What does a positive alpha 1 antitrypsin (A1AT) test result indicate?

Understanding Positive Alpha-1 Antitrypsin Test Results

A "positive" alpha-1 antitrypsin (A1AT) test result is ambiguous terminology that requires clarification: if it means a normal or elevated A1AT level, this generally indicates the absence of severe A1AT deficiency (though it can be falsely elevated during acute inflammation), whereas if it means detection of deficiency, this indicates a genetic disorder requiring immediate intervention to prevent irreversible lung and liver damage. 1

Critical Interpretation Framework

The term "positive" is problematic in A1AT testing because it lacks standardized meaning. The interpretation depends entirely on what was measured:

If "Positive" Means Normal/Elevated A1AT Levels (≥23 mmol/L or ≥1.2 g/L):

• This rules out severe A1AT deficiency in most cases, except for rare dysfunctional variants like Pi*F where circulating A1AT is present but nonfunctional 1
• However, A1AT is an acute phase reactant, meaning levels rise during infections, inflammation, or acute exacerbations of chronic disease 2
• Levels as high as 1.4 g/L may occur in patients with underlying deficiency during acute illness, creating false reassurance 2
• If clinical suspicion remains high despite normal levels, proceed directly to SERPINA1 gene sequencing rather than repeat protein measurements 1

If "Positive" Means Detection of A1AT Deficiency (Low Levels <11 mmol/L or <0.57 g/L):

• This indicates severe A1AT deficiency, a genetic disorder with autosomal codominant inheritance caused by SERPINA1 gene mutations 3, 4
• The most common mutation is Pi*Z (p.E342K at codon 342), accounting for 95% of severe deficiency cases 4
• This finding has profound implications for both pulmonary and hepatic health 3, 5

Clinical Implications of Confirmed A1AT Deficiency

Pulmonary Manifestations:

• Panacinar emphysema is the most prevalent consequence, typically presenting between ages 32-41 in smokers 3, 5
• The protease-antiprotease imbalance allows neutrophil elastase to destroy lung parenchyma unopposed 5, 6
• Late diagnosis is associated with reduced functional status, quality of life, and worse overall survival 1, 3
• In one study, patients diagnosed 5.3 years after symptom onset (mean FEV1 52% predicted) had significantly worse transplant-free survival 1
• 72% of deaths in untreated patients are due to emphysema 3

Hepatic Manifestations:

• Liver disease is the second most frequent complication, presenting as neonatal cholestasis in infancy or progressing to cirrhosis and hepatocellular carcinoma in adults 3, 6
• The Z mutation causes abnormal protein folding in hepatocyte endoplasmic reticulum, leading to intracellular retention and hepatotoxicity 7

Immediate Management Actions Required

For Confirmed Deficiency:

• Absolute smoking cessation is mandatory - life expectancy is 69 years in non-smokers versus 49 years in smokers 3
• Avoid environmental irritants, vaping, and inhaled cannabis 1
• Maintain up-to-date vaccinations, exercise, healthy diet, and pulmonary hygiene 1
• Avoid occupational exposures to dust, fumes, and respiratory irritants 3

Family Screening:

• Test all first-degree relatives (parents, siblings, children) immediately - this is a Type A recommendation (strongest level) from the American Thoracic Society/European Respiratory Society 3
• First-degree relatives have significantly increased risk of being homozygous (PiZZ) or heterozygous (PiMZ, Pi*SZ) 3
• Even heterozygotes may have increased lung disease risk, particularly with smoking or occupational exposures 3

Augmentation Therapy Consideration:

• Augmentation therapy with intravenous A1AT is indicated only for patients with severe deficiency (<11 mmol/L) AND clinically evident emphysema 5
• Standard dosing is 60 mg/kg weekly, targeting serum levels >11 mmol/L (though this threshold's clinical benefit remains unproven in randomized trials) 5
• The RAPID trial demonstrated that A1AT replacement therapy slows lung density decline on CT, providing the first evidence of disease modification 8
• However, the FDA notes that clinical efficacy in influencing pulmonary exacerbations has not been demonstrated in adequately powered randomized controlled trials 5

Long-term Surveillance:

• Establish monitoring for early detection of progressive lung disease (spirometry, CT lung density) and liver disease (liver function tests, ultrasound) 1, 3
• Not all individuals with severe genetic variants develop emphysema, but risk stratification and monitoring are essential 5

Diagnostic Pitfalls to Avoid

• Never test during acute illness - inflammation falsely elevates A1AT levels, potentially missing underlying deficiency 2
• Do not rely solely on A1AT levels in high clinical suspicion cases - proceed directly to SERPINA1 DNA sequencing (exons 2-5) as the gold standard 1
• Recognize that some variants (Pi*F) have normal circulating A1AT levels but the protein is dysfunctional, requiring genetic confirmation 1
• Genetic mutations are invariable while A1AT levels fluctuate, making DNA-based diagnosis more definitive 1, 4

Recommended Testing Algorithm

For patients with COPD, adult-onset asthma with persistent airflow obstruction, or unexplained bronchiectasis 1:

Moderate Clinical Suspicion:

• Measure serum/plasma A1AT level first
• If ≥23 mmol/L (≥1.2 g/L): severe deficiency excluded (except rare dysfunctional variants)
• If <23 mmol/L: proceed to SERPINA1 DNA sequencing 1

High Clinical Suspicion:

• Proceed directly to SERPINA1 DNA sequencing as initial test 1
• This avoids the variability and acute phase reactant issues with protein measurements 1, 2