Cholestatic Drug-induced Liver Injury Research Articles

A case of refractory cholestatic drug-induced liver injury caused by amoxicillin/clavulanate effectively treated with phenobarbital

A case of refractory cholestatic drug-induced liver injury caused by amoxicillin/clavulanate effectively treated with phenobarbital

P02-12 Development of a hepatic spheroid co-culture model for prediction of cholestatic drug-induced liver injury

P02-12 Development of a hepatic spheroid co-culture model for prediction of cholestatic drug-induced liver injury

Refractory pruritus in cholestatic drug-induced liver injury secondary to androgenic anabolic steroids: Plasmapheresis to the rescue

Abstract: Anabolic androgenic steroids (AASs) have long been misused by professional athletes. Easy online and over-the-counter availability of AASs makes it an alluring option even among amateurs for their desired cosmetic and performance-enhancing effects. AASs have been associated with distinct forms of liver injury including transient transaminitis, peliosis hepatis, and hepatic tumors. An acute cholestatic syndrome with bland histology is another characteristic form of liver injury rarely reported with AASs. Plasmapheresis may provide a long-lasting relief of symptoms when conventional pharmacotherapeutic measures fail. Herein, we report a challenging case of a young male with refractory pruritus secondary to AASs, managed effectively with plasmapheresis.

Drug-induced cholestatic liver diseases.

Cholestatic DILI is an important and frequently challenging differential diagnosis in patients presenting with elevated liver tests with predominant elevation in alkaline phosphatase. A number of competing etiologies need to be ruled out, such as hepatobiliary malignancy, choledocholithiasis, cholestatic forms of viral hepatitis, cholestasis of sepsis, primary and secondary cholangitis, and right-sided cardiac failure to name a few. Important advances have occurred in the understanding and knowledge of the clinical phenotypes, new etiological agents, risk factors, pathophysiology, and genetic determinants of drug-induced cholestasis since the last review on drug-induced cholestasis was published in Hepatology in 2011. Secondary sclerosing cholangitis (SSC) due to drugs has been well documented for several different drugs. Checkpoint inhibitors are one of the types of drugs shown to lead to secondary sclerosing cholangitis. Several new herbal and dietary supplements have recently been shown to lead to cholestatic liver injury. A number of genetic risk factors for cholestasis due to drugs have been identified in the last decade, and the pathogenesis behind cholestatic injury is better defined. In this review, the focus is on diagnostic approach and description of new clinical phenotypes such as secondary sclerosing cholangitis and vanishing bile duct syndrome. Furthermore, the review provides an overview of the risk factors, genetic determinants, and the pathophysiology of hepatobiliary transporters leading to cholestasis. Management, areas of uncertainty, and future direction are also presented.

Cholestatic Drug Induced Liver Injury From Rad-140 Successfully Treated With Corticosteroids

Cholestatic Drug Induced Liver Injury From Rad-140 Successfully Treated With Corticosteroids

S3827 Cholestatic Drug-Induced Liver Injury in a Patient Taking High-Dose Niacin for Hyperlipidemia

S3827 Cholestatic Drug-Induced Liver Injury in a Patient Taking High-Dose Niacin for Hyperlipidemia

Culture methods focusing on bile canalicular formation using primary human hepatocytes in a short time.

The development of models for predicting hepatotoxicity is warranted, as the hepatotoxicity risk of 38-51% of compounds is undetectable in nonclinical studies. Cholestatic drug-induced liver injury (DILI) is a condition in which bile acids are abnormally excreted into the capillary bile canaliculi and are accumulated in hepatocytes, caused by the inhibition of bile salt export pump (BSEP), a transporter that is mainly associated with excretion of bile acids. Although laboratory animals are used as models, the use of human-derived cells is required owing to species differences. Unfortunately, primary human hepatocytes (PHHs) show rapid loss of function in culture and difficulties in forming bile canaliculi. Therefore, we aimed to develop an in vitro culture method for the efficient formation of bile canaliculi and for assessing the function of BSEP in PHHs. Here, PHHs were cultured from 1h after thawing to day 2 with Z-VAD-FMK, a total caspase inhibitor, and RevitaCell™ supplement, an irreversible Rho-associated coiled-coil forming kinase (ROCK) inhibitor, in combination with RM-101. The PHHs formed bile canaliculi and showed BSEP function on day 6 of culture. Our findings suggest that cultured PHHs may improve the prediction accuracy of the risks of cholestatic DILI-contained toxicity on bile canaliculi.

Unraveling the mechanisms underlying drug-induced cholestatic liver injury: identifying key genes using machine learning techniques on human in vitro data sets

Drug-induced intrahepatic cholestasis (DIC) is a main type of hepatic toxicity that is challenging to predict in early drug development stages. Preclinical animal studies often fail to detect DIC in humans. In vitro toxicogenomics assays using human liver cells have become a practical approach to predict human-relevant DIC. The present study was set up to identify transcriptomic signatures of DIC by applying machine learning algorithms to the Open TG-GATEs database. A total of nine DIC compounds and nine non-DIC compounds were selected, and supervised classification algorithms were applied to develop prediction models using differentially expressed features. Feature selection techniques identified 13 genes that achieved optimal prediction performance using logistic regression combined with a sequential backward selection method. The internal validation of the best-performing model showed accuracy of 0.958, sensitivity of 0.941, specificity of 0.978, and F1-score of 0.956. Applying the model to an external validation set resulted in an average prediction accuracy of 0.71. The identified genes were mechanistically linked to the adverse outcome pathway network of DIC, providing insights into cellular and molecular processes during response to chemical toxicity. Our findings provide valuable insights into toxicological responses and enhance the predictive accuracy of DIC prediction, thereby advancing the application of transcriptome profiling in designing new approach methodologies for hazard identification.

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

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

Investigating bile acid-mediated cholestatic drug-induced liver injury using a mechanistic model of multidrug resistance protein 3 (MDR3) inhibition.

Inhibition of the canalicular phospholipid floppase multidrug resistance protein 3 (MDR3) has been implicated in cholestatic drug-induced liver injury (DILI), which is clinically characterized by disrupted bile flow and damage to the biliary epithelium. Reduction in phospholipid excretion, as a consequence of MDR3 inhibition, decreases the formation of mixed micelles consisting of bile acids and phospholipids in the bile duct, resulting in a surplus of free bile acids that can damage the bile duct epithelial cells, i.e., cholangiocytes. Cholangiocytes may compensate for biliary increases in bile acid monomers via the cholehepatic shunt pathway or bicarbonate secretion, thereby influencing viability or progression to toxicity. To address the unmet need to predict drug-induced bile duct injury in humans, DILIsym, a quantitative systems toxicology model of DILI, was extended by representing key features of the bile duct, cholangiocyte functionality, bile acid and phospholipid disposition, and cholestatic hepatotoxicity. A virtual, healthy representative subject and population (n = 285) were calibrated and validated utilizing a variety of clinical data. Sensitivity analyses were performed for 1) the cholehepatic shunt pathway, 2) biliary bicarbonate concentrations and 3) modes of MDR3 inhibition. Simulations showed that an increase in shunting may decrease the biliary bile acid burden, but raise the hepatocellular concentrations of bile acids. Elevating the biliary concentration of bicarbonate may decrease bile acid shunting, but increase bile flow rate. In contrast to competitive inhibition, simulations demonstrated that non-competitive and mixed inhibition of MDR3 had a profound impact on phospholipid efflux, elevations in the biliary bile acid-to-phospholipid ratio, cholangiocyte toxicity, and adaptation pathways. The model with its extended bile acid homeostasis representation was furthermore able to predict DILI liability for compounds with previously studied interactions with bile acid transport. The cholestatic liver injury submodel in DILIsym accounts for several processes pertinent to bile duct viability and toxicity and hence, is useful for predictions of MDR3 inhibition-mediated cholestatic DILI in humans.

Investigating bile acid-mediated cholestatic drug-induced liver injury using a mechanistic model of multidrug resistance protein 3 (MDR3) inhibition

Investigating bile acid-mediated cholestatic drug-induced liver injury using a mechanistic model of multidrug resistance protein 3 (MDR3) inhibition

Treatment of Drug-Induced Liver Injury.

Current pharmacotherapy options of drug-induced liver injury (DILI) remain under discussion and are now evaluated in this analysis. Needless to say, the use of the offending drug must be stopped as soon as DILI is suspected. Normal dosed drugs may cause idiosyncratic DILI, and drugs taken in overdose commonly lead to intrinsic DILI. Empirically used but not substantiated regarding efficiency by randomized controlled trials (RCTs) is the intravenous antidote treatment with N-acetylcysteine (NAC) in patients with intrinsic DILI by N-acetyl-p-aminophenol (APAP) overdose. Good data recommending pharmacotherapy in idiosyncratic DILI caused by hundreds of different drugs are lacking. Indeed, a recent analysis revealed that just eight RCTs have been published, and in only two out of eight trials were DILI cases evaluated for causality by the worldwide used Roussel Uclaf Causality Assessment Method (RUCAM), representing overall a significant methodology flaw, as results of DILI RCTs lacking RUCAM are misleading since many DILI cases are known to be attributable erroneously to nondrug alternative causes. In line with these major shortcomings and mostly based on anecdotal reports, glucocorticoids (GCs) and other immuno-suppressants may be given empirically in carefully selected patients with idiosyncratic DILI exhibiting autoimmune features or caused by immune checkpoint inhibitors (ICIs), while some patients with cholestatic DILI may benefit from ursodeoxycholic acid use; in other patients with drug-induced hepatic sinusoidal obstruction syndrome (HSOS) and coagulopathy risks, the indication for anticoagulants should be considered. In view of many other mechanistic factors such as the hepatic microsomal cytochrome P450 with a generation of reactive oxygen species (ROS), ferroptosis with toxicity of intracellular iron, and modification of the gut microbiome, additional therapy options may be available in the future. In summation, stopping the offending drug is still the first line of therapy for most instances of acute DILI, while various therapies are applied empirically and not based on good data from RCTs awaiting further trials using the updated RUCAM that asks for strict exclusion and inclusion details like liver injury criteria and provides valid causality rankings of probable and highly probable grades.

„Vanishing bile duct syndróm“ ako prejav poliekového poškodenia pečene u pacienta po polytraume

Summary: Vanishing bile duct syndrome is a type of drug-induced cholestatic liver injury that occurs when the body is exposed to drugs or other foreign substances. We hospitalized a 44-year-old, so far healthy, male with gradually developing painless icterus and pruritus of the whole body after severe polytrauma. The patient had previously undergone a complex treatment (antibio tics, antifungals, parenteral nutrition, LMWH). Laboratory tests revealed a several-fold elevation of total and conjugated bilirubin with a 3-fold increase in ALP levels, no signifi cant elevation of transaminases, a decrease in prothrombin time and IgG4 antibody positivity. An MRCP scan was performed revealing irregular intrahepatic bile ducts, a dilated common bile duct and characteristics of primary or secondary sclerosing cholangitis. Further examinations ruled out infectious, metabolic, toxic and oncological causes of hepatopathy. A liver bio psy ruled out both autoimmune hepatitis and IgG4 hepatopathy and displayed images of “vanishing bile duct syndrome” in drug-induced liver injury (DILI). Empirical treatment with high-dose intravenous N-acetylcysteine and other hepatoprotective agents led to a gradual decrease of bilirubin, normalization of coagulation parameters and remission of icterus and clinical complaints. This case report points to a cholestatic type of drug-induced liver injury with histologically confi rmed vanishing bile duct syndrome and the need to think of DILI as one of the causes of the otherwise unexplained hepatopathy. Key words: cholangitis – DILI – hepatopathy – IgG4 – vanishing bile duct syndrome

Amoxicillin/Clavulanic Acid induced Hyperbilirubinemia in A Patient with Melanoma: A Rare Case Report

Amoxicillin/Clavulanate is a synthetic Penicillin that is widely used today, particularly to treat respiratory and cutaneous infections. It is a generally well-tolerated oral antibiotic. However, in some cases, Amoxicillin/Clavulanate can cause side effects, primarily cutaneous, gastrointestinal, hepatic, and hematologic. Amoxicillin/Clavulanate has been linked to hundreds of cases of clinically obvious Acute Liver Injury, and this combination is now the most common cause of drug-induced liver disease in the majority of large case series. The onset of injury can range from a few days to up to 8 weeks after the start of therapy. Hyperbilirubinemia is seen in Drug-induced Cholestatic Liver Injury, but direct inhibition of transporter proteins that facilitate bilirubin transport also results in Hyperbilirubinemia. We present a case of Hyperbilirubinemia following Amoxicillin/Clavulanate administration.

S3307 ‘Yogi Herbal Tea’ Consumption Causing a Cholestatic Drug-induced Liver Injury

S3307 ‘Yogi Herbal Tea’ Consumption Causing a Cholestatic Drug-induced Liver Injury

S3229 A Case of Cholestatic Drug-Induced Liver Injury After Ashwagandha Root Supplementation

Introduction: Ashwagandha root is an ancient Indian Ayurvedic herbal medicine sometimes referred to as “Indian Winter cherry” or “Indian Ginseng,” that is growing in popularity for its purported benefits of weight loss, muscle building and stamina benefits, and cognition promoting effects. In vitro studies suggest possible benefits of ashwagandha to include muscle growth, exercise stamina, weight loss, hepatocellular carcinoma targeting, and others, but no large scale studies have been done to test for safety or adverse effects. Rare case reports of drug induced liver injury (DILI) related to ashwagandha have been documented. Case Description/Methods: 19-year-old male presented to our hospital with severe pruritus and new onset jaundice after starting Ashwagandha. Two weeks after starting he developed progressive pruritus without any noted rash. Five days after the onset of pruritis he noted jaundice with nausea and dark urine, no abdominal pain. Initial labs showed a total bilirubin 7.6, AP 149, ALT 144 and AST 74. He had imaging including MRI and CT scan which were unremarkable. He was discharged with prn hydroxyzine for itching and told his DILI would resolve with time. A month since discontinuing the ashwagandha supplements his pruritus and jaundice worsened and he arrived to our hospital for evaluation. He was treated with cholestyramine, ursodiol and antihistamines. His bilirubin ultimately nadired at 30. Was also started on low dose naltrexone, and discharged. Returned for short hospital stay with severe pruritis. His t. bili remained similar compared to prior at 29, with normal INR. He was started on low dose rifampin given persistent pruritus, with mild improvement, and ultimately discharged with close follow-up. Discussion: Ashwagandha root is a rare cause of cholestatic liver injury. The Drug Induced Liver Injury Network (DILIN) were able to identify five incidences of drug induced liver injury related to ashwagandha. The clinical course of our patient closely matches the six total cases described in the literature so far. Latency period of 2 weeks to the development of jaundice. He then had a prolonged course of cholestatic liver injury after discontinuing supplements that lasted several months. Ashwagandha-containing herbal medications can result in severe cholestatic liver injury, without the development of chronic DILI or progression to acute liver failure. This case report further re-enforces the importance of careful monitoring and awareness of our patients’ supplemental health products. Table 1. - Bilirubin and symptoms trend Days since Symptom onset 6 days 36 days 42 days 44 days 46 days 49 days 52 days 56 days 67 days Total Bilirubin Level 7.6 25 30 29 31.3 21.2 18 16.6 - Symptoms Jaundice/pruritis Worsening jaundice/pruritis/pale stools Persistent pruritis AMS vs. panic attack, persistent pruritis Mild improvement pruritis - Pruritis improving - Pruritis resolved, visible jaundice improving

Cholestatic drug induced liver injury in active pulmonary tuberculosis patient: a case report

Drug induced liver injury (DILI) has been a long-standing concern in the treatment of tuberculosis. Anti-tuberculosis therapy (ATT) is known to have hepatotoxicity effect. DILI is diagnosed clinically using liver biochemical test, such as alanine transaminase (ALT), alkaline phosphatase (ALP), and total bilirubin. Calculating ratio (R) of ALT over ALP, is useful to classify types of injury pattern in DILI. Roussel Uclaf causality assessment method (RUCAM) scale serves as a method to assess the causality agents for DILI. Here we report a case of 59 years old male who developed cholestatic DILI on fourth weeks of ATT. Patient came in with loss of consciousness, jaundice, nausea, pruritus, and abdominal tenderness. Patient’s ALT level was normal, but ALP and total bilirubin was significantly elevated, with R values less than 2, indicating a cholestatic type of injury. Patient sputum was positive for tuberculosis bacteria, showing an active infection. Patient was admitted and ATT was discontinued. Patient showed improvement, but eventually fall into sepsis and developed respiratory distress on sixth day of admission despite adequate treatment and close monitoring. Despite most of the cases resolves spontaneously upon cessation of the toxic agents, in the severe form, it may fall into chronic liver injury, acute liver failure, and eventually death. Preventing DILI is readily important by educating, screening for risk factors, and routine evaluation of liver enzymes in patient under ATT. Early diagnosis and prompt treatment are needed to avoid poor prognosis in the course of the disease.

Ultra-performance chromatography-electrospray tandem mass spectrometry analysis of bile acid profiles in the enterohepatic circulation following geniposide and acetaminophen-induced liver injury

Bile acids (BAs) play an important role in pre-diagnosing drug-induced liver injury (DILI). However, in clinical practice, different types of liver injury are characterized by different pathogeneses and pathological manifestations. Therefore, whether BAs can be used as biomarkers across different DILIs remains unclear. In this study, an ultra-performance chromatography–mass spectrometry (MS)/MS-based technique was developed for the simultaneous quantitative analysis of 31 BAs in the serum, liver, feces, urine, and intestinal contents of rats treated with acetaminophen (APAP) and geniposide to induce liver injury. The total extraction recovery for representative analytes ranged between 80.60% and 99.23% in the serum, urine, liver, feces, and intestinal contents. The correlation coefficients for all standard curves of the different matrices were at least 0.99. Validation of the BA analytical method including selectivity, residue, lower limit of quantification, accuracy, precision, matrix effect, and stability conformed with the biospecimen quality control standards of the Chinese Pharmacopoeia (version 2020). Serum biochemical and pathohistological analyses revealed APAP- and geniposide-induced hepatocellular and cholestatic DILI, respectively, with different effects on BA profiles in the enterohepatic circulation. Metabolomics further revealed that the trends in BA changes in the serum, feces, urine, and intestinal tissues were consistent between the geniposide- and APAP-treated groups. However, in the liver, the total BAs (TBA) concentration increased by 1.70 fold in the geniposide group but decreased by 43% in the APAP group compared with the control group. Multivariate analysis revealed differentially expressed BAs, including TCA, CA, and GCA, which are potential biomarkers for DILI, in the serum, liver, and urine following treatment with geniposide. Interestingly, the differentially expressed BAs in the APAP group were similar to those in the control group. Additionally, the magnitude of changes in the TBA in the urine (3.3 fold and 15.5 fold in the APAP and geniposide groups, respectively) was higher than that in the blood (290 fold and 640 fold in the APAP and geniposide groups, respectively). However, given the BA profiles after geniposide- and APAP-induced liver injury, BAs were found to be more suitable as biomarkers for diagnosing cholestatic liver injury. Overall, the BA assay developed in this study is rapid, simple, accurate, validated, sensitive, and suitable for analyzing the levels and distribution of BAs in various parts of the enterohepatic circulation.

Hierarchy-Assembled Dual Probiotics System Ameliorates Cholestatic Drug-Induced Liver Injury via Gut-Liver Axis Modulation.

Cholestatic drug‐induced liver injury (DILI) induced by drugs or other xenobiotics is a severe and even fatal clinical syndrome. Here, living materials of hierarchy‐assembled dual probiotics system are fabricated by sequentially encapsulating probiotic Lactobacillus delbrueckii subsp. bulgaricus (LDB) and Lactobacillus rhamnosus GG (LGG) into Ca2+‐complexed polymer microspheres for effective prevention of cholestatic DILI. Upon entering intestinal tract of the constructed living materials, LGG is released because of pH‐triggered dissolution of outer enteric polymer coating. The released LGG can inhibit hepatic bile acids (BAs) synthesis by activating intestinal farnesoid X receptor‐fibroblast growth factor 15（FGF‐15) signaling pathway. BAs excretion is also facilitated by LGG through increasing the abundance of bile salt hydrolase (BSH)‐active gut commensal bacteria. Furthermore, exposed positively‐charged chitosan shell can absorb the excessive BAs via electrostatic interaction, which leads to steady BAs fixation by the imprisoned LDB, decreasing the total BAs amounts in enterohepatic circulation. Together, the fabricated living materials, obtained here, can effectively prevent cholestatic DILI through dredging cholestasis via gut‐liver axis modulation. The therapeutic effect is demonstrated in α‐naphthylisothiocyanate and clinical antiepileptic drug valproate acid‐induced cholestatic DILI mouse models, which reveal the great potential for effective cholestatic DILI management.

Farnesoid X receptor contributes to oleanolic acid-induced cholestatic liver injury in mice.

Farnesoid X receptor (FXR) is a nuclear receptor involved in the metabolism of bile acid. However, the molecular signaling of FXR in bile acid homeostasis in cholestatic drug‐induced liver injury remains unclear. Oleanolic acid (OA), a natural triterpenoid, has been reported to produce evident cholestatic liver injury in mice after a long‐term use. The present study aimed to investigate the role of FXR in OA‐induced cholestatic liver injury in mice using C57BL/6J (WT) mice and FXR knockout (FXR−/−) mice. The results showed that a significant alleviation in OA‐induced cholestatic liver injury was observed in FXR−/− mice as evidenced by decreases in serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase as well as reduced hepatocyte necrosis. UPLC‐MS analysis of bile acids revealed that the contents of bile acids decreased significantly in liver and serum, while increased in the bile in FXR−/− mice compared with in WT mice. In addition, the mRNA expressions of hepatic transporter Bsep, bile acid synthesis enzymes Bacs and Baat, and bile acids detoxifying enzymes Cyp3a11, Cyp2b10, Ephx1, Ugt1a1, and Ugt2b5 were increased in liver tissues of FXR−/− mice treated with OA. Furthermore, the expression of membrane protein BSEP was significantly higher in livers of FXR−/− mice compared with WT mice treated with OA. These results demonstrate that knockout of FXR may alleviate OA‐induced cholestatic liver injury in mice by decreasing accumulation of bile acids both in the liver and serum, increasing the export of bile acids via the bile, and by upregulation of bile acids detoxification enzymes.