Update on Alpha‐1 Antitrypsin Deficiency in Liver Disease

Abstract

Alpha-1-Antitrypsin (A1AT) deficiency (A1ATD) is typically discussed in the context of lung disease as a major cause of panacinar emphysema because of impaired inhibition of neutrophil elastase. SERPINA1, the gene encoding A1AT, has an autosomal recessive inheritance with codominant expression. Large numbers of mutations in the gene are associated with lung disease and a subset with liver disease. Mutations in SERPINA1 causing liver disease do so by the formation of harmful aggregates of mutant A1AT protein within hepatocytes, which results in diverse manifestations, from devastating neonatal cholestasis to late-onset cirrhosis and hepatocellular carcinoma (HCC) in adults. Here, we summarize advances in our understanding and management of A1ATD liver disease with particular focus on the significance of A1ATD heterozygosity and its putative role as a cofactor in common causative factors for liver disease. MOleCUlar Basis anD PaTHOPHYsiOlOGYA1AT is a large, 52-kDa serum glycoprotein abundantly produced by the liver. It is a serine protease inhibitor whose primary function depends on its secretion from the liver and its physiological action in the lungs to prevent excessive tissue destruction by neutrophil elastase. A1AT is also an acute-phase reactant with a presumed inflammatory role. 1 Certain missense mutations in A1AT result in the accumulation of toxic aggregates of misfolded protein in hepatocytes and, consequently, deficiency in the circulation. These A1AT aggregates appear as periodic acid-Schiff (PAS)-positive, diastase-resistant inclusions, the pathological hallmark of A1ATD liver disease (Fig. 1, right).

Cellular Mechanisms of Liver Fibrosis

“…Shortage of α1-antitrypsin in the lung can be partially overcome by intravenous replacement therapy, while this therapy is not appropriate to people with liver disease. In respective patients, there is emphasis on efforts to prevent progression of related liver injury by reducing of modifiable risk factors (overweight, tobacco, alcohol, non-steroidal anti-inflammatory drugs) or finally liver transplantation that still remains the sole curative option ( Narayanan and Mistry, 2020 ). In cystic fibrosis resulting of mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) the application of Ursodeoxycholic acid (UDCA) is the mainstay of therapy.…”

Pediatric metabolic liver diseases: Evolving role of liver transplantation

“…Alpha-1 antitrypsin (A1AT) deficiency is a common inherited metabolic liver disease in the western hemisphere with an estimated incidence of 1:1600 to 1:3500 cases[ 12 ]. SERPINA1 , the gene encoding A1AT, has an AR inheritance with codominant expression[ 13 ]. The liver injury is caused by aggregates of misfolded protein in the hepatocyte whereas the lung injury is caused by unopposed action of neutrophil elastase[ 13 ].…”

“…SERPINA1 , the gene encoding A1AT, has an AR inheritance with codominant expression[ 13 ]. The liver injury is caused by aggregates of misfolded protein in the hepatocyte whereas the lung injury is caused by unopposed action of neutrophil elastase[ 13 ]. Hence the progression of lung pathology can be prevented with enzyme replacement, but the liver dysfunction does not have a standard medical therapy[ 14 ].…”

“…The commonest presentation is as infantile cholestasis, and it can mimic biliary atresia both clinically and radiologically. Liver biopsy shows eosinophilic intracytoplasmic globules in hepatocytes, which are periodic acid-schiff (PAS) positive and diastase resistant, and genetic analysis confirms the diagnosis[ 13 ]. LT is indicated for ESLD and also for those with HCC[ 13 , 15 ].…”

Erratum

“…In the article by Narayanan and Mistry (2020), 1 the authors have identified an error in the estimated population count reported as 4 million. The corrected sentence should read as follows:…”