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Rationale: Methimazole (MMI) is the first-line agent in the treatment of hyperthyroidism. However, rare but severe cholestatic jaundice may occur. Therapeutic plasma exchange (TPE) may provide an alternative treatment for such patients and they received thyroidectomy/radioactive iodine ablation or continued oral anti hyperthyroidism medication immediately after TPE session in the reported literatures. The case reported here is, to our knowledge, the first to describe the long interval between anti hyperthyroidism therapy and TPE in such patients., Patient Concerns: A 49-year-old Chinese woman had developed worsening jaundice 3 weeks after receiving methimazole (20 mg/day) for the treatment of hyperthyroidism secondary to Graves' disease (GD). Additionally, she had a 2-year history of type 2 diabetes., Diagnosis: Hyperthyroidism secondary to GD, MMI-induced severe cholestatic jaundice and type 2 diabetes., Interventions: Methimazole was discontinued and the patient received 3 times of TPE, about 3-month glucocorticoid treatment, insulin administration accordingly and other conventional liver-protecting therapy., Outcomes: Her thyroid function was stabilized with small dose of thyroxine substitution and euthyroid status persisted after thyroxine discontinuation until hyperthyroidism recurred 7 months later while her cholestatic jaundice was eventually recovered by about 3-month glucocorticoid therapy., Lessons: Due to the complex interplay between liver function and thyroid hormones, there may be unusual changes of thyroid function in GD patients with severe liver injury after TPE. By this case, we want to highlight the importance of a closely following up of thyroid function in order to deliver appropriate health suggestions for patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Rationale: We present a case of a 43-year-old female patient diagnosed with hyperthyroidism. This study aims to demonstrate the rare association between hyperthyroidism and severe cholestatic jaundice, and the effectiveness of methimazole treatment., Patient Concerns: The patient developed severe jaundice, a typically mild symptom in most hyperthyroidism cases., Diagnosis: The severe jaundice was suspected to be a result of cholestasis induced by hyperthyroidism, with other potential causes such as drug-induced or autoimmune liver dysfunction being ruled out., Outcomes: The patient was effectively treated with methimazole. Outcomes: Treatment with methimazole alleviated the severe cholestatic jaundice and restored normal thyroid function., Lessons: The specific mechanism of cholestasis as a secondary complication of hyperthyroidism remains unclear, and there are no specific biochemical markers for cholestasis caused by this hormonal disease. This case underscores the possibility of severe jaundice as a clinical manifestation of hyperthyroidism, and highlights antithyroid drug treatment as an effective strategy for managing severe cholestatic jaundice., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: It is well known that obstructive jaundice could affect the pharmacodynamics of some anesthetics, and the sensitivity of some anesthetics would increase among icteric patients. Remimazolam is a new ultra-short-acting intravenous benzodiazepine sedative/anesthetic, which is a high-selective and affinity ligand for the benzodiazepine site on the GABAA receptor. However, no study has reported the pharmacodynamics of remimazolam in patients with obstructive jaundice. We hypothesize that obstructive jaundice affects the pharmacodynamics of remimazolam, and the sensitivity of remimazolam increases among icteric patients., Methods/design: The study will be performed as a prospective, controlled, multicenter trial. The study design is a comparison of remimazolam requirements to reach a bispectral index of 50 in patients with obstructive jaundice versus non-jaundiced patients with chronic cholecystitisor intrahepatic bile duct stones. Remimazolam was infused at 6 mg/kg/h until this endpoint was reached., Discussion: Remimazolam could be suitable for anesthesia of patients with obstructive jaundice, because remimazolam is not biotransformed in the liver. Hyperbilirubinemia has been well-described to have toxic effects on the brain, which causes the increasing of sensitivity to some anesthetics, such as desflurane, isoflurane, and etomidate. Furthermore, remimazolam and etomidate have the same mechanism of action when exerting an anesthetic effect. We aim to demonstrate that obstructive jaundice affects the pharmacodynamics of remimazolam, and the dose of remimazolam when administered to patients with obstructive jaundice should be modified., Trial Registration: Chinese Clinical Trial Registry ChiCTR2100043585 . Registered on 23 February 2021., (© 2022. The Author(s).)

An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.

Drug induced cholestatic liver injury can posed a great diagnostic difficulty as a result of its long non-exhaustive list of potential offending causes which can be either prescribed or over-the-counter medications, such as medicinal herbs and remedies. Phaleria macrocarpa, or more commonly known as the 'God's crown' by the local people of South East Asia, is not listed as one of the causes. This medicinal plant extract has been increasingly used for traditional treatment for various ailments. Here, we report a case of a young man who has no known medical illness presented with cholestatic pattern of liver injury which caused by chronic ingestion of Phaleria macrocarpa. The objective of this case report is to share the uncommon side effect of taking this traditional product which may have been under-reported due to the unknown effect.

Objectives The uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1)*28 allele in HIV-positive patients receiving atazanavir (ATV) might be associated with the risk of hyperbilirubinemia. Owing to mixed and inconclusive results, a meta-analysis was conducted to systematically summarize and clarify this association. Methods Based on a comprehensive search of PubMed, Embase and Web of Science databases, studies investigating the association between UGT1A1 alleles and hyperbilirubinemia was retrieved. We evaluated the strength of this relationship using odds ratios (ORs) with 95% confidence intervals (CIs). Sensitivity analysis was performed by removing each study one at a time and calculating the pooled ORs of the remaining studies to test the robustness of the meta-analysis results. The Q statistic and the I 2 index statistic were used to assess heterogeneity. Publication bias was evaluated using Orwin's fail-safe N test. Results A total of six individual studies were included in this meta-analysis. A significantly increased risk of hyperbilirubinemia was observed in HIV-positive patients receiving ATV with the UGT1A1*1/*28 or UGT1A1*28/*28 genotype, and the risk was higher with the UGT1A1*28/*28 genotype than with the UGT1A1*1/*28 genotype. (UGT1A1*28/*28 versus UGT1A1*1/*28: OR = 3.69, 95%CI = 1.82-7.49; UGT1A1*1/*28 versus UGT1A1*1/*1: OR = 3.50, 95%CI = 1.35-9.08; UGT1A1*28/*28 versus UGT1A1*1/*1: OR = 10.07, 95%CI = 4.39-23.10). All of the pooled ORs were not significantly affected by the remaining studies and different modeling methods, indicating robust results. Conclusions This meta-analysis suggests that the UGT1A1*28 allele represents a biomarker for an increased risk of hyperbilirubinemia in HIV-positive patients receiving ATV., (© 2019 The Author(s).)

Background: Direct-acting Antivirals (DAA) are currently used in the treatment of chronic HCV infection. In patients with renal failure Glecaprevir/Pibrentasvir (genotype 1-6) is recommended for its safety and efficacy., Case Presentation: Although these pharmacological characteristics, an adverse drug reaction (ADR) has been reported during Glecaprevir/Pibrentasvir treatment, such as the development of cholestatic jaundice in an elderly patient with chronic HCV (genotype 2) infection. At examination, patient was jaundiced associated with intense pruritus., Results: Ultrasound and laboratory biochemical tests excluded a liver failure (e.g. liver cancer, and liver lithiasis) or pancreatic cancer while Naranjo probability scale (score 6) suggested an association between cholestatic jaundice and Glecaprevir/Pibrentasvir administration. About 1 month after drug discontinuation, an improvement has been documented in both jaundice and pruritus, with a normalization in bilirubin levels (total bilirubin: 0.96 mg/dL), HCV-RNA was undetected also. It is worth mentioning that although we reported the development of cholestatic jaundice upon treatment with Glecaprevir/Pibrentasvir we recorded a clinical efficacy (HCV-RNA <15 IU/L) after 4 weeks from the beginning of the treatment, with a complete remission of clinical symptoms until 7 months after drug discontinuation., Conclusion: These data support the clinical efficacy of Glecaprevir/Pibrentasvir association in elderly patients, despite the sub-optimal period of treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: To establish a new rat model, the pathogenesis of which is closer to the clinical occurrence of chronic obstructive jaundice with liver fibrosis., Methods: 90 SD rats were randomly divided into 3 groups. Group A common bile duct ligation, group B common bile duct injection compont and group C injection saline. The serum of three groups was extracted, and the liver function was detected by ELISA. HE staining, Masson staining and immunohistochemistry were used to detect liver pathology., Results: Group B showed a fluctuant development of jaundice, obstructive degree reached a peak at 2 weeks, and decreased from 3 weeks. HA, LA and PCIII were significantly higher than control group. 3 weeks after surgery, liver tissue fibrosis occurred in group B, and a wide range of fiber spacing was formed at 5 weeks. Immunohistochemistry showed that hepatic stellate cells were more active than the control group., Conclusion: Intra-biliary injection of Compont gel is different from the classic obstructive jaundice animal model caused by classic bile duct ligation, which can provide an ideal rat model of chronic obstructive jaundice with liver fibrosis.

We herein report a patient with a history of rheumatoid arthritis treated with methotrexate, which caused methotrexate-associated lymphoproliferative disorder and obstructive jaundice due to an enlarged lymph node. The obstructive jaundice was treated with endoscopic biliary stenting. A histopathological examination revealed features of Hodgkin's lymphoma, and chemotherapy with brentuximab vedotin was administered. Cholangiography and duodenoscopy after four rounds of chemotherapy revealed a choledochoduodenal fistula that developed in response to chemotherapy. It should be noted that, in cases of lymphoma infiltrating the gastrointestinal wall, fistulae can occur because of rapid regression due to regimens comprising monoclonal antibodies, such as rituximab and brentuximab vedotin.

This case highlights a patient with Gilbert syndrome who underwent endoscopic retrograde cholangiopancreatography (ERCP) with removal of bile duct stones, who then experienced an unexplained increase in bilirubin, with total bilirubin (TBIL) levels increasing from 159.5 μmol/L to 396.2 μmol/L and to a maximum of 502.8 μmol/L after 9 d. Following the decrease in the TBIL level, enhanced magnetic resonance cholangiopancreatography (MRCP) was performed to exclude any possible remaining choledocholithiasis. Nevertheless, the serum bilirubin level increased again, with TBIL levels rising from 455.7 μmol/L to 594.8 μmol/L and a maximum level of 660.3 μmol/L with no remaining bile duct stones. A liver biopsy showed severe bile duct cholestasis with no inflammation. Based on the exclusion of other potential causes of hyperbilirubinemia and the fact that both instances of increased bilirubin occurred after ERCP and MRCP, the contrast agents iopromide and gadoterate meglumine were suspected to be the causes of the hyperbilirubinemia. As of the writing of this report, the patient's bilirubin levels have spontaneously returned to baseline levels. In summary, ERCP and MRCP utilizing the contrast agents iopromide and gadoterate meglumine may possibly induce prolonged hyperbilirubinemia., Competing Interests: Conflict-of-interest statement: The authors of this manuscript have no conflicts of interest to disclose.

Background: Methimazole is an antithyroid drug that is widely used for the treatment of hyperthyroidism. As an inhibitor of the enzyme thyroperoxidase, methimazole is generally well-tolerated. However, there have been increasing reports of methimazole-induced liver damage, although this effect of methimazole has been limited by the absence of objective diagnosis of the liver condition or the inappropriate use of the Naranjo scale. We present the case of an elderly man with hyperthyroidism, gastritis, and epilepsy who developed liver damage after administration of multiple drugs., Key Points From the Case: Considering the low sensitivity of the Naranjo scale in detecting rare reactions associated with liver damage, we used the Roussel-Uclaf Causality Assessment Method scale, with a finding of cholestatic jaundice hepatitis induced by methimazole. The patient's liver enzyme levels improved after discontinuation of methimazole., Main Lessons Learned: Our case underlines the possible hepatoxicity associated with the use of methimazole. A review of the literature confirmed a selective hepatoxicity risk in individuals of Asian ethnicity, which has not been identified in Caucasian or Black populations. Physicians should be aware of the risk of hepatoxicity when prescribing oral methimazole to patients of Asian ethnicity.

Bile cast nephropathy is a tubulo-interstitial nephropathy. Its diagnosis may be under-estimated. It develops in patients who have cholestatic jaundice, with high bilirubinemia. Bile salts are freely filtered through glomerulus. Under certain circumstances, it forms casts into the tubule and cause an acute tubular necrosis. The diagnosis evidence is histologic, but fulfilment of renal biopsy is often made difficult, because of the hemostatic abnormalities that patients with hepatocellular injury develop. The treatment is supportive and etiological. We report here the case of a patient who presented a drug-induced hepatic jaundice, complicated with acute kidney failure secondary to bile cast nephropathy. We present the histological diagnosis evidence., (Copyright © 2016 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.)

Background and Aims: Amoxicillin-clavulanate (AC) is the most frequent cause of idiosyncratic drug-induced injury (DILI) in the US DILI Network (DILIN) registry. Here, we examined a large cohort of AC-DILI cases and compared features of AC-DILI to those of other drugs., Methods: Subjects with suspected DILI were enrolled prospectively, and cases were adjudicated as previously described. Clinical variables and outcomes of patients with AC-DILI were compared to the overall DILIN cohort and to DILI caused by other antimicrobials., Results: One hundred and seventeen subjects with AC-DILI were identified from the cohort (n = 1038) representing 11 % of all cases and 24 % of those due to antimicrobial agents (n = 479). Those with AC-DILI were older (60 vs. 48 years, P < 0.001). AC-DILI was more frequent in men than women (62 vs. 39 %) compared to the overall cohort (40 vs. 60 %, P < 0.001). The mean time to symptom onset was 31 days. The Tb, ALT, and ALP were 7 mg/dL, 478, and 325 U/L at onset. Nearly all liver biopsies showed prominent cholestatic features. Resolution of AC-DILI, defined by return of Tb to <2.5 mg/dL, occurred on average 55 days after the peak value. Three female subjects required liver transplantation, and none died due to DILI., Conclusion: AC-DILI causes a moderately severe, mixed hepatocellular-cholestatic injury, particularly in older men, unlike DILI in general, which predominates in women. Although often protracted, eventual apparent recovery is typical, particularly for men and usually in women, but three women required liver transplantation.

Bile cast nephropathy is a condition of renal dysfunction in the setting of hyperbilirubinemia. There are very few cases of this condition reported in the last decade and a lack of established treatment guidelines. While the exact etiology remains unknown, bile cast nephropathy is presumed to be secondary to multiple concurrent insults to the kidney including direct toxicity from bile acids, obstructive physiology from bile casts, and systemic hypoperfusion from vasodilation. Therapy directed at bilirubin reduction may improve renal function, but will likely need dialysis or plasmapheresis as well. We report our case of bile cast nephropathy and the therapeutic measures undertaken in a middle-aged male with chronic renal insufficiency that developed hyperbilirubinemia and drug-induced liver injury secondary to antibiotic use. He developed acute renal injury in the setting of rising bilirubin. He subsequently had a progressive decline in renal and hepatic function, requiring dialysis and plasmapheresis with some improvement, ultimately requiring transplantation.

Renal dysfunction in cholestatic liver disease is multifactorial. Acute kidney injury may develop secondary to renal vasoconstriction in the setting of peripheral vasodilation and relative hypovolemia, tubular obstruction by bile casts, and direct tubular toxicity from bile. Anabolic steroids are frequently used by athletes to boost endurance and increase muscle mass. These agents are a recently recognized cause of hepatotoxicity and jaundice and may lead to acute kidney injury. To increase awareness about this growing problem and to characterize the pathology of acute kidney injury in this setting, we report on a young male who developed acute kidney injury in the setting of severe cholestatic jaundice related to ingestion of anabolic steroids used for bodybuilding. Kidney biopsy showed bile casts within distal tubular lumina, filamentous bile inclusions within tubular cells, and signs of acute tubular injury. This report supports the recently re-emerged concept of bile nephropathy cholemic nephrosis.

Methimazole is commonly prescribed for patients who are thyrotoxic. Cholestatic hepatitis is a rare but serious adverse event which may be associated with interventional therapy. In this case report, we present two Chinese women with cholestatic jaundice due to methimazole treatment. Both patients had a history of hyperthyroidism; initial laboratory studies of liver function were normal and cholestatic hepatitis occurred after treatment with methimazole. Concomitant liver disease, such as viral hepatitis (A, B, C, D, E), autoimmune hepatitis, primary biliary cirrhosis and calculus of bile duct, were excluded. Liver enzyme levels in both patients returned to normal after stopping methimazole therapy and taking hepatoprotective drugs. It is essential that patients are informed about the earliest symptoms of serious adverse effects of antithyroid drugs, such as hepatic toxicity, and that they are advised to stop taking the drug immediately and contact their physician if such symptoms occur.

Therapeutic voriconazole concentrations have a narrow window of effectiveness before causing cholestatic hepatitis. After undergoing 1 year of voriconazole therapy for pulmonary aspergillosis, a 44-year-old man began treatment with 30 mg lansoprazole for gastroesophageal reflux symptoms. Within 5 days of starting treatment with lansoprazole, the patient presented with fatigue, jaundice, and cholestatic hepatitis. The hepatitis promptly resolved after stopping lansoprazole treatment. Sixteen months later, the patient was given simvastatin therapy, as recommended by the American Diabetes Association to prevent cardiovascular disease for patients with diabetes who are aged >40 years and have one additional risk factor. Within 2 weeks of taking simvastatin, a 3-hydroxy-3-methylglutaryl CoA reductase (statin) therapy, the patient redeveloped fatigue, jaundice, and cholestatic hepatitis. He described both episodes of fatigue and jaundice similarly in terms of onset and intensity. Voriconazole is metabolized by both CYP2C19 and CYP3A4 isoenzymes. Lansoprazole is an inhibitor of the CYP2C19 isoenzyme. Competition between voriconazole and lansoprazole likely led to increased voriconazole serum concentration and acute cholestatic hepatitis in this patient. Simvastatin inhibits the CYP3A4 isoenzyme. After the patient took 10 mg simvastatin daily for 2 weeks, cholestatic hepatitis occurred. The voriconazole concentration remained elevated (4.1 μg/ml) when measured 15 days after stopping simvastatin. The patient's Naranjo Adverse Drug Reaction Probability Scale score of 7 revealed that the cholestatic hepatitis was probably precipitated by lansoprazole. Likewise, the patient's Naranjo score of 9 also revealed that cholestatic hepatitis was attributable to a definite adverse drug reaction precipitated by the addition of simvastatin to the stable baseline regimen of voriconazole. In a single patient, two different inhibitors of the cytochrome P450 pathway stimulated voriconazole-induced cholestatic hepatitis. Although the major cytochrome P450 pathways for the metabolism and clearance of lansoprazole and simvastatin are different, they both likely contributed to the reduced hepatic clearance of voriconazole in this patient., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

Ecballium elaterium is an herbaceous plant belonging to the Cucurbitaceae family. This plant is fairly common in the Mediterranean regions. It is frequently consumed in infusion, mixture of fruit or even in aerosol in cases of fever or flu. This plant is known for its respiratory and ocular toxicity. Hepatotoxicity has never been described in the literature. We report a case of acute cholestatic hepatitis due to Ecballium elaterium in a 39 years old patient, with no past medical history., (Copyright © 2014. Published by Elsevier Masson SAS.)

Elevated level of bile can cause bile cast nephropathy, which can be seen in patients with severe cholestatic liver disease. Stanozolol is a C17α-alkylation steroid derived from dihydrotestosterone and its major adverse effect is cholestatic jaundice. We report 2 bodybuilders who received stanozolol for 6 weeks and developed icterus. Serum total bilirubin was around 50 mg/dL. Liver biopsy showed intrahepatic cholestasis. In spite of fluid and albumin therapy, serum creatinine increased and the patients experienced oliguria. Urine sediment showed granular cast and normal erythrocyte count. Protein excretion in 24-hour urine was less than 1000 mg in both patients. Hemodialysis was started on and renal biopsy revealed acute tubular epithelial cell damage along with bile pigment (cast) deposition, compatible with bile cast-related nephropathy. Serum bilirubin decreased gradually and urine output increased. Serum creatinine was around 1.5 mg/dL in both of the patients 2 months after discharge.

Stevens-Johnson syndrome (SJS) is an uncommon life-threatening skin disease, generally induced by drugs. Extracutaneous manifestations of the syndrome can occur, and may involve the conjunctiva, buccal mucosa, gastrointestinal and genitourinary tracts. Cholestatic hepatitis has been rarely described in SJS. A 29-year-old woman was admitted with generalized cutaneous eruption. A self-medication with paracetamol had been started three days earlier. Clinical signs and skin biopsy were consistent with SJS. Five days later, the patient developed jaundice. Serial liver function tests showed rising transaminases, bilirubin, alkaline phosphatase and γ-glutamyl transferase. Liver biopsy was performed and was consistent with the diagnosis of drug-induced cholestatic hepatitis. Adequate supportive care was provided to the patient. Skin lesions disappeared within two weeks. Jaundice disappeared progressively, and liver tests returned to normal. Herein, we report the first case of SJS associated with cholestatic hepatitis after ingestion of therapeutic doses of paracetamol.

Sclerosing cholangitis (SC) is a rarely reported morbidity secondary to transcatheter arterial chemoembolization (TACE) with bleomycin-iodinated oil (BIO) for liver cavernous hemangioma (LCH). This report retrospectively evaluated the diagnostic and therapeutic course of a patient with LDH who presented obstructive jaundice 6 years after TACE with BIO. Preoperative imaging identified a suspected malignant biliary stricture located at the convergence of the left and right hepatic ducts. Operative exploration demonstrated a full-thickness sclerosis of the hilar bile duct with right hepatic duct stricture and right lobe atrophy. Radical hepatic hilar resection with right-side hemihepatectomy and Roux-en-Y hepaticojejunostomy was performed because hilar cancer could not be excluded on frozen biopsy. Pathological results showed chronic pyogenic inflammation of the common and right hepatic ducts with SC in the portal area. Secondary SC is a long-term complication that may occur in LCH patients after TACE with BIO and must be differentiated from hilar malignancy. Hepatic duct plasty is a definitive but technically challenging treatment modality for secondary SC.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely consumed drugs throughout the world for pain relief. Although the adverse effects of NSAIDs to the liver are well known, flurbiprofen-induced liver cholestasis is extremely rare. Herein, we present a patient with prolonged icterus that is associated with the use of flurbiprofen without causing ductopenia., (© The Author(s) 2013.)

Background: Ajmaline is a pharmaceutical agent now administered globally for a variety of indications, particularly investigation of suspected Brugada syndrome. There have been previous reports suggesting that repetitive use of this agent may cause severe liver injury, but little evidence exists demonstrating the same effect after only a single administration., Case Presentation: A 33-year-old man of Libyan origin with no significant past medical history underwent an ajmaline provocation test for investigation of suspected Brugada syndrome. Three weeks later, he presented with painless cholestatic jaundice which peaked in severity at eleven weeks after the test. Blood tests confirmed no evidence of autoimmune or viral liver disease, whilst imaging confirmed the absence of biliary tract obstruction. A liver biopsy demonstrated centrilobular cholestasis and focal rosetting of hepatocytes, consistent with a cholestatic drug reaction. Over the course of the next few months, he began to improve clinically and biochemically, with complete resolution by one year post-exposure., Conclusion: Whilst ajmaline-related hepatotoxicity was well-recognised in the era in which the drug was administered as a regular medication, clinicians should be aware that ajmaline may induce severe cholestatic jaundice even after a single dose administration.

Hyperthyroidism is one of the most frequent endocrine disorders and its current treatment is based on drugs, surgery and radioactive iodine. Methimazole is the antithyroid drug of choice because of its potency and infrequent side effects, usuaIly mild. This medication is rarely associated with liver toxicity, usually manifested as cholestatic jaundice. Here we report the case of a 33-year-old woman treated at the University Hospital Fundación Santa Fe de Bogota, with hepatotoxicity induced by a methimazole-based treatment for Graves' disease. The pruritus and jaundice appeared after three weeks of therapy, viral hepatitis markers were negative, hepatobiliary ultrasonography was normal, and an increase of the levels of alkaline phosphatase, total bilirubin and aminotransferases was found The causal diagnosis of methimazole-induced hepatotoxicity was supported by the results of a liver biopsy. According to the CIOMS scale the score was 10, and the causal relationship of the hepatic adverse reaction by methimazole is highly probable. The clinical course was satisfactory when the medication was suspended, with clinical improvement at 5 days, and normalization of liver tests at 5 weeks. We discuss this case from a diagnostic and therapeutic approach.

Case Description: We report a patient with growth hormone deficiency that developed cholestatic hepatitis during treatment with recombinant human growth hormone (HGH). The patient developed jaundice and pruritus during treatment with growth hormone. She did not use any other medications. Her jaundice and pruritus were disappeared and liver enzyme disturbances were normalized after HGH discontinuation., Conclusion: Clinician should be aware of this potential adverse drug reaction and frequent checking of liver enzymes is recommended in patients treating with HGH.

Prolonged antimicrobial therapy is recommended for methicillin-susceptible Staphylococcus aureus (MSSA) bone and joint infections (BJI), but its safety profile and risk factors for severe adverse events (SAE) in clinical practice are unknown. We addressed these issues in a retrospective cohort study (2001 to 2011) analyzing antimicrobial-related SAE (defined according to the Common Terminology Criteria for Adverse Events) in 200 patients (male, 62%; median age, 60.8 years [interquartile range {IQR}, 45.5 to 74.2 years]) with MSSA BJI admitted to a reference regional center with acute (66%) or chronic arthritis (7.5%), osteomyelitis (9.5%), spondylodiscitis (16%), or orthopedic device-related infections (67%). These patients received antistaphylococcal therapy for a median of 26.6 weeks (IQR, 16.8 to 37.8 weeks). Thirty-eight SAE occurred in 30 patients (15%), with a median time delay of 34 days (IQR, 14.75 to 60.5 days), including 10 patients with hematologic reactions, 9 with cutaneomucosal reactions, 6 with acute renal injuries, 4 with hypokalemia, and 4 with cholestatic hepatitis. The most frequently implicated antimicrobials were antistaphylococcal penicillins (ASP) (13 SAE/145 patients), fluoroquinolones (12 SAE/187 patients), glycopeptides (9 SAE/101 patients), and rifampin (7 SAE/107 patients). Kaplan-Meier curves and stepwise binary logistic regression analyses were used to determine the risk factors for the occurrence of antimicrobial-related SAE. Age (odds ratio [OR], 1.479 for 10-year increase; 95% confidence interval [CI], 1.116 to 1.960; P = 0.006) appeared to be the only independent risk factor for SAE. In patients receiving ASP or rifampin, daily dose (OR, 1.028; 95% CI, 1.006 to 1.051; P = 0.014) and obesity (OR, 8.991; 95% CI, 1.453 to 55.627; P = 0.018) were associated with the occurrence of SAE. The high rate of SAE and their determinants highlighted the importance of the management and follow-up of BJI, with particular attention to be paid to older persons, especially for ASP dosage, and to rifampin dose adjustment in obese patients.

Therapeutic plasma exchange (TPE) is an alternative treatment for hyperthyroidism, resulting in a rapid decline in plasma thyroid hormones and anti-thyroid antibodies. TPE has also been used both in primary liver disease and in drug-induced cholestasis. Data on thyrotoxic patients with severe hepatic complications are scarce. Cholestasis induced by imidazol-derived anti-thyroid drugs is extremely rare. The use of TPE for treating this complication was not previously reported. We report the experience of one such patient with a favorable response to TPE. A 45-year-old male patient with Graves' disease, presented with severe jaundice and extremely high serum bilirubin levels due to hepatotoxicity induced by tiamazol. Through extensive investigation primary liver disease, including viral, metabolic, neoplastic and autoimmune disease, as a cause of cholestasis were all ruled out. The patient underwent total of 6 TPEs which in combination with low dose of glucocorticoids and standard supportive measures, resulted in normalization of thyroid hormones and normal liver function tests. TPE provided a safe, rapid and effective treatment of severe drug-induced cholestasis and auto immune hyperthyroidism. From this case we conclude that TPE should be considered as a valuable alternative therapeutic option in thyrotoxic patients with severe complications. Guidelines and indication criteria for TPE treatment in patients with hyperthyroidism are still lacking., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: To report a case of cholestatic jaundice as a result of combination herbal and designer supplement use., Case Summary: A 50-year-old Hispanic male presented to the hospital with a 1-week history of significant painless jaundice; total bilirubin on admission was 29.4 mg/dL. He reported use of both herbal (creatine and whey protein) and designer (Incredible Bulk and Spartan 45) supplements concurrently for approximately 2 months. Upon admission, all supplements were discontinued and multiple laboratory and diagnostic tests were ordered. On day 6 of his hospital admission, a liver biopsy was performed, the results of which indicated drug-induced hepa to toxicity. On day 9 he was discharged with prescriptions for ursodeoxycholic acid and hydroxyzine. Three months post hospital discharge, the patient continued to be supplement-free and bilirubin had decreased substantially., Discussion: Anabolic-androgenic steroids are capable of causing hepatotoxicity, and multiple cases reported in the literature support this. A case report described hepato toxicity secondary to both creatine and whey protein consumption, and several reports have described liver damage secondary to designer supplement use. To our knowledge, this is the first case to describe hepatotoxicity as a result of combination herbal and designer supplement use. The Roussel Uclaf Causality Assess ment Method (RUCAM) score for drug-induced hepatotoxicity indicated a highly probable correlation between the use of combination supplements and cholestatic jaundice., Conclusions: Health care professionals need to be aware of complications associated with designer supplement use and should be able to identify patients who would benefit from education on herbal and designer supplement use.

Triptans are a class of drugs with proven efficacy in the acute treatment of migraine headache. The first component of these drugs was sumatriptan, with various derivatives subsequently emerging. Until now, there has only been one reported case of liver toxicity with zolmitriptan. We now present a case of hepatotoxicity related to another drug in this group: rizatriptan., (Copyright © 2012 Elsevier España, S.L. and AEEH y AEG. All rights reserved.)

Drug-induced liver injury (DILI) is a leading cause of liver failure and an important safety issue in drug development. Thalidomide is nowadays used for the treatment of several conditions including multiple myeloma (MM). Several adverse effects have been described but liver toxicity was seldom reported. We describe a case of thalidomide-induced hepatitis in a man treated for MM. The clinical setting and temporal association between the start of the drug and liver injury allowed the assumption of the causative role of thalidomide. As its clinical indications expand we wish to increase awareness of a new potential side effect of thalidomide. A short review on thalidomide-induced liver injury is also presented., (Copyright © 2012 Elsevier España, S.L. and AEEH y AEG. All rights reserved.)

The objective was to determine whether protective effects of JBP485 on biliary obstruction induced by alpha-naphthylisothiocyanate (ANIT) are mediated by the organic anion transporters Oat1, Oat3 and the multidrug resistance-associated protein Mrp2. The ANIT-induced increases in bilirubin (BIL), alanine aminotransferase (ALT) and aspartate transaminase (AST) in rat serum were inhibited significantly by oral administration of JBP485. The plasma concentration of JBP485 which is the substrate of Oat1 and Oat3 determined by LC-MS/MS was markedly increased after intravenous administration in ANIT-treated rats, whereas cumulative urinary excretion of JBP485 in vivo and the uptake of JBP485 in kidney slices were decreased remarkably. RT-PCR and Western blot showed the decreased expression of Oat1 and Oat3, increased expression of Mrp2 in ANIT-induced rats, meanwhile, the expression levels of Mrp2 and Oat1 were up-regulated after administration of JBP485. The up-regulation of Mrp2 and Oat1 was associated with a concomitant increase in urinary BIL after treatment with JBP485 in ANIT-treated rats. The mechanism for JBP485 to restore liver function might be related to improvement of the expression and function for Oat1 and Mrp2 as well as facilitation of urinary excretion for hepatoxic substance., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The anticancerous chemotherapies are often responsible for toxic injury of the nontumoral liver. Two types of histological lesions were recently reported during the treatment of digestive cancers: the sinusoidal obstruction syndrome (SOS); or veno-occlusive disease associated with the use of oxaliplatine, and steatohepatitis associated with the use of irinotecan. The SOS is a cause of increased postoperative morbidity, particularly during major hepatectomy or when more than six cycles of chemotherapy are administered. Steatohepatitis increases the postoperative morbidity and mortality. The new targeted molecules do not seem to modify the postoperative course. Hepatic injury and postoperative complications associated with chemotherapies used in the treatment of digestive cancers are summarized in this review., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Methimazole is a widely used antithyroid agent. Although methimazole is generally well tolerated, rare but severe cholestatic jaundice may occur. We described a 74-year-old woman who had a 10-year history of type 2 diabetes had developed severe jaundice and itching 1 month after receiving methimazole (10 mg tid) and propranolol (10 mg tid) for the treatment of hyperthyroidism. Clinical investigations revealed no evidence of any mechanical obstruction in the common bile duct or other obvious causes of hepatic injury, and the diagnosis methimazole-induced cholestasis was made on the basis of the temporal relationship between initiation of methimazole and onset of cholestasis. Methimazole was hence discontinued. However, the patient experienced a progressive worsening in cholestasis after receiving 2 weeks of ursodeoxycholic acid (UDCA) therapy. Prednisone therapy was then attempted. Liver function tests eventually improved with combination of glucocorticoids and ursodeoxycholic acid therapy. This case clearly showed that glucocorticoids could be a possible additional way of treatment for some cases of drug-induced cholestatic jaundice even in diabetic patients.

Hydralazine has been widely used for treating hypertension, particularly in patients with renal failure. We report a case on a patient in whom we believe the drug was implicated in an otherwise unexplained disturbance of liver function. A 63-year-old African-American female with medical history of hypertension and end-stage renal disease (on hemodialysis) was admitted to the hospital with epigastric pain and jaundice. The symptoms started about 1 week ago. Initial laboratory tests showed abnormal liver enzymes with elevated conjugated bilirubin and alkaline phosphatase suggestive of cholestatic jaundice. Amylase and lipase were normal. Abdominal ultrasound showed normal caliber common bile duct without evidence of obstruction. Abdominal CT scan does not show any evidence of intra- or extrahepatic biliary ductal dilatation, and no mass lesions were seen in the pancreas. Further blood chemistry showed worsening of liver enzymes and increased bilirubin over the next 2-3 days. Magnetic resonance cholangiopancreatography failed to show any evidence of intra- or extrahepatic biliary ductal dilatation. No other laboratory evidence of cholestatic jaundice was found. Before proceeding for invasive diagnostic procedure, that is, endoscopic retrograde cholangiopancreatography, the patient's drug history was reviewed. She was on hydralazine 75 mg 3 times per day, started 5 months ago. At that time, her liver function tests were normal. As we could not find any other cause of cholestatic jaundice, we attributed this as a side effect of hydralazine. A trial was given by stopping the hydralazine. It was seen that there was significant improvement in the liver function enzymes over the next week. Complete clinical and biochemical recovery occurred over the next 4 weeks. Liver injury after long-term therapy with hydralazine and after short-term therapy with hydralazine (2-10 days) has been described. Hydralazine-induced hepatotoxicity may manifest as hypersensitivity-type injury, mixed hepatocellular injury, acute hepatitis, cholestatic jaundice, or centrilobular necrosis. The Hydralazine-induced cholestatic liver injury seems to be fully reversible. Complete clinical and biochemical recovery occurs after discontinuation of the drug. Also, the differential diagnosis of any patient with hepatocellular injury should include medications. This will prevent unnecessary diagnostic tests.

We report on a patient with active acromegaly and Gilbert's syndrome who developed severe hepatic dysfunction during pegvisomant (PEGv) monotherapy. She was partially resistant to all previous therapies, including long-acting somatostatin analogs and cabergoline. Five months after starting PEGv therapy, with an already normalized IGF1, she developed cholestatic liver dysfunction with jaundice. Liver or biliary diseases including biliary sludge, cholelithiasis or liver steatosis were excluded. A liver biopsy was in keeping with drug-induced liver injury. The discontinuation of PEGv was followed by full clinical and biochemical recovery in 6 weeks. PEGv therapy was not resumed. Apart from a minimal increase of bilirubin levels, no liver function test abnormalities were found during the 4-year follow-up period after the PEGv was discontinued. Drug-induced liver injury is the most serious systemic adverse event resulting from PEGv therapy. Since patients with mild and asymptomatic liver disease could be at a higher risk of PEGv-induced hepatotoxicity, frequent monitoring of hepatic enzymes should be required in these cases.

In patients undergoing percutaneous coronary intervention and in those with acute coronary syndromes, clopidogrel plus aspirin is the first-line antiplatelet therapy for reducing cardiovascular events. Although clopidogrel is generally well tolerated, with rash, indigestion, vomiting, diarrhea, and bleeding being the most common adverse effects, rare but serious complications may occur. We describe a 78-year-old woman who underwent percutaneous coronary intervention with drug-eluting stents; clopidogrel and aspirin were started as antiplatelet therapy. Three weeks later, the patient developed mixed hepatocellular and cholestatic liver injury. Clopidogrel was discontinued, and her liver profile results began to improve. Her diagnostic work-up included screening for hepatitis, infectious mononucleosis, and rheumatologic diseases, as well as ultrasonography, magnetic resonance imaging, and endoscopic retrograde cholangiopancreaticography; all results were normal. On day 5 of hospitalization, because of the patient's risk for thrombosis secondary to the drug-eluting stents, clopidogrel was reintroduced; her liver enzyme levels increased. In the absence of any biliary obstruction or other obvious causes of hepatic injury, drug-induced hepatocellular injury and cholestatic jaundice were suspected, and clopidogrel was again discontinued. The patient's liver function tests gradually improved 3 days later and showed marked improvement at her 2-week follow-up visit after discharge. Use of the Maria and Victorino scale for diagnosis of drug-induced hepatotoxicity indicated a probable (score of 14) relationship between clopidogrel and mixed hepatocellular injury and cholestatic jaundice in this patient. Although routine liver function testing is not recommended in patients who receive clopidogrel, having a high index of clinical suspicion, drug rechallenge, and excluding other obvious causes are required to establish the diagnosis of a rare drug complication such as clopidogrel-induced hepatic injury.

Biliary obstructive jaundice (OJ) is an important clinical consideration concerning high bacteremic risk. Hepatocyte apoptosis is one of the causes of cholestatic liver injury. The aim of the current study was to examine the precise pathway and time course of hepatocyte apoptosis during OJ with LPS administration and to determine if OJ sensitizes the liver to endotoxemia. Male C57BL/6 mice were subjected to bile duct ligation and division and were administered with LPS at 3 (OJ3) or 14 (OJ14) days after surgery. Fas ligand expression, poly (adenosine diphosphate-ribose) polymerase p85 fragment immunohistochemistry, activation of caspases 3, 8, and 9, serum alanine aminotransferase levels, and hepatic adenosine triphosphate (ATP) contents were examined. Survival after LPS administration in male C57BL/6 or gld/gld (Fas ligand-deficient) mice was determined. The expression of Fas ligand increased during OJ. After LPS administration, the expression of cleaved caspases 3 and 8 increased in Sham3, Sham14, OJ3, and OJ14 mice, and it significantly increased in OJ14 compared with other mice. Poly (adenosine diphosphate-ribose) polymerase p85 immunohistochemistry showed significant hepatocyte apoptosis after LPS administration in OJ14 mice relative to OJ3. In OJ14 with LPS administration, ATP contents significantly decreased and alanine aminotransferase levels increased. Hepatocyte apoptosis was decreased in gld/gld OJ14 mice compared with C57BL/6 OJ14. All C57BL/6 OJ14 mice with LPS died, but survival in gld/gld OJ14 significantly ameliorated. In prolonged OJ with LPS administration, hepatocyte apoptosis depending on Fas ligand expression significantly increased in association with a decrease in ATP contents, thus resulting in liver necrapoptosis.

Objective: To describe a case of fosinopril-induced severe cholestatic jaundice successfully treated with plasma exchange., Case Summary: A 78-year-old Taiwanese male presented with yellowish skin and generalized itching one month after starting fosinopril 10 mg once a day. Other drugs taken by the patient were excluded as the probable cause of jaundice. Diagnostic modalities, including abdominal ultrasound, computed tomography, and endoscopic retrograde cholangiopancreatography, revealed no evidence of biliary tract obstruction or intraabdominal tumor. According to the Council for International Organizations of Medical Science (CIOMS) scale, fosinopril was a highly probable cause of the patient's jaundice. Liver biopsy showed cholestasis without bile duct damage. Based on results of the CIOMS scale assessment and pathological characteristics of the liver, the diagnosis was highly probable that fosinopril had induced cholestatic jaundice in our patient. During hospitalization, the patient developed severe jaundice and liver failure, despite conservative treatment and withdrawal of fosinopril. He underwent a 5-day course of plasma exchange therapy, and the serum bilirubin level declined rapidly after treatment. His liver function returned to normal 2 months after treatment., Discussion: Angiotensin-converting enzyme (ACE) inhibitor-induced hepatotoxicity is rare and only a few cases, with most involving captopril, have been reported in the English-language literature. Hepatotoxicity caused by fosinopril is extremely rare. Most ACE inhibitor-induced hepatotoxicity is mild and transient, but it can be fatal. Although orthotopic liver transplantation (OLT) is the standard method for treating drug-induced liver failure, plasma exchange therapy is an alternative therapeutic method or a bridge to OLT for treating liver failure., Conclusions: Plasma exchange therapy may play a valuable role in the treatment of fosinopril-induced cholestatic jaundice and liver failure. This intervention can be considered for temporary liver support until recovery or OLT.

Ciprofloxacin, a commonly prescribed fluoroquinolone antibiotic, has generally been well-tolerated; however, there are rare reports of associated hepatic failure or renal failure. We describe a case of a 65 year-old man with a history of ischemic cardiomyopathy who was treated with ciprofloxacin 500 mg twice daily for cellulitis. Six days into his treatment course, he developed acute cholestatic jaundice and acute anuric renal failure. Clinical, laboratory, and pathologic data suggest that the patient had developed reversible, severe ciprofloxacin-induced cholestatic liver injury and acute tubular necrosis requiring hemodialysis. Within two months of stopping the ciprofloxacin, the patient was off dialysis and back to his baseline creatinine in three months. Liver tests normalized by five months. This report illustrates a case of cholestatic liver injury and renal failure involving ciprofloxacin use. We review the literature regarding hepatic and renal injury as it relates to ciprofloxacin. To our knowledge, this represents the first case report of simultaneous acute cholestatic liver injury and renal failure secondary to ciprofloxacin.

We present a case report of a posttransplant patient who had hepatotoxicity due to both tacrolimus and cyclosporine and cholestatic jaundice due to tacrolimus. The patient did not show sustained improvement in enzyme and bilirubin abnormalities after an initial change from tacrolimus to cyclosporine or with a change back to tacrolimus, but he ultimately showed improvement when the blood concentration of tacrolimus was lowered. A 56-year-old man with subacute fulminant hepatitis induced by acarbose was admitted to our hospital for living donor liver transplantation. The liver graft consisted of the left lobe from his ABO-identical son. The early posttransplant course was uneventful. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin improved initially, but the ALT and AST levels later increased. A liver biopsy suggested a presumptive diagnosis of drug reaction. All drugs were discontinued, the immunosuppressive agent was changed from tacrolimus to cyclosporine. After initial improvement, the ALT and AST levels increased again. Assuming a reaction to cyclosporine, we decreased the concentration of cyclosporine in the blood. The enzyme levels improved temporarily but again began to rise. We changed the immunosuppressive agent to tacrolimus, which resulted in improvements in the ALT and AST levels; however, the total bilirubin level increased. We interpreted this increase as tacrolimus-induced cholestasis; in response, we decreased the blood concentration of tacrolimus to between 3 and 5 ng/dL and added 1,000 mg of mycophenolate mofetil to the drug regimen. The patient recovered without further complications. Repeated liver biopsies throughout the hospital course suggested that the mild mononuclear cell infiltration observed in a few triads had not been caused by acute rejection but had possibly been drug-induced.