REVIEW: α₁‐Antitrypsin deficiency associated liver disease

Abstract

alpha 1-Antitrypsin (alpha 1-AT) deficiency is the most common genetic cause of liver disease in children and genetic disease for which children undergo liver transplantation. It also causes cirrhosis and hepatocellular carcinoma in adults. Studies by Sveger in Sweden have shown that only a subgroup of the population with homozygous PiZZ alpha 1-AT deficiency develop clinically significant liver injury. Other studies have shown that the mutant alpha 1-AT Z molecule undergoes polymerization in the endoplasmic reticulum and that a subpopulation of alpha 1-AT-deficient individuals may be susceptible to liver injury because they also have a trait that reduces the efficiency by which the mutant alpha 1-AT Z molecule is degraded in the endoplasmic reticulum.

The management of childhood liver diseases in adulthood

“…Its primary function is as a neutrophil protease inhibitor. A1AT deficiency remains the most common inherited (autosomal dominant) cause of infantile liver disease [80]. More than 100 variant alleles of A1AT gene (SERPINA1) have been identified but the majority of patients with liver disease are homozygous for the Z mutant allele referred to as ZZ or Pi ⁄ ZZ [81].…”

Liver Disease in Alpha-1 Antitrypsin Deficiency

“…Only some adults with AAT deficiency eventually develop cirrhosis and/or hepatocellular carcinoma. 30,35 The risk for adult liver disease increases with age. The reason for the variability in severity of liver disease is the subject of ongoing research.…”

The ER Glycoprotein Quality Control System

“…In another approach, to the accumulation of a mutant variant (PiZ) that is mostly retained in the ER (Qu et al, 1997) osmolytes such as trimethylamine-N-oxide and sarcosine significantly reduce the rate of α 1 -antitrypsin mutant polymerization with no effect on the normal inhibitory function of α 1 -antitrypsin for serine proteases (Chow et al, 2001).…”

“…Liver diseases/Hereditary emphysema (Qu et al, 1997; α1-Antitrypsin (PiZ variants) + CNX Coakley et al, 2001) Congenital hypothyroidism/related disorders (Kim and Arvan, 1998) Thyroglobulin deficiency (Kim and Arvan, 1995) Thyroglobulin + CNX/CRT, Prolonged Assoc. Thyroid peroxidase deficiency (de Carvalho et al, 1994; Thyroid peroxidase + CNX/CRT Kim and Arvan, 1995;Fayadat et al, 2000) Thyroxin-binding globulin deficiency ¶ Thyroxin-binding globulin + (Miura et al, 1994;Refetoff et al, 1996) Osteogenesis imperfecta (Lamande and Bateman, 1999) Type I procollagen + Hereditary hypofibrinogenemia (Roy et al, 1996) Fibrinogen + CNX α1-Antichymotrypsin (ACT) deficiency (Callea et al, 1992) α1-Antichymotrypsin + CNX Neurophyseal diabetes insipidus (Morello et al, 2001) Vasopressin precursor protein + CNX, Prolonged Assoc.…”