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Alpha-1 Antitrypsin Deficiency

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Overview

Alpha-1 antitrypsin (α1AT) is a glycoprotein produced in the liver and plays a role in inhibiting the action of protease enzymes released from neutrophils, such as neutrophil elastase released in inflammation, infection, or smoking.

α1AT deficiency is an inherited condition in which the α1AT protein’s structure is modified. This can lead to excess elastin breakdown leading to the destruction of alveolar walls and COPD. The α1AT can accumulate in the liver, leading to liver cell destruction and cirrhosis. In exams, α1AT deficiency classically causes COPD in young people and non-smokers.

Epidemiology

  • α1AT deficiency is one of the most common inherited disorders in white people
  • Around 5% of people diagnosed with COPD are thought to have α1AT deficiency

Genetics

α1AT deficiency is caused by a mutation in the SERPINA1 gene on chromosome 14. The consensus is that inheritance is codominant. M alleles are normal variants of the gene. S and Z are other common variants.

  • MM genotype: produce normal amounts of α1AT
  • MS or MZ genotype: carrier and produce around 35% of normal α1AT
  • SS, ZZ, MS, MZ, SZ genotype: α1AT deficiency

It is important to appreciate that not everyone with α1AT deficiency develops clinically significant disease. These different genotypes lead to varying amounts of α1AT. Most patients with clinically significant α1AT deficiency have the SS or ZZ genotype. 

Presentation

α1AT deficiency should be considered in any young patient presenting with features consistent with COPD, or any patient with severe and aggressive COPD. Features may be:

  • Early presentation of COPD symptoms
  • Imaging shows emphysema in the lower lobes of the lung
  • Cirrhosis and hepatocellular carcinoma may be present, even in the absence of alcohol consumption
    • Not every patient with α1AT deficiency will develop liver disease

Investigations

All patients

  • Serum α1AT levels:
    • All patients with COPD, non-responsive asthmatic adults/adolescents, and people with liver disease of unknown aetiology should be screened using this test
  • Spirometry:
    • FEV1: significantly reduced
    • FVC: significantly reduced
    • FEV1/FVC: significantly reduced
  • Chest x-ray:
    • Usually shows emphysematous changes – particularly in the lower lobes
  • Liver function tests (LFTs):
    • ALT, bilirubin, and ALP may be raised

Management

Overview

  • Currently, replacement α1AT is not recommended. Patients should stop smoking and be given supportive therapies such as bronchodilators and pulmonary rehabilitation.
  • In some patients, lung volume reduction surgery may be considered.

Complications

  • Emphysematous changes in the lungs and worsening COPD
  • Liver cirrhosis and hepatocellular carcinoma

Prognosis

  • People who have symptoms at diagnosis tend to have a worse prognosis
  • Increased severity of airflow obstruction is associated with a worse prognosis
  • Patients who smoke have a poorer prognosis and should be offered help with smoking cessation. 

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