A prospective clinical study of isoniazid-rifampicin-pyrazinamide-induced liver injury in an area endemic for hepatitis B

In order to evaluate the incidence, predisposing factors and clinical course of antituberculous drug-induced liver injury in hepatitis B surface antigen (HBsAg)-positive carriers and non-carriers, in an area endemic for hepatitis B, we prospectively followed 240 patients (154 male, 86 female; mean age 40 years) who had received daily isoniazid, rifampicin, ethambutol and pyrazinamide for the treatment of pulmonary tuberculosis. Patients with heavy alcohol consumption, with pretreatment serum alanine aminotransferase (ALT) elevation and who had less than 3 months post-treatment follow-up were excluded from the study. Thirty-one (13%) patients were positive for serum HBsAg before treatment. Sixty-three (26%; 95% CI: 21–32%) patients developed antituberculous drug-induced liver injury. The incidence of drug-induced liver injury was significantly more frequent in patients > 35 years of age than in patients > 35 years of age (33 vs 17%; P < 0.05), but was not different between HBsAg carriers and non-carriers (29 vs 26%; P > 0.05). Using step-wise logistic regression analysis, patient age > 35 years was the only independent variable for predicting antituberculous drug-induced liver injury, while sex, acetylator phenotype, HBsAg carrier status and severity of tuberculosis were not. The peak serum ALT levels in antituberculous drug-induced liver injury were not significantly different between HBsAg carriers and non-carriers. Only one 61-year-old HBsAg carrier developed severe jaundice after 6 months antituberculous therapy; he subsequently died of hepatic failure. In conclusion, the incidence of antitubercuious drug-induced liver injury was significantly higher in patients > 35 years of age than in patients > 35 years of age, but was not different between HBsAg carriers and non-carriers. Mortality occurred in an aged HBsAg carrier superimposed with antituberculous drug-induced liver injury.     

Liver injury induced by a Japanese herbal medicine, sairei-to (TJ-114, Bupleurum and Hoelen Combination, Chai-Ling-Tang) R1

The case is reported of a man who showed acute hepatitis with jaundice after he was given a Japanese herbal medicine, sairei-to (TJ-114, Bupleurum and Hoelen Combination, Chai-Ling-Tang). Unusually, the component thought to be responsible for the observed drug-induced liver injury was able to be identified. Lymphocyte migration inhibition testing indicated that the tuber of the perennial herbage Pinellia ternate was the causative agent.     

Severe cholestasis due to adalimumab in a Crohn’s disease patient

Elevation of liver biochemistry has been reported with anti-tumor necrosis factor agents, but overt liver failure rarely reported. Autoimmune hepatitis has been more commonly reported with infliximab than adalimumab(ADA). Our case, however, describes the first reported case of ADA-associated severe cholestatic injury. A 39-year-old female with Crohn’s disease developed severe jaundice after initiation of ADA. All serologic tests and imaging studies were normal. Liver biopsy showed prominent pericentral canalicular cholestasis,without features of steatosis or sclerosing cholangitis,consistent with drug-induced cholestasis. The serum total bilirubin peaked at 280 μmol/L, and improvement was seen after 5 wk with eventual normalization of liver enzymes at 10 wk. Our case describes the first reported case of ADA-associated severe cholestatic liver disease and the first histopathologic examination of this adverse drug effect. Clinicians need to be aware of this potential drug-induced liver injury when prescribing this commonly used biologic medication.     

心脏外科围手术期急性药物性肝损伤12例

目的:分析心脏外科围手术期发生12例急性药物性肝损伤的临床特点及治疗效果.方法:回顾分析2009-2011年桂林医学院附属医院围手术期发生急性药物性肝损伤的12例心脏外科患者的临床表现、治疗情况及预后.结果:引起药物性肝损害的药物主要是抗生素、抗结核药物.主要临床表现是黄疸9例(82%),化验肝功能发现明显异常3例(18%).心脏手术前出现9例,手术后出现3例.其中2例为缩窄性心包炎,7例为感染性心内膜炎,冠状动脉粥样硬化性心脏病2例,风湿性心脏病1例.12例患者均治愈出院.随访6-44mo,10例有随访应答,复查肝功能正常,无中期并发症.结论:心脏外科围手术期急性药物性肝损伤多发生于右心功能不全、营养差的患者.对心脏手术前药物致肝损伤的早期诊断和及时合理的治疗,可以使患者的肝功能恢复正常,帮助患者度过围手术期,预后良好.     

Protracted cholestasis probably induced by oral contraceptive.

The case of a patient with intrahepatic cholestasis, probably induced by an oral contraceptive agent, is reported. Initially, early primary biliary cirrhosis was suspected, but this diagnosis could not be verified either clinically or by immunological tests. Re-examination and re-evaluation of the liver biopsy revealed some eosinophilia and sinusoidal dilatation, changes indicative of drug-induced liver injury. The cholestasis gradually disappeared as indicated both biochemically and histologically, but the elevation of serum alkaline phosphatase levels persisted for some 10 years after termination of drug therapy. Oral contraceptive agent-induced jaundice or cholestasis is generally reported to disappear when the drug is stopped, and we are unaware of similar cases in the literature with a protracted course such as that described here. Still, the circumstances of this patient suggest that a correlation between the oral contraceptive agent and the hepatic reaction is most likely, and we consider it important that colleagues pay attention to this possibility.     

Cholestatic hepatitis following flutamide

Summary Previous reports have indicated that administration of flutamide—a nonsteroidal antiandrogen drug—may induce hepatic toxicity. However, cholestatic hepatitis following flutamide is a rare event. This case report describes a 72-year-old male with metastatic adenocarcinoma of the prostate who underwent bilateral orchiectomy and treatment with flutamide. After seven weeks he developed jaundice and elevated AST and ALT levels. A liver biopsy showed cholestatic hepatitis without signs of biliary obstruction. The patient's clinical symptoms and elevated bilirubin resolved after the flutamide was discontinued. Monitoring of serum liver enzyme tests is advocated during flutamide administration to identify drug-induced liver injury.     

Jaundice Due to Suspected Statin Hepatotoxicity: A Case Series

Statin drugs are widely used worldwide and are generally considered safe and well tolerated. Only small proportion of patients receiving statins develop elevations of liver enzymes and an even smaller proportion will have clinically significant hepatitis induced by statins. We describe four patients with jaundice caused by drug-induced liver injury, where the most likely agent was a statin drug, over a period of approximately three year in Iceland. We calculate the risk of jaundice caused by statin drugs, from sale in the whole country of Iceland, to be one in 17,434 users a year. This is a higher risk than has previously been estimated and we challenge the current opinion that statins rarely cause clinically significant drug-induced liver injury and encourage alertness when managing patients with statins with regard to clinical signs of hepatitis before jaundice occurs.     

Hydrochlorothiazide-induced hepatotoxicity: A rare case of DILI

Thiazide diuretics are prescribed daily and rarely hepatotoxic. We report the case of 86-year-old woman who was admitted in hospital for jaundice after taking hydrochlorothiazide. All differential diagnoses have been eliminated. The liver biopsy was compatible with drug-induced hepatitis. Clinical and biological manifestations improved after discontinuation of the treatment. The reported case is compared to three other cases in the literature.     

A Case of Jaundice of Obscure Origin

Background

Idiopathic painless jaundice with significant elevations in serum transaminases, occurring in a previously healthy patient, invokes a circumscribed set of possibilities including viral hepatitis, auto-immune hepatitis (AIH) and drug-induced liver injury (DILI).

Methods

In this described case, common causes of cholestatic jaundice were considered including drug-induced liver injury, viral causes of hepatitis, and auto-immune antibodies. Biliary obstruction was excluded by appropriate imaging studies. Liver biopsy was obtained, though not definitive.

Results

After detailed investigation failed to reveal a cause of the jaundice, an empiric trial of steroids was initiated on the possibility that our patient had antibody-negative AIH and not DILI, with an associated grave prognosis.

Conclusions

Empiric treatment with prednisone led to rapid resolution of jaundice and to the conclusion that the correct diagnosis was antibody-negative AIH.     

Flutamide-induced toxic hepatitis

Summary Flutamide is a nonsteroidal antiandrogen commonly used in the treatment of prostate cancer. Hepatic toxicity associated with flutamide has been reported with an incidence from less than 1% to about 5%. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, has been widely used in the treatment of cholesterol gallstones and of several liver diseases, but few data are now available concerning its use in the management of drug-induced hepatitis.The case of a patient who presented severe hepatitis with jaundice following use of flutamide is reported. UDCA treatment was started on admission and, contemporaneously, flutamide was withdrawn. Clinical and biochemical improvement was progressively observed, and the patient was discharged six weeks after the admission. Since fatal flutamide-related hepatitis has been reported, monitoring of serum liver tests is advocated during flutamide administration, and the effectiveness of UDCA in the treatment of drug-induced hepatotoxicity requires further study.     

Unusual case of drug-induced cholestasis due to glucosamine and chondroitin sulfate

Glucosamine(GS) and chondroitin sulfate(CS) are common over-the-counter(OTC) supplements used in the treatment of osteoarthritis. These medications are seemingly safe, but there are increasing reports of hepatotoxicity with these supplements. We reported a unique case of drug-induced cholestasis caused by GS and CS in a combination tablet. The etiology of the jaundice was overlooked despite extensive investigations over a three-month period. Unlike drug-induced hepatocellular injury, drug-induced cholestatic jaundice with GS and CS has only been reported twice before. This case emphasizes the importance of a complete medication history, especially OTC supplements, in the assessment of cholestasis.     

Severe jaundice in a gunshot casualty due to the coexistence of Dubin-Johnson and glucose-6-phosphate dehydrogenase deficiency.

We report an unusual case of a 21-year-old man who was shot in his abdomen in the course of a robbery. He was previously diagnosed as glucose-6-phosphate dehydrogenase deficient. Mild icterus was noticed on admission to the emergency room. Exploratory laparotomy revealed a perforated ileal loop that was resected, and because the liver color was greenish black, a liver biopsy was performed during the operation. After operation the patient went through a severe icteric state that resolved spontaneously within a few days. Urinary coproporphyrin levels, along with compatible liver biopsy, confirmed the diagnosis of Dubin-Johnson disease. Severe hyperbilirubinemia after an abdominal injury is uncommon and is usually due to either a biliary duct injury or iatrogenic injury. This case presents an unusual cause of severe postoperative jaundice due to the rare coexistence of two inherited disorders.     

Flutamide-induced hepatotoxicity: report of a case series.

OBJECTIVE: To evaluate the characteristics of flutamide induced hepatotoxicity. MATERIAL AND METHODS: In this retrospective study we have analyzed all cases of flutamide hepatotoxicity submitted to the Andalucian Registry of drug-induced liver disease. Data were collected using a structured reporting form. Causality assessment was performed using two clinical scales: the standard CIOMS scale and the recently developed María and Victorino scale. RESULTS: Nine of 185 patients (4.9%) were identified. In 8 male patients, mean age 75 years (range 65-83), flutamide was indicated for palliative therapy of disseminated prostatic carcinoma, and in one young female (14 years) was given for the treatment of facial hirsutism. The mean duration of the flutamide therapy was 151 days (range 4-443). All patients presented with overt liver injury, the most frequent features being asthenia, anorexia, weight loss, nausea, vomiting and jaundice. No patient showed hypersensitivity features. In two patients (22%) the hepatic damage evolved to fulminant liver failure, one of them undergoing a liver transplantation and the other subsequently died. An additional patient died of a non-hepatic related cause when his liver function was improving. Causality assessment by the two clinical scales did not exclude any case, but the two patients who died where classified as unlikely by the María and Victorino scale. CONCLUSIONS: Flutamide can induce severe acute hepatitis, probably due to an idiosyncratic metabolic mechanism. Liver tests monitoring should probably be mandatory during the first months of flutamide therapy and the drug withdrawn if transaminases began to increase.     

老年肺结核的抗结核药物性肝损害分析

目的探讨老年人抗结核药物性肝损的特点。方法统计两组在抗结核药抗结核治疗中出现药物性肝损的发生率,对比两组间肝损发生率、肝损情况、引起肝损的原因、出现药物性肝损的时间及临床症状的差异,统计学处理用SPSS11.0软件,P<0.05为差异有显著性。结果实验组肝损发生率、ALT200U以上和合并黄疸的例数、临床症状的严重程度均较对照组升高,而ALT120~200U的例数较对照组降低(P<0.05),两者存在显著性差异。两组资料显示引起药物性肝损的原因中以利福平为主,出现药物性肝损的时间以2~4周为高峰,而引起药损的三种药物的构成比、出现肝损与时间之间两组均没有显著性差异(P>0.05)。结论老年人的肝损发生率高且肝损程度严重。     

Hepatotoxicity from ingestion of wild mushrooms of the genus Amanita section Phalloideae collected in Mexico City: two case reports

We present two cases of acute liver injury resulting from consumption of wild mushrooms. The first case was a male who developed acute hepatitis after ingestion of diverse mushrooms including Amanita species. His clinical course was favorable with complete recovery of liver function. The second case was a male who developed acute liver failure (ALF) after ingestion of Amanita bisporigera. He required MARS therapy as a bridge to liver transplantation but transplantation was not performed because he succumbed to multiorgan failure. There are few trials demonstrating the efficacy of the different treatments for mushroom poisoning. These cases demonstrate that the consumption of wild mushrooms without proper knowledge of toxic species represents a serious and under recognized health problem.     

Intrahepatic cholestasis and sicca complex after thiabendazole. Report of a case and review of the literature

Thiabendazole is a relatively safe and effective agent with a wide range of activity against nematodes infesting the gastrointestinal tract. A 55-yr-old man developed prolonged jaundice and sicca complex after a course of thiabendazole therapy. Endoscopic retrograde cholangiopancreatography demonstrated normal biliary tree and pancreatic ducts. Liver biopsy was consistent with a drug-induced intrahepatic cholestatic reaction. The patient recovered completely from his liver injury, but the sicca complex persisted 1 yr after the drug was given. The literature on thiabendazole-induced cholestasis and its association with sicca complex is reviewed.     

A case of Venoplant-induced hepatic injury

The first case of hepatic injury induced by Venoplant, extracts of Aesculus Hippocastanum, having antiinflammatory activities, was described. A 37 yr-old man was admitted for treatment of pathological fracture of the left brachial bone. He had been received 65 mg Venoplant at another hospital several hours before admission. 17 days later, a liver function test showed mild abnormality and 60 days after injection, he complained of pruritus and jaundice. Laboratory studies revealed moderate elevation of total bilirubin, ALP, gamma-GTP and mild eosinophilia. CT studies and ERC showed no signs of extrahepatic obstructive jaundice. The lymphocyte stimulation test was positive. The liver biopsy demonstrated marked cholestasis with zonal necrosis in the centrilobular areas but showed little or no changes in the portal tracts. These features are consistent with drug-induced hepatic injury.     

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

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