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PubMed1993

Toxic hepatic injury is associated with proliferation of portal nerve fibers.

Hepatic innervation is thought to play an important role in the regulation of metabolism. Regenerating liver nodules in cirrhosis have a paucity of nerve fibers. The situation in chronic necroinflammatory and cholestatic liver diseases is unclear. We have therefore evaluated hepatic innervation in toxic hepatitis and non-specific reactive hepatitis. Liver biopsies from 42 patients considered to have chronic toxic liver injury, 25 patients with chronic reactive inflammatory infiltrates and variable degree of hepatic fibrosis and the control group comprising of 23 individuals who had undergone laparotomy for non-hepatic reasons (trauma etc.) and who had entirely normal hepatic histology were studied histologically and immunohistochemically for the presence of nerve fibres. Semiquantitative analysis showed significant proliferation of portal nerve fibers in biopsies confirmatory of toxic liver injury. Assessment of hepatic neural elements may be useful in the differential diagnosis of unspecified liver injury where toxic injury may be implicated.

Adolescent↗
PubMed1992

Methionine enkephalin accumulates in plasma but not in brain or cerebrospinal fluid of rats with acute toxic hepatitis.

In order to determine whether acute toxic hepatitis in the rat is associated with an accumulation of methionine enkephalin in plasma and increased blood-to-brain transfer of methionine enkephalin, immunoreactive methionine enkephalin levels were determined by radioimmunoassay in plasma, cerebrospinal fluid and whole brain samples from rats with thioacetamide induced acute toxic hepatitis. Thioacetamide treatment was associated with an 8.7-fold increase in plasma immunoreactive methionine enkephalin levels (P less than or equal to 0.005) 24 h after treatment. However, this marked elevation in plasma immunoreactive methionine enkephalin levels was not associated with an increase in whole brain or cerebrospinal fluid immunoreactive methionine enkephalin levels. These data suggest that increased plasma-to-brain transfer of methionine enkephalin does not occur in this model of acute toxic hepatitis.

Acute Disease↗
PubMed1989

Model systems for detecting the hepatic toxicity of pyrrolizidine alkaloids and pyrrolizidine alkaloid N-oxides.

Indicine N-oxide (INO) is a pyrrolizidine alkaloid (PA) with antitumor activity in animals and humans. Prior studies showed that despite the known hepatic toxicity of the PAs, INO did not produce hepatic toxicity in animals but caused unpredictable lethal hepatic toxicity in humans. In this study we have attempted to find a model system for predicting the hepatotoxic potential of antitumor PAs. Primary cultures of rat hepatocytes showed toxicity only with the most hepatotoxic PAs such as lasiocarpine, but did not detect toxicity with other PAs. Subchronic intraperitoneal administration of PAs to weanling rats and adult mice produced, in surviving animals, hepatic megalocytosis and centrilobular necrosis with heliotrine (H) and 9-O-(R(-)-2-(4'-chlorophenyl)-2-hydroxybutyryl)retronecine N-oxide (RC1NO) but only megalocytosis with INO. Thus, despite previous reports, weanling rats offered no advantage over adult mice for detecting significant hepatic toxicity with PAs. Phenobarbital pretreatment of the mice did not increase the hepatic toxicity of any of the PAs. Subchronic oral administration of PAs to adult mice produced hepatic megalocytosis and centrilobular necrosis in surviving animals with H and RC1NO and megalocytosis with INO. Animals that died acutely following oral administration of INO showed hepatic centrilobular necrosis. Administration of several courses of INO intravenously to dogs produced histological evidence of centrilobular hemorrhagic necrosis. It is concluded that there is no single animal model that will predict hepatic toxicity of the type seen in humans with the antitumor PAs. A combination of studies using adult mice and dogs and lethal doses of the PAs offers the best way of detecting potential hepatic toxicity.

Administration, Oral↗
PubMedDate not supplied

[Effect of chloride-hydrocarbonate sodium mineral water Rychal-Su on some physiological and biochemical indicators of the liver in rats with experimental toxic hepatitis].

Rats with tetrachlormethan-induced toxic hepatitis were given mineral water Rychal-Su from the spring in Dagestan. Investigation of some physiological and biological parameters has shown that Ry-chal-Su mineral water has a hepatoprotective action, in toxic hepatitis improves protein spectrum in the serum, inhibits transaminase activity and accumulation of malonic dialdehyde in the liver, improves excretory and antitoxic functions.

Animals↗
PubMed2000

Amanita virosa induced toxic hepatitis: report of three cases.

We report here three cases of Amanita virosa induced toxic hepatitis. Two of the three cases recovered but the other died 10 days after mushroom ingestion. Since the mortality of Amanita mushroom induced toxic hepatitis is very high, prompt diagnosis and aggressive therapeutic measures should be initiated as soon as possible. Our cases showed that the initial serum aminotransferase levels might not predict the clinical outcome of the patient, but that the prothrombin time (PT) seemed to be a more useful prognostic marker. Close monitoring of aminotransferase levels and PT as well as appropriate therapy are recommended. All three cases showed signs of proteinuria and we were able to characterize mixed tubular and glomerular type proteinuria at 3 or 4 days after ingestion in two cases. Among the previously reported Korean cases of suspected Amanita induced toxic hepatitis, most species could not be identified except for four cases of Amanita virosa. No cases of Amanita phalloides induced toxic hepatitis have been identified in Korea so far.

Adult↗
PubMedDate not supplied

[Regulatory properties of glucose-6-phosphate dehydrogenase from rat liver under conditions of the intensification of free-radical oxidation stimulated by toxic hepatitis].

Rat liver oxidative stress caused by toxic hepatitis is accompanied by increased activity of glucose-6-phospate dehydrogenase (EC 1.1.1.4.9; G6PDG). Electrophoretically homogenous G6PDG preparations purified from livers control rats and animals with hepatitis had specific activity of 4.13 and 6.54 EU, respectively. Fe2+ and Cu2+ ions showed non-competetive type inhibition of G6PDG at normal and under pathological condition, whereas Ca2+ activated G6PDG. Hydrogen peroxide exhibited mixed type inhibition of G6PD (K(i) 0.36 mM and 0.95 mM at norm and experimental toxic hepatitis, respectively). The participation of oxidised and reduced glutathione in G6PDG activity regulation has been shown.

Animals↗
PubMed1981

[Comparative hepatic toxicity of perhexiline maleate and griseofulvin in mice].

Hepatic toxicity was observed in mice which had received Griseofulvin or Perhexilin Maleate over a period of several months. Treatment of griseofulvin alone gave rise to hepatitis with the presence of Mallory bodies (MB) whereas the same length of treatment with Perhexilin Maleate was associated with steatonecrosis with an absence of MB. When treatment was followed by a one month rest period hepatic lesions disappeared with no trace of sequelae. Cross-treatment studies showed that one week of Perhexiline Maleate was sufficient to induce MB in mice pretreated with Griseofulvin. Similarly, Griseofulvin administered to mice pretreated with Perhexilin Maleate gave rise to MB formation after one week as opposed to the usual two months incubation time (DENK et al.). The histological nature and mode of formation of these MB was identical to that encountered in acute alcoholic hepatitis. On addition, combined drug therapy employing Perhexilin Maleate suggests a particular hepatic toxicity in man in cases where the liver has become predisposed due to other therapeutic.

Animals↗
PubMed1994

Comparison of in vivo and in vitro rat hepatic toxicity of coumarin and methyl analogues, and application of quantitative morphometry to toxicity in vivo.

The rat hepatic toxicity of coumarin and methyl analogues (3-,4-methyl coumarin and 3,4-dimethylcoumarin) has been determined in vivo and in vitro (freshly-isolated cells). Coumarin at a dose of approximately 1 mmol/kg produced clear histological evidence of centrilobular necrosis, while the methyl analogues at an equivalent dose were much less toxic. By use of a systematic random sampling protocol and quantitative morphometry it was determined that there was a lobar variation in the extent of hepatic damage but that this exhibited random inter-animal variation. The order of cytotoxicity in vitro was identical to that observed in vivo. In hepatocytes depleted of glutathione the toxicity of all four compounds was increased. This was particularly marked for the 3-methyl analogues, such that the order of toxicity was different to that observed in vivo and in hepatocytes not depleted of glutathione.

Animals↗
PubMed1989

[Anatomo-pathologic study of hepatic toxicity in intra-arterial hepatic chemotherapy].

Intra-arterial hepatic chemotherapy is effective in the treatment of colorectal or endocrine carcinomas liver metastasis. However it is potentially toxic for the healthy liver. To check this, we studied non tumoral liver specimens in 14 patients treated by intra-arterial chemotherapy with 5 fluorouracil, 5 fluoro-2 deoxyuridine and an association of 5 fluorouracil and streptozotocin. The main hepatic lesions observed were: sclerosing cholangitis, central vein (dilatation and fibrosis) and moderate hepatocellular necrosis or cholestasis in the centrolobular area. Thus intra-arterial hepatic chemotherapy has important toxic effects on healthy liver, even if clinical and biological liver disturbances are minimal in most cases. Caution must be exercised in using this method.

Adult↗
PubMed1990

[Fatal toxic hepatitis in pregnancy. A discussion of the role of methyldopa].

The authors report a case of toxic hepatitis in a woman of 22 years of age in the third trimester of her first pregnancy treated by methyldopa for hypertension of pregnancy which was diagnosed at 33 weeks of amenorrhoea. The prodromal symptoms were mild and consisted of nausea, vomiting and rise in temperature and this phase was associated with febrile jaundice without pruritus and it was only associated with coagulation disorders in the third stage of labour. This was a case of mixed cytolytic hepatitis (ASAT x 3N) and cholestasis (x 1.5N). The outcome was fatal. The patient died three days after delivery following haematemesis and renal failure as well as hepatic encephalopathy. The main diagnostic feature was acute hepatic stasis in spite of the absence of pruritus and the presence of a raised temperature after hematolytic, viral and obstructive causes had been eliminated. Histology confirmed that there was toxic hepatitis. This aetiology was suggested by the timing of the symptoms after MD (methyldopa) had been taken. Elkington described methyldopa hepato-toxicity in 1969. Fatal cases in the literature were in patients who were over 40 years of age. Methyldopa is used in pregnant women because of its safety as far as the fetus is concerned. Mechanism by which it causes toxic hepatitis is a combination of abnormal metabolism (the cytochrome P450 chain produces an antigen) and an immune reaction in response to this antigen and these explain why such severe and potentially fatal forms of the condition exist.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Acute hepatic toxicity during cyclic chemotherapy in non Hodgkin's lymphoma.

BACKGROUND AND OBJECTIVE: Hepatic toxicity directly related to the drugs administered in cyclic chemotherapy (CT), although sometimes serious, does not limit the treatment of non-Hodgkin's lymphoma (NHL). Nevertheless, reports of reactivation of viral hepatitis in NHL patients with B virus (HBV) infection are becoming more frequent. The recent observation of two cases of severe liver toxicity directly correlated to CT and a case of fatal hepatic failure due to HBV replication prompted us to evaluate the hepatic toxicity of CT in 98 consecutive B-cell NHL patients treated with relatively homogeneous cyclic CT. METHODS: Acute hepatic toxicity was retrospectively evaluated in 98 consecutive B-cell NHL patients who received induction CT. HBV and HCV markers were checked at presentation. All patients were tested for ALT and bilirubin before every CT course, while tests for HBV-DNA and/or for HCV-RNA were performed with PCR only when hepatitis occurred. RESULTS: At presentation 22 patients (22.4%) were positive for HBsAg, and 11 (15.9%) were positive for anti-HCV. Acute hepatitis developed in 12 (12.2%) NHL patients: 8 (out of 22) in HBsAg-positive and anti-HCV-negative patients, 3 (out of 76) in HBsAg-negative patients, and 1 (out of 11) in anti-HCV-positive patients. Hepatitis was attributed to reactivation of chronic B hepatitis in 3 patients and to drug toxicity in 3 others; hepatitis was undefined in 6 cases. INTERPRETATION AND CONCLUSIONS: Drug-related liver toxicity is not a rare occurrence in NHL patients. Reactivation of HBV replication is responsible for a relevant number of the hepatitis cases observed. We did not detect acute hepatitis due to the reactivation of HCV replication (in chronic C hepatitis carriers).

Adult↗
PubMed2006

Correlation between melphalan pharmacokinetics and hepatic toxicity following hyperthermic isolated liver perfusion for unresectable metastatic disease.

BACKGROUND: In the present work, we report on the results of our pilot study of hyperthermic isolated hepatic perfusion (IHP) with melphalan alone for patients with unresectable metastatic liver tumors refractory to conventional treatments, with particular regard to the correlation between pharmacokinetic findings and hepatic toxicity. PATIENTS AND METHODS: Inclusion criteria were unresectable liver metastases, hepatic parenchyma replacement <or=50%, normal liver function, and previous failure of at least one conventional treatment. IHP was performed under hyperthermic conditions with melphalan (1.5 mg/kg body weight). Completeness of vascular isolation of the liver and drug distribution volumes of the perfusion circuit were assessed by a radiolabeled albumin-based method. Drug concentrations in perfusate and plasma were measured by means of high-performance liquid chromatography (HPLC). RESULTS: Twenty patients with unresectable liver metastases underwent IHP. No intraoperative mortality occurred. Treatment-related systemic toxicity was minimal and reversible. Three patients (15%) experienced grade 4 hepatic toxicity and died due to liver failure and subsequent multiorgan failure. Other six patients had significant (grade 3-4) but transitory hepatic toxicity. Complete and partial responses were observed in three and nine out of 17 evaluable patients, respectively (overall response rate = 70%). The pharmacokinetics study showed a 3% mean perfusate-to-plasma drug leakage (range 1-6%). Logistic regression analysis showed that drug concentration in the perfusate circuit, but not preoperative tests, significantly and independently correlated with hepatic toxicity (P = 0.028). CONCLUSIONS: Following melphalan-based IHP, objective tumor regression could be observed in a remarkable percentage of patients refractory to standard treatments. However, hepatic toxicity and related mortality were significant. Our findings suggest that drug dosage personalization based on the measurement of drug distribution volumes might minimize hepatic toxicity.

Adult↗
PubMed1990

Severe hepatic toxicity after treatment with vincristine and dactinomycin using single-dose or divided-dose schedules: a report from the National Wilms' Tumor Study.

To evaluate the effect of dactinomycin (AMD) dose and schedule on the frequency of severe hepatic toxicity in unirradiated National Wilms' Tumor Study-4 (NWTS-4) patients, we reviewed the records of 154 children randomized to single-dose AMD and 176 children randomized to divided-dose AMD administration. All the children also received vincristine in identical dose schedules for the first 10 weeks. The frequency of severe hepatic toxicity encountered in the early weeks of therapy was 14.3% (five of 35) among patients treated with 60 micrograms/kg of AMD, 3.7% (four of 108) among patients given 45 micrograms/kg, and 2.8% (five of 176) among patients treated with 15 micrograms/kg per dose times five doses (P = .025). The data suggest an increased frequency of severe hepatic toxicity with the higher, single-dose schedule of administration. However, the frequency of severe hepatic toxicity among the patients in the two remaining groups is markedly higher than the 0.4% observed among similar unirradiated patients in NWTS-3. The relationship of this toxicity to factors such as anesthetic agents, blood transfusions, intercurrent viral infection, or other presently unrecognized causes can be further evaluated only with a detailed investigation such as a case-control study.

Antineoplastic Combined Chemotherapy Protocols↗