Early recognition and long-term copper chelation therapy (with D-penicillamine or Trientine) or zinc-based therapy (which inhibits copper uptake in the gut) has dramatically altered the usual progressive downhill course. Individuals with hepatitis or advanced cirrhosis require liver transplantation, which can be curative.
α1-Anti-trypsin deficiency is an autosomal recessive disorder marked by very low levels of circulating α1-antitrypsin (α1AT) that is caused by mutations that lead to misfolding of α1AT. The major function of α1AT is to inhibit proteases, particularly neutrophil elastase, cathepsin G, and proteinase 3, which are released from neutrophils at sites of inflammation. α1AT deficiency leads to the development of pulmonary emphysema because the activity of destructive proteases is not inhibited (Chapter 13). It also causes liver disease as a consequence of hepatocellular accumulation of the misfolded α1AT protein.
α1AT is a small 394–amino acid plasma glycoprotein synthesized predominantly by hepatocytes. The gene, located on chromosome 14, is very polymorphic. At least 75 α1AT variants have been identified, denoted alphabetically by their relative migration on an isoelectric gel. The general notation is “Pi” for “protease inhibitor” and an alphabetic letter for the position on the gel; two letters denote the genotype of the two alleles. The most common genotype is PiMM, occurring in 90% of individuals (the “wild-type”).
The most common clinically significant mutation is PiZ; PiZZ homozygotes have circulating α1AT levels that are only 10% of normal. These individuals are at high risk for developing clinical disease. Variant alleles are codominant, and, consequently, PiMZ heterozygotes have intermediate plasma levels of α1AT. Among individuals of northern European descent, the PiZZ state affects 1 in 1800 live births. Because of the early presentation of the liver disease, α1AT deficiency is the most commonly diagnosed genetic hepatic disorder in infants and children.
The PiZ polypeptide is prone to misfolding and aggregation due to a single amino acid glutamine-to-lysine http://ebooksmedicine.net substitution at residue 342 (E342K). This in turn creates endoplasmic reticulum stress and triggers the unfolded protein response, which ultimately leads to apoptosis. It is worth emphasizing that the liver damage is caused by protein misfolding, whereas lung damage leading to emphysema stems from the loss of α1AT function and excessive protease activity. Although all individuals with the PiZZ genotype accumulate α1AT-Z in the endoplasmic reticulum of hepatocytes, only 10% to 15% develop overt clinical liver disease; thus, other genetic factors or environmental factors must also play a role in the development of liver disease.
Fig.16.21 ).Periportalhepatocytesaremostaffectedinearlyandinmildformsofthedisease,withcentrallobularhepatocytesbeingaffectedlaterorinmoreseveredisease.Otherpathologicfeaturesvary,rangingfromhepatitistofibrosistofull-blowncirrhosis.