Human leukocyte antigen genetic risk factors of drug-induced liver toxicology

Grove, Jane I.; Aithal, Guruprasad P.

doi:10.1517/17425255.2015.992414

Cited by 49 publications

(28 citation statements)

References 94 publications

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“…Our study provides strong evidence that prospective HLA‐B*35:01 screening may identify patients with the greatest risk of PM‐DILI, such as HLA‐A*31:01 testing for carbamazepine‐induced hypersensitivity and HLA‐B*57:01 screening for hypersensitivity to abacavir . Despite the small sample sizes of subjects included in this work, our data were significant and in line with other GWAS demonstrating an association of HLA genotype and DILI susceptibility . Based on the assumption that the approximate prevalence of PM‐DILI is 8.3% (6/72) in Han Chinese, the HLA‐B*35:01 allele increases the risk of DILI to 37% (3/8), whereas the risk of DILI in noncarriers is 4.7% (3/64).…”

Section: Discussionsupporting

confidence: 78%

HLA‐B*35:01 Allele Is a Potential Biomarker for Predicting Polygonum multiflorum–Induced Liver Injury in Humans

et al. 2019

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Polygonum multiflorum (PM) is a well‐known Chinese herbal medicine that has been reported to induce inflammation‐associated idiosyncratic liver injury. This study aimed to identify the genetic basis of susceptibility to PM‐drug‐induced liver injury (PM‐DILI) and to develop biological markers for predicting the risk of PM‐DILI in humans. The major histocompatibility complex (MHC) regions of 11 patients with PM‐DILI were sequenced, and all human leukocyte antigen (HLA)–type frequencies were compared to the Han‐MHC database. An independent replication study that included 15 patients with PM‐DILI, 33 patients with other DILI, and 99 population controls was performed to validate the candidate allele by HLA‐B PCR sequence‐based typing. A prospective cohort study that included 72 outpatients receiving PM for 4 weeks was designed to determine the influence of the risk allele on PM‐DILI. In the pilot study, the frequency of HLA‐B*35:01 was 45.4% in PM‐DILI patients compared with 2.7% in the Han Chinese population (odds ratio [OR], 30.4; 95% confidence interval [CI], 11.7‐77.8; P = 1.9 × 10−10). In the independent replication study and combined analyses, a logistic regression model confirmed that HLA‐B*35:01 is a high‐risk allele of PM‐DILI (PM‐DILI versus other DILI, OR, 86.5; 95% CI, 14.2‐527.8, P = 1.0 × 10−6; and PM‐DILI versus population controls, OR, 143.9; 95% CI, 30.1‐687.5, P = 4.8 × 10−10). In the prospective cohort study, an asymptomatic increase in transaminase levels was diagnosed in 6 patients, representing a significantly higher incidence (relative risk, 8.0; 95% CI, 1.9‐33.2; P < 0.02) in the HLA‐B*35:01 carriers (37.5%) than in the noncarriers (4.7%). Conclusion: The HLA‐B*35:01 allele is a genetic risk factor for PM‐DILI and a potential biomarker for predicting PM‐DILI in humans.

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Section: Discussionsupporting

confidence: 78%

HLA‐B*35:01 Allele Is a Potential Biomarker for Predicting Polygonum multiflorum–Induced Liver Injury in Humans

et al. 2019

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“…An example of the possible clinical relevance of the pi hypothesis has been proposed for the hepatotoxic drug ximelegatran since the drug does not covalently bind proteins to form neoantigens. However, in vitro studies have shown a direct inhibition by ximelegatran of peptide binding to HLA DRB1*0701, supporting direct interaction of the drug with this HLA binding site [112]. …”

Section: Pathogenesis Of Idiosycratic Drug-induced Liver Injury (Imentioning

confidence: 99%

Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

Iorga

Dara

Kaplowitz

2017

IJMS

224

133

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Drug-induced liver injury (DILI) can broadly be divided into predictable and dose dependent such as acetaminophen (APAP) and unpredictable or idiosyncratic DILI (IDILI). Liver injury from drug hepatotoxicity (whether idiosyncratic or predictable) results in hepatocyte cell death and inflammation. The cascade of events leading to DILI and the cell death subroutine (apoptosis or necrosis) of the cell depend largely on the culprit drug. Direct toxins to hepatocytes likely induce oxidative organelle stress (such as endoplasmic reticulum (ER) and mitochondrial stress) leading to necrosis or apoptosis, while cell death in idiosyncratic DILI (IDILI) is usually the result of engagement of the innate and adaptive immune system (likely apoptotic), involving death receptors (DR). Here, we review the hepatocyte cell death pathways both in direct hepatotoxicity such as in APAP DILI as well as in IDILI. We examine the known signaling pathways in APAP toxicity, a model of necrotic liver cell death. We also explore what is known about the genetic basis of IDILI and the molecular pathways leading to immune activation and how these events can trigger hepatotoxicity and cell death.

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“…Blood pyrrole–protein adducts have been proposed for pyrrolizidine‐DILI 16. Also, genome‐wide association studies have linked certain human leukocyte antigen (HLA) alleles with DILI; examples include HLADRB1*1501 in amoxicillin–clavulanate17 and HLA‐A*33:01 for a cholestatic or mixed pattern of DILI 18. The index case was diagnosed as DILI‐ALF based on history, exclusion of other etiologies as per American College of Gastroenterology guidelines, temporal correlation, postmortem liver biopsy findings, and RUCAM score 8…”

Section: Discussionmentioning

confidence: 99%

Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: Case report and mini‐review of the literature

Verma

Kumar

Mitra

et al. 2017

Hepatology Communications

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Idiosyncratic drug‐induced liver injury (DILI) is ranked among the top most common etiologies of acute liver failure (ALF). It carries poor transplant‐free survival. Pirfenidone is an anti‐inflammatory and antifibrotic drug that is commonly used for the treatment of idiopathic pulmonary fibrosis (IPF). Hepatotoxicity due to pirfenidone is rare and generally manifests as a mild rise in serum aminotransferases. In this mini‐review, we report an unusual case of idiosyncratic DILI due to pirfenidone presenting as ALF, with emphasis on the definition, classification, diagnostic criteria, histopathology, molecular markers, and treatment options for DILI and related ALF. A 77‐year‐old man with known Parkinson's disease and IPF presented with jaundice for 7 days and altered mental status for 4 days. His long‐term medications included a levodopa/carbidopa combination with a recent addition of pirfenidone over the previous 1 month; there was no monitoring of liver function tests. The evaluation suggested features of acute liver failure with grade III hepatic encephalopathy, acute kidney injury, and metabolic acidosis. The diagnostic workup ruled out viral, toxic, ischemic, and other etiologies for acute liver failure. Based on a Roussel Uclaf Causality Assessment Method score of 7 and possible DILI‐ALF, pirfenidone was withdrawn. He was evaluated for liver transplantation but was declined. Despite all supportive measures in intensive care, organ failure progressed and he succumbed to the illness on day 4. Postmortem liver biopsy revealed findings consistent with DILI (final Roussel Uclaf Causality Assessment score, 10). Conclusion: DILI‐ALF carries poor prognosis, and liver transplantation should be considered early in the course. Characterization, reporting, monitoring, and labeling of pirfenidone‐related hepatotoxicity is vital given its common use in IPF. (Hepatology Communications 2018;2:142–147)

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Human leukocyte antigen genetic risk factors of drug-induced liver toxicology

Cited by 49 publications

References 94 publications

HLA‐B*35:01 Allele Is a Potential Biomarker for Predicting Polygonum multiflorum–Induced Liver Injury in Humans

HLA‐B*35:01 Allele Is a Potential Biomarker for Predicting Polygonum multiflorum–Induced Liver Injury in Humans

Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: Case report and mini‐review of the literature

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