Identifying who is at risk of drug-induced liver injury: Is human leukocyte antigen specificity the key?

Abstract

In the classical form of alpha1-antitrypsin (AT) deficiency, a point mutation in AT alters the folding of a liver-derived secretory glycoprotein and renders it aggregation-prone. In addition to decreased serum concentrations of AT, the disorder is characterized by accumulation of the mutant alpha1-antitrypsin Z (ATZ) variant inside cells, causing hepatic fibrosis and/or carcinogenesis by a gain-of-toxic function mechanism. The proteasomal and autophagic pathways are known to mediate degradation of ATZ. Here we show that the autophagy-enhancing drug carbamazepine (CBZ) decreased the hepatic load of ATZ and hepatic fibrosis in a mouse model of AT deficiency-associated liver disease. These results provide a basis for testing CBZ, which has an extensive clinical safety profile, in patients with AT deficiency and also provide a proof of principle for therapeutic use of autophagy enhancers. CommentWith an expected prevalence of 0.02%, alpha-1-antitrypsin (AAT) deficiency is one of the most common genetic origins of liver disease in childhood and an important hereditary cause of cirrhosis and hepatocellular carcinoma in adulthood. AAT is an important serine protease inhibitor that is synthesized in the liver (normally as the protease inhibitor M [PiMM] protein), is found in the circulation at substantial levels (>0.8 g/L in serum), and inhibits proteolytic enzymes such as elastase released by neutrophils and macrophages (Fig. 1A). The most common initial clinical presentation of AAT deficiency is chronic obstructive pulmonary disease with typically severe, early-onset panacinar emphysema with a basilar predominance in adults. Emphysema in patients with AAT deficiency is thought to result from increased activity of neutrophil elastase in the lungs, which destroys alveolar septa and other components of the lung interstitium because of the lack of sufficient elastase inhibition by circulating AAT (Fig. 1B).1 The classic form of AAT deficiency is caused by a glutamate-to-lysine exchange at position 342 in the serpin peptidase inhibitor A1 gene [called the protease inhibitor ZZ (PiZZ) genotype], which leads to hepatic synthesis of mutant alpha-1-antitrypsin Z (ATZ) proteins. These mutant ATZ proteins are prone to polymerization and form polymers between the mutated reactive center loop and the beta sheet of the next molecule within the endoplasmatic reticulum (ER) of the hepatocytes. 2 The massive formation of insoluble aggregates of mutant ATZ proteins in the hepatocytic ER results in apoptosis, hepatic inflammation, and fibrosis/cirrhosis and strongly predisposes patients to hepatocellular carcinoma (Fig. 1B). 3 The diagnosis of AAT deficiency is established by low serum AAT levels, which are measured for the screening of suspected patients; this is followed by genotyping (with PiZZ-specific polymerase chain reaction) and protein phenotyping (with isoelectric focusing gel) as verification tests. 4 In liver histology, periodic acid-Schiff-positive, diastaseresistant globules containing ATZ protein polymers in ...

HLA-DQ B1*0201 and A1*0102 Alleles Are Not Responsible for Antituberculosis Drug-Induced Hepatotoxicity Risk in Spanish Population

“…Interestingly, HLA variants have been linked to autoimmune hepatitis (7, 11, 12). Association of HLA variants has been described with different drugs as amoxicilin-clavulanate (16, 17), flucoxacilin (11), ximelagatran (11), lapatinib (18), lumiracoxib (19, 20), and neviparine (21). Sharma et al showed a fourfold increased risk of ATDH in patients without HLADQA1*0102 haplotype suggesting to play a role in pathogenic development of ATDH (12).…”

Drug-Induced Liver Injury and Individual Cell Models

“…For this study, patients were selected by ALT and/or AST ≥ 3ULN under lumiracoxib and compared to a lumiracoxib-treated control group without liver enzyme elevations. The clinical relevance of such findings may be limited since, in contrast to the flucloxacillin study, most patients exhibiting this polymorphism were asymptomatic [26] . Thus, differentiation may be difficult between frequent asymptomatic elevations of liver enzymes and rare but severe DILI.…”

Microphysiological Models for Mechanistic-Based Prediction of Idiosyncratic DILI

“…Other medications such as ximelagatran, an anticoagulant which was voluntarily withdrawn from the global market by AstraZeneca in 2006, exhibit immunemediated hepatotoxicity that may be predisposed by allelic variants in the HLA major histocompatibility complex (MHC) class II region, providing a platform to recapitulate known genomic associations [39]. Similarly, research has found that lumiracoxib, removed from the Australian market in 2007, has a strong association between the hepatotoxicity and HLA alleles within the MHC class II region, for example, DQA*0102, inferring that these HLA alleles have higher sensitivity in the identified 41 cases of lumiracoxib-induced liver injury compared to control lumiracoxib-exposed liver tissue [40,41]. These examples highlight why it is critical to include immune cells and other parenchyma cellsl/NPC in a microphysiological model to effectively investigate the interaction of the immune-mediated and non-immune-mediated mechanisms of iDILI.…”