Review of liver injury associated with dietary supplements

Dietary supplements (DS) are easily available and increasingly used, and adverse hepatic reactions have been reported following their intake. To critically review the literature on liver injury because of DSs, delineating patterns and mechanisms of injury and to increase the awareness towards this cause of acute and chronic liver damage. Studies and case reports on liver injury specifically because of DSs published between 1990 and 2010 were searched in the PubMed and EMBASE data bases using the terms ‘dietary/nutritional supplements’, ‘adverse hepatic reactions’, ‘liver injury’; ‘hepatitis’, ‘liver failure’, ‘vitamin A’ and ‘retinoids’, and reviewed for yet unidentified publications. Significant liver injury was reported after intake of Herbalife^® and Hydroxycut products, tea extracts from Camellia sinensis, products containing usnic acid and high contents of vitamin A, anabolic steroids and others. No uniform pattern of hepatotoxicity has been identified and severity may range from asymptomatic elevations of serum liver enzymes to hepatic failure and death. Exact estimates on how frequent adverse hepatic reactions occur as a result of DSs cannot be provided. Liver injury from DSs mimicking other liver diseases is increasingly recognized. Measures to reduce risk include tighter regulation of their production and distribution and increased awareness of users and professionals of the potential risks.     

Cholestatic and hepatocellular injury associated with erythromycin esters

A combined cholestatic and hepatocellular injury occurred in nine patients, following therapy with erythromycin estolate (EE) or other erythromycin derivatives. Eight of the nine patients developed jaundice within three weeks after initiation of treatment; pain was one of the main symptoms in five patients while fever and itching were noted in four patients. Symptoms and signs subsided and abnormal tests of liver function returned to normal after withdrawal of the drug. The major histologic finding was cholestasis, but the majority of cases also had evidence of hepatocellular injury of variable severity; one biopsy specimen showed centrilobular necrosis. Ultrastructural findings in one case included changes related to cholestasis as well as hepatocellular injury with striking mitochondrial abnormalities. Our data are compared with those of the literature, with special reference to morphologic features.     

Cholestatic liver disease associated with diphenylhydantoin therapy

Summary A ten-year-old boy presented with a prolonged cholestatic liver disease 5 weeks after starting diphenylhydantoin therapy. The initial phase of his illness was characterized by hepatocellular damage with swollen liver cells and centrilobular cholestasis. Severe hyperlipoproteinemia with eruptive xanthomata developed within 3 weeks of his initial jaundice. The second phase of his illness was characterized by portal tract inflammation with bile ductular proliferation and chronic cholestasis gradually resolving over a period of 15 months.It is postulated that diphenylhydantoin sensitivity produced swollen hepatocytes with hypertrophy of the smooth endoplasmic reticulum, reducing hepatic sinusoidal blood flow and the clearance of secondary bile salts. A fall in clearance of lipoproteins, including the cholesterol precursor of primary bile acid synthesis, may have been responsible for a reduction in serum bile acid concentration. High levels of serum lithocholic acid, largely unsulfated presumably due to decreased hepatic uptake, may have produced the prolonged second phase of this illness when histological changes resembled that seen in experimental animals following lithocholic acid administration.     

Cholestatic liver injury after glimepiride therapy

Drug induced hepatotoxicity has been reported infrequently with sulfonylureas. For glimepiride, a second-generation sulfonylurea there is no report of hepatotoxicity in English literature. A patient with non-insulin-dependent diabetes mellitus who developed cholestatic liver injury soon after initiation of glimepiride therapy is presented. Complete work-up disclosed no other cause for hepatotoxicity including negative serological results for viral hepatitis. Liver biopsy was consistent with drug-induced cholestasis. The patient recovered 50 days after stopping glimepiride with no further recurrences.     

中草药和相关保健食品引起药物性肝病的研究

目的 分析因服用中草药或含草药成分的保健食品引起肝损害的情况。方法收集1982年至2005年诊断为“药物性肝病”患者82例。诊断根据为病史、药物史、临床表现、肝功能及其他实验室检查。最后回顾诊断，按药物性肝损伤评分进行评估。结果24年中诊断的82例“药物性肝病”患者占同期因肝功能异常住院患者的2．2％。其中男性28例，女性54例，年龄16～81岁．平均（50．1±16．9）岁。服用的与肝损伤有关药物中，减肥保健品占30．5％、皮肤科用药占12．2％、抗风湿病用药占8．5％、心血管用药占8．5％、妇科疾病用药占7．3％、肝病药占6．1％、调节血脂药占6．1％、乳房小叶增生药占3．7％、甲状腺肿块用药占3．7％、其他用药占13．4％。用药疗程6d～6个月不等．潜伏期6d～3个月。临床表现中，肝细胞损伤型占36．59％、胆汁淤积型占39．02％，其他为混合型，尚有10％的患者同时伴有变态反应表现。所有患者在停药后一般病情恢复较快，预后良好。结论中药和草药是引起药物性肝病的重要原因，应提高临床医师对药物引起肝损伤的认知及在治疗过程中加强监测。     

Cholestatic liver injury due to ibuprofen.

Ibuprofen is a member of the propionic acid class of NSAID. We report a 35-year-old man with ibuprofen-induced acute severe cholestatic liver injury. He recovered after seven months.     

Cholestatic liver disease and thrombocytopenia associated with long exposure to ticlopidine

A 45-year-old woman was admitted to the hospital because of cholestatic liver disease and severe thrombocytopenia following a 4-day history of fever and malaise. In her childhood the patient suffered from acute rheumatic fever with secondary mitral stenosis. Three years before admission, an atrial fibrillation had been diagnosed for which the patient was put on ticlopidine, 250 mg daily, that was taken regularly, without any adverse event. The patient had no history of cholestatic hepatitis or biliary colic. The abdominal ultrasonography was negative for biliary tract diseases and histological features were compatible with drug induced hepatotoxicity. Laboratory tests for viral and bacterial infection were negative. No other medications, apart from 2 doses of nimesulide, had been taken by the patient in the previous days. Ticlopidine was discontinued on admission and both bilirubin and platelet count rapidly normalized. We think that, in our patient, ticlopidine may be responsible of concomitant hematologic and hepatic toxicity and the trigger event might have been the reduced renal excretion of the drug following acute renal failure.     

Cholestatic liver injury after prolonged exposure to methyldopa

We describe a 75-year-old patient who presented with severe cholestatic liver disease. He had been receiving methyldopa, 250 mg daily, for 6 years. An extensive evaluation failed to reveal extrahepatic obstruction or serologic evidence of viral hepatitis. A liver biopsy disclosed marked cholestasis, without hepatitis, and was compatible with a rare form of methyldopa-induced liver injury. Cessation of drug treatment was followed by a slow but complete recovery. Cholestasis is a rare manifestation of methyldopa hepatotoxicity. Although methyldopa-associated liver injury usually appears after about 4 weeks of treatment, a history of a much longer exposure does not exclude this entity.     

Cholestatic jaundice associated with D-penicillamine therapy

Cholestatic jaundice is a rare complication of penicillamine therapy. We report here a 35-year-old patient who developed fever, a rash and cholestatic jaundice 16 days after commencing treatment with penicillamine for cystinuria. The jaundice subsided slowly after discontinuation of the drug and with prolonged therapy with prednisone. The literature on penicillamine-induced liver injury is reviewed.     

Acute liver injury induced by weight-loss herbal supplements

We report three cases of patients with acute liver injury induced by weight-loss herbal supplements. One patient took Hydroxycut while the other two took Herbalife supplements. Liver biopsies for all patients demonstrated findings consistent with drug-induced acute liver injury. To our knowledge, we are the first institute to report acute liver injury from both of these two types of weight-loss herbal supplements together as a case series. The series emphasizes the importance of taking a cautious approach when consuming herbal supplements for the purpose of weight loss.     

Cholestatic interleukin-6-deficient mice succumb to endotoxin-induced liver injury and pulmonary inflammation

Circulating and hepatic interleukin (IL)-6 levels are strongly increased during clinical and experimental cholestasis. Cholestatic liver injury is associated with increased susceptibility to endotoxin-induced toxicity. To determine the role of IL-6 herein, extrahepatic cholestasis was induced by bile duct ligation (BDL) in IL-6-gene deficient (IL-6(-/-)) and normal (IL-6(+/+)) mice. BDL elicited increased levels of hepatic IL-6 mRNA and protein in normal mice. Hepatocellular injury 2 weeks after BDL was similar in IL-6(-/-) and IL-6(+/+) mice as demonstrated by clinical chemistry and histopathology. Administration of endotoxin to cholestatic mice 2 weeks after BDL was associated with enhanced cytokine release, severe liver damage, and death when compared with sham-operated mice. Effects of endotoxin were largely similar in sham-operated IL-6(-/-) and IL-6(+/+) mice, but cholestatic IL-6(-/-) mice were more susceptible to the toxic effects of endotoxin, as reflected by increased cytokine release, more profound liver injury and lung inflammation, and higher mortality. Although endogenous IL-6 is not important in the development of liver injury after experimentally induced obstructive jaundice, this cytokine plays an important role in decreasing hypersensitivity to endotoxin in cholestatic mice.     

Cholestatic liver disease and its management

Cholestatic syndromes present symptomatically with pruritus and biochemically either with elevated levels of serum bile acid as an early manifestation of hepatocellular disease or with elevated levels of serum alkaline phosphatase if the disease originates in the biliary tree. Slow progression to cirrhosis occurs, with recurrent cholangitis and/or pancreatitis as the major problems if the obstruction is in the larger duct system. Maintenance of nutrition and relief of pruritus are important supportive measures. Colchicine and ursodeoxycholic acid administered orally have been proposed as useful therapies for delaying the progression to cirrhosis. Liver transplantation has proven successful in those patients in whom spontaneous remission does not occur.