Drug-induced liver diseases.

Drug-induced liver injuries make up a persisting and challenging problem for physicians, health agencies and pharmaceutical firms. The clinical expression is polymorphous, acute hepatitis being predominant. The diagnosis is frequently difficult because of the absence of specific signs in most cases and mainly relies on the exclusion of other causes. The diagnosis should be particularly evoked in patients over 50 yr who are taking many drugs, after viral infections have been ruled out. Acute hepatocellular hepatitis is particularly severe because of the risk of fulminant hepatitis or of a more insidious course leading to cirrhosis. Cross hepatotoxicity can sometimes occur. One should avoid re-administration of not only the causative agents but also of other drugs belonging to the same family or having a related chemical structure. The prediction of the hepatotoxicity of new drugs must be improved. Investigations would be particularly useful for drugs having critical chemical structures and belonging to families with an established history of hepatotoxicity.

Small hepatocellular carcinoma in patients undergoing liver transplantation: detection with CT after injection of iodized oil.

PURPOSE: To assess computed tomography (CT) with iodized oil for depiction of small hepatocellular carcinoma (HCC) before liver transplantation. MATERIALS AND METHODS: Thirty-five consecutive cirrhotic patients underwent CT with iodized oil to determine the presence, number, size, and location of possible nodules. All patients underwent liver transplantation within 4 months after CT. Explanted livers were cut in 8-mm slices that corresponded to axial CT scan planes. Comparison between CT staging and pathologic findings was made. RESULTS: Pathologic studies showed 17 HCC nodules (diameter, 0.9-4.0 cm) in nine of the 35 livers. CT depicted nine of these 17 nodules. Lesion-by-lesion analysis revealed a sensitivity of 53%; CT falsely depicted three additional nodules not confirmed with pathologic findings. Patient-by-patient analysis revealed an 89% sensitivity and an 88% specificity. CONCLUSION: CT with iodized oil, when assessed lesion by lesion, has a low sensitivity. These results must be considered when liver resection is proposed for HCC.

[Liver involvement in the course of phytotherapy]. / Accidents hépatiques de la phytothérapie.

The development of herbal medicine has follow in line with increased popular interest in ecology. Emphasis has been placed on the safety of natural herbs in contrast with the risks involved with "classical" medicines. But recent publications have revealed that several herbal medicines are toxic for the liver. For example, in France we have observed cases of hepatitis after ingestion of germander (Teucrium chamaedrys). Clinicians should also be aware of other well documented toxic effects of herbs used in popular medicines in Africa, Asia or Central America. The toxicity of pyrrolizidine alkaloids was recognized over 40 years ago. More than 300 plant species, including Heliotropium, Crotalaria, Senecio and Symphytum, are implicated. In Africa or Central America, intoxication is sometimes endemic since these plants are often used for making tea. In Western countries, cases of herb-induced hepatitis have been observed after use of preparations containing Symphytum or Chinese herbs. Pyrrolizidine alkaloids cause obstruction of the hepatic venous system and can lead to hepatonecrosis. Clinical manifestations include abdominal pain, ascitis, hepatomegaly and raised serum transaminase levels. Prognosis is often poor with death rates of 20 to 30% being reported. Atractylis gummifera is another example of herbal toxicity. Twenty-six species of this plant are used for medicinal purposes or for chewing gum. Intoxication usually occurs in the spring and is related to chewing the roots of these plants. Severe hepatocellular lysis may occur less than 24 hours after ingestion. Clinical manifestations are related to the induced hypoglycemia and neurovegetative disorders or subsequent renal failure. These compounds have an inhibitor effect on the Krebs cycle and can lead to severe or fatal liver failure. Other similar cases of fatal liver accidents have been reported after ingesting Callilepis laureola, a herb used by the Zoulous in Natal for medicinal purposes or after use of products containing extracts of Teucrium chamaedrys, which was nevertheless authorized in France in 1986 for use in preparations for weight loss. These examples emphasize the importance of remembering that herbal medicine is not harmless. Faced with the extensive distribution of many herbal preparations and the risk of self-medication, consumers and clinicians alike should be increasingly vigilant with these potentially hepatotoxic products.

[Treatment of acute alcoholic alcoholism]. / Le traitement de l'hépatite alcoolique aiguë.

Acute alcoholic hepatitis is the first alcoholic lesion of the liver in the process of progression to cirrhosis. It is due to the toxic action of alcohol on hepatocytes, in particular in the centrolobular region. It may affect a liver which is the site of fatty infiltration, fibrosis or cirrhosis, i.e. during all the stages of alcoholic liver disease. Its severity depends upon the degree of alcoholic intoxication. It may be fatal by malignant hepatic failure in a quarter of cases or, at the extreme, be totally asymptomatic. The aims of treatment are: 1) in the immediate, to prevent death; 2) subsequently, to prevent progression to cirrhosis. The majority of the wide range of treatments suggested have been evaluated in controlled trials. It is thus easy to show that corticosteroids are effective in severe acute alcoholic hepatitis, i.e. with encephalopathy and coagulation disturbances, but no in ordinary forms. Although logical, nutritional supplements, whether enteral or parenteral, have no influence on the course of acute alcoholic hepatitis. The same applies to anabolic steroids, the association insulin-glucagon, antifibrosis agents or "hepatoprotectors". The elimination of alcoholic intoxication remains the most important point, accepted by all hepatologists.

Hepatitis after germander (Teucrium chamaedrys) administration: another instance of herbal medicine hepatotoxicity.

OBJECTIVE: To show that germander (Teucrium chamaedrys), an herbal medicine used to facilitate weight loss, may be hepatotoxic and to delineate the nature of the injury. DESIGN: Retrospective study. SETTING: Liver units of several centers in the French Network of Pharmacovigilance. PATIENTS: Seven patients who developed hepatitis after germander administration and who had no other cause of liver injury. MEASUREMENTS: Clinical examination, liver function tests, various serologic tests, ultrasonography, and histologic study. RESULTS: Hepatitis characterized by jaundice and a marked increase in serum aminotransferase levels occurred 3 to 18 weeks after germander administration. Liver biopsy specimens in three patients showed hepatocyte necrosis. After discontinuing treatment with germander, jaundice disappeared within 8 weeks and recovery was complete in 1.5 to 6 months. In three cases, germander readministration was followed by the prompt recurrence of hepatitis. CONCLUSION: Germander may be hepatotoxic, which supports the view that herbal medicines are not always as safe as generally assumed.

[Hepatitis observed during a treatment with a drug or tea containing Wild Germander. Evaluation of 26 cases reported to the Regional Centers of Pharmacovigilance]. / Hépatites observées au cours d'un traitement par un médicament ou une tisane contenant de la Germandrée petit-chêne. Bilan des 26 cas rapportés aux Centres Régionaux de Pharmacovigilance.

Twenty-six patients developed acute hepatitis after taking Germander, an herbal medicine used to facilitate weight loss. Hepatitis occurred within 9 weeks of treatment and was characterized by jaundice and a high level of aminotransferases. Recovery was obtained between 1.5 and 6 months after withdrawal. In 12 cases, readministration was followed by prompt recurrence of hepatitis. The causal relationship is probable but the mechanism remains unclear: there was no relationship with the daily intake and the duration of treatment; there are no toxicological data on Germander compounds; contamination by an unidentified product is possible but has not been demonstrated. It should be emphasized that readministration of Germander produced recurrence of the hepatitis whenever it was performed. As a result, the French Ministry of Health recently decided to prohibit national-wide all Germander containing medicinal products.

Tianeptine, a new tricyclic antidepressant metabolized by beta-oxidation of its heptanoic side chain, inhibits the mitochondrial oxidation of medium and short chain fatty acids in mice.

Tianeptine is a new tricyclic antidepressant which is metabolized mainly by beta-oxidation of its heptanoic side chain. We determined the effects of tianeptine on the mitochondrial oxidation of natural fatty acids in mice. In vitro, tianeptine (0.5 mM) inhibited by only 32% the formation of beta-oxidation products from [1-14C]palmitic acid by hepatic mitochondria, but inhibited by 71% that from [1-14C]octanoic acid and by 51% that from [1-14C]butyric acid. The activity of the tricarboxylic acid cycle, assessed as the in vitro formation of [14C]CO2 from [1-14C]acetylcoenzyme A was decreased by 51% in the presence of tianeptine (0.5 mM). The inhibition of both beta-oxidation and the tricarboxylic acid cycle appeared reversible in mitochondria from mice exposed to tianeptine in vivo but incubated in vitro without tianeptine. In vivo, administration of tianeptine (0.0625 mmol/kg i.p.), decreased by 53 and 58%, respectively, the formation of [14C]CO2 from [1-14C]octanoic acid and [1-14C]butyric acid, but did not significantly decrease that from [1-14C]palmitic acid. After administration of high doses of tianeptine, however, formation of [14C]CO2 from [1-14C]palmitic acid became inhibited as well, transiently after 0.25 mmol/kg and durably (greater than 24 hr) after 0.75 mmol/kg i.p. Hepatic triglycerides were increased 24 hr after administration of 0.75 mmol/kg i.p. of tianeptine, but not after 0.25 mmol/kg i.p. Microvesicular steatosis of the liver was observed in some mice after 0.75 mmol/kg i.p., but not after 0.5 mmol/kg i.p. We conclude that tianeptine inhibits the oxidation of medium- and short-chain fatty acids in mice. Microvesicular steatosis, however, requires very large doses in mice (0.75 mmol/kg i.p., i.e. 600-times the oral dose in humans), and is therefore unlikely to occur in humans.