Alpha-1-antitrypsin deficiency

Alpha-1-antitrypsin (A1AT) deficiency is an autosomal codominant metabolic disorder and is the most common genetic cause of emphysema and metabolic liver disease in children. It results in the unopposed action of neutrophil elastase and subsequent severe basal panlobular emphysema and respiratory symptoms. Accumulation of altered alpha-1-antitrypsin in hepatocytes incites an inflammatory response and chronic liver disease ¹.

Epidemiology

Estimated prevalence is thought to be around 1 in 1,500 to 3,500 individuals with European ancestry. It is reported to be uncommon in people of Asian descent.

Associations

• asthma

• pancreatitis

• aneurysms, including intracranial aneurysms ¹⁸

Clinical presentation

The classic presentation of the disease is with dyspnea in the 4^th to 5^th decades of life. 

Pathology

Alpha-1-antitrypsin (A1AT) is a protein that prevents enzymes such as elastase from degrading normal host tissue. Over 90% of the alpha-1-antitrypsin protein is produced in hepatocytes by codominant expression of the SERPINA1 gene on chromosome 14.

The most common alleles of this gene are designated M, Z, or S, prefixed by PI (standing for protease inhibitor). Normal individuals have two copies of the M allele so are designated 'PIMM'. The most common abnormal allele is Z, and individuals homozygous for this (i.e. 'PIZZ') have severe alpha-1-antitrypsin deficiency. Heterozygous individuals (i.e. 'PIMZ') are usually asymptomatic. The S allele confers a partially functional alpha-1-antitrypsin protein, and only usually causes symptoms when combined with the Z allele (i.e. 'PISZ') ²⁶.

The alpha-1-antitrypsin protein inhibits neutrophil elastase. In patients with severe deficiency, the neutrophil elastase acts unopposed resulting in damage to the lower respiratory tract. This damage is predominantly basal because of the gravitational distribution of pulmonary blood flow.

Radiographic features

Thoracic manifestations

Plain radiograph and CT

• panlobular emphysema

  • the emphysema pattern was traditionally thought to be panlobular, although more recent studies have also suggested a variable pattern to the emphysema

  • basal predominance, in contradistinction to centrilobular emphysema, which shows apical predominance; the two conditions can coexist in smokers

  • emphysema may develop in 75-85% of cases ¹²

• bronchiectasis: up to 40% ⁹

• frank bulla formation: non-specific feature ¹³

• bronchial wall thickening: non-specific feature ¹³

• hepatopulmonary syndrome

Nuclear medicine

Reduced perfusion and ventilation in the lower zones on a ventilation/perfusion (V/Q) study.

Abdominal manifestations

Hepatic manifestations of this disease are those of cirrhosis.

Treatment and prognosis

Emphysema and cirrhosis are usually considered the most common causes of death ⁸.

Survival is substantially worse in smokers, who have a 20-year decrease in longevity relative to non-smokers. According to one study, the overall median survival time was ~55 years ⁷.

Alpha-1-antitrypsin replacement therapy, most often by weekly intravenous infusions of alpha-1-antitrypsin purified from human plasma, has been used in some situations to partially correct the biochemical defect ^14,15.  

While randomized, placebo-controlled clinical trials have confirmed a reduction in the decline in lung density in patients receiving augmentation therapy ¹⁴, its efficacy in reducing mortality is uncertain ¹⁶. Other management strategies include avoidance of smoking and of other risk factors for cirrhosis.

Lung and liver transplant is generally reserved for those with end stage disease ^24,25.

Complications

• cirrhosis with increased risk of hepatocellular carcinoma ¹⁹

• although carriers of the deficient gene are generally asymptomatic and do not suffer significant pulmonary or hepatic complications, they are at 70-100% increased risk of lung cancer ²⁰

Differential diagnosis

The differential will depend on the organ involved:

• for thoracic manifestations: see differential for panlobular emphysema

  • near identical imaging appearances with ritalin lung

• for hepatic manifestations: see differential for cirrhosis