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Curr Pathobiol Rep. 2017;5(3):243-252. doi: 10.1007/s40139-017-0147-5. Epub 2017 Jul 10.

Liver Disease in Alpha-1 Antitrypsin Deficiency: Current Approaches and Future Directions.

Mitchell EL1,2, Khan Z1,2,3,4,5.

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1Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Faculty Pavilion 6th Fl, Pittsburgh, PA 15224-1334 USA.
2Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA USA.
3Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA.
4McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA USA.
5Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA USA.


Purpose of Review:

The aim of the study is to review the liver disease caused by alpha-1 antitrypsin deficiency (A1ATD), including pathogenesis, epidemiology, diagnostic testing, and recent therapeutic developments.

Recent Findings:

Therapeutic approaches target several intracellular pathways to reduce the cytotoxic effects of the misfolded mutant globular protein (ATZ) on the hepatocyte. These include promoting ATZ transport out of the endoplasmic reticulum (ER), enhancing ATZ degradation, and preventing ATZ globule-aggregation.


A1ATD is the leading genetic cause of liver disease among children. It is a protein-folding disorder in which toxic insoluble ATZ proteins aggregate in the ER of hepatocytes leading to inflammation, fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma. The absence of the normal A1AT serum protein also predisposes patients to pan lobar emphysema as adults. At this time, the only approved therapy for A1ATD-associated liver disease is orthotopic liver transplantation, which is curative. However, there has been significant recent progress in the development of small molecule therapies with potential both to preserve the native liver and prevent hepatotoxicity.


ATZ; Autophagy; Bile acid; Liver transplantation; PiZ mouse; SERPINA1

Conflict of interest statement

Compliance with Ethical StandardsThe authors declare that they have no conflict of interest.All reported studies with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards, including national and institutional research standards and guidelines.

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