Abstract
A1AT deficiency has a complex pathophysiology, is highly variable in clinical course, and is under diagnosed. The association with chronic lung disease was first described by Eriksson and Laurell in 1963, and later, Sharp and colleagues recognized A1AT deficiency as a cause of liver disease. In 2013 an international meeting was held to review the intervening 50 years of basic and clinical science, with a focus on liver disease [1,2]. Leaders in basic science investigation and in clinical medicine presented both retrospective commentary and new data relating to A1AT liver disease. A1AT is the archetype of the Serine Protease Inhibitor (SERPIN) family and is encoded by the gene SERPINA1. A1AT protein is produced in the liver and secreted in the serum in large quantities. The function of A1AT is to inhibit neutrophil proteases released non-specifically during periods of inflammation [1-4]. Over 100 variant alleles of the A1AT gene have been described but the overwhelming majority of patients with liver disease are homozygous for the Z mutant allele. Homozygosity for this autosomal co-dominant Z mutant of A1AT, referred to as ZZ or “PIZZ” in World Health Organization nomenclature, is the classical form of A1AT deficiency. The mutant Z protein accumulates within hepatocytes rather than being efficiently secreted (see below). This results in a lower, “deficient” level of protease inhibitor activity in serum. Within the hepatocyte, the Z mutant protein accumulates in the Endoplasmic Reticulum (ER), and may attain an altered conformation in which many A1AT mutant Z molecules aggregate to form large polymers. ZZ homozygous adults have a markedly increased risk of developing emphysema by a loss-of-function mechan ism in which insufficient circulating A1AT is available in the lung to inhibit non-specific connective tissue breakdown, which can occur during granulocyte phagocytosis. A subgroup of ZZ homozygous children and adults may also develop liver disease and Hepatocellu lar Carcinoma [HCC] via a toxic, gain-ofAbstract
Highlights
Alpha-1-Antitrypsin (A1AT) deficiency is a common genetic disease found predominantly in North American and European populations
In the 50 years since this disease was first described there has been an evolution in understanding of how accumulation of the mutant Z protein in hepatocytes triggers liver injury
Transcription Factor EB (TFEB) is a promising candidate to clear the toxic polymers of A1AT Z protein from liver by enhancing autophagy. He studied the TFEB gene incorporated into Helper Dependent Adenoviral (HDAd) and the effect of its hepatocyte specific hepatocyte expression following intravenous injection in PiZ mouse model of A1AT liver disease
Summary
Alpha-1-Antitrypsin (A1AT) deficiency is a common genetic disease found predominantly in North American and European populations. In the 50 years since this disease was first described there has been an evolution in understanding of how accumulation of the mutant Z protein in hepatocytes triggers liver injury. Several mouse models of ZZ liver disease have been created, but the PiZ mouse developed 25 years ago by Woo and colleagues has been an invaluable resource for the study of injury pathways and to investigate therapeutic strategies.
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