Presentation and prognosis of liver disease in alpha-1 antitrypsin deficiency

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Alpha-1 antitrypsin deficiency (AATD) affects approximately 3 million people worldwide, and yet its pathophysiology is poorly understood. In the lung, lack of alpha-1 antitrypsin leads to proteolytic damage to the connective tissue matrix, resulting in emphysema in approximately 75% of PiZZ patients. Point mutations lead to altered folding of the protein during biosynthesis, resulting in misfolded proteins being retained within hepatocytes. The aggregation of antitrypsin polymers within the endoplasmic reticulum (ER) of liver cells forms periodic acid-Schiff positive inclusions, which cause endoplasmic reticular stress, mitochondrial dysfunction and trigger autophagy. Hepatocytes with less abundance of mutant Z protein proliferate, and this chronic cycle of cell death and regeneration activates hepatic stellate cells and initiates hepatic fibrosis, although the true mechanism of injury is yet to be fully elucidated . A conundrum in AATD remains the phenotypic variability in both lung and liver disease. Children may experience jaundice during infancy but have no further complications, whilst others develop liver cirrhosis and require liver transplantation.

The ability to predict which individuals are at highest risk of developing significant liver disease would be useful clinically for prognostic purposes, planning of clinical services, and influencing lifestyle behaviors where appropriate. For example, in AATD-related lung disease, cigarette smoking is the greatest predictor of lung function deterioration, and so smoking cessation is strongly advised in these individuals. Here we summarize the patterns of presentation and prognosis in AATD-related liver disease in children and adults, and review the evidence for factors which may be influential in disease progression.
Original languageEnglish
JournalExpert review of gastroenterology & hepatology
Early online date28 May 2018
Publication statusE-pub ahead of print - 28 May 2018


  • Alpha-1-antitrypsin deficiency
  • Liver cirrhosis
  • Liver fibrosis
  • PiZZ
  • PiSZ
  • Liver transplantation
  • Prognosis


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