Alpha-1 Antitrypsin Deficiency

Overview
  • Alpha-1 Antitrypsin Deficiency is a hereditary disease caused by mutation of the Alpha-1 Antitrypsin gene, primarily resulting in respiratory and hepatic pathology. Alpha-1 Antitrypsin is a liver-derived anti-protease secreted into the serum which inhibits a variety of proteases released by neutrophils at sites of inflammation.
Etiology
  • Alpha-1 Antitrypsin Deficiency is caused by hereditary mutations in the alpha-1 antitrypsin gene which reduces the activity of this anti-protease. A variety of alleles are present in the population with varying levels of activity. PiM is the normal allele which is present in the vast majority of the population. PiZ is an allele with significantly reduced activity and only homozygotes with this allele (PiZ/PiZ) display clinical symptomology.
Pathogenesis
  • Lung
    • As discussed in emphysema the "Protease-Antiprotease Hypothesis" posits that the lung parenchyma depends on a delicate balance between the activities of neutrophil-derived proteases and anti-proteases such as Alpha-1 Antitrypsin. In PiZ/PiZ homozygotes, anti-protease activity is sufficiently reduced that pathological proteolysis of the delicate lung parenchyma ensues. This results in panacinar emphysema, resulting in COPD and thus obstructive lung disease.
  • Liver
    • Only a small subset of PiZ/PiZ homozygotes develop liver pathology and the precise pathogenesis is not well-understood. It does not appear to be related to reduced anti-protease activity and may be due to accumulation of the misfolded PiZ isoform in the hepatic endoplasmic reticulum. Whatever the pathogenesis, some individuals develop inflammation and scarring of the liver which usually manifests very early in life.
Morphology and Clinical Consequences
  • Lung:
    • The majority of PiZ/PiZ individuals develop panacinar emphysema resulting in COPD and thus obstructive lung disease. The incidence and severity increases if the affected individual is a smoker.
  • Liver:
    • Only a small subset of PiZ/PiZ individuals develop liver pathology which manifests as small, round cytoplasmic inclusions of retained Alpha-1 Antitrypsin in hepatocytes. Liver disease is extremely variable but usually manifests during infancy or childhood. Generally, bouts of hepatitis may occur with attendant jaundice. In some cases, inflammation may continue to something similar to chronic viral hepatitis and end in cirrhosis. Additionally, there is a slight increase in incidence of hepatocellular carcinoma.