Alpha 1-antitrypsin deficiency

Alpha 1-antitrypsin deficiency (A1AD) is a genetic disorder caused by reduced levels of alpha 1-antitrypsin in blood. It leads to pulmonary (lung) emphysema and, in severe cases, to liver disease.

Epidemiology

Northwest Europeans are at the highest risk for A1AD, with 4% carrying the PiZ allele and - therefore - a risk of homozygosity in about 1:625 to 1:2000.

Associated diseases

α1-antitrypsin deficiency has been associated with a number of diseases:

• Asthma
• Wegener's granulomatosis
• Pancreatitis
• Gallstones
• Bronchiectasia (possibly)
• Prolapse
• Cancer
  • Hepatocellular carcinoma (liver)
  • Bladder carcinoma
  • Gallbladder carcinoma
  • Lymphoma
  • Lung cancer

Signs and symptoms

These are generally undistinguishable from the "normal" emphysema and cirrhosis.

Pathophysiology

Please refer to the alpha 1-antitrypsin for the various protease inhibitor (Pi) genotypes and phenotypes.

Normally, alpha 1-antitrypsin is produced in the liver and exists in levels of 1.5-3.5 gram/litre. When the levels are reduced (40-60%, in the PiSS, PiMZ and PiSZ phenotypes), most people will only suffer symptoms if they smoke, as the levels are still sufficient to counteract "normal" elastase activity in inflammation. Only in the PiZZ phenotype, when the levels are less than 15%, emphysema develops at a young age, and 50% will develop liver cirrhosis due to the accumulated protein, which is not secreted properly. On liver biopsy, they show as PAS-positive, diastase-negative granules.

Apart from increasing the inflammatory reaction in the airways, cigarette smoke also directly inactivates alpha 1-antitrypsin by oxidizing essential methionine residues to sulfoxide forms, decreasing the enzyme activity by a rate of 2000.

Treatment

There is no specific treatment for A1AD; present management is identical for the "normal" treatment of emphysema and cirrhosis.

As α1-antitrypsin is an acute phase reactant, its transcription is markedly increased during inflammation elsewhere in response to increased interleukin-1 and 6 and TNFα production. Any treatment that blunts this response, specifically paracetamol, can delay the accumulation of A1AD polymers in the liver and (hence) cirrhosis. A1AT patients are therefore encouraged to use paracetamol when slightly to moderately ill, even if they would otherwise not have used antipyretics.

Experimental therapies are aimed at the prevention of polymer formation in the liver.