Medicine – α1-Antitrypsin Deficiency

α1-Antitrypsin deficiency (AATD) is an inherited disorder caused by pathogenic variants in the SERPINA1 gene on chromosome 14. It primarily affects the lungs and liver and is an important genetic cause of early-onset emphysema, particularly in patients who smoke.

1. Inheritance

α1-Antitrypsin deficiency is inherited in an autosomal codominant manner.

This means that both inherited alleles contribute to the amount and type of α1-antitrypsin produced. Different combinations of alleles therefore produce different serum concentrations and different risks of developing disease.

2. Function of α1-Antitrypsin

α1-Antitrypsin (AAT) is a circulating protease inhibitor produced mainly by hepatocytes.

Its major pulmonary role is to protect lung tissue from proteolytic enzymes released by inflammatory cells, particularly neutrophil elastase.

Normally, AAT neutralises elastase and prevents excessive degradation of elastin and other structural proteins within the alveolar walls.

3. Mechanism of Emphysema

When AAT concentrations are severely reduced, the lungs become inadequately protected against neutrophil elastase and other proteases.

Unopposed proteolytic activity gradually destroys alveolar walls, reducing the surface area available for gas exchange and producing emphysema.

Smoking accelerates this process by increasing pulmonary inflammation and neutrophil recruitment while also impairing the protective activity of AAT.

4. Pattern of Emphysema

The characteristic pulmonary abnormality is panacinar or panlobular emphysema.

Unlike the centriacinar emphysema typically associated with cigarette smoking, which often has an upper-lobe predominance, AAT deficiency classically produces emphysema that is most pronounced in the lower lobes and lung bases.

5. Protective Threshold

Severe deficiency increases the likelihood of progressive lung injury.

Older teaching sometimes describes tissue destruction occurring when AAT levels fall below approximately 40% of normal, but contemporary assessment more commonly considers the absolute serum concentration and the patient’s genotype rather than relying on a single percentage threshold.

The greatest pulmonary risk occurs in individuals with severe AAT deficiency, particularly those with the ZZ genotype.

Genotypes

The traditional genotype nomenclature uses letters such as M, S, and Z to describe different forms of the AAT protein.

6. MM Genotype

The MM genotype is considered the normal genotype.

People with PiMM generally have normal circulating α1-antitrypsin concentrations and are not considered to have clinically significant AAT deficiency.

7. MZ Genotype

People with the MZ genotype have one normal M allele and one deficient Z allele.

Serum AAT levels are moderately reduced, traditionally quoted at around 60% of normal, although the exact concentration varies.

Most nonsmokers with MZ do not develop severe early emphysema, but smoking and other respiratory exposures can increase their risk.

8. SZ Genotype

The SZ genotype produces a greater reduction in circulating AAT than MZ.

Older teaching commonly quotes levels of approximately 40% of normal.

The risk of emphysema is intermediate and becomes substantially greater with cigarette smoking.

9. ZZ Genotype

The ZZ genotype is the classic form associated with severe α1-antitrypsin deficiency.

Circulating levels may be only around 10–20% of normal, often quoted historically as approximately 15%.

These patients have a particularly high risk of early-onset panacinar emphysema and liver disease.

Clinical Presentation

10. Early-Onset Emphysema

Severely affected individuals may develop respiratory symptoms in the third or fourth decade of life.

Typical features include progressive exertional breathlessness, wheezing, chronic cough, and reduced exercise tolerance.

Smoking can cause symptoms to appear much earlier and can dramatically accelerate the decline in lung function.

11. Pulmonary Function

Pulmonary function testing typically demonstrates an obstructive ventilatory defect, with reduced FEV₁ and FEV₁/FVC ratio.

Gas transfer may also be reduced because destruction of alveolar walls decreases the surface area available for diffusion.

Liver Disease

12. Mechanism of Liver Injury

AAT deficiency can also cause liver disease, particularly with the Z allele.

The mechanism is different from that causing lung disease. In the liver, abnormal Z-type AAT proteins are misfolded and become retained within hepatocytes rather than being efficiently secreted into the circulation.

This intracellular accumulation causes progressive hepatocellular injury.

13. Clinical Liver Manifestations

Severe AAT deficiency can cause neonatal hepatitis, chronic hepatitis, fibrosis, cirrhosis, and an increased risk of hepatocellular carcinoma.

Thus, the disorder simultaneously produces low circulating AAT—predisposing to lung destruction—and abnormal AAT accumulation in the liver—predisposing to hepatic damage.

Diagnosis

Diagnosis involves measurement of the serum α1-antitrypsin concentration, often followed by phenotyping or SERPINA1 genotyping when deficiency is suspected.

Testing should be considered particularly in patients with emphysema at a young age, basilar-predominant emphysema, unexplained airflow obstruction, unexplained liver disease, or a family history of AAT deficiency.

Management

The most important intervention is complete avoidance of cigarette smoking, including avoiding significant occupational exposure to respiratory irritants.

Treatment of associated COPD includes appropriate inhaled therapies, vaccination, pulmonary rehabilitation, and management of exacerbations.

Selected patients with severe deficiency and established emphysema may be considered for intravenous AAT augmentation therapy, depending on clinical criteria and local availability.

Advanced pulmonary disease may eventually require lung transplantation, while severe liver disease may require liver transplantation.

Key Clinical Pattern

Think of α1-antitrypsin deficiency in a relatively young patient with early-onset emphysema, particularly when CT shows lower-lobe predominant panacinar emphysema.

The key mechanism is failure to inhibit neutrophil elastase → destruction of alveolar walls → emphysema.

Remember the genotype pattern: MM = normal, MZ = mild reduction, SZ = intermediate deficiency, ZZ = severe deficiency.

Also remember the important contrast: lung disease results from too little circulating AAT, whereas liver disease results from accumulation of abnormal AAT within hepatocytes.