Smoking Does Not Decrease Alpha-1 Antitrypsin Levels
Smoking does not reduce the actual serum levels of alpha-1 antitrypsin (A-1 AT), but it functionally inactivates the enzyme through oxidative damage, creating a critical protease-antiprotease imbalance that accelerates emphysema development. 1
The Mechanism: Functional Inactivation, Not Level Reduction
Cigarette smoke contains oxidants that convert the active site methionine (Met358) to methionine sulfoxide, reducing the association rate constant for neutrophil elastase inhibition by approximately 2,000-fold. 1
The serum concentration of A-1 AT remains unchanged by smoking—what changes is the functional activity of the protein already present. 1
This oxidative inactivation occurs in the lower respiratory tract where cigarette smoke oxidants directly interact with A-1 AT molecules. 1
Why This Distinction Matters Clinically
For Patients with Normal A-1 AT Levels
Individuals with normal A-1 AT levels (PI*MM phenotype) who smoke still develop COPD, but at older ages and with less severe disease compared to A-1 AT deficient smokers. 1
The oxidative inactivation from smoking can be partially compensated by the large reserve of functional A-1 AT in normal individuals. 1
For Patients with A-1 AT Deficiency
In A-1 AT deficiency (particularly PI*ZZ phenotype with levels <11 μM), smoking creates a catastrophic situation: already low baseline levels are further functionally impaired by oxidative inactivation. 1, 2
Smoking is the single most important modifiable risk factor for emphysema development in A-1 AT deficient individuals, with smokers developing severe disease in their 40s versus near-normal life expectancy in never-smokers. 1
Among PI*ZZ individuals, current smokers show FEV1 decline of 70 ml/year versus 47 ml/year in never-smokers and 41 ml/year in ex-smokers. 1
Life expectancy is less than 20 years after diagnosis in A-1 AT deficient patients who cannot stop smoking. 1
Additional Smoking-Related Mechanisms Beyond Oxidation
Cigarette smoke recruits inflammatory cells, particularly neutrophils, into the airways, increasing the neutrophil elastase load that must be inhibited. 1
Smoking reduces sputum interleukin-8 levels when stopped, which may decrease neutrophil influx and explain the slower disease progression in ex-smokers. 3
In A-1 AT deficient patients, greater airways inflammation occurs with increased leukotriene B4, myeloperoxidase, and neutrophil elastase activity compared to those with normal A-1 AT levels. 3
Critical Clinical Implications
For Heterozygotes (PIMZ, PISZ)
PIMZ and PISZ individuals who smoke have 2.73 and 4.34 times higher odds of being current smokers compared to PI*ZZ individuals, suggesting behavioral differences by genotype. 4
The PISZ phenotype shows profound smoking effects producing FEV1 reduction often as marked as in PIZZ smokers, despite having intermediate A-1 AT levels. 1
Smoking PI*MZ individuals develop mild spirometric abnormalities manifesting later in life, with substantially increased COPD risk in heavy smokers with occupational exposures. 1
For Children with Low A-1 AT Levels
School children with low A-1 AT levels (≤116 mg/dL) exposed to environmental tobacco smoke show pronounced decrements in mid- to end-expiratory flow rates compared to exposed children with normal levels. 5
Parents of children with heterozygous A-1 AT deficiency should be counseled to prevent environmental tobacco smoke exposure and discourage smoking initiation. 5
Common Pitfall to Avoid
Do not confuse "decreased A-1 AT levels" with "decreased A-1 AT function." When counseling patients, explain that smoking doesn't lower their blood test numbers, but it chemically damages the A-1 AT molecules, rendering them unable to protect the lungs—this distinction helps patients understand why smoking cessation is critical even if their A-1 AT levels remain stable. 1