Cases Of Drug-induced Liver Injury Research Articles

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.

A Rare Case of Drug Induced Liver Injury Secondary to Empagliflozin

Drug induced liver injury (DILI) is a condition with a wide clinical spectrum. The diagnosis represents a challenge not only due to the large number of known hepatotoxic products but especially when the substance involved is not known to induce liver damage. Empagliflozin is linked to several adverse effects but has not been convincingly associated to DILI. We report a case of a 70-year-old type 2 diabetic woman that presented with gastrointestinal symptoms 1 month after empagliflozin introduction. Elevated hepatic enzymes were found and despite ultrasound evidence of vesicular microlithiasis, no biliary obstruction was confirmed. Other causes of liver injury were excluded and the diagnosis of DILI secondary to empagliflozin was made after liver biopsy. Complete clinical and laboratorial resolution was verified after empagliflozin withdrawal. Only two cases of DILI were reported since empagliflozin licensure which makes this case more interesting, alerting clinicians to an early diagnosis and appropriate treatment.

Causality Evaluation of Drug-Induced Liver Injury in Newborns and Children in the Intensive Care Unit Using the Updated Roussel Uclaf Causality Assessment Method

Purpose: Drug-induced liver injury (DILI) is a common adverse reaction in the clinic; however, there are relatively few reports of DILI in critically ill newborns and children. Making use of the Pediatric Intensive Care database (PIC), this study identifies which drugs are related to DILI in neonates and children in China. Methods: Using the PIC, we screened for patients whose liver was suspected of being injured by drugs during hospitalization. The medicine they used was then assessed by the Roussel Uclaf Causality Assessment Method (RUCAM). At the same time, we also collated drug combinations that may affect CYP (Cytochrome P) enzyme metabolism, which may cause DILI. Results: A total of 13,449 patients were assessed, of whom 77 newborns and 261 children were finally included. The main type of liver injury in neonates was mixed (83.1%), while the hepatic injury types of children were mostly distributed between hepatocellular (59.4%) and cholestatic (28.4%). In terms of the RUCAM assessment, the drugs that were most considered to cause or be associated with hepatic injury in newborns were medium and long chain fat emulsions (17%), sodium glycerophosphate (12%), and meropenem (9%); while omeprazole (11%), methylprednisolone sodium succinate (10%), and meropenem (8%) were the primary culprits of DILI in children. Drug combinations frequently seen in neonates that may affect CYP enzyme metabolism are omeprazole + budesonide (16.9%), dexamethasone + midazolam (10.4%), and midazolam + sildenafil (10.4%). In children, the commonly used drug combinations are fentanyl + midazolam (20.7%), ibuprofen + furosemide (18.4%), and diazepam + omeprazole (15.3%). Conclusions: In this study, medium and long chain fat emulsions and sodium glycerophosphate have been strongly associated with DILI in newborns, while omeprazole and methylprednisolone sodium succinate play an important role in the DILI of children. Also, attention should be paid to the effect on CYP enzymes when using multiple drugs at the same time. In future DILI cases, it is advisable to use the latest RUCAM for prospective study design so that complete case data and high RUCAM scores can be collected.

Predictive Model for Drug-Induced Liver Injury Using Deep Neural Networks Based on Substructure Space.

Drug-induced liver injury (DILI) is a major concern for drug developers, regulators, and clinicians. However, there is no adequate model system to assess drug-associated DILI risk in humans. In the big data era, computational models are expected to play a revolutionary role in this field. This study aimed to develop a deep neural network (DNN)-based model using extended connectivity fingerprints of diameter 4 (ECFP4) to predict DILI risk. Each data set for the predictive model was retrieved and curated from DILIrank, LiverTox, and other literature. The best model was constructed through ten iterations of stratified 10-fold cross-validation, and the applicability domain was defined based on integer ECFP4 bits of the training set which represented substructures. For the robustness test, we employed the concept of the endurance level. The best model showed an accuracy of 0.731, a sensitivity of 0.714, and a specificity of 0.750 on the validation data set in the complete applicability domain. The model was further evaluated with four external data sets and attained an accuracy of 0.867 on 15 drugs with DILI cases reported since 2019. Overall, the results suggested that the ECFP4-based DNN model represents a new tool to identify DILI risk for the evaluation of drug safety.

Drug-Induced Hepatocellular Injury Due to Herbal Supplement Ashwagandha

A 39-year-old female presented with a one-week history of jaundice and nausea after taking an over-the-counter herbal supplement containing ashwagandha root extract. Initial investigations revealed a hepatocellular pattern of liver enzyme abnormality with jaundice. Investigations, including viral serology, liver specific autoantibodies and an ultrasound scan of the abdomen, were unremarkable. Liver biopsy showed an acute cholestatic hepatitis with confluent necrosis but no features of chronicity. These histopathological findings differ to that of a previously reported case. Review of recent literature revealed that some clinical features and the time course of liver injury were similar to previous reports of ashwagandha drug-induced liver injury (DILI). The patient received treatment with ursodeoxycholic acid. We compare this case to previous reported cases of ashwagandha DILI and discuss the biochemical and histopathological features of ashwagandha DILI, therapeutic strategies and the importance of recognising herbal supplements as a possible cause of DILI.

Real-World Data of Tigecycline-Associated Drug-Induced Liver Injury Among Patients in China: A 3-year Retrospective Study as Assessed by the Updated RUCAM.

Background: Tigecycline, a glycylcycline antibiotic, is increasingly used clinically for the treatment of severe infections caused by multidrug-resistant bacteria, but it is also associated with hepatotoxicity. However, the incidence and risk factors of tigecycline-associated drug-induced liver injury (DILI) are unclear. We conducted this study to investigate the incidence, characteristics and risk factors of tigecycline-associated DILI in the real-world clinic setting. Patients and Methods: A retrospective analysis was conducted in inpatients who received tigecycline treatment from January 2018 to January 2020. Based on the biochemical criteria of DILI and the causality assessment by Roussel Uclaf Causality Assessment Method (RUCAM) using cases with a probable or highly probable causality grading, two clinical pharmacists and one clinician worked together to screen patients for tigecycline-associated DILI. Then patients with DILI were randomly matched by gender in a ratio of 1:2 to the remaining patients in the tigecycline cohort without biochemical abnormalities to identify risk factors. Results: A total of 973 patients from 1,250 initial participants were included. The incidence of tigecycline-associated DILI was 5.7% (55/973). Among 55 DILI patients, 10 cases presented with the hepatocellular pattern, 4 cases belonged to the mixed pattern, and 41 presented with the cholestatic pattern. Most cases reached the severity of grade 1 and 2. The rate of recovery in hepatocellular pattern, mixed pattern, and cholestatic pattern was 70.0, 50.0, and 41.5%, respectively. The proportion of the DILI cases treated with high dose (100 mg) and prolonged duration (>14 days) was significantly higher than standard dose and routine duration (100.0% vs. 18.1%, p < 0.05). Logistic regression analysis showed that high maintenance dose (OR = 1.028, p = 0.002), prolonged duration (OR = 1.208, p = 0.000), and number of hepatotoxic drugs (OR = 2.232, p = 0.000) were independent factors of tigecycline-associated DILI. Conclusion: Tigecycline was associated with liver injury, with a slightly higher incidence (5.7%) than the frequency of “frequent” (5%) defined by the Medical Dictionary for Regulatory Activities. Patients with a high maintenance dose and prolonged tigecycline regimen, as well as concomitant use of multiple hepatotoxic drugs should be paid more attention.

The Unmet Needs of Hepatitis E Virus Diagnosis in Suspected Drug-Induced Liver Injury in Limited Resource Setting.

Background: Currently, there are no specific biomarkers for drug-induced liver injury (DILI), and the diagnosis of DILI is based mainly on the exclusion of other causes of liver dysfunction and the recognition of potential causative drugs. Hepatitis E virus (HEV) diagnosis is not routinely enrolled in many countries, and HEV infection could be misdiagnosed as DILI.Methodology: We retrospectively analyzed plasma samples (n = 80) collected from suspected DILI for HEV markers such as anti-HEV IgM, anti-HEV IgG, and HEV RNA. Anti-HEV antibodies were assessed using commercial ELISA kits. HEV RNA was tested by RT-qPCR targeting HEV ORF2/3, the receiver operating characteristic (ROC) curve was plotted, and a putative threshold for liver function parameters was determined.Results: Out of 80 samples, 12 samples were positive for anti-HEV IgM and anti-HEV IgG, and HEV RNA was detected in seven samples. The median viral load was 3.46 × 103 IU/ml, and the isolated viruses belonged to HEV genotype 1. The level of liver enzymes such as alanine transaminase (ALT) and aspartate transaminase (AST), but not alkaline phosphatase (ALP), was significantly higher in HEV confirmed cases than in non-HEV confirmed cases. We identified a plasma ALT level of at least 415.5 U/L and AST level of at least 332 U/L; ALT/ALP ratio of at least 5.08 could be used as a guide for the patients diagnosed as DILI to be tested for HEV infection. The previous liver function parameters showed high sensitivity and good specificity.Conclusion: Hepatitis E virus was detected in suspected DILI cases. The diagnosis of DILI is not secure until HEV testing is done. Liver function parameters can be used as a guide for HEV testing in suspected DILI cases in countries with limited resources.

S2844 Topiramate as the Solitary Cause of Idiosyncratic Drug-Induced Liver Injury

Introduction: Anticonvulsant agents have been associated with drug induced liver injury (DILI). Topiramate, an anticonvulsant agent used to treat seizures disorders and migraine headaches, has been reported as a cause of DILI only when combined with other anticonvulsants. Here we present a unique case of DILI caused solely by Topiramate. Case Description/Methods: A 42-year-old White female with a past medical history of anxiety, depression, migraine headaches, and hypertension presented to the liver clinic for evaluation of elevated liver enzymes. She had been experiencing increasing headaches, fatigue, joint pain, anxiety, and depression after contracting COVID-19. She started topiramate in September 2020 in an attempt to palliate her headaches. In December as part of her workup for continued fatigue, an elevated ALT/AST of 88 U/L and 40 U/L was noted. Approximately 3 weeks later repeat labs showed an increase in the ALT and AST to 194 U/L and 80 U/L respectively. She was referred to the liver clinic and repeated labs showed ALT/AST of 314 U/L and 184 U/, normal ALK.P, bilirubin, albumin, and INR. She had negative abdominal ultrasound and negative autoimmune and viral serology and genetic disease. Given the temporality of starting topiramate and the elevation of liver enzymes she was counseled on discontinuing topiramate. A liver biopsy was perused and showed compatible findings of drug induced liver injury. The patient returned for follow-up approximately 6 weeks after stopping Topamax and her liver enzymes returned to normal. Discussion: Most cases of DILI involving topiramate are in the setting of concomitant use of antipsychotic medications. Topiramate interferes with the metabolism of the antipsychotic medication leading to hepatotoxicity. This interference is thought to involve inducing the CYP3A4 or inhibiting the CYP 2C19 enzymes. This case shows Topiramate alone may cause DILI. This is noteworthy given the increasing number of prescriptions for CNS agents written, the increasing uses approved by the FDA for topiramate, and the increase in primary care physicians writing these prescriptions. This case shows how treating DILI will require a collaborative effort between the prescribing doctor and the gastroenterologist.

S3675 Azithromycin-Induced Acute Liver Injury

Introduction: Idiosyncratic drug-induced liver injury (DILI) is a subtype of drug-induced liver injury that is typically variable in presentation and independent of medication dose or duration. A great number of commonly used medications and herbal supplements have been associated with idiosyncratic drug-induced liver injury. DILI is of clinical significance due to the potential for progression to chronic liver disease or acute liver failure, and may be caused by drugs not commonly associated with liver injury. Case Description/Methods: A 60 year old female was admitted after presenting with sore throat, fever, cough, diarrhea, rash and generalized malaise for 4 days prior to admission. Her past medical history was significant for mixed connective tissue disease, rheumatoid arthritis, and a remote history of alcohol abuse. She was on day two of an outpatient Azithromycin course prescribed for community acquired pneumonia. Physical exam showed diffuse, blanching, maculopapular rash along chest wall and dorsum of her upper extremities. Hepatic panel showed AST 64, ALT 42, Total bilirubin 1.1, and alkaline phosphatase of 68. Liver chemistries peaked during admission to AST 607, ALT 936, Total Bilirubin 20.8, ALP 739. MRCP demonstrated gallbladder adenomyomatosis and multiple simple hepatic cysts. Azithromycin was discontinued, and patient was started on N-acetylcysteine infusion. Workup for viral hepatitis was negative, as were EBV, CMV, HSV and HIV serologies. Immunologic workup showed positive ANA with chromatin of 6.5, SMRNP >8, and RNP of 8. AMA and ASMA were < 1:20. Given rising liver chemistries and history of autoimmune disease, a liver biopsy was obtained and revealed mild chronic hepatitis with minimal periportal activity, moderate bile duct injury with marked cholestasis, pseudoxanthomatous degeneration, and mild anisonucleosis consistent with DILI. Liver chemistries began improving on day 11 of admission. Patient’s maculopapular rash was largely cleared prior to discharge. Discussion: Azithromycin is recognized as a common agent in DILI. In this case, Azithromycin was recognized early as a potential cause of the patient’s worsening liver chemistries. Cessation of the offending agent will resolve most cases of DILI. This case demonstrates how a commonly prescribed medication may cause DILI with risk of progression to acute liver failure. Medications not typically associated with hepatic injury should be assessed when considering DILI.Figure 1.: Portal area with reactive atypia in bile ducts consistent with cholestasis. Mixed inflammatory infiltrate surrounding portal area.

S2727 The First Reported Case of Drug-Induced Liver Injury Caused by Semaglutide

S2727 The First Reported Case of Drug-Induced Liver Injury Caused by Semaglutide

S2851 Harm by SARM: A Case of Drug-Induced Liver Injury in an Amateur Bodybuilder

S2851 Harm by SARM: A Case of Drug-Induced Liver Injury in an Amateur Bodybuilder

S1691 Smoke but No Fire: A Case of Massive CA 19-9 Elevation From NSAID Use

Introduction: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed medication for pain and inflammation, but are a leading cause of drug-induced liver injury (DILI). What is not well documented is ibuprofen-induced elevated carbohydrate antigen (CA) 19-9, which raises concern for pancreatic cancer. This case demonstrates liver injury and markedly elevated CA 19-9 in the 1000s, which resolved with cessation of ibuprofen use in the setting of negative endoscopic ultrasound (EUS) with fine needle aspiration (FNA). Case Description/Methods: 45 year old male with no history of liver or biliary disease presented with painless jaundice. Status post hemorrhoidectomy with daily ibuprofen use (400mg, 8 tablets) for pain. New-onset upper extremity pruritus with 13 lbs. unintentional weight loss. Upon evaluation, patient had AST 217 U/L, ALT 157 U/L, alkaline phosphatase (ALP) 964 U/L, and bilirubin 13.6 mg/dL without leukocytosis, platelet dysfunction, coagulopathy, or systemic symptoms. Right upper quadrant ultrasound did not demonstrate any obstruction. Screening CA 19-9 of 1046 U/mL prompted diagnostic EUS-FNA of pancreas, which was normal. Interval liver function tests and CA 19-9 demonstrated marked downtrend with cessation of ibuprofen use—AST 25 U/L, ALT 21 U/L, ALP 152 U/L, bilirubin 2 mg/dL, and CA 19-9 84 U/mL. Discussion: NSAIDs-induced DILI has an estimated incidence of 1-23 cases per 100,000 patient-years. Ibuprofen makes up ∼10% of DILI cases in developed countries. Time to onset is 12 days. Serum CA 19-9 is the only validated tumor marker for pancreatic cancer, which has an annual incidence of 3.9 per 100,000. Higher CA 19-9 serum levels with cut off of 90 U/mL have a sensitivity of 86% and specificity of 39% for malignancy. Our patient had a CA 19-9 >1000 U/mL with weight loss, which required evaluation with EUS-FNA to rule out malignancy. Elevated CA 19-9 secondary to ibuprofen has only been noted on a single center retrospective study as a statistically significant incidence of 7.1% of 581 patients, p = 0.034 when compared to controls. However, the underlying mechanism has not been defined on literature review. Thus, this case is a rare presentation of elevated CA 19-9 secondary to ibuprofen instead of something more sinister as a pancreatic malignancy. Thorough evaluation is necessary to provide reassurance that this is a transient process that will resolve with cessation of the offending agent.Figure 1.: On non enhanced images pancreas appear enlarged and hypodense with irregular margins.

S2867 Turmeric-Induced Hepatitis

Introduction: Dietary supplementation use has been on an exponential rise for the past few years. Turmeric is one of the most used, with curcumin being its major active ingredient. Recently, cases of turmeric induced autoimmune hepatitis as well as herbal induced liver injury (HILI) have been documented. We present a case of turmeric induced hepatotoxicity in a 64-year-old female. Case Description/Methods: A 64-year-old female with a history of hypertension, presents with jaundice and abdominal discomfort. Vitals were normal. Exam showed scleral icterus with an unremarkable abdominal exam. Lab findings revealed a normal CBC, INR, and a negative blood alcohol level, a total bilirubin of 13.6 mg/dl with a direct bilirubin of 9.2 mg/dl, an ALP of 248 IUnits/L, a GGT of 616 Units/L, an AST of 2789 IUnits/L, and an ALT of 3296 IUnits/L. Hepatitis panel with HEV were negative. ANA, AMA, ASMA, tTg antibody, Ig levels, TSH, and T4 were all negative or within normal limits. Patient had a normal iron saturation, negative ceruloplasmin, Tylenol and ASA levels. COVID19 PCR test was negative. CT abdomen/pelvis was non-diagnostic. An EGD/EUS/ERCP showed a mildly thickened gallbladder wall. Liver biopsy showed portal and lobular hepatitis with spotty necrosis, without evidence of an autoimmune process, suggesting a drug induced liver injury. Patient then admitted to the use of turmeric in the past 3-4 weeks. Turmeric was discontinued and patient’s lab values normalized within 1 month. Discussion: Turmeric has been used for thousands of years as a spice, and has been linked to antioxidant, anti-inflammatory and anti-cancer effects. Clinical studies have popularized its use for patients with immune disorders such as autoimmune thyroiditis, and rheumatoid arthritis, despite the associated risk of autoimmune hepatitis in such patients. Curcumin is the major active ingredient in turmeric, however when taken alone, it has a poor bioavailability, with extensive 1st pass metabolism. Turmeric contains Piperine (a black pepper extract), that augments and increases curcumin doses up to 2000-fold by inhibiting hepatic drug-metabolizing enzymes. Multiple RCTs have studied the safety of curcumin showing minimal side effects. In 2013, HILI accounted for 20% of drug-induced liver injury cases. Liver enzymes resolve within 1 month of discontinuation. Due to turmeric’s possible increased risk for hepatotoxicity, clinicians should highlight this to their patients and make them aware of the potential risks that exist when using turmeric.Figure 1.: 400x H&E stain): The portal areas are expanded by predominantly lymphocytic inflammation with scattered eosinophils and rare plasma cells. Figure 2 (400 x PAS): There is spotty necrosis. There is no steatosis, ballooned hepatocytes, granulomas, or viropathic changes. Figure 3 (400x): The Reticulum stain shows a mild increase in portal/periportal fibrosis.Table 1.: RUCAM (Roussel Uclaf Causality Assessment Method) Score: Method for detecting drug-induced liver injury or herb-induced liver/hepatocellular injury (modified) ALT: Alanine Transaminase, AST: Aspartate Transaminase, EBV: Epstein-Barr Virus, HSV: Herpes Simplex Virus, VZV: Varicella-Zoster Virus, PSC: Primary Sclerosing Cholangitis.

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.

Drug-induced liver injury and COVID-19: A review for clinical practice.

Coronavirus disease 2019 (COVID-19) consists of a systemic disease that can present many complications. The infection presents broad clinical symptoms and a high rate of transmissibility. In addition to severe acute respiratory syndrome, the patients manifest complications beyond the respiratory system. The frequency of liver damage in COVID-19 patients ranges from 14.8% to 53% of patients. One should pay attention to drug-induced liver injury (DILI) in patients with COVID-19, especially considering the off-label use of drugs in prophylactic and therapeutic regimens applied on large scales. This review aims to present relevant information on the medication used so far in COVID-19 patients and its possible hepatotoxicity. We reviewed liver damage in patients with COVID-19 on PubMed and Virtual Health Library to investigate DILI cases. Four studies were selected, involving the medicines remdesivir, tocilizumab and a pharmacovigilance analysis study. The hepatotoxicity profile of drugs presented in the literature considers use in accordance to usual posology standards for treatment. However, drugs currently used in the management of COVID-19 follow different dosages and posology than those tested by the pharmaceutical industry. The deficiency of uniformity and standardization in the assessment of hepatotoxicity cases hinders the publication of information and the possibility of comparing information among healthcare professionals. It is suggested that severe liver injury in COVID-19 patients should be reported in pharmacovigilance institutions, and physicians should pay attention to any considerable abnormal liver test elevation as it can demonstrate unknown drug hepatotoxicity. Liver disorders in COVID-19 patients and the use of several concomitant off-label medications — with a potential risk of further damaging the liver - should at least be a warning sign for rapid identification and early intervention, thus preventing liver damage from contributing to severe impairment in patients.

P-12 QUALITATIVE EVALUATION OF NATURAL PRODUCTS USED BY PATIENTS IN A BRAZILIAN HEPATOTOXICITY AMBULATORY

Drug-induced liver injury (DILI) can be caused by more than 900 drugs, toxins, and herbs, making it a major problem of clinical importance. The use of food supplements and/or herbal products has become increasingly common in the daily lives of the population worldwide. Natural products can be used for a variety of therapeutic purposes, such as treating gastrointestinal disorders and relieving menopausal symptoms. To evaluate the hepatotoxic activity of extracts of herbal medicines and dietary supplements used by patients with suspected DILI at a hepatotoxicity ambulatory. This is an experimental study and was carried out through chemical screening of plant species and dietary supplements for the determination of phytochemical classes. The samples were obtained of patients had DILI suspect, in ambulatorial care of a University Hospital. The experiments were made at Pharmacognosy laboratory. 18 samples were received from January 2019 to March 2020. Of these samples, 10 were leaves or stems, and 08 were herbal products or food supplements, with 02 samples being excluded due to contamination. Of the 10 (55%) samples that went to the analysis process, the presence of groups of chemical compounds from secondary plant metabolism was found, where 07 (36%) showed positive results for the presence of triterpenes and steroids. Of these 07 samples, 02 (11%) showed positive results for the presence of alkaloids. There is a profile of liver damage caused by medicinal plants and the compounds present in them, which are mostly: alkaloids, triterpenes, steroids and anthraquinones. After conducting qualitative tests, triterpenes and steroids were identified in most samples (70%), in addition the presence of alkaloids (28%), suggesting that these can be responsible for the cases of DILI, but more robust studies on these samples are needed to identify chemical structure species.

Drug-induced liver injury associated with lopinavir-ritonavir in patients with COVID-19: a disproportionality analysis of U.S. food and drug administration adverse event reporting system (FAERS) data.

Background Liver injury has been documented independently in novel coronavirus disease 2019 (COVID-19) patients and patients treated with lopinavir-ritonavir. Objective to investigate the drug-induced liver injury associated with lopinavir-ritonavir among the patients with COVID-19. Methods We conducted a disproportionality analysis of US Food and Drug Administration Adverse Event Reporting System (FAERS) between 2020Q1 and 2021Q1 to evaluate the association between lopinavir-ritonavir and risk of drug-induced liver injury (or severe drug-induced liver injury) and calculated their reporting odds ratios (RORs) with 95% confidence intervals (CIs). Results A total of 3,425 cases of drug-induced liver injury were reported in 19,782 patients with COVID-19. The ROR for drug-induced liver injury was 2.99 (2.59–3.46), 3.16 (2.68–3.73), and 5.39 (4.63–6.26) when comparing lopinavir-ritonavir with all other drugs, hydroxychloroquine/chloroquine only, and remdesivir, respectively. For severe drug-induced liver injury, RORs for lopinavir-ritonavir provided evidence of an association compared with all other drugs (3.98; 3.15–5.05), compared with hydroxychloroquine/chloroquine only (5.33; 4.09–6.94), and compared with remdesivir (3.85; 3.03–4.89). Conclusions In the FAERS, we observed a disproportional signal for drug-induced liver injury associated with lopinavir-ritonavir in patients with COVID-19.

Using an Automated Algorithm to Identify Potential Drug-Induced Liver Injury Cases in a Pharmacovigilance Database.

IntroductionDrug-induced liver injury (DILI) is the most frequent cause of acute liver failure in North America and Europe, but it is often missed because of unstandardized diagnostic methods and criteria. This study aimed to develop and validate an automated algorithm to identify potential DILI cases in routine pharmacovigilance (PV) activities.MethodsPost-marketing hepatic adverse events reported for a potentially hepatotoxic drug in a global PV database from 19 March 2017 to 18 June 2018 were assessed manually and with the automated algorithm. The algorithm provided case assessments by applying pre-specified criteria to all case data and narratives simultaneously.ResultsA total of 1456 cases were included for analysis and assessed manually. Sufficient data for algorithm assessment were available for 476 cases (32.7%). Of these cases, manual assessment identified 312 (65.5%) potential DILI cases while algorithm assessment identified 305 (64.1%) potential DILI cases. Comparison of manual and algorithm assessments demonstrated a sensitivity of 97.8% and a specificity of 79.3% for the algorithm. Given the prevalence of potential DILI cases in the population studied, the algorithm was calculated to have positive predictive value 56.3% and negative predictive value 99.2%. The time required for manual review compared to algorithm review suggested that application of the algorithm prior to manual screening would have resulted in a time savings of 42.2%.ConclusionAn automated algorithm to identify potential DILI cases was developed and successfully implemented. The algorithm demonstrated a high sensitivity, a high negative predictive value, along with significant efficiency and utility in a real-time PV database.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01856-x.

Drug-induced liver injury at a tertiary care centre in Germany: Model for end-stage liver disease is the best predictor of outcome.

Agents most frequently inducing idiosyncratic drug-induced liver injury (DILI) differ between countries worldwide. Besides, there is no consistent data on the best model predicting mortality or the need for liver transplantation in DILI. We here analysed the DILI cohort of our centre with regard to causative drugs and clinical outcome. A retrospective analysis of 157 consecutive severe DILI patients presenting to our tertiary care centre in Hamburg, Germany, from 2008 to 2018, was performed. The most frequent putatively causative drugs were phenprocoumon (n=21), metamizole (n=17) and flupirtine (n=6). The mean values of ALT, bilirubin and Model for End-stage Liver Disease (MELD) score at the time of hospitalisation were 1201U/L (SD: 1169U/L), 6.8mg/dL (SD: 7mg/dL) and 17 (SD: 8). About 71% of all cases were treated with steroids or steroids combined with n-acetylcysteine. About 12.1% of all DILI cases had a poor outcome (liver transplantation and/or death). At the time of admission, MELD score performed better than Hy's law, the ratio (R) or the new ratio (nR) on their own or combined with bilirubin, regarding sensitivity or specificity for poor outcome. MELD score had a c-statistic of 0.847 (95% CI: 0.731-0.964). Furthermore, the cut-off of 18 MELD points had a sensitivity of 88% and a specificity of 72% for poor outcome. Phenprocoumon and metamizole are frequent causative drugs for DILI in Germany. In comparison to other prognostic scores, MELD score ≥18 at the time of admission performed best in our cohort for the prediction of poor outcome in DILI.

Herb-induced liver injury (HILI) with 12,068 worldwide cases published with causality assessments by Roussel Uclaf Causality Assessment Method (RUCAM): an overview.

Herbal products including herbal medicines are worldwide used in large amounts for treating minor ailments and for disease prevention. However, efficacy of most herbal products has rarely been well documented through randomized controlled trials in line with evidence-based medicine concepts, which could be used to estimate the benefit/risk ratio. Instead, much better documented are adverse reactions such as liver injury associated with the consumption of some herbal products, so called herb-induced liver injury (HILI), which represents a clinical challenge. In order to establish HILI as valid diagnosis, the use of a diagnostic algorithms such as Roussel Uclaf Causality Assessment Method (RUCAM) is widely recommended, although physicians in some countries are reluctant to use RUCAM for their HILI cases. This review on worldwide HILI and RUCAM, developed as part of the artificial intelligence ideas, reveals that China is the leading country with 24 publications on HILI cases that were all assessed for causality using RUCAM, followed by Korea with 15 reports, Germany with 9 reports, the US with 7 reports, and Spain with 6 reports, whereas the remaining countries provided less than 4 reports. The total number of assessed HILI cases is 12,068 worldwide derived from 80 publications but in each report HILI case numbers were variable in a range from 1 up to 6,971. This figure compares with 46,266 cases of drug-induced liver injury (DILI) published worldwide from 2014 to early 2019 also assessed for causality by RUCAM. The original version of RUCAM was validated and established in 1993 and updated in 2016 that should be used in future HILI cases. RUCAM is an objective, structured, and validated method, specifically designed for liver injury. It is a scoring system including case data elements to be assessed and scored individually to provide a final score in five causality gradings. Among the 11,404/12,068 HILI (94.5%) cases assessable for evaluation, causality gradings were highly probable in 4.2%, probable in 15.5%, possible in 70.3%, and unlikely or excluded in 10.0%. To improve the future reporting of RUCAM based HILI cases, recommendations include the strict adherence to instructions outlined in the updated RUCAM and, in particular, to follow prospective data collection on the cases to ensure completeness of case data. In conclusion, RUCAM can well be used to assess causality in suspected HILI cases, and additional efforts are now required to increase the quality of the reported cases.