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alpha-1-Antitrypsin
(Serine Protease Inhibitor – Pi System – Liver-Synthesized Acute Phase Protein)
Synonyms
- Alpha-1-Antitrypsin
- AAT
- α1-Protease inhibitor (α1-PI)
- Serpin A1
- Pi protein (Protease inhibitor protein)
- α1-Antiproteinase
Units of Measurement
mmol/L, µmol/L, g/L, mg/dL, mg/100mL, mg%, mg/mL
Description
Alpha-1-Antitrypsin (AAT) is a major serine protease inhibitor synthesized in the liver and released into the bloodstream. It protects tissues-especially lungs—from neutrophil elastase and other proteolytic enzymes.
AAT is essential for preventing:
- Emphysema
- COPD
- Liver disease in infants and adults
- Tissue destruction during inflammation
AAT is also a positive acute-phase reactant, increasing 3–5× during inflammation.
Physiological Role
1. Protection Against Neutrophil Elastase
AAT binds and neutralizes neutrophil elastase, preventing:
- Alveolar wall destruction
- Premature emphysema
- Bronchial damage
- COPD progression
2. Anti-Inflammatory Roles
- Downregulates inflammatory cytokines
- Protects endothelium
- Reduces oxidative injury
3. Liver Function
AAT is produced in hepatocytes; abnormal variants accumulate in liver cells leading to:
- Hepatitis
- Cirrhosis
- Neonatal cholestasis
Clinical Significance
Increased AAT
Typical in inflammation:
- Sepsis
- Pneumonia
- Autoimmune disease
- Cancer
- Pregnancy
(not usually clinically important unless evaluating deficiency)
Decreased AAT - Clinically Critical
Low levels occur in:
1. Genetic AAT Deficiency (SERPINA1 gene)
Common pathogenic alleles:
- Pi*ZZ (severe deficiency)
- Pi*SZ
- Pi*SS (mild)
- Null alleles (no protein produced)
Leads to:
- Early-onset emphysema (basilar, panacinar)
- COPD in non-smokers
- Liver disease (neonatal hepatitis → cirrhosis)
- Adult hepatitis, fibrosis
2. Liver Failure (reduced synthesis)
- Cirrhosis
- Fulminant hepatitis
3. Protein-Losing States
- Nephrotic syndrome
- Protein-losing enteropathy
4. Severe malnutrition
Reference Intervals
(Tietz 8E + Mayo Clinic + ATS/ERS + IFCC)
Adults
- 0.90 – 2.0 g/L
- 90 – 200 mg/dL
- ≈ 21 – 48 µmol/L
(based on MW ≈ 52,000 g/mol)
Children
- Similar to adults, but infants may have slightly higher values.
Interpretation
- AAT < 0.6 g/L strongly suggests deficiency → order phenotyping or genotyping.
- AAT > 3.0 g/L indicates acute-phase reaction.
AAT Phenotypes (Pi System)
| Phenotype | AAT Level | Clinical Significance |
|---|---|---|
| Pi*MM | Normal | No disease |
| PiMS / PiMZ | Mild decrease | Carrier state |
| Pi*SZ | Moderate deficiency | Risk for emphysema |
| Pi*ZZ | Severe deficiency | High risk: COPD & liver disease |
| Null variants | No protein | Very severe lung disease |
When to Order AAT Testing
- Early-onset COPD (<45 yrs)
- Basilar panacinar emphysema
- Non-smokers with COPD
- Neonatal cholestasis
- Unexplained chronic liver disease
- Family history of AAT deficiency
- Adults with cirrhosis or hepatocellular carcinoma
Unit Meanings
| Unit | Meaning |
|---|---|
| mmol/L | millimole per liter |
| µmol/L or umol/L | micromole per liter |
| g/L | grams per liter |
| mg/dL | milligrams per deciliter |
| mg/100 mL | mg% |
| mg% | milligrams per 100 mL |
| mg/mL | milligrams per milliliter |
Analytical Notes
- Measured using immunoturbidimetry or nephelometry.
- Always pair quantitative level with phenotyping or genotyping if deficiency suspected.
- AAT increases during inflammation → testing should ideally be done when CRP is normal.
- Serum is preferred; hemolysis/lipemia minimally interfere.
Clinical Pearls
- AAT deficiency is underdiagnosed; one of the most common genetic diseases worldwide.
- Smoking dramatically worsens emphysema in AAT-deficient individuals.
- Very low AAT < 0.3 g/L is almost always Pi*ZZ or null allele.
- AAT testing must be interpreted with CRP due to its acute-phase nature.
- Augmentation therapy is available for severe deficiency.
Interesting Fact
Alpha-1-Antitrypsin was one of the first inherited protease inhibitor disorders discovered (1963), marking a milestone in molecular medicine and genetic hepatology.
References
- Tietz Clinical Chemistry and Molecular Diagnostics, 8th Edition - Proteins & Serpins.
- Mayo Clinic Laboratories - Alpha-1-Antitrypsin Testing.
- ATS/ERS Clinical Guidelines - AAT Deficiency.
- ARUP Consult - AAT Phenotype Interpretation.
- IFCC Protein Standardization Guidelines.
- NIH / MedlinePlus - Alpha-1-Antitrypsin Deficiency.
- de Serres FJ. “Worldwide distribution of AAT deficiency.” Chest Journal.