Idiosyncratic Drug-induced Liver Injury Research Articles

S3317 Acute Hepatitis C Infection Accounts for Suspected Isoniazid Hepatitis in a Patient With Controlled HIV Infection on Antiretroviral Therapy

Introduction: Acute hepatitis C (HCV) infection is rising in intravenous drug users/non-monogamy. Isoniazid (INH), commonly used for tuberculosis, may cause idiosyncratic drug-induced liver injury (DILI). Acute HCV infection was reported in 1.5% of suspected DILI. We here report a case of acute HCV infection for suspicious INH hepatitis in a patient with controlled human immunodeficiency virus (HIV) infection on antiretroviral therapy (ART). Case Description/Methods: A 54 years-old Caucasian male was admitted for several days of fatigue/nausea/abdominal pain with elevated ALT/AST at 179/93. He has a history of controlled HIV infection on dolutegravir/tenofovir/emtricitabine, non-monogamy (men having sex with men), marijuana/herbal use, and latent tuberculosis (with a normal liver test/negative HCV antibody) treated with INH for 3 months. Serology for acute hepatitis A, B, C infection, other work-ups, and abdominal ultrasound/CT were negative. INH rather than ART/herbals was suspected as the possible culprit for hepatotoxicity and was continued due to ALT < 5 times upper normal limit. Patient was discharged after a negative esophagogastroduodenoscopy and symptomatic improvement. He presented again 2 days later with ALT/AST of 287/153 then to 984/388 on the 9th day after INH cessation. Total bilirubin and INR had remained normal with minimally elevated ALP. HCV RNA was detected at 16.5 million IU/ml. A liver biopsy was performed for rising liver enzymes and excluding autoimmune hepatitis. Moderate portal/lobular inflammation with abundant hepatocyte apoptosis and mild intra-canalicular cholestasis without autoimmune hepatitis was reported, suggesting possible DILI with viral hepatitis per pathologist. However, with a strong competing diagnosis of acute HCV hepatitis, persistently rising ALT/AST despite cessation of INH, and only possible causality score for INH-DILI, the suspected INH hepatitis was adjudicated as acute HCV infection. Sofosbuvir-velpatasvir treatment was initiated with rapid normalization of ALT/AST and decreasing HCV RNA. Discussion: This is the first reported case of acute HCV infection for suspected INH hepatitis in a patient with controlled HIV infection on ART. The case emphasizes the importance of early HCV RNA testing for diagnosing/excluding acute HCV infection in suspicious DILI due to delayed seroconversion of HCV antibody. Prompt treatment with highly potent antiviral agents leads to eradication of HCV with potential public health benefit.

S2952 Cefepime-Induced Liver Injury

Introduction: Drug induced liver injury can be a result of many medications and remains as one of the most challenging disorders faced by GI specialists. The most common causes in the Western world include antimicrobials, antiepileptics, anticancer medications, herbal and dietary supplements. It is important to make the distinction between intrinsic and idiosyncratic types of DILI. Intrinsic DILI is capable of causing injury in a predictable pattern in humans when given in high doses. Idiosyncratic DILI only affects susceptible individuals and has less of an association to dosing. The latter being the more difficult type to diagnose and treat. An important value, the R-factor, is used to define hepatotoxicity injury patters. An R-factor < 2 suggests a cholestatic pattern, R-factor > 5 suggests a hepatocellular pattern, and in between a mixed pattern of injury. Early withdrawal of the offending agent is the treatment of choice for any cause of DILI as this prevents progression of acute liver failure. Case Description/Methods: We present a case of a 61 year old male (S, J) with acute elevations in his liver enzymes and alkaline phosphatase. Patient was admitted for alcohol withdrawal. The following day, patient was intubated secondary to hypercapnic respiratory failure and days later developed ventilator associated pneumonia for which he was started on antimicrobial therapy, cefepime and vancomycin. After 9 days of receiving cefepime, patient’s alkaline phosphatase and liver transaminases acutely increased. Patient’s baseline levels were normal on arrival to the hospital. His lab values were the following: ALT 263, AST 507, and alkaline phosphatase 279 with an R factor of 2.8 showing a mixed injury pattern. A right upper quadrant ultrasound showed hepatomegaly and an acute hepatitis panel was ordered which resulted negative. No episodes of significant hypotension were reported. The antibiotic was immediately discontinued with resolution of patient’s levels back to normal. Discussion: Though not as commonly reported, increased ALT, AST or alkaline phosphatase can be a result of cefepime use. Our patient on admission did not have abnormal liver chemistry tests despite his history of alcohol use. R-factor for our patient showed a mixed pattern of liver injury. First line tests when suspecting DILI such as acute viral hepatitis serologies and imaging studies were ordered. Our patient was not re-started on cefepime and his liver enzymes returned to baseline.

S3315 Acute Cholestatic Hepatitis Following m-RNABNT162b2 SARS-CoV-2 Vaccination: Could It Be Genetic?

Introduction: Given the morbidity and mortality of COVID-19, development of vaccines targeting SARs-CoV-2 was essential. Despite their overall safety and efficacy, atypical complications have been reported. We report a case of post-vaccination acute cholestatic hepatitis, consistent with drug-induced liver injury (DILI). Case Description/Methods: A 61-year-old man with no past medical history presented with 2 weeks of jaundice and pruritus, 1 month after his second dose of the m-RNABNT162b2 SARS-CoV-2 vaccine. He denied use of any medications, supplements, tobacco, alcohol, drugs, or family history of liver disease. Vital signs and physical exam were unremarkable. Admission labs included ALP 265 U/L, AST 50 U/L, ALT 68 U/L, total bilirubin 14.9 mg/dL, and direct bilirubin 12 mg/dL. Ultrasound revealed normal liver surface without ductal dilatation, confirmed by MRCP. Serologies (HIV, HAV IgM, HBV core IgM, HBV surface antigen, HCV antibody), autoimmune markers (ANA, anti-mitochondrial, anti-actin, anti-liver-kidney-microsomal), and respiratory viral panel (SARS-CoV-2, influenza A/B, RSV) were negative. Hemoglobin, platelets, INR, albumin, gamma-glutamyl transpeptidase (GGT), and immunoglobulins were normal. Percutaneous liver biopsy revealed cholestasis with mild portal lymphocytic infiltrates and lobular inflammation (Figure 1), without portal fibrosis, PAS+ globules, or iron deposition. Molecular genetic testing (Next Generation Sequencing, Prevention Genetics® 77 Gene Cholestasis Panel) was performed. No genetic variants were identified in 77 genes associated with cholestasis, though single copy variants of several autosomal recessive genes were detected. Symptoms resolved with supportive care. Labs one month later were notable for ALP 175 U/L, (AST hemolyzed), ALT 68 U/L, and total bilirubin 3.2 mg/dL. Discussion: Prior reports have described cholestasis due to immune-mediated hepatitis after COVID mRNA vaccination1, but these features were absent in this case. Given the patient’s normal GGT, we hypothesized that increased cytokine release led to cholestatic injury in an individual genetically predisposed to cholestasis by genetic variation in ATP8B1 or ABCB11. Future studies comparing genetic variants in patients with liver injury may provide insight into mechanisms of idiosyncratic DILI following mRNA vaccination against SARS-CoV-2.Figure 1.: Liver biopsy showing cholestasis in a patient who developed jaundice after COVID mRNA vaccination.

Hepatotoxicity of Green Tea Extract: Idiosyncratic or Indirect Drug-induced Liver Injury?

Hepatotoxicity of Green Tea Extract: Idiosyncratic or Indirect Drug-induced Liver Injury?

DILI Cases in Registries and Databases: An Analysis of Quality

: Data quality of idiosyncratic drug-induced liver injury (iDILI) cases is insufficient in the US LiverTox database due to the lack of a robust causality assessment method such as the Roussel Uclaf Causality Assessment Method (RUCAM), not allowing for appropriate use of included cases by physicians. Despite some shortcomings, case quality is much better in national DILI registries using the prospective RUCAM, with a few exemptions.

AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury.

AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury.

Identification of intrinsic hepatotoxic compounds in Polygonum multiflorum Thunb. using machine-learning methods

Ethnopharmacological relevancePolygonum multiflorum Thunb. (PM) is a herb, extracts of which have been used as Chinese medicine for years. Although it is believed to be beneficial to the liver, heart, and kidneys, it causes idiosyncratic drug-induced liver injury (DILI). Aim of the studyWe propose that the intrinsic DILI caused by natural products in PM (NPPM) is an important complementary mechanism to PM-related herb-induced liver injury, and aim to identify the ingredients with high DILI potential by machine learning methods. Materials and methodsOne hundred and ninety-seven NPPM were collected from the literature to identify the intrinsic hepatotoxic compounds. Additionally, a DILI-labeled dataset consisting of 2384 compounds was collected and randomly split into training and test sets. A diparametric optimization method was developed to tune the parameters of extended-connectivity fingerprints (ECFPs), Rdkit, and atom-pair fingerprints as well as those of machine-learning (ML) algorithms. Subsequently, K means were employed to cluster the NPPM that were predicted to have a high DILI risk. An in vitro cell-viability assay was performed using HepaRG cells to validate the prediction results. ResultsECFPs with the top 35% of features ranked by the F-value with support vector machine (SVM) yielded the best performance. The optimized SVM model achieved an accuracy of 0.761 and recall value of 0.834 on the test dataset. The silico screening for NPPM resulted in 47 ingredients with high DILI potential, which were clustered into six groups based on the elbow method. A representative subgroup that contained 21 ingredients, of which two dianthrones exhibited the lowest IC50 value (0.7–0.9 μM) and anthraquinones showed moderate toxicity (15–25 μM), was constructed. ConclusionUsing ML methods and in vitro screening, two classes of compounds, dianthrones and anthraquinones, were predicted and validated to have a high risk of DILI. The diparametric optimization method used in this study could provide a useful and powerful tool to screen toxicants for large datasets and is available at https://github.com/dreadlesss/Hepatotoxicity_predictor.

Idiosyncratic Drug-Induced Liver Injury Associated With and Without Drug Reaction With Eosinophilia and Systemic Symptoms.

Immunoallergic drug-induced liver injury (DILI) presenting with features of drug reaction with eosinophilia and systemic symptoms (DRESS) is a distinct phenotype. We describe the clinical characteristics, hepatitis pattern, severity, complications, and implicated medications in DILI patients with and without DRESS. Using established criteria, we analyzed DILI registry patients with and without DRESS from 1998 to 2021. DILI associated with DRESS (DwD) comprised 179 among 943 cases (19%) of DILI. Compared with the cohort without DRESS, patients with DwD are more often women and have shorter latency, lesser degrees of injury ( P < 0.01), and lower mortality (7.8%) than those without DRESS (16%). Antiepileptic drugs (36%), sulfonamides (19%), antituberculosis drugs (14%), antibiotics (10%), and antiretroviral drugs (8%) account for 87% of the cases of DwD. A limited number of drugs cause DwD, representing a fifth of patients with DILI. DwD is characterized by lesser degrees of liver injury and mortality likely because of earlier presentation.

Impact of SLCO1B1*5 on Flucloxacillin and Co-Amoxiclav-Related Liver Injury.

Background: Idiosyncratic drug-induced liver injury (DILI) is a serious uncommon disease that may develop as a result of the intake of certain drugs such as the antimicrobials flucloxacillin and co-amoxiclav. The reported cases showed significant associations between DILI and various human leukocyte (HLA) markers. The solute carrier organic anion transporter 1B1 (SLCO1B1), a non-HLA candidate gene, was previously reported as a risk factor for liver injury induced by rifampin and methimazole. This study presumed that SLCO1B1 may play a general role in the DILI susceptibility and therefore investigated the association of rs4149056 (SLCO1B1*5, T521C) polymorphism with flucloxacillin- and co-amoxiclav–induced liver injury. Methodology: We recruited 155 and 165 DILI cases of white ancestral origin from various European countries but mainly from the United Kingdom owing to flucloxacillin and co-amoxiclav, respectively. Only adult patients (≥18 years) who were diagnosed with liver injury and who showed i) clinical jaundice or bilirubin >2x the upper limit of normal (ULN), ii) alanine aminotransferase (ALT) >5x ULN or iii) alkaline phosphatase (ALP) >2x ULN and bilirubin > ULN were selected. The population reference sample (POPRES), a European control group (n = 282), was used in comparison with the investigated cases. TaqMan SNP genotyping custom assay designed by Applied Biosystems was used to genotype both DILI cohorts for SLCO1B1 polymorphism (rs4149056). Allelic discrimination analysis was performed using a step one real-time PCR machine. Genotype differences between cases and controls were examined using Fisher’s exact test. GraphPad Prism version 5.0 was used to determine the p-value, odds ratio, and 95% confidence interval. Compliance of the control group with Hardy–Weinberg equilibrium was proven using a web-based calculator available at https://wpcalc.com/en/equilibrium-hardy-weinberg/. Results: A small number of cases failed genotyping in each cohort. Thus, only 149 flucloxacillin and 162 co-amoxiclav DILI cases were analyzed. Genotyping of both DILI cohorts did not show evidence of association with the variant rs4149056 (T521C) (OR = 0.71, 95% CI = 0.46–1.12; p = 0.17 for flucloxacillin cases and OR = 0.87, 95% CI = 0.56–1.33; p = 0.58 for co-amoxiclav), although slightly lower frequency (22.8%) of positive flucloxacillin cases was noticed than that of POPRES controls (29.4%). Conclusion: Carriage of the examined allele SLCO1B1*5 is not considered a risk factor for flucloxacillin DILI or co-amoxiclav DILI as presumed. Testing a different allele (SLCO1B1*1B) and another family member gene (SLCO1B3) may still be needed to provide a clearer role of SLCO1B drug transporters in DILI development–related to the chosen antimicrobials.

Efficacy and safety of bicyclol for treating patients with idiosyncratic acute drug‐induced liver injury: A multicenter, randomized, phase II trial

Evidence for using bicyclol in drug-induced liver injury (DILI) is limited. This study aimed to explore the efficacy and safety of bicyclol in acute DILI. This was a multicenter, randomized, double-blinded, double-dummy, active-controlled, superiority and phase II trial. Patients with idiosyncratic acute DILI were randomized 1: 1:1 to low-dose bicyclol (25 mg times a day [TID]), high-dose bicyclol (50 mg TID) and polyene phosphatidylcholine (control) groups. The primary endpoint was the decrease from baseline in serum alanine aminotransferase (ALT) levels at post-treatment for 4 weeks. Overall, 241 patients were included in the full analysis set, with 81, 82 and 78 patients in the low-dose bicyclol, high-dose bicyclol, and control groups respectively. ALT levels decreased across groups (-249.2 ± 151.1, -273.6 ± 203.1, and -180.8 ± 218.2U/L in the low-dose bicyclol, high-dose bicyclol and control groups, respectively; both p < .001, the bicyclol-dependent groups vs. control group). The ALT normalization rates at weeks 1, 2, 4, 6 and 8 were higher in the bicyclol-dependent groups than in the control group (p=.002 at week 1 and all p < .001 at weeks 2, 4, 6 and 8 respectively). The median times to ALT normalization in the low-dose bicyclol, high-dose bicyclol and control groups were 29, 16 and 43 days respectively. Adverse events, serious adverse events and adverse drug reactions were similar across groups. Bicyclol (25 and 50 mg TID) appeared efficacious and safe for treating idiosyncratic acute DILI, while bicyclol 50 mg TID showed higher efficacy. www. gov (registration no. NCT02944552).

Newly identified genetic variants associated with idiosyncratic drug-induced liver injury.

Datasets of well characterized drug or herbal and dietary supplement-associated liver injury has provided a rich resource to identify genetic variants associated with hepatic injury that further supports the role of immune activation in drug-induced liver injury (DILI). Using DNA microarrays, whole genome sequencing, HLA-restricted DNA sequencing with appropriate ethnically matched population controls have identified HLA-specific genetic variants for drugs or botanical compounds with the same HLA variant associated with different agents. In addition to HLAs, two genes involved with immune signaling were also identified: a functional PTPN22 variant associated with increased DILI risk to any agent or clinical presentation and a variant in ERAP2 hepatic gene expression that trims peptide in preparation for presentation in the HLA cleft increased the risk for DILI in amoxicillin-clavulanate DILI when present with known HLA risk alleles. Variants in HLA and other genes involved in immune regulations further supports immune system activation in DILI. In the future, identifying these variants before exposure may minimize the risk for DILI events, help with assessment of drug causality for causing DILI and with greater understanding of DILI mechanisms, has important implication for future drug development.

From the Editor’s Desk...

From the Editor’s Desk...

Severe Hepatocellular Liver Injury After COVID-19 Vaccination Without Autoimmune Hepatitis Features: A Case Series

ABSTRACT Various vaccines were developed and administered to end the pandemic caused by the novel coronavirus diseases 2019 (COVID-19). These vaccines caused rare side effects not known during clinical trials. We report 2 cases of idiosyncratic drug-induced liver injury where the Pfizer BioNTech COVID-19 mRNA vaccine was administered. Both cases showed hepatocellular liver injury with negative autoimmune features on serology and histology and progressed to a protracted course of severe jaundice and pruritus before resolving without any immunosuppressants. We hope to raise awareness of possible rare side effects of the COVID-19 vaccine so that physicians can be vigilant.

Utility of Lymphocyte Transformation Test for Assisting Updated Roussel Uclaf Causality Assessment Method in Drug-Induced Liver Injury: A Case-Control Study.

Background: The Roussel Uclaf Causality Assessment Method (RUCAM) is a validated tool for assessing causality in cases of suspected drug-induced liver injury (DILI). However, RUCAM cannot discriminate between concomitant hepatotoxic drugs with the same temporal sequence. Objective: To analyse the utility of the lymphocyte transformation test (LTT) for assisting updated RUCAM in 45 patients and 40 controls with a clinical diagnosis of DILI. Methods: Suspected DILI cases were detected through the Prospective Pharmacovigilance Program from Laboratory Signals in Hospital (PPLSH) or by consultations. The controls completed the drug therapy with no adverse reactions during the study period. A receiver operating characteristics (ROC) curve analysis was performed to calculate the optimal cut-off value for the stimulation index (SI), corresponding to the largest sum for the specificity and sensitivity values of LTT for true DILI cases. Results: Out of 45 patients diagnosed with DILI, 42 cases were detected by the PPLSH, two cases by consultation and one case by both methods. Most DILI cases (64.4%) arose during hospitalization. According to the biochemical parameters, 24 cases (53.3%) had the hepatocellular phenotype, 14 (31.1%) had the cholestatic phenotype, and 7 cases (15.6%) had the mixed phenotype. Considering the severity criteria, 7 (15.5%) cases were classified as moderate DILI, and 4 (8.9%) were severe DILI; there were no fatal cases. A total of 149 drugs (median/case, 3; IQR, 2–5) were suspected to be involved in the DILI cases (RUCAM score ≥3). In 8 cases, only one drug was suspected, and polypharmacy (≥5 drugs) was identified in 29% of the cases. Of all DILI cases, 46 (30.9%) of the 149 suspected drugs produced positive LTT results, and the LTT was positive in 34 (75.5%) of the 45 patients. No exposed controls produced positive LTT results. The optimal cut-off of 1.95 for the SI was obtained with a sensitivity of 77% and specificity of 100% (area under the curve, 0.91; 95% asymptotic confidence interval 0.84–0.97; p < 0.001). The sensitivity of the hepatocellular phenotype was 92%. Conclusion: Our results demonstrate that LTT is an add on strengthening causality in cases of suspected idiosyncratic DILI, especially for patients with several suspected drugs and a hepatocellular phenotype.

Impact of Prior Drug Allergies on the Risk, Clinical Features, and Outcomes of Idiosyncratic Drug-Induced Liver Injury in Adults.

Prior drug allergies are common and may increase susceptibility to adverse medication effects. The aim of this study was to compare the frequency, clinical features, and outcomes of DILI among patients with and without a history of prior drug allergy. The EMR at a large liver referral center was searched for all DILI encounters using ICD-10T-codes for drug poisoning/toxicity and K-71 codes for toxic liver injury between 10/1/2015 and 9/30/2019. Clinically significant liver injury was identified using predefined laboratory criteria, and cases were adjudicated using a 5-point expert opinion scale: 1/2/3 = probable DILI and 4/5 = non-DILI. Drug allergy was defined as a history of anaphylaxis, hives, rash, or pruritus after drug exposure. Among 766,930 patient encounters, 127 unique patients met inclusion criteria with 72 (56.7%) cases adjudicated as probable DILI and 55 (43.3%) as non-DILI. In the probable DILI group, the most frequent suspect drug classes were: antimicrobials (41.9%), herbal and dietary supplements (9.5%), and antineoplastics (8.1%). Twenty-three of the 72 DILI patients (31.9%) had a history of drug allergy before the DILI episode compared to 16 (29.1%) of the 55 non-DILI cases (p = 0.89). However, none of the allergy drugs and suspect DILI drugs were the same although many were in the same drug class. DILI patients with a prior drug allergy were more likely to be female (73.9% vs. 44.9%, p = 0.04) and have lower serum bilirubin (4.0 vs. 7.8, p = 0.08) and INR (1.1 vs. 1.6, p = 0.043) levels at presentation. The likelihood of death or liver transplantation among probable DILI cases with prior drug allergy was lower than those without prior drug allergy (0% vs. 8.2%, p = 0.35). The suspect drug was subsequently documented in the "Drug Allergy" section of the EMR in only 23 (31.9%) of the 72 probable DILI patients, and these patients were more likely to present with a rash (7% vs. 2%, p = 0.006) and higher serum bilirubin levels (10.5 vs. 4.7, p = 0.008) compared to those in whom the suspect drug was not listed as "drug allergy." A prior drug allergy history was not associated with a greater likelihood of developing DILI compared to other causes of acute liver injury. However, the probable DILI patients with a history of prior drug allergy tended to have less severe liver injury and clinical outcomes. The low rate of suspect drug documentation in the "Drug Allergy" section of EMR after a DILI episode is of concern and could lead to avoidable harm from inadvertent suspect drug re-challenge.

Secular Trends in Severe Idiosyncratic Drug-Induced Liver Injury in North America: An Update From the Acute Liver Failure Study Group Registry.

Idiosyncratic drug-induced liver injury (DILI) is the second leading cause of acute liver failure (ALF) in the United States. Our study aims were to characterize secular trends in the implicated agents, clinical features, and outcomes of adults with DILI ALF over a 20-year period. Among 2,332 patients with ALF enrolled in the ALF Study Group registry, 277 (11.9%) were adjudicated as idiosyncratic DILI ALF (INR ≥ 1.5 and hepatic encephalopathy) through expert opinion. The 155 cases in era 1 (January 20, 1998-January 20, 2008) were compared with the 122 cases in era 2 (January 21, 2008-January 20, 2018). Among 277 cases of DILI ALF, 97 different agents, alone or in combination, were implicated: antimicrobials, n = 118 (43%); herbal/dietary supplements (HDS), n = 42 (15%); central nervous system agents/illicit substances, n = 37 (13%); oncologic/biologic agents, n = 29 (10%); and other, n = 51 (18%). Significant trends over time included (i) an increase in HDS DILI ALF (9.7% vs 22%, P < 0.01) and decrease in antimicrobial-induced DILI ALF (45.8% vs. 38.5%, P = 0.03) and (ii) improved overall transplant-free survival (23.5%-38.7%, P < 0.01) while the number of patients transplanted declined (46.4% vs 33.6%, P < 0.03). DILI ALF in North America is evolving, with HDS cases rising and other categories of suspect drugs declining. The reasons for a significant increase in transplant-free survival and reduced need for liver transplantation over time remain unclear but may be due to improvements in critical care, increased NAC utilization, and improved patient prognostication.

Value of liver biopsy in the diagnosis of drug-induced liver injury

The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. The aim of this study was to determine whether liver histology impacted causality assessment in suspected DILI using a novel simulation model. Fifty patients enrolled in the DILI Network (DILIN) who had liver biopsies performed within 60 days of DILI onset were randomly selected. All had standard DILIN consensus causality scoring using a 5-point scale (1=definite, 2=highly likely, 3=probable, 4=possible, 5=unlikely) based on 6-month post-injury data. Three experienced hepatologists independently performed a causality assessment using redacted case records, with the biopsy and selected post-biopsy laboratory data removed. The 3 hepatologists also reviewed the liver histology with a hepatopathologist and then repeated causality assessment for each case. Of the 50 cases, there were 42 high causality DILI cases (1, 2 or 3) and 8 low causality cases (4 and 5). The hepatologists judged that liver biopsy was indicated in 62% of patients; after histology review, biopsy was judged to have been helpful in 70% of patients. Histology review changed the causality score in 68% of patients, with an increase in DILI likelihood in 48% and a decrease in 20%. Biopsy results changed diagnostic certainty from less certain (3 or 4) to highly certain (1, 2 or 5) in 38% of patients. Liver histologic findings may help clarify the diagnosis of DILI. Histology appears to be particularly helpful in cholestatic or equivocal cases of DILI (possible or probable), shifting assessment toward a greater or lower certainty of a DILI diagnosis. The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. Herein, we show that, in patients with suspected DILI, a liver biopsy can help physicians diagnose DILI or other causes of liver injury with more certainty.

Egr1 confers protection against acetaminophen‑induced hepatotoxicity via transcriptional upregulating of Acaa2.

Background: Acetaminophen (APAP)-induced liver injury (AILI) is a common cause of drug-induced liver injury (DILI). The mechanism underlying protection in AILI or DILI remains to be elucidated, and the role of early growth response 1 (Egr1) in AILI and potential mechanisms remain to be known.Methods: The role of Egr1 was studied both in vivo and in vitro. Liver-specific Egr1-knockout (Egr1LKO) mice and those overexpressing Egr1 via tail vein injection of Egr1-expressing adenovirus (Ad-Egr1) were utilized with AILI. Chromatin immunoprecipitation-sequencing, RNA-sequencing, seahorse XF analysis, and targeted fatty acid analysis were performed. EGR1 levels were also studied in liver tissues and serum samples from AILI/DILI patients.Results: In this study, we have demonstrated that Egr1 was upregulated in AILI models in vivo and in vitro. liver-specific Egr1 knockout aggravated AILI; however, Ad-Egr1 treatment ameliorated this. Mechanistically, Egr1 deficiency inhibited, whereas overexpression promoted, mitochondrial respiratory function and fatty acid β-oxidation (FAO) activity in AILI. Egr1 transcriptionally upregulated FAO-related genes in hepatocytes. Notably, the knockdown of acetyl-coenzyme A acyltransferase 2 (Acaa2), a key gene involved in FAO, diminished this protective effect of Egr1. Clinically, EGR1 was markedly increased in liver tissues from AILI patients. Interestingly, EGR1 levels of liver tissues and serum samples were also obviously higher in idiosyncratic DILI patients.Conclusions: Egr1 confers adaptive protection in AILI, mediated via the transcriptional upregulation of Acaa2, which improves mitochondrial FAO, and might be a potential biomarker and novel therapeutic target for AILI.

Clinical correlation between serum cytokines and the susceptibility to Polygonum multiflorum-induced liver injury and an experimental study.

Polygonum multiflorum (PM), a popular functional food, and a herbal and dietary supplement, is widely used as a tonic in China and East Asia. In recent years, it has attracted great concern for its ability to cause idiosyncratic drug-induced liver injury (IDILI). However, identifying individuals susceptible to IDILI remains challenging. This is a prospective study. For 6 patients whose serum alanine aminotransferase (ALT) levels after consuming PM were abnormally elevated (susceptible group), 15 patients with normal levels of liver injury markers were matched (tolerant group) based on similar baseline characteristics. ProcartaPlex immunoassays were adopted to quantitatively detect 33 serum cytokines in the two groups of patients before consuming PM, to characterize the cytokine profile and screen differential cytokines. Subsequently, the susceptibility of a potential biomarker to regulate PM-induced liver injury was validated in animal models. There were significant differences in the cytokine profiles between the susceptible and tolerant groups, wherein the susceptible patients showed immune perturbation characterized by high expression of multiple inflammatory cytokines, especially the proinflammatory cytokine TNF-α (P = 0.006). Among them, the cytokine TNF-α had the strongest correlation with ALT, where the correlation coefficient was greater than 0.6, and the area under the receiver operating characteristic curve was more than 0.8. Animal experiments revealed that both PM water extract and its susceptibility component of liver injury, cis-stilbene glucoside, could cause liver injury in the mice pre-stimulated using TNF-α. Conversely, administration of the same dose of drugs on control mice did not show any hepatotoxicity. In conclusion, immune perturbation mainly mediated by TNF-α may regulate the susceptibility to PM-induced liver injury. This provides a new perspective for the study of susceptibility to IDILI.

Acute Liver Injury after Three Doses of Nitrofurantoin

A 56-year-old lady presented to the hospital with 2-day history of flu like symptoms. These had begun within a few hours after starting Nitrofurantoin for urinary tract infection that was prescribed by her primary care doctor. Blood tests upon admission revealed elevated aminotransferase levels with normal bilirubin levels. The medication was stopped, and other causes of hepatitis were investigated. Nitrofurantoin induced idiosyncratic drug-induced liver injury (IDILI) was confirmed by excluding all other causes. Patient’s symptoms and liver enzymes improved the next day and she was discharged. A follow-up on the laboratory's nine-days later revealed liver enzymes almost back to normal.