele (c.1024G>A) are not detected

Analytic sensitivity may be compromised by rare primer site mutations

Test name: Alpha-1-Antitrypsin Phenotype (Includes Alpha-1-Antitrypsin)

ARUP #: 0080500

Methodology: Qualitative Isoelectric Focusing/Immunoturbidimetric

Use:

Identifies AAT protein variants and AAT deficiency

Limitations: