Alpha-1 Antitrypsin Deficiency

From Paeds.co.uk the online paediatrician's encyclopaedia

Jump to: navigation, search

Contents


Alpha-1 Antitrypsin (AAT) is a glycoprotein and a serine protease inhibitor (serpin). Defiency is associated with childhood liver disease and later pulmonary emphysema (usually in smokers). Produced in the liver, it is secreted into the blood and diffuses into lung tissue where it predominantly inhibits the protease neutrophil elastase, protecting alveolar cell walls.


Alpha-1 antitrypsin deficiency is the commonest inherited cause of liver disease in children.

  • 1 in 10 northern Europeans carry the gene which is inherited as autosomal dominant.


There are three main phenotypes of the alpha-1 antitrypsin inhibitor gene, although over 75 different alleles have been described.

  • PiMM - normal
  • PiMZ / PiMS - heterozygous deficiency (35% AAT levels)
  • PiZZ - homozygous deficiency (10% AAT levels)


Incidence

  • Incidence = 1 in 5000
  • Age: deficiency present at birth. Variable timing of presentation. Liver disease can present early in childhood. COPD present in the fourth decade in smokers and the fifth decade in non-smokers.
  • Sex: equal incidence.
  • Ethnicity: predominantly affects caucasians of northern european descent.


Aetiology

The phenotypes of Alpha-1 antitrypsin deficiency are characterised by their mobility during electrophoresis: medium (M), slow (S), very slow (Z).


The normal genotype is protease inhibitor MM (PiMM). Other phenotypes are PiMZ, PiSZ (heterozygotes) and PiZZ (homozygous).


S and Z variants are due to single amino acid replacement of glutamate at positions 264 and342, respectively. This results in decreased synthesis and secretion of alpha-1 antitrypsin by the liver.


Most patients with disease are homozygotes with PiZZ phenotype. 10-15 % of adults develop cirrhosis while 75% will have respiratory problems. Heterozygotes may develop liver disease, though the risk is small.


The mechanism of injury in liver disease is not known though may be related to impaired secretion of the abnormal AAT protein from hepatocytes.


Clinical features

  • Cholestasis in infancy
  • Cirrhosis in late childhood / adolescence
    • Cirrhosis and hepatocellular carcinoma affect 25% in late adulthood
  • Emphysema / Chronic Obstructive Airways Disease - (panacinar) commonest presentation in adulthood (usually smokers).


Morbidity and Mortality

Rates are variable and unknown, though in those with advanced disease, mortality is high.


Investigations

Serum alpha-1 antitrypsin levels - low

  • PiZZ: 10% of normal
  • PiSZ: 60% of normal


Alpha-1 antitrypsin phenotyping (isoelectric focusing)


Liver function Tests


Liver biopsy - PAS-positive (periodic acid-Schiff) diastase-resistant globules are seen in periportal hepatocytes. Fibrosis and cirrhosis may be present.


Spirometry / Lung Function testing / CT Chest - if indicated (Pan-acinar emphysema).


Management

Treatment is of the complications, Liver disease in particular.

  • Children with decompensated liver disease should be considered for liver transplantation.


Patients should be strongly advised against smoking, as appropriate.


Human plasma protein concentrates may be available for selected patients at risk of developing emphysema to replace the missing AAT. Weekly IV infusions are required.


References


Patient Support Information

Personal tools
Recommend