What does a low alpha-1 (alpha-1) antitrypsin level indicate in an adult patient?

What Does a Low Alpha-1 Antitrypsin Level Mean?

A low alpha-1 antitrypsin (AAT) level indicates alpha-1 antitrypsin deficiency, a hereditary disorder that significantly increases your risk for developing early-onset emphysema (particularly panacinar emphysema with basilar predominance) and liver disease, requiring immediate smoking cessation, further diagnostic testing to determine your specific genetic variant, and consideration for augmentation therapy if you have documented emphysema. 1, 2

Understanding the Severity of Deficiency

The interpretation of your AAT level depends on the specific threshold:

• Severe deficiency: <11 μmol/L (<0.57 g/L) - This indicates you are at markedly increased risk for developing COPD and emphysema, typically associated with the Pi*ZZ genotype (approximately 95% of severe cases) or Pi(null)(null) variants 2, 3

• Intermediate/borderline levels: 12-23 μmol/L (0.57-1.2 g/L) - These levels may correspond to intermediate phenotypes (PiSZ, PiSS, Pi*MZ) and warrant genetic testing, as even some individuals in this range can develop emphysema 4, 5

• Normal levels: >22 μmol/L (>1.2 g/L) - This essentially excludes severe AAT deficiency 2, 5

What Happens Next: Required Follow-Up Testing

You must undergo qualitative genetic testing (phenotyping or genotyping) to identify your specific genetic variant, as serum AAT level alone should never be used as the sole basis for diagnosis. 5 The optimal approach involves:

• DNA sequencing of the SERPINA1 gene (increasingly preferred as the gold standard) to detect specific mutations and provide definitive results that don't fluctuate 5
• Isoelectric focusing (IEF) for phenotyping, though this may miss rare variants 5

Clinical Implications for Your Lungs

Low AAT disrupts the protease-antiprotease balance in your lungs, allowing neutrophil elastase to act uninhibited and destroy lung tissue and alveolar structures. 6 The specific manifestations include:

• Panacinar emphysema with basal (lower lung) predominance - This is the pathologic hallmark seen in all adult patients with severe AAT deficiency at autopsy 4

• Typical age of symptom onset: 32-41 years in smokers - Symptoms rarely present before age 25, but smoking dramatically accelerates disease progression 4

• Common symptoms include:

  • Dyspnea on exertion (84% of patients) 4
  • Wheezing during respiratory infections (76%) 4
  • Chronic cough with or without sputum production (42-50%) 4
  • Bronchiectasis in some cases 4

Critical caveat: Many nonsmokers with severe deficiency develop no symptoms at all or have nearly normal life expectancy (69 years for nonsmokers versus 49 years for smokers). 1 However, even nonsmokers can develop emphysema, as demonstrated by autopsy findings in an 11-year-old girl with AAT deficiency. 4

Clinical Implications for Your Liver

Liver disease is the second most frequent clinical complication of AAT deficiency. 1 The characteristic Pi*Z mutation results in hepatic Z-AAT protein accumulation, which can cause:

• Pediatric presentation: Cholestasis in infancy, which usually resolves by adolescence 1
• Adult presentation: 30-40% of patients over age 50 develop cirrhosis or hepatocellular carcinoma 2, 7
• Testing recommendation: All individuals with cirrhosis of unknown etiology should be tested for AAT deficiency 4

Immediate Actions You Must Take

1. Absolute Smoking Cessation (Non-Negotiable)

If you smoke, you must stop immediately - smoking with AAT deficiency reduces life expectancy to less than 20 years after diagnosis. 2 Smoking is the single most important modifiable risk factor, and augmentation therapy cannot even be considered until you have been smoke-free for at least 6 months. 2

2. Avoid Environmental and Occupational Exposures

You must avoid dust, fumes, respiratory irritants, and occupational exposures that could accelerate lung damage. 1, 2

3. Obtain Baseline Testing

• Pulmonary function tests (spirometry) to assess FEV1 2
• Chest CT scan to document presence and extent of emphysema 2
• Liver function tests, particularly if you are over 50 years old 2

4. Update Vaccinations

• Annual influenza vaccination 2
• Pneumococcal vaccination 2
• Hepatitis B vaccination (especially if you have liver disease) 4, 2

Who Else in Your Family Needs Testing?

All first-degree relatives (parents, siblings, children) must be tested, even if they have no symptoms. 1 This is a Type A recommendation (the strongest level) from the American Thoracic Society/European Respiratory Society. 1 First-degree relatives have significantly increased risk of being homozygous (PiZZ) or heterozygous (PiMZ, Pi*SZ), and early identification allows implementation of crucial preventive measures. 1

Treatment Considerations: Augmentation Therapy

Augmentation therapy with intravenous AAT should be considered if you meet ALL of the following criteria: 2

• Severe AAT deficiency (<11 μmol/L or <0.57 g/L) 2
• Documented SERPINA1 deficiency genotype 2
• Documented emphysema on CT scan 2
• FEV1 <80% predicted 2
• Never smoker OR former smoker (smoke-free ≥6 months) 2
• On optimal standard COPD therapy 2

Important limitation: The clinical efficacy of augmentation therapy in influencing the course of pulmonary emphysema has not been conclusively demonstrated in adequately powered, randomized controlled trials, though it remains the only FDA-approved specific treatment for AAT deficiency. 3, 6

Standard COPD Management (Required Regardless)

All patients with AAT deficiency and lung disease require standard COPD management: 4, 2

• Bronchodilators (even if objective bronchodilator responsiveness is lacking, most patients find symptomatic benefit) 4
• Inhaled corticosteroids if evidence of bronchial hyperreactivity 4
• Early antibiotic therapy for all purulent exacerbations (due to increased elastolytic burden risk) 2
• Pulmonary rehabilitation 4
• Supplemental oxygen if hypoxemic 4

Prognosis Without Treatment

Without appropriate management, AAT deficiency leads to premature disability and death, with 72% of deaths due to emphysema. 1 However, with smoking avoidance and appropriate care, life expectancy can approach normal in nonsmokers. 1

Common Pitfalls to Avoid

• Never rely on AAT level alone - Always confirm with genetic testing 5
• Don't overlook liver disease monitoring - This affects 30-40% of patients over 50 and is a significant cause of death in nonsmoking Pi*ZZ individuals 2
• Don't assume heterozygotes (Pi*MZ) are safe - They still have increased risk, particularly with smoking or occupational exposures 1
• Don't delay family screening - Early detection in relatives enables life-saving preventive interventions 1