Management Of Drug-induced Liver Injury Research Articles

Drug-induced liver injury

Drug-induced liver injury (DILI) remains an important disease in clinical practice. It is difficult to predict, diagnose and manage. Studies in the peer-reviewed literature in the last 2 years, focusing on the diagnosis, prediction and management of DILI will be reviewed. Antibiotics remain the most common drug causing DILI in the United States and Europe. Expert opinion may still be the better method of diagnosing DILI compared with an objective tool such as the Roussel-Uclaf Causality Assessment Method. Hepatitis E represents an alternative diagnosis to some cases of presumed drug hepatotoxicity. There is ongoing research into the genetics of the pathophysiology and susceptibility of DILI. A genome-wide association study confirmed the association between human leukocyte antigen (HLA) class II and susceptibility to coamoxiclav (amoxicillin-clavulanic acid) induced DILI. There is new information on the protective effect of HLA-DRB1*07 family of alleles. MicroRNAs are a potential marker of DILI. Keratin variants may predict outcome of acute liver failure. N-acetylcysteine may be protective against DILI while taking antituberculosis medication. Recent findings in the genetics of pathophysiology and susceptibility of DILI can help with predicting and avoiding DILI in clinical practice and provide the foundation for ongoing research.

High plasma efavirenz level and CYP2B6*6 are associated with efavirenz-based HAART-induced liver injury in the treatment of naïve HIV patients from Ethiopia: a prospective cohort study

The objective of this study was to assess the incidence, timing and identify pharmacogenetic, efavirenz (EFV) pharmacokinetic and biochemical predictors of EFV-based antiretroviral therapy (ART) drug-induced liver injury (DILI). ART-naïve HIV patients (n = 285) were prospectively enrolled. Pretreatment laboratory evaluations included hepatitis B surface antigen and C antibody, CD4 count and viral load. Liver tests were done at baseline, 1st, 2nd, 4th, 8th, 12th, 24th and 48th weeks during ART. Plasma EFV and 8-hydroxyefvairenz concentration was determined at week 4 using liquid chromatography-mass spectrometry. CYP2B6, CYP3A5, ABCB1 3435C/T and UGT2B7*2 genotyping was done using Taqman genotyping assay. Data were analyzed using survival analysis and Cox proportional hazards model. The incidence of DILI was 15.7% or 27.9 per 100 person-years and that of severe injury was 3.4% or 6.13 per 100 person-years. The median time for the development of DILI and severe injury was 2 and 4 weeks after initiation of ART, respectively. There was significant association of DILI with lower baseline platelet, albumin, log plasma viral load and CD4 count (P = 0.031, 0.037, 0.06 and 0.019, respectively). Elevated baseline alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, plasma EFV level and CYP2B6*6 were good predictors for the development of DILI (P = 0.03, 0.01, 0.016, 0.017 and 0.04, respectively). We report for the first time CYP2B6*6 as a putative genetic marker and high plasma EFV concentration as intermediate biomarker for vulnerability to EFV-induced liver injury in HIV patients. CYP2B6 genotyping and/or regular monitoring of EFV and lever enzymes level during early therapy is advised for early diagnosis and management of DILI.

Biomarkers for the Diagnosis and Management of Drug-Induced Liver Injury

There is a pressing need for new clinical tests that will help physicians distinguish drug-induced liver injury (DILI) from other, more common causes of liver injury, and that can identify which specific drug is the culprit when DILI occurs in the setting of polypharmacy. In situations where there are few alternative treatments, new tests are needed that can differentiate patients with DILI who would develop progressive liver injury if treatment is not stopped from patients who can safely continue drug therapy via "adaptation." Although there has been little progress in developing and validating such tests, new insights into the mechanisms underlying DILI suggest that the desired biomarkers probably exist and can be discovered through the application of new technologies for blood and possibly urine analyses. Such discovery efforts will require the establishment of well-annotated serum and urine banks from prospective clinical trials of drugs capable of causing progressive liver injury.

Acetaminophen dosing of humans results in blood transcriptome and metabolome changes consistent with impaired oxidative phosphorylation

The diagnosis and management of drug-induced liver injury (DILI) is hindered by the limited utility of traditional clinical chemistries. It has recently been shown that hepatotoxicants can produce compound-specific changes in the peripheral blood (PB) transcriptome in rodents, suggesting that the blood transcriptome might provide new biomarkers of DILI. To investigate in humans, we used DNA microarrays as well as serum metabolomic methods to characterize changes in the transcriptome and metabolome in serial PB samples obtained from six healthy adults treated with a 4-g bolus dose of acetaminophen (APAP) and from three receiving placebo. Treatment did not cause liver injury as assessed by traditional liver chemistries. However, 48 hours after exposure, treated subjects showed marked down-regulation of genes involved in oxidative phosphorylation/mitochondrial function that was not observed in the placebos (P < 1.66E-19). The magnitude of down-regulation was positively correlated with the percent of APAP converted to the reactive metabolite N-acetyl-p-benzoquinone-imide (NAPQI) (r= 0.739;P= 0.058). In addition, unbiased analysis of the serum metabolome revealed an increase in serum lactate from 24 to 72 hours postdosing in the treated subjects alone (P< 0.005). Similar PB transcriptome changes were observed in human overdose patients and rats receiving toxic doses. The single 4-g APAP dose produced a transcriptome signature in PB cells characterized by down-regulation of oxidative phosphorylation genes accompanied by increased serum lactate. Similar gene expression changes were observed in rats and several patients after consuming hepatotoxic doses of APAP. The timing of the changes and the correlation with NAPQI production are consistent with mechanisms known to underlie APAP hepatoxicity. These studies support the further exploration of the blood transcriptome for biomarkers of DILI.

Human drug hepatotoxicity: a contemporary clinical perspective

Background: Drug-induced liver injury (DILI) constitutes a significant medical challenge. The rising number of marketed drugs, aging population and polypharmacy make it imperative to understand the clinical presentation of DILI and the processes used in the assessment of causality and early detection. Objective: This article reviews the current clinical understanding of DILI including presentation patterns, causality assessment, risk factor ascertainment and early detection strategies including liver test monitoring. Significant initiatives such as the Drug-Induced Liver Injury Network (DILIN) are also discussed. Methods: A narrative review of clinical studies of DILI, with emphasis on clinical features, causality and surveillance. Conclusion: DILI remains a serious challenge in contemporary clinical practice. Further research and collaboration in the areas of epidemiology, causality and early detection are required to enhance the diagnosis and management of DILI.

Practical guidelines for diagnosis and early management of drug-induced liver injury

The spectrum of drug-induced liver injury (DILI) is both diverse and complex. The first step in diagnosis is a suspicion of DILI based on careful consideration of recent comprehensive reports on the disease. There are some situations in which the suspicion of DILI is particularly strong. Exclusion of other possible etiologies according to the pattern of liver injury is essential for the diagnosis. In patients with suspected DILI, diagnostic scales, such as the Councils for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method (CIOMS/RUCAM) scale, may be helpful for the final diagnosis. Early management of DILI involves prompt withdrawal of the drug suspected of being responsible, according to serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin (T-Bil). However, as DILI patients may show resolution of liver injury without discontinuation of the drug, it should be carefully evaluated whether the suspected drug should be discontinued immediately with adequate consideration of the importance of the medication.