A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury

Cirulli, Elizabeth T.; Nicoletti, Paola; Abramson, Karen; Andrade, Raúl J.; Chalasani, Naga; Fontana, Robert J.; Hallberg, Pär; Li, Yi-Ju; Lucena, M. Isabel; Long, Norton E.; Molokhia, Mariam; Nelson, Matthew R.; Odin, Joseph A.; Pirmohamed, Munir; Rafnar, Thorunn; Serrano, José; Stefánsson, Kári; Stolz, Andrew; Daly, Ann K.; Aithal, Guruprasad P.; Watkins, Paul B.; Bessone, Fernando; Bjõrnsson, Einar; Cascorbi, Ingolf; Dillon, John F.; Day, Christopher P.; Hernández, Nelia; Ibáñez, Luisa; Kullak‐Ublick, Gerd A.; Laitinen, Tarja; Larrey, Dominique; Zee, Anke‐Hilse Maitland‐van der; Martin, Jennifer; Menzies, Dick; Qin, Shengying; Wadelius, Mia

doi:10.1053/j.gastro.2019.01.034

Cited by 109 publications

(104 citation statements)

References 38 publications

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“…According to a previous study, the incidence of DILI is approximately 2.7 cases of DILI per 100 000 adults, and because the prevalence of DILI is quite low, the sample size was insufficient to determine the frequency of DILI development in a clinical trial . Furthermore, the universal risk factor for DILI remains unclear, although genetic risk might be associated with DILI . Several studies suggested that the pathophysiology of DILI might be multifactorial; thus, establishing an examination with high sensitivity for prediction of idiosyncratic DILI is difficult .…”

Section: Discussionmentioning

confidence: 99%

Unfavorable prognosis of patients with acute liver injury due to drug‐induced liver injury and acute exacerbation of hepatitis B virus infection

Kakisaka

Suzuki

Jinnouchi

et al. 2019

Hepatology Research

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Aim Acute liver injury (ALI) has a favorable prognosis, whereas acute liver failure (ALF) leads to organ failure and thus has an unfavorable prognosis. The effect of each etiology on the clinical course of ALI remains unclear. This study aimed to determine how each etiology and glucocorticoid on the unfavorable etiology affects the clinical course of ALI. Methods This prospective observational study enrolled 522 patients with ALI/ALF from 2004 and 2017. To evaluate the influence of etiology on prognosis, decision tree analysis was carried out using age, disease type, etiology, and the presence of hepatic encephalopathy. Results Of 522 patients, 398 patients satisfied the ALI criteria at registration in this study. The ALI etiologies were as follows: viral hepatitis through oral infection (n = 54), acute hepatitis B virus (HBV) infection (n = 24), acute exacerbation of HBV infection (n = 30), de novo hepatitis due to HBV (n = 5), autoimmune hepatitis (n = 59), drug‐induced liver injury (DILI; n = 85), other viruses (n = 12), and undetermined (n = 129). ALI in 46 patients progressed to ALF after registration. Of 11 patients (age >52 years) with ALF due to acute exacerbation of HBV infection or DILI, seven patients (63.6%) died. Whether glucocorticoid affected the clinical course of ALI due to acute exacerbation of HBV infection or DILI was evaluated using propensity score matching (age, sex, alanine aminotransferase, total bilirubin, and prothrombin time‐international normalized ratio). Glucocorticoid did not improve the prognosis of ALI patients due to the two etiologies. Conclusions Progression of ALI due to DILI or acute exacerbation of HBV infection to ALF showed a poor prognosis.

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Section: Discussionmentioning

confidence: 99%

Unfavorable prognosis of patients with acute liver injury due to drug‐induced liver injury and acute exacerbation of hepatitis B virus infection

Kakisaka

Suzuki

Jinnouchi

et al. 2019

Hepatology Research

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“…Mild immune stress (MIS) may be an important mechanism mediating the susceptibility to PM-IDILI by upregulating the levels of chemokines and metabolic reprogramming induced by MIS (Tu et al, 2019). Moreover, recently, a genome-wide association study identified an association between rs2476601 in nonreceptor type 22 gene (PTPN22) and an increased risk of developing idiosyncratic DILI (Cirulli et al, 2019). Finally, indirect DILI is a new and not yet fully accepted category of hepatotoxicity, which results from the action of the drug rather than from its inherent hepatotoxic effects or immunogenicity.…”

Section: Introductionmentioning

confidence: 99%

Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives

Jiang

et al. 2020

Front. Pharmacol.

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Drug-induced liver injury (DILI) is one among the common adverse drug reactions and the leading causes of drug development attritions, black box warnings, and post-marketing withdrawals. Despite having relatively low clinical incidence, its potentially severe adverse events should be considered in the individual patients due to the high risk of acute liver failure. Although traditional liver parameters have been applied to the diagnosis of DILI, the lack of specific and sensitive biomarkers poses a major limitation, and thus accurate prediction of the subsequent clinical course remains a significant challenge. These drawbacks prompt the investigation and discovery of more effective biomarkers, which could lead to early detection of DILI, and improve its diagnosis and prognosis. Novel promising biomarkers include glutamate dehydrogenase, keratin 18, sorbitol dehydrogenase, glutathione S-transferase, bile acids, cytochrome P450, osteopontin, high mobility group box-1 protein, fatty acid binding protein 1, cadherin 5, miR-122, genetic testing, and omics technologies, among others. Furthermore, several clinical scoring systems have gradually emerged for the diagnosis of DILI including the Roussel Uclaf Causality Assessment Method (RUCAM), Clinical Diagnostic Scale (CDS), and Digestive Disease Week Japan (DDW-J) systems. However, currently their predictive value is limited with certain inherent deficiencies. Thus, perhaps the greatest benefit would be achieved by simultaneously combining the scoring systems and those biomarkers. Herein, we summarized the recent research progress on molecular biomarkers for DILI to improved approaches for its diagnosis and clinical management.

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“…). Recently, a polymorphism in the protein tyrosine phosphatase nonreceptor type 22 gene ( PTPN22 ) coding for lymphoid protein tyrosine phosphatase has been associated with DILI caused by multiple drugs . A switch in function associated with variant allele reduces immune tolerance of T cells, promoting autoimmunity.…”

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confidence: 99%

Of Potions, Poisons, Polygonum, and Pre‐emptive Polymorphism

Aithal

2019

Hepatology

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A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury

Abstract: on behalf of Drug-Induced Liver Injury Network (DILIN) investigators and International DILI consortium (iDILIC)

Cited by 109 publications

References 38 publications

Unfavorable prognosis of patients with acute liver injury due to drug‐induced liver injury and acute exacerbation of hepatitis B virus infection

Unfavorable prognosis of patients with acute liver injury due to drug‐induced liver injury and acute exacerbation of hepatitis B virus infection

Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives

Of Potions, Poisons, Polygonum, and Pre‐emptive Polymorphism

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