Patterns Of Drug-induced Liver Injury Research Articles

Systematic review and meta-analysis: Comparing hepatocellular and cholestatic patterns of drug-induced liver injury

Drug-induced liver injury (DILI) is a leading cause of death from acute liver failure (ALF). Hy's law warns that a hepatocellular pattern of injury accompanied by jaundice and normal alkaline phosphatase (ALP) levels is associated with a 10% or greater chance of progression to transplant or liver-related death. This meta-analysis of DILI studies evaluates acute and chronic outcomes of DILI according to clinical pattern of injury. We conducted a systematic search using electronic databases PubMed and EMBASE through to 8 March 2022. Our primary outcome was to compare acute outcomes including ALF, liver-related death, and liver transplant between patients experiencing hepatocellular, cholestatic, and mixed patterns of DILI. Our secondary outcome was to compare the rate of DILI chronicity between patients of these three differing patterns of injury. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Overall, 12 studies comprising 4290 patients were included. Patients with cholestatic DILI demonstrated similar rates of ALF (OR: 0.80, 95% CI: 0.46–1.40, p = 0.429) and liver-related death (OR: 0.92, 95% CI: 0.50–1.69, p = 0.792) compared to patients with hepatocellular DILI. Patients with cholestatic DILI were significantly more likely to experience chronicity compared to patients with hepatocellular DILI (OR: 2.53, 95% CI: 1.34–4.79, p = 0.004). Hy's law conceives severe DILI as an exclusive consequence of hepatocellular pattern of injury. Our results demonstrate that cholestatic injury can be associated with similarly poor rates of ALF and liver-related fatality, as well as higher rates of chronic DILI.

Association between the Treatment Pattern of Drug-Induced Liver Injury and Clinical Outcomes: A Retrospective Study

What is Known and Objective? In China, patients with drug-induced liver injury (DILI) are commonly treated with one or more types of hepatoprotective drugs, despite a lack of evidence. We performed this study to investigate the association between the treatment pattern of DILI, including withdrawal of suspected drugs and use of hepatoprotective drugs, and recovery following DILI. Methods. A retrospective study was conducted at a tertiary hospital in Central China. Data of patients with a diagnosis of DILI hospitalized between January 2015 and December 2020 were collected through the Electronic Medical Records System. We excluded cases that did not meet the biochemical criteria of DILI and had a Roussel Uclaf Causality Assessment Method score of less than 3. Univariate and multivariate logistic regression models were used to analyze the association between treatment patterns and clinical outcomes. Results and Discussion. In total, 699 patients were included. Suspected drugs were discontinued in 619 patients (88.6%). 693 patients (99.1%) were treated with hepatoprotective drugs, among whom only 14.7% patients received monotherapy with hepatoprotective drugs. Recovery following DILI was seen in 593 cases (84.8%). By multivariate analysis, the number of hepatoprotective drugs combined did not show significance ( p = 0.363 ), while the withdrawal of suspected drugs was associated with recovery following DILI ( p = 0.015 ). What is New and Conclusion. The withdrawal of suspected drugs is associated with the recovery following DILI, and hepatoprotective drug combinations do not contribute to better outcomes than monotherapy. The findings indicate that DILI patients should stop suspected drugs as soon as possible and the combination therapy of hepatoprotective drugs is unnecessary.

Abstracts 13th PCNE Working Conference “Pharmacies' new roles in pharmaceutical care: bridging research and practice”

Abstracts 13th PCNE Working Conference “Pharmacies' new roles in pharmaceutical care: bridging research and practice”

Evaluation of a Clinically Relevant Drug-Drug Interaction Between Rosuvastatin and Clopidogrel and the Risk of Hepatotoxicity.

Purpose: The combination therapy of rosuvastatin (RSV) and the platelet inhibitor clopidogrel (CP) is widely accepted in the management of cardiovascular diseases. The objective of the present study was to identify the mechanism of RSV–CP DDI and evaluate the risk of hepatotoxicity associated with the concomitant use of CP. Methods: We first studied the effect of CP and its major circulating metabolite, carboxylic acid metabolite (CPC), on RSV transport by overexpressing cells and membrane vesicles. Second, we investigated whether a rat model could replicate this DDI and then be used to conduct mechanistic studies and assess the risk of hepatotoxicity. Then, cytotoxicity assay in hepatocytes, biochemical examination, and histopathology were performed to measure the magnitude of liver injury in the presence and absence of DDI. Results: CP inhibited OATP1B1-mediated transport of RSV with an IC50 value of 27.39 μM. CP and CPC inhibited BCRP-mediated RSV transport with IC50 values of <0.001 and 5.96 μM, respectively. The CP cocktail (0.001 μM CP plus 2 μM CPC) significantly inhibited BCRP-mediated transport of RSV by 26.28%. Multiple p.o. doses of CP significantly increased intravenous RSV plasma AUC0-infinity by 76.29% and decreased intravenous RSV CL by 42.62%. Similarly, multiple p.o. doses of CP significantly increased p.o. RSV plasma AUC0-infinity by 87.48% and decreased p.o. RSV CL by 43.27%. CP had no effect on cell viability, while RSV exhibited dose-dependent cytotoxicity after 96 h incubation. Co-incubation of 100 μM CP and RSV for 96 h significantly increased intracellular concentrations and cell-to-medium concentration ratios of RSV and reduced hepatocyte viability. Histological evaluation of liver specimens showed patterns of drug-induced liver injury. Cholestasis was found in rats in the presence of DDI. Conclusion: CP is not a clinically relevant inhibitor for OATP1B1 and OATP1B3. The primary mechanism of RSV–CP DDI can be attributed to the inhibition of intestinal BCRP by CP combined with the inhibition of hepatic BCRP by CPC. The latter is likely to be more clinically relevant and be a contributing factor for increased hepatotoxicity in the presence of DDI.

Role of the Surgical Pathologist in Diagnosis of Drug-induced Liver Injury: Recognizing Specific Patterns of Drug Injury.

Eighteen histologic patterns of drug-induced liver injury (DILI) are described, most of which are also seen in other commonly occurring acute and chronic liver diseases. However, certain patterns such as sinusoidal obstruction syndrome/veno-occlusive disease, "bland" cholestasis and cholestatic hepatitis are more often caused by drugs than other competing etiologies. Amiodarone, acetaminophen, anabolic androgenic steroids and estrogens, result in histologic patterns that are virtually diagnostic of the respective drug. Recognition of a DILI or drug specific injury pattern enables the clinician to focus on eliciting an appropriate history to identify the offending agent, which may otherwise be rare and not immediately apparent. Although drugs can mimic any and every liver disease, the mimicry is often imperfect. Unusual features that do not completely fit the clinicopathologic paradigm of the mimicked liver disease are clues to diagnosis of DILI. When mimicking a liver disease, drugs tend to hasten or accelerate the natural progression of the disease. Novel immunomodulatory drugs for inflammatory disorders and cancer may cause unintended effects on the immune system, resulting in immune-related side effects. The role of the pathologist in diagnosis of DILI is to recognize known patterns of DILI, and either confirm a diagnosis when clinically suspected, or alert the clinician to the possibility of DILI when it is not suspected. The latter is particularly vital in contemporary practice, which is witnessing an accelerated pace of drug development, and a surge in consumption of nutritional supplements and herbal compounds by an increasingly health conscious society.

Drug-induced liver injury-significance of pathology

Many different medical agents, herbal products, and dietary supplements can induce drug-induced liver injury (DILI) as aclinically relevant complication. DILI, which is direct toxic or idiosyncratic, can have abroad spectrum of clinical appearances from elevation of liver enzymes to acute liver failure. DILI is categorized clinically according to the pattern of serum parameters or pathologically according to the pattern of histomorphology. Histopathological patterns can be described as hepatitic, granulomatous, cholestatic, ductopenic, fibrotic, steatotic, steatohepatitic, and vascular. Correlation to the corresponding drug can be carried out with the corresponding databases (US National Library of Medicine, Liver Tox; www.ncbi.nlm.nih.gov/books/NBK547852/ ). Liver biopsy, in contrast to a clinical/serological diagnostic, has the advantage of an exact resolution with evidence of pathophysiology, activity, regeneration, chronification, and prognosis. Co-occurrence of underlying liver disease can be excluded or confirmed. Histological patterns of DILI are described and illustrated. Adiagnostic algorithm for the interpretation of liver biopsies is provided.

Prevalence and risk factors for drug-induced liver injury among patients with rheumatic diseases treated with biological therapy: a single-center experience.

Drug-induced liver injury (DILI) is a common event in patients with rheumatic diseases (RD) on biological therapy (BT). We aimed at evaluating the prevalence and pattern of DILI. Consecutive RD patients treated with BT were followed for 6 months. ALT and ALP >the upper limit normal (ULN) and <to 3xULN defined injury Grade 1 and >3xULN injury Grade 2. 582 liver function tests (LFTs) in 199 patients were evaluated, median age 53y, 59.3 % females, RA in 108, AS 49, and PsA 42 patients. ALT Grade 1 elevation was observed in 25.6 %, transient in 18.6 %, persisting in 7 %, Grade 2 in 1.5 %, ALP Grade 1 in 3.5 %, transient in 2 %, persisting in 1.5 %. We report no case of ALP Grade 2 or Hy´s law (ALT>3xULN, bilirubin>2xULN). Patients with persisting ALT elevation had higher BMI (28.23 vs. 25.74, p=0.016), lower DAS28 (2.22 vs. 5.28, p=0.046). ALT Grade 1 injury was more frequent with solo tocilizumab compared with other agents (27.5 % vs. 13.6 %, p=0.01). DILI was frequent, in 18.6 % transient, in 7 % persisting, Grade 2 in 1.5 %, led to treatment alteration in 0.5 %, with higher prevalence on solo tocilizumab therapy. We report no new safety signals for BT in RD.

Etiology and Pattern of Drug Induced Liver Injury in a Tertiary Care Hospital of Nepal

Drug induced liver injury (DILI) is one of the common cause of liver toxicity. Most of the drugs used today are hepatotoxic. DILI accounts for approximately one-half of the cases of acute liver failure and mimics all forms of acute and chronic liver disease. It is the single most common adverse drug reaction leading to a halt in the development of new medication by pharmaceutical company, failure of new drug to obtain regulatory approval, and withdrawal or restriction of existing drug from the market. The aim of this study is to evaluate common causes and patterns of DILI in our setting. Twenty-seven patients were enrolled in the study. Ant tubercular drugs were most common cause of DILI, accounting for 48.2%. Other common causes of DILI were paracetamol (14.8%) and NSAID’s (11.1%). The most common pattern of liver injury seen was mixed pattern which was present in63%, followed by cholestatic and hepatocellular pattern. Hence, we should be very careful while prescribing these frequently used drugs.

2291 Drug-Induced Autoimmune Hepatitis Secondary to Infliximab

INTRODUCTION: The increased utilization of Infliximab therapy has produced a small number of reported cases associating Infliximab with varying patterns of drug-induced liver injury. We present a rare case report of drug-induced autoimmune hepatitis that embodies a realistic presentation of a potentially underreported liver injury pattern that can occur following the induction of Infliximab therapy. CASE DESCRIPTION/METHODS: A 36 yo female with a PMHx significant for Crohn’s Disease, HTN and chronic alcohol abuse was admitted for generalized body aches, right upper quadrant abdominal pain, and shortness of breath. The patient described a recent increase to her alcohol consumption from 48 to 120 oz of beer daily for the last two weeks. The patient otherwise denied: smoking tobacco, illicit drugs, and naturopathic or over the counter medications. Physical examination revealed jaundice and tenderness to the RUQ of the patient’s abdomen. No evidence of ascites, palmar erythema, spider angiomata or protein malnutrition were present. Lab Findings revealed: AST/ALT: 1135/175, T. Bili: 10.9, AP: 230, Albumin: 2.7, Platelets: 233, INR: 1.1. The patient’s lab findings and subjective history validated continued concern for alcoholic hepatitis. Viral hepatitis serologies and autoimmune markers were collected and produced negative results except for a positive Anti-Nuclear Ab; ANA Titer: 1:2560. A RUQ Ultrasound with Doppler revealed hepatomegaly without signs of cirrhosis. Histopathologic results from biopsy revealed florid lymphoplasmacytic portal inflammation, stage 2-3 with periportal/bridging fibrosis and was without steatosis or steatohepatitis; findings consistent with the diagnosis of autoimmune hepatitis and drug induced liver injury. DISCUSSION: A detailed review of the patient’s medications revealed Infliximab infusions were initiated 5 months prior ,with the most recent being 3 weeks before presentation. The patient had no new medication exposures. Despite an initial concern for alcoholic hepatitis, the patient’s biopsy results showed no evidence of an alcoholic liver injury pattern. The positive ANA, histopathology, favorable response to infliximab withdrawal followed by steroid induced immunosuppression was consistent with the diagnosis of drug-induced autoimmune hepatitis (DIAIH). This case suggests patients receiving Infliximab therapy with elevations in liver function tests require thorough evaluation and strong consideration of biopsy for appropriate diagnosis.

Co-infection with hepatitis B virus among tuberculosis patients is associated with poor outcomes during anti-tuberculosis treatment

BackgroundTuberculosis (TB) and chronic Hepatitis B virus (HBV) infection are common in China. Fist-line anti-TB medications often produce drug-induced liver injury (DILI). This study sought to investigate whether TB patients with chronic HBV co-infection are more susceptible to liver failure and poor outcomes during anti-TB treatment.MethodsEighty-four TB patients developed DILI during anti-TB treatment and were enrolled, including 58 with chronic HBV co-infection (TB-HBV group) and 26 with TB mono-infection (TB group). Clinical data and demographic characteristics were reviewed. The severity of DILI and incidences of liver failure and death were compared. Risk factors of clinical outcomes were defined.ResultsThe patterns of DILI were similar in both groups. Compared with patients in the TB group, patients in the TB-HBV group who did not receive anti-HBV therapy before anti-TB treatment were more susceptible to Grade-4 severity of DILI (36.2% vs. 7.7%, P = 0.005), liver failure (67.2% vs. 38.5%, P = 0.013) and poor outcomes (37.9% vs. 7.7%, P = 0.005). Age > 50 years (48.1% vs. 22.6%, P = 0.049), cirrhosis (50.0% vs. 15.4%, P = 0.046) and total bilirubin > 20 mg/dl (51.6% vs. 14.8%, P = 0.005) were independent risk factors for the rate of death in the TB-HBV group, and HBV DNA > 20,000 IU/ml had borderline significance (44.1% vs. 20.8%, P = 0.081). In the TB-HBV group, nucleos(t)ide analogues as rescue therapy were not able to reduce short-term death (33.3% vs. 36.8%, P = 0.659) once liver failure had occurred.ConclusionsPatients on anti-TB therapy with chronic HBV co-infection are more susceptible to developing liver failure and having poor outcomes during anti-TB treatment. Regular monitoring of liver function and HBV DNA level is mandatory. Anti-HBV treatment should be considered in those with high viral levels before anti-TB treatment.

Drug-Induced Liver Injury in HIV-Infected Patients with Opportunistic Infections: Causes, Clinical Features and Predictors in Chinese Patients

Objective: To evaluate the prevalence, causes, patterns, severity and risk factors of drug-induced liver injury (DILI) in Chinese HIV-infected patients with opportunistic infections. Methods: HIV-infected patients with opportunistic infections with DILI were studied in Beijing Ditan Hospital between Jan.1, 2009 and Nov.30, 2012, and risk factors of DILI were evaluated using multivariate Cox Proportional Hazards Model. Results: In 797 patients, 144 (18.1%) were diagnosed as DILI after receiving treatment of opportunistic infections or antiretroviral therapy. The leading causes were Trimethoprim/sulfamethoxazole (TMP-SMX) (43.9%), anti-tuberculosis medications (13.7%), nevirapine (6.9%), anti-fungal drugs (4.7%) and efavirenz (1.2%). The median duration between agents’ exposure and DILI recognition for hepatocellular, cholestatic and mixed pattern was statistically significant difference among 3 patterns of DILI (p=0.009), and the duration was positively correlated with CD4 count (r=0.223, p=0.007) and R value (r=0.238, p=0.004). Male sex and baseline CD4 counts were significant protective predictors for DILI. Conclusion: TMP-SMX, anti-tuberculosis medications, non-nucleoside reverse transcriptase inhibitors (NNRTIs) and anti-fungal drugs were the leading causes of DILI. The DILI in HIV-infected patients with opportunistic infections was negatively associated with male sex and CD4 counts.

Drug-Induced Liver Injury

Drug-induced liver injury (DILI) refers to liver damage caused by over-the-counter and prescription drugs as well as herbal and dietary supplements. Hepatocytes, the main factory cells of the liver, are the primary targets of drug-related injury. During hepatocyte injury, loss of cell integrity results in a leak of liver contents, including a variety of enzymes, into the circulation. Currently, more than 1,000 drugs and herbal products have recognized hepatotoxic properties, with acetaminophen (APAP) being the most common cause of acute liver failure in the United States and amoxicillin-clavulanate the most common cause of severe liver injury worldwide. This review of DILI addresses the epidemiology, classification, pathophysiology, clinical manifestations, diagnosis, common idiosyncratic drug reactions, unusual drug reactions, treatment, and prognosis, with special sections on APAP hepatotoxicity and the approval of prescription drugs by the Food and Drug Administration. Figures show histologic features of DILI, mechanisms of liver injury, genome-wide association study results for lumiracoxib, APAP metabolism, and the Rumack-Matthew nomogram. Tables list classification of DILI, features of idiosyncratic drug reactions, histologic patterns of DILI, haplotypes associated with specific drug-related disorders, and the Roussel-Uclaf causality assessment method. This review contains 5 highly rendered figures, 5 tables, and 54 references.

Characteristic molecular and proteomic signatures of drug-induced liver injury in a rat model.

Drug-induced liver injury (DILI) is a major safety concern during drug development and remains one of the main reasons for withdrawal of drugs from the market. Although it is crucial to develop methods that will detect potential hepatotoxicity of drug candidates as early and as quickly as possible, there is still a lack of sensitive and specific biomarkers for DILI that consequently leads to a scarcity of reliable hepatotoxic data. Hence, in this study, we assessed characteristic molecular signatures in rat liver treated with drugs (pyrazinamide, ranitidine, enalapril, carbamazepine and chlorpromazine) that are known to cause DILI in humans. Unsupervised hierarchical clustering analysis of transcriptome changes induced by DILI-causing drugs resulted in three different subclusters on dendrogram, i.e., hepatocellular, cholestatic and mixed type of DILI at early time points (2 days), and multiclassification analysis suggested 31 genes as discernible markers for each DILI pattern. Further analysis for characteristic molecular signature of each DILI pattern provided a molecular basis for different modes of DILI action. A proteomics study of the same rat livers was used to confirm the results, and the two sets of data showed 60 matching classifiers. In conclusion, the data of different DILI-causing drug treatments from genomic analysis in a rat model suggest that DILI-specific molecular signatures can discriminate different patterns of DILI at an early exposure time point, and that they provide useful information for mechanistic studies that may lead to a better understanding of the molecular basis of DILI.

F-2 Pattern of drug-induced liver injury: The impact of amoxicillin-clavulanate on clinical course

F-2 Pattern of drug-induced liver injury: The impact of amoxicillin-clavulanate on clinical course