Incidence Of Drug-induced Liver Injury Research Articles

Frequency of null genotypes of glutathione S-transferase M1 and T1 in Japanese patients with drug-induced liver injury.

Previous reports suggest that the null genotype (*0/*0) of glutathione S-transferase (GST) M1 and/or GSTT1 could be risk factors for drug-induced liver injury (DILI). However, multi-institutional pharmacogenetic research with various suspected drugs has rarely been performed in Japan. Therefore, the aim of this study was to investigate the role of GSTM1 and GSTT1 null genotype in the occurrence of DILI in Japanese patients. Blood samples of 270 DILI patients from 23 hospitals throughout Japan collected between 2010 and 2018 were subjected to genotyping of null genotypes of GSTM1 and GSTT1 using the SmartAmp-2 method. We also collected information on DILI types, time to onset of DILI, pharmacological classification of suspected drugs and Digestive Disease Week-Japan score, as well as genotypes of GSTM1 and GSTT1 in each patient with DILI. The distribution of a combination of null genotypes of GSTM1 and GSTT1 in Japanese patients with DILI was significantly different from that reported in the general Japanese population. Notably, the incidence of the GSTM1 null genotype in patients with DILI was significantly higher than that of the control population. A significant relationship between the frequency of GSTM1 and GSTT1 null genotypes and pharmacological classification of suspected drugs, clinical laboratory data for liver function, time to onset of DILI, and Digestive Disease Week-Japan scores was not observed. The GSTM1 null genotype was associated with an increased incidence of DILI in Japanese patients.

Tandem mass tag-based proteomics analysis reveals the effects of Guri Gumu-13 pill on drug-induced liver injury

The incidence of drug-induced liver injury (DILI) is second only to viral hepatitis and steatohepatitis in China, and DILI has become a serious public health problem that cannot be ignored. Guri Gumu-13 pill (GRGM) is a traditional Chinese medicine (TCM), which has a protective effect on liver diseases. However, the underlying therapeutic mechanisms of GRGM for DILI are still vague. In this study, the protective effect of GRGM on acetaminophen (APAP)-induced DILI was investigated based on the proteomics clues. The effects of GRGM on APAP-induced DILI in rats were studied using tandem mass tag (TMT)-based quantitative proteomics technology. Besides, western blotting was exerted to verify related proteins. Using the TMT-based quantitative proteomics approach, 237 proteins were identified as regulated in APAP-induced DILI and 58 proteins were regulated by GRGM. The 17 overlapping differentially expressed proteins (DEPs) were identified, and 7 proteins were inversely regulated. Enrichment analysis of KEGG indicated that metabolic pathways, linoleic acid metabolism, and retinol metabolism might be affected in DILI. Next, Cyp2c11, Aldh1a1, and Fads2 were verified with molecular biotechnology. GRGM exerts therapeutic effects through multi-pathways regulation in the treatment of DILI. This work may provide proteomics clues for the continuation of research on DILI treatment with GRGM.

Drug-induced Liver Injury in Pediatrics.

Drug-induced liver injury (DILI) is a rare, underdiagnosed cause of liver disease in children. The incidence of DILI in the pediatric population is unknown but it represents around 10% of all DILI cases. The most common hepatotoxic drugs in children are antibiotics and antiepileptics. DILI is classified as intrinsic or idiosyncratic and it presents mostly with 2 patterns of injury: hepatocellular or cholestatic. Diagnosis can be done with help of the Roussel Uclaf Causality Assessment Method (RUCAM) casualty assessment. The mainstay of treatment is prompt withdrawal of the suspect drug.

Drug-Induced Liver Injury during Consolidation Therapy in Childhood Acute Lymphoblastic Leukemia as Assessed for Causality Using the Updated RUCAM.

Purpose The presence of serious toxicities is a major problem in the treatment of childhood acute lymphoblastic leukemia (ALL). The objective of this research is to evaluate drug-induced liver injury (DILI) during consolidation therapy in childhood ALL. Methods Clinical data of pediatric patients who received consolidation therapy between August 2012 and July 2018 were collected. Characteristics (incidences and patterns) of DILI at different stratifications were determined. Risks of DILI were evaluated using binary logistic regression analysis. Drug causality assessment was carried out by the updated Roussel Uclaf Causality Assessment Method (RUCAM). Results Patients with high risk (HR) and standard risk (SR)/intermediate risk (IR) received 270 and 1539 courses of consolidation therapy, respectively; among these courses, 15 (5.6%) and 38 (2.5%) developed DILI. The occurrences of DILI in SR/IR patients were primarily associated with age (≤5.2 years), treatment course (≥5), and baseline serum parameters before treatment (cystatin C > 0.79 mg/L, albumin ≤45 g/L, and gamma-glutamyl transpeptidase (GGT) > 17 U/L). The ROC curve generated using the parameters assigned to specific values achieved an area under the curve (AUC) of 0.846 (95% CI 0.827–0.863) with a cutoff value of 3, and the sensitivity and specificity were 94.7% and 62.3%, respectively. For HR patients, a decrease in baseline albumin and elevation of baseline liver enzymes (GGT and aspartate aminotransferase) were observed in DILI cases compared with the non-DILI subjects. In the SR/IR group with DILI, the causality gradings for high-dose methotrexate (HD-MTX) were highly probable in 5 (13.2%) cases, probable in 31 (81.6%) cases, and possible in 2 (5.3%) cases. Among the DILI cases in HR-1, HR-2, and HR-3 groups, high causality gradings (probable + highly probable) were detected in “100% of HD-MTX + 57% of high-dose cytarabine (HD-Ara-C),” “100% of HD-MTX + 20% of pegylated asparaginase (PEG-ASP),” and “100% of HD-Ara-C + 33.3% of PEG-ASP,” respectively. Conclusion Incidence of DILI in HR patients was significantly higher than that in SR/IR patients. A number of potential risk factors were identified, among which the preexisting liver conditions were suggested as shared risk factors in all stratification groups. HD-MTX, HD-Ara-C, and PEG-ASP were the main causative agents of DILI. The knowledge generated from this study will be helpful for understanding characteristics of DILI during consolidation treatment in childhood ALL.

Association Between Drug Treatments and the Incidence of Liver Injury in Hospitalized Patients With COVID-19.

The outbreak of coronavirus disease 2019 (COVID-19) has led to the emergence of global health care. In this study, we aimed to explore the association between drug treatments and the incidence of drug-induced liver injury (DILI) in hospitalized patients with COVID-19. A retrospective study was conducted on 5113 COVID-19 patients in Hubei province, among which 395 incurred liver injury. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards models. The results showed that COVID-19 patients who received antibiotics (HR 1.97, 95% CI: 1.55–2.51, p < 0.001), antifungal agents (HR 3.10, 95% CI: 1.93–4.99, p < 0.001) and corticosteroids (HR 2.31, 95% CI: 1.80–2.96, p < 0.001) had a higher risk of DILI compared to non-users. Special attention was given to the use of parenteral nutrition (HR 1.82, 95% CI: 1.31–2.52, p < 0.001) and enteral nutrition (HR 2.71, 95% CI: 1.98–3.71, p < 0.001), which were the risk factors for liver injury. In conclusion, this study suggests that the development of DILI in hospitalized patients with COVID-19 needs to be closely monitored, and the above-mentioned drug treatments may contribute to the risk of DILI.

Evaluating the impact of a Risk Evaluation and Mitigation Strategy with tolvaptan to monitor liver safety in patients with autosomal dominant polycystic kidney disease.

On approval of JYNARQUE (tolvaptan) for use in patients with autosomal dominant polycystic kidney disease (ADPKD) at risk for rapid progression, the US Food and Drug Administration required a Risk Evaluation and Mitigation Strategy (REMS) from the sponsor, which includes collection of post marketing liver safety data. This is a retrospective interim analysis of the ongoing REMS. The period evaluated was from REMS implementation (14 May 2018) at tolvaptan commercialization to the analysis cutoff date (23 February 2021). Patients were previously tolvaptan-naïve and initiated tolvaptan in the post marketing setting. Reports of possible severe drug-induced liver injury (DILI) were evaluated for severity based on the evidence obtained (e.g. liver enzyme levels, symptoms, diagnostic tests and event outcomes). The incidence of DILI was compared between the REMS and tolvaptan clinical trials in ADPKD. Among 6711 REMS patients, 60 (0.9%) cases of possible severe DILI were reported, 4 of which were confirmed as serious and potentially fatal by the sponsor. One of these four patients met Hy's law criteria. In all four patients, liver enzymes normalized after tolvaptan discontinuation. The duration of tolvaptan exposure in the REMS is currently shorter than in completed clinical trials, but within this limitation, the incidence of possible severe DILI was lower in the REMS than in clinical trials (incidence rate ratio 0.587; P = .000411). In interim data on >6000 tolvaptan REMS patients, <1% experienced possible severe DILI. Monthly monitoring, as described in the tolvaptan prescribing information, enables the prompt detection of liver enzyme abnormalities and appropriate drug discontinuation.

Comparison between the Effects of Loxoprofen and Acetaminophen on Postoperative Pain Following Radical Prostatectomy: A Propensity Score Matching Analysis

Non-steroidal anti-inflammatory medications are associated with renal impairment. However, there is little information on whether these medications affect postoperative renal function compared with acetaminophen. The objective of this study was to compare the effects of acetaminophen and loxoprofen, used as postoperative analgesic, effect on postoperative analgesia using propensity score matching analysis. We retrospectively enrolled 328 patients treated with loxoprofen or acetaminophen after open radical prostatectomy between October 2017 and February 2020. We analyzed postoperative pain intensity, the incidence rate of acute kidney injury, drug-induced liver injury, and rate of elevation in serum creatinine after open radical prostatectomy. Eighty-one matched pairs of patients treated with loxoprofen or acetaminophen were selected using propensity score matching analysis. The postoperative numerical rating scale was significantly higher in the acetaminophen group than in the loxoprofen group on postoperative day 5. The use of patient-controlled anesthesia and rescue analgesics was significantly higher in the acetaminophen group than in the loxoprofen group. The loxoprofen group had a significantly higher postoperative increase in serum creatinine than the acetaminophen group on postoperative days 5 and 8. The incidence of acute kidney injury was 4.9% in the loxoprofen group and 0% in the acetaminophen group, while the incidence of drug-induced liver injury was 0% in both groups. Acetaminophen appears to be safer than loxoprofen in terms of effects on renal function. Nevertheless, the number of acetaminophen doses and the dose per dose may need to be increased for patients with significant postoperative pain.

Characterisation of Drug-Induced Liver Injury in Patients with COVID-19 Detected by a Proactive Pharmacovigilance Program from Laboratory Signals.

Coronavirus disease 2019 (COVID-19) has a wide spectrum of clinical manifestations. An elevation of liver damage markers has been observed in numerous cases, which could be related to the empirical use of potentially hepatotoxic drugs. The aim of this study was to describe the clinical and analytical characteristics and perform a causality analysis from laboratory signals available of drug-induced liver injury (DILI) detected by a proactive pharmacovigilance program in patients hospitalised for COVID-19 at La Paz University Hospital in Madrid (Spain) from 1 March 2020 to 31 December 2020. The updated Roussel Uclaf Causality Assessment Method (RUCAM) was employed to assess DILI causality. A lymphocyte transformation test (LTT) was performed on 10 patients. Ultimately, 160 patients were included. The incidence of DILI (alanine aminotransferase >5, upper limit of normal) was 4.9%; of these, 60% had previous COVID-19 hepatitis, the stay was 8.1 days longer and 98.1% were being treated with more than 5 drugs. The most frequent mechanism was hepatocellular (57.5%), with mild severity (87.5%) and subsequent recovery (88.1%). The most commonly associated drugs were hydroxychloroquine, azithromycin, tocilizumab and ceftriaxone. The highest incidence rate of DILI per 10,000 defined daily doses (DDD) was with remdesivir (992.7/10,000 DDD). Some 80% of the LTTs performed were positive, with a RUCAM score of ≥4. The presence of DILI after COVID-19 was associated with longer hospital stays. An immune mechanism has been demonstrated in a small subset of DILI cases.

A Retrospective Cohort Study: Safety and Effectiveness of Elbasvir/Grazoprevir ± Ribavirin Compared With Ombitasvir/Paritaprevir/Ritonavir/Dasabuvir ± Ribavirin in Patients With Chronic Hepatitis C Genotype 1 Infection.

Background: The direct-acting antiviral (DAA) agents are widely used to treat hepatitis C virus (HCV) genotype (GT) 1 infection, while it may cause severe liver damage. The objectives of the study were to evaluate the incidence of drug-induced liver injury (DILI), sustained virologic response at post-treatment week 12 (SVR12), and recurrence rates in HCV GT 1 infection.Methods: This was a retrospective cohort study that included patients diagnosed with HCV GT 1 infection, who had received intervention and treatment with elbasvir/grazoprevir (EBR/GZR) ± ribavirin (RBV) versus ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) + dasabuvir ± RBV (as control group) for 12 or 24 weeks at a regional hospital in southern Taiwan between April 2016 and August 2018. The primary outcome of the study was to compare the incidence rate ratio (IRR) of DILI via Poisson regression, and the secondary outcome was to evaluate the effectiveness of two treatment regimens expressed as a percentage.Results: The study included 149 patients in the control group and 105 patients in the intervention group of which 99.33 and 98.1% patients, respectively, achieved SVR12. In the control group, one patient experienced relapse, whereas in the intervention group, two patients relapsed. Furthermore, in the control group, a total of nine patients developed DILI as determined during follow-up care. Of these patients, three were 55–84 years old. In the intervention group, six patients developed DILI. The IRR of DILI caused by EBR/GZR treatment was 2.84 times higher than that caused by the OBV/PTV/r treatment regimen.Conclusion: There was no significant difference between the studied DAA regimens regarding the incidence of DILI and effectiveness during the treatment. DILI occurrence during therapy did not affect the cure rate of medication. The present study results can provide reference data for drug selection among patients with HCV.Trial registration: The study was approved by DMF-CYCH (CYCH IRB No: 2018067).

Incidence, characteristics and risk factors for drug-induced liver injury in hospitalized patients: A matched case-control study.

The diagnosis of drug-induced liver injury (DILI) is relatively complex and involves a wide variety of drugs. The purpose of this study was to use algorithms to quickly screen DILI patients, determine its incidence and identify risk factors. The Adverse Drug Events Active Surveillance and Assessment System-2 was used to extract the data of patients hospitalized in 2019 according to the set standards and the Roussel Uclaf Causality Assessment Method was used to evaluate patients who met the standards. A retrospective case-control study was conducted according to suspected drugs, length of hospital stay and height- and weight-matched controls, and logistic regression was used to identify risk factors. Among the 156 570 hospitalized patients, 480 patients (499 cases) with DILI were confirmed and the incidence of DILI was 0.32%. Anti-infective agents, antineoplastic agents and nonsteroidal anti-inflammatory drugs were the major categories of drugs causing DILI, and the highest incidence of DILI was due to voriconazole. The latency period and hospital stay of patients with cholestasis were both relatively long. Patients with hyperlipidaemia (adjusted odds ratio [AOR] 1.884), cardiovascular disease (AOR 1.465), pre-existing liver disease (AOR 1.827) and surgical history (AOR 1.312) were at higher risk for DILI. The incidence of DILI in hospitalized patients was uncommon (0.32%) and its pathogenic drugs were widely distributed. The incidence of DILI for many drugs has been seriously underestimated. It is recommended to focus on patients with hyperlipidaemia, cardiovascular disease, pre-existing liver disease and surgical history.

Antibiotic‑associated drug‑induced liver damage with cholestasis: actualization of problem in COVID‑19 era

Drug-induced liver injury (DILI) is a fairly frequent adverse drug reaction, which accounts for about half (40–50 %) of cases of acute liver damage. The cholestatic variant of DILI is characterized by an increase in the activity of alkaline phosphatase (ALP) above the two upper limits of the norm (ULN) or the ratio of alanine aminotransferase (ALT) / ALP ≤ 2 in chronic course. A common cause of the cholestatic variant of DILI is a use of drugs for the treatment of infectious diseases, such as beta-lactam antibiotics, Aminoglycosides, Amphenicol, Lincosamides, macrolides, fluoroquinolones, antituberculosis drugs, etc. This problem has acquired particular urgency during the COVID-19 pandemic. The widespread use of azithromycin, hydroxychloroquine, interferons, lopinavir, and other drugs for the treatment of COVID-19 also contributed to an increase in the incidence of DILI. In accordance with clinical guidelines in case of suspicion of a drug-induced liver damage, one should stop use of suspected drug and, if necessary, prescribe hepatoprotectors, for example, ursodeoxycholic acid (UDCA). The effectiveness of the use of UDCA in patients with DILI, including those caused by the intake of antibacterial drugs, has been confirmed by randomized placebo-controlled clinical trials. The effectiveness of UDCA -drug Ursosan®has been confirmed in real life clinical practice. This drug can be used for long-term (up to several months), or lifelong treatment with hepatotoxic drugs like antituberculosis and antirheumatic drugs. The daily dose of Ursosan®is 12–15 mg/kg, if necessary – 20 mg / kg (with a weight of a patient about 75–100 kg, daily dose will be equal to two tablets of Ursosan Forte®, 500 mg).

Drug Induced Liver Injury in Geriatric Patients Detected by a Two-Hospital Prospective Pharmacovigilance Program: A Comprehensive Analysis Using the Roussel Uclaf Causality Assessment Method.

Background/aim: A prospective evaluation of drug-induced liver injury (DILI) in two tertiary hospitals was conducted through a pharmacovigilance program from laboratory signals at hospital (PPLSH) to determine the principal characteristics of DILI in patients older than 65 years, a growing age group worldwide, which is underrepresented in the literature on DILI. Methods: All DILI in patients older than 65 years detected by PPLSH in two hospitals were followed up for 8 years in the La Paz Hospital and 2 years in the Getafe Hospital. A descriptive analysis was conducted that determined the causality of DILI and suspected drugs, the incidence of DILI morbidities, DILI characteristics, laboratory patterns, evolution and outcomes. Results: 458 DILI cases in 441 patients were identified, 31.0% resulting in hospitalisation and 69.0% developing during hospitalisation. The mean age was 76.61 years old (SD, 7.9), and 54.4% were women. The DILI incidence was 76.33/10,000 admissions (95%CI 60.78–95.13). Polypharmacy (taking >4 drugs) was present in 86.84% of patients, 39.68% of whom took >10 drugs. The hepatocellular phenotype was the most frequent type of DILI (53.29%), a higher proportion (65%) had a mild severity index, and, in 55.2% of the evaluated drugs the RUCAM indicated that the causal relationship was highly probable. The most frequently employed drugs were paracetamol (50-cases), amoxicillin-clavulanate (42-cases) and atorvastatin (37-cases). The incidence rate of in-hospital DILI per 10,000 DDDs was highest for piperacillin-tazobactam (66.96/10,000 DDDs). A higher risk of in-hospital DILI was associated with the therapeutic chemical group-J (antiinfectives for systemic use) (OR, 2.65; 95%CI 1.58–4.46) and group-N (central nervous system drugs) (OR, 2.33; 95%CI 1.26–4.31). The patients taking >4 medications presented higher maximum creatinine level (OR, 2.01; 95%CI 1.28–3.15), and the patients taking >10 medications had a higher use of group J drugs (OR, 2.08; 95%IC 1.31–3.32). Conclusion: The incidence rate of DILI in the patients older than 65 years was higher than expected. DILI in elderly patients is mild, has a good outcome, has a hepatocellular pattern, develops during hospitalisation, and prolongs the hospital stay. Knowing the DILI incidence and explanatory factors will help improve the therapy of the elderly population.

The Effect of acetyl-L-carnitine, Alpha-lipoic Acid, and Coenzyme Q10 Combination in Preventing Anti-tuberculosis Drug-induced Hepatotoxicity: A Randomized, Double-blind, Placebo-controlled Clinical Trial.

Drug-induced liver injury (DILI) is one of the most serious adverse effects of anti-tuberculosis (TB) drugs. A suggested mechanism of this adverse effect is mitochondrial dysfunction (MDF). The purpose of this study was an evaluation of the possible preventive effects of the combination of acetyl-L-carnitine (ALCAR), alpha-lipoic acid (ALA), and coenzyme Q10 (CoQ10), as mitochondrial nutrients (MNs), against anti-TB DILI. In this clinical trial, patients who met the inclusion criteria were randomly assigned to either experimental (n = 44) or placebo (n = 43) groups. The experimental group received capsules containing CoQ10 (200 mg) + ALA (250 mg) + ALCAR (250 mg) orally twice daily for two weeks, and the placebo group received oral placebo capsules with the same interval and duration. The mean serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBil) at the end of the first and second weeks as well as the incidence of DILI during the intervention were recorded and compared between the two groups. At the end of the study, the mean serum levels of AST and ALT in the experimental group were significantly lower than the placebo group (36.27 ± 36.43 vs. 86.02 ± 97.23 and 28.41 ± 27.41 vs. 78.80 ± 118.28, respectively, P = 0.003 for both). Also, the incidence of anti-TB DILI was significantly lower in the experimental group than the placebo group (6.8% vs. 25.6%, P = 0.017). In conclusion, using the combination of ALCAR, ALA, and CoQ10 may provide an effective strategy in preventing anti-TB DILI.

Clinical features of drug-induced liver failure and related diagnosis and treatment strategies

The incidence of drug-induced liver injury (DILI) has risen considerably in recent years. Drug-induced liver failure tends to have severe conditions, limited therapeutic strategy, and a high mortality rate and should thus be taken seriously by clinicians. N-acetyl-p-aminophenol is the most common cause of acute liver failure (ALF) in Western countries; for ALF associated with idiosyncratic DILI (iDILI), since there is little in-deep understanding of host susceptibility and pathogenesis, it is difficult to identify ALF caused by iDILI in the early stage, and due to a low rate of spontaneous recovery and poor prognosis, it has become a major indication for emergency liver transplantation in many countries. A comprehensive understanding of the clinical features and prognostic prediction of drug-induced liver failure and the search for new reliable diagnostic methods and effective treatment strategies are of vital importance in reducing the disease burden of drug-induced liver failure.

Characteristics of Drug-Induced Liver Injury in Northeast China: Disease Spectrum and Drug Types.

The aim of this study was to determine the disease spectrum and drug types causing drug-induced liver injury (DILI) in northeast China, so that the affected population can be reminded of the need to increase their post-medication monitoring. A total of 470 DILI patients hospitalized at Shengjing Hospital between 2013 and 2016 were involved in this retrospective study. There were significant differences in the disease spectrum of the different age groups (P < 0.001) and genders (P = 0.009). Drugs used to treat osteopathies, dermatitis and infections, as well as health care supplements, each accounted for > 10% of all drugs that caused DILI. The percentage of DILIs related to Chinese herbal medicines (CHMs) gradually increased with patient age (P = 0.002). The percentage of males taking health supplements or CHMs was significantly lower compared with females. Total bilirubin (β = 0.01, OR = 1.01, P < 0.001) and INR (β = 0.74, OR = 2.11, P < 0.001) were found to be independent predictors of liver damage. The main type of drug that causes DILI in northeast China is a CHM. There are differences in the disease spectrum found in DILI patients of different ages and gender. Making appropriate changes in the drug-taking habits of high-risk groups and the drugs used to treat high-risk underlying diseases, as well as increasing patient monitoring, may help to reduce the incidence of DILIs.

Evaluation of Drug-Induced Liver Injury Developed During Hospitalization Using Electronic Health Record (EHR)-Based Algorithm.

PurposeThe incidence of drug-induced liver injury (DILI) has been increasing; however, few algorithms are available to identify DILI in electronic health records (EHRs). We aimed to identify and evaluate DILI with an appropriate screening algorithm.MethodsWe collected data from 3 university hospitals between June 2015 and May 2016 using our newly developed algorithm for identifying DILI. Among patients with alanine transferase (ALT) ≤ 120 IU/L and total bilirubin (TB) ≤ 2.4 mg/dL in blood test results within 48 hours of admission, those who either had 1) ALT > 120 IU/L and TB > 2.4 mg/dL or 2) ALT > 200 IU/L at least once during hospitalization were identified. After excluding patients with liver disease-related diagnosis at discharge, medical records were retrospectively reviewed to evaluate epidemiological characteristics of DILI.ResultsThe total number of inpatients was 256,598, of whom 1,100 (0.43%) were selected by the algorithm as suspected DILI. Subsequently, 365 cases (0.14% of total inpatients, 95% confidence interval, 0.13–0.16) were identified as DILI, yielding a positive predictive value of 33.1%. Antibiotics (n = 214, 47.2%) were the major class of causative drug followed by chemotherapeutic agents (n = 87, 19.2%). The most common causative drug was piperacillin-tazobactam (n = 38, 8.4%); the incidence of DILI by individual agent was highest for methotrexate (19.4 cases/1,000 patients administered the drug). Common reasons for excluding suspected DILI cases were ischemic hepatitis and postoperative liver dysfunction.ConclusionsUsing our EHR-based algorithm, we identified that approximately 0.14% of patients developed DILI during hospitalization. Further studies are needed to modify criteria for more accurate identification of DILI.

2483 Amoxicillin-Induced Eosinophilia in Portal Tracts—A Rare Case of Idiosyncratic Acute Cholestatic Hepatitis

INTRODUCTION: Drug induced liver injury (DILI) accounts for approximately 10 percent of all cases of acute hepatitis. Amoxicillin/clavulanic acid induced liver injury is a well-recognized complication but amoxicillin alone has rarely been linked with clinically significant idiosyncratic liver injury. It is exceedingly uncommon to see eosinophilic penetration of portal tracts with amoxicillin induced liver injury. CASE DESCRIPTION/METHODS: A 21 year old obese woman presented with jaundice preceded by fever and right upper quadrant abdominal pain for 1 week. She had completed a 10 day course of amoxicillin for an ear infection 3 weeks back. She denied any alcohol, acetaminophen, herbal medications, recent travels or exposure to sick contacts. She had scleral icterus and tender hepatomegaly with no rash on exam. Serum AST, ALT and ALP were moderately elevated with peaks of 216 U/L, 296 U/L and 466 U/L respectively. Serum bilirubin peaked at 13.1 mg/dL with direct component of 9.7 mg/dL. Blood differential count was significant for elevated eosinophils 0.8 k/uL (range 0.1-0.3 k/uL). Work up was negative for viral and autoimmune hepatitis. The levels of ceruloplasmin, alpha-1-antitrypsin and immunoglobulins were normal. Ultrasound and MRCP showed an enlarged fatty liver with no evidence of biliary ductal dilatation. Liver biopsy showed expanded portal tracts with marked inflammatory infiltrate composed predominantly of neutrophils with many eosinophils, and scattered lymphocytes and plasma cells. There was hepatocellular and canalicular cholestasis with no bile ductular reaction. DISCUSSION: The incidence of DILI with amoxicillin alone is 0.3 per 10,000 prescriptions compared to 1.7 per 10,000 prescriptions with amoxicillin/clavulanic acid. Risk factors are older age, female sex, pregnancy, high BMI and excessive alcohol intake. Signs and symptoms begin within 6 weeks of initiating amoxicillin, including nausea, abdominal pain, jaundice, fever, pale stools, dark urine, and pruritus. The mechanism of amoxicillin hepatotoxicity is unknown with possibility of idiosyncratic immune allergic reaction. Histologically liver injury appears most often as a cholestatic hepatitis and may have associated bile duct injury manifesting as extensive infiltration of the biliary epithelium with inflammatory cells accompanied by nuclear irregularity, cytoplasmic vacuolization and eosinophilia of the biliary epithelium. The primary treatment is the withdrawal of the drug.

Exosomal Transport of Hepatocyte-Derived Drug-Modified Proteins to the Immune System.

Idiosyncratic drug‐induced liver injury (DILI) is a rare, often difficult‐to‐predict adverse reaction with complex pathomechanisms. However, it is now evident that certain forms of DILI are immune‐mediated and may involve the activation of drug‐specific T cells. Exosomes are cell‐derived vesicles that carry RNA, lipids, and protein cargo from their cell of origin to distant cells, and they may play a role in immune activation. Herein, primary human hepatocytes were treated with drugs associated with a high incidence of DILI (flucloxacillin, amoxicillin, isoniazid, and nitroso‐sulfamethoxazole) to characterize the proteins packaged within exosomes that are subsequently transported to dendritic cells for processing. Exosomes measured between 50 and 100 nm and expressed enriched CD63. Liquid chromatography–tandem mass spectrometry (LC/MS‐MS) identified 2,109 proteins, with 608 proteins being quantified across all exosome samples. Data are available through ProteomeXchange with identifier PXD010760. Analysis of gene ontologies revealed that exosomes mirrored whole human liver tissue in terms of the families of proteins present, regardless of drug treatment. However, exosomes from nitroso‐sulfamethoxazole‐treated hepatocytes selectively packaged a specific subset of proteins. LC/MS‐MS also revealed the presence of hepatocyte‐derived exosomal proteins covalently modified with amoxicillin, flucloxacillin, and nitroso‐sulfamethoxazole. Uptake of exosomes by monocyte‐derived dendritic cells occurred silently, mainly through phagocytosis, and was inhibited by latrunculin A. An amoxicillin‐modified 9‐mer peptide derived from the exosomal transcription factor protein SRY (sex determining region Y)‐box 30 activated naïve T cells from human leukocyte antigen A*02:01–positive human donors. Conclusion: This study shows that exosomes have the potential to transmit drug‐specific hepatocyte‐derived signals to the immune system and provide a pathway for the induction of drug hapten‐specific T‐cell responses.

Dyslipidemia is a Risk Factor for the Incidence and Severity of Drug-Induced Liver Injury (DILI): A Retrospective Population-Based Study in China.

BackgroundA Chinese population-based study aimed to investigate the risk factors for the incidence and severity of drug-induced liver injury (DILI) from Chinese herbal medicines and conventional Western medicines.Material/MethodsLiver biopsy and routine laboratory testing, including serum lipid measurements, was performed on 465 patients, including 168 patients with DILI and 297 patients without DILI. Histological grading of DILI used the METAVIR scoring system and the severity of DILI was graded as levels 0–5. Multivariate and univariate regression analysis were used to compare the two study groups, using a risk-adjusted odds ratio (AOR).ResultsThere was no significant association between age, alcohol status, cardiovascular disease (CVD), hypertension, or type 2 diabetes mellitus and development of DILI. However, when compared with controls, patients with dyslipidemia (AOR, 2.173; 95% CI, 1.388–3.401; P=0.001) had an increased incidence of DILI, and men had a reduced incidence of DILI when compared with women (AOR, 0.276; 95% CI, 0.169–0.450; P<0.001). Risk factors for severe DILI (≥level 3) included drinking alcohol (AOR, 6.506; 95% CI, 2.184–19.384; P=0.001), and dyslipidemia (AOR, 3.095; 95% CI, 1.345–7.123; P=0.008). Patients with an increased duration of drug treatment of >1 year had a reduced risk of developing severe DILI compared with patients with a medication duration of ≤1 month (AOR, 0.259; 95% CI, 0.084–0.802).ConclusionsIncreased risk of the incidence of DILI was significantly associated with female gender and dyslipidemia, and the risk of developing severe DILI was associated with drinking alcohol and dyslipidemia.

Epidemiology of drug-induced liver injury in a University Hospital from Colombia: Updated RUCAM being used for prospective causality assessment

Introduction and aimEpidemiological information regarding drug-induced liver injury in some Latin American countries remains limited. Therefore, disease prevention and health promotion strategies are imperative to reduce drug-induced liver injuries and its fatal outcomes. This study aimed to collect epidemiological data regarding drug-induced liver injury and identify associated factors in patients admitted to a university hospital in Colombia. Methods and patientsA prospective study was conducted for 1 year to assess the incidence of drug-induced liver injury in patients aged >18 years who showed elevated values in liver tests. Data were collected after obtaining informed consent from the patients. The updated Roussel Uclaf Causality Assessment Method was applied to assess the causality of drug-induced liver injury. ResultsThe study included 286 patients with elevated values in liver tests, 18 of whom presented with drug-induced liver injury. The mean age of patients was 54.7±19.1 years. The associated pharmacological groups were anti-infectives and anticonvulsants (isoniazid, rifampicin, nitrofurantoin, phenytoin, and valproic acid), with a total of 15 drugs. The affected patients presented with cytopenia, jaundice, nausea, vomiting, or hepatomegaly. The most common type of liver injury was hepatocellular, and most patients recovered satisfactorily. The number of patients who had highly probable and probable causality grading was 1 and 9, respectively. ConclusionThe incidence of drug-induced liver injury in a university hospital in Colombia was 6%. Comorbidities and concomitant drugs are risk factors for drug-induced liver injury. Trial registrationRegistered in The Cuban Public Registry of Clinical Trials (identifier RPCEC00000242).