Pathogenesis of Alpha-1 Antitrypsin Deficiency in the Liver: New Approaches to Old Questions

Abstract

Alpha-1 Antitrypsin deficiency (A1ATD) can progress to cirrhosis and hepatocellular carcinoma; however, not all patients are susceptible to severe liver disease. Liver transplantation is the only cure for A1ATD-related liver disease. A1ATD is caused by a toxic gain-of-function mutation in the human SERPINA1 gene, generating mis folded ATZ protein "globules" in hepatocytes. These insoluble aggregates overwhelm protein clearance pathways and lead to chronic intracellular stress. This review serves to summarize the basic hepatic mechanisms involved in A1ATD, as described in relevant in vitro and animal models. Potential treatments such as autophagy-enhancing agents and molecular therapies are also discussed. Clinical trials are underway to further assess some of these novel approaches in patients, but more safety and efficacy data is needed to successfully translate these interventions from the laboratory to the clinic.

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

“…( 4 ) increase secretion: phenylbutyrate. IC intercellular, EC extracellular, rER rough endoplasmic reticulum, AP autophagosome, L lysosome (modified from Khan 2016 [ 2 ]) …”

“…Alpha-1 antitrypsin deficiency (A1ATD) is a common inherited cause of liver disease, with the most severe mutation found in 1:3500 live births and currently 180,000 individuals worldwide [ 1 ]. In children, A1ATD is the most frequent genetic etiology for pediatric liver disease and transplantation [ 2 ]. Caused by a mutation in chromosome 14, the disease is inherited in an autosomal recessive manner with codominant expression [ 3 ].…”

A Challenging Case of Severe Infantile Cholestasis in Alpha-1 Antitrypsin Deficiency

“…A1ATD is the most common inherited pediatric liver disorder and the most frequent genetic cause of liver transplantation in children (reviewed in Ghouse et al 14,15 ). In its classical form, A1ATD is an autosomal co-dominant disorder that affects as many as 1 in 3000 live births in the United States and Europe.…”

Deficit Alfa-1 Antitripsina

“…Osnovu rane ekspresije bolesti čini progresivni holestazni sindrom koji se registruje kod 10-20% nosilaca PiZZ genotipa, odnosno kod 5-10% bolesnika sa sindromom neonatalnog hepatitisa (5). U 1-2% slučajeva bolest ima fulminantni tok, te deficit alfa-1 antitripsina predstavlja najčešće genetski uzrokovano oboljenje koje iziskuje transplantaciju jetre u detinjstvu (6,10).…”