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

Abstract

Purpose of ReviewThe 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 FindingsTherapeutic 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.SummaryA1ATD 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.

Targeting the site encoded by SERPINA1*E342K for treating alpha‐1 antitrypsin deficiency‐associated liver diseases

“…Misfolded AAT protein forms polymeric aggregates in the endoplasmic reticulum of the liver cells where it is synthesized. The deposition of the polymers causes damage to hepatocytes which promotes liver inflammation . Aggregated AAT polymers cannot be efficiently secreted to the blood to inhibit neutrophil elastase during lung infection.…”

Diagnosis and treatment of lung disease associated with alpha one‐antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand*

“…Management also focuses on supportive measures such as nutrition, bone health and mental health to reduce the complications of chronic liver disease. Encouragingly, current research is exploring several innovative small molecule and gene‐based strategies which are now in clinical trials and aim to reduce proteotoxicity and maintain protein homeostasis in the liver …”

“…Encouragingly, current research is exploring several innovative small molecule and gene-based strategies which are now in clinical trials and aim to reduce proteotoxicity and maintain protein homeostasis in the liver. 117…”

Deficit Alfa-1 Antitripsina

“…Alfa-1 antitripsin je glikoprotein molekulske težine 52 kDa iz familije serin proteaza inhibitora (serpin) sa posebnim afinitetom prema granulocitnoj elastazi (2,(6)(7)(8). Primarno nastaje u hepatocitima (~80%) iz kojih se pod uticajem proinflamatornih citokina eksportuje u krvotok gde čini 80% alfa-1 globulinske frakcije (2,7).…”

“…Najčešći normalni alel, prisutan kod 95% evropske populacije je M, a deficitni S i potom Z (4). Ove dve mutacije, bilo u homozigotnom (PiZZ) ili heterozigotnom (PiZS) stanju, su odgovorne za oko 95% klinički ispoljenih oblika bolesti (2,6,8). F, Null, Siiyama, Mmalton, Mduarte, Mprocida, Mheerlen, Mmineral springs, Mnichinan, Pduarte, Wbethesda Zaugsberg, Zbristol, Pittsburgh i druge patološke mutacije su mnogo ređe ili izuzetno retke (2,4).…”