Alpha-1 antitrypsin and liver disease: mechanisms of injury and novel interventions

Abstract

α-1-Antitrypsin (α1AT) is a serum glycoprotein synthesized in the liver. The majority of patients with α1AT deficiency liver disease are homozygous for the Z mutant of α1AT (called ZZ or ‘PIZZ’). This mutant gene directs the synthesis of an abnormal protein which folds improperly during biogenesis. Most of these mutant Z protein molecules undergo proteolysis; however, some of the mutant protein accumulates in hepatocytes. Hepatocytes with the largest mutant protein burdens undergo apoptosis, causing compensatory hepatic proliferation. Cycles of hepatocyte injury, cell death and compensatory proliferation results in liver disease ranging from mild asymptomatic enzyme elevations to hepatic fibrosis, cirrhosis and hepatocellular carcinoma. There is a high variability in clinical disease presentation suggesting that environmental and genetic modifiers are important. Management of α1AT liver disease is based on standard supportive care and liver transplant. However, increased understanding of the cellular mechanisms of liver injury has led to new clinical trials.

Keywords:

• α-1-antitrypsin
• apoptosis
• autophagy
• hepatocellular proliferation
• liver

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• α-1-Antitrypsin (α1AT) deficiency is a relatively common ‘rare disease’ in North America and Europe.

• This disease is underdiagnosed and underappreciated, partly because the patients present at different ages and often with either lung or liver disease, such that no single specialty receives all the referrals.

• Patients are best served with routine follow-up focused on both the lung and the liver.

• The gold standard for diagnosis is serum or DNA testing, and does not require a liver biopsy.

• Genetic counseling and family testing should be made available to patients.

• Lung and liver disease result from different mechanisms, and protein replacement therapy for lung disease has no effect on the liver.

• Liver disease results from the intrahepatic accumulation of the α1AT mutant Z protein, which triggers a cell injury cascade of hepatocellular death, a low level of compensatory liver regeneration and, ultimately fibrosis, cirrhosis and hepatocellular carcinoma.

• Current management of liver disease focuses on supportive care, although the outlook for novel human trials in the near future is good.

• New biotechnology is being focused on therapeutic development in α1AT deficiency with the expectation of new human trials in the near future.

Notes