Hepatic Enzyme Concentrations Research Articles

Elevated hepatic enzymes and incidence of venous thromboembolism: a prospective study

PurposeApproximately 10% of the general population has elevated blood concentrations of hepatic enzymes, which are linked to increased coagulation markers. We tested whether elevated hepatic enzymes are associated with increased risk of venous thromboembolism (VTE). MethodsWe followed 12,604 adults with measurements of alanine transaminase, aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT) prospectively for VTE occurrence. ResultsAST and GGT above the laboratory normal values were associated over two decades of follow-up with increased risk of total (n = 532) and provoked VTE (n = 332), but with not unprovoked VTE (n = 200). In a model adjusted for age, race, sex, hormone replacement, alcohol intake, diabetes, body mass index, estimated glomerular filtration rate, and C-reactive protein, the hazard ratios (HR) (95% confidence interval) for high versus normal AST were 1.46 (1.00–2.11) for total VTE and 1.83 (1.21–2.79) for provoked VTE. For high GGT, the HR were 1.34 (1.06–1.69) for total VTE and 1.43 (1.07–1.91) for provoked VTE. When follow-up was limited to the first 10 years, associations were even stronger (HR ≈ 1.7 for total VTE). ConclusionsElevated concentrations of two hepatic enzymes (AST and GGT) in this general middle-aged population are associated with a modestly increased risk of VTE.

English

The aim of the study was to investigate the effects of taurine on biochemical parameters in male Wistar rats co-exposed to chlorpyrifos and lead. Fifty rats were divided into five groups of ten rats each. The distilled water (DW) group received distilled water and the soya oil (SO) group received soya oil (1 ml/kg). Other groups were treated sequentially with taurine (50 mg/kg), chlorpyrifos (4.25 mg/kg, 1/20th LD50) and lead (233.25 mg/kg, 1/20th LD50), and the last group received taurine (50 mg/kg), chlorpyrifos (4.25 mg/kg) and lead (233.25 mg/kg). The treatments were administered once daily by oral gavage. The rats were sacrificed and blood samples were collected after 16 weeks. The serum samples were analyzed for proteins, enzymes, urea and creatinine concentration. The hepatic and renal malondialdehyde concentration and activities of hepatic and renal antioxidant enzymes were evaluated. The results indicated that chronic co-administration of chlorpyrifos (CPF) and lead acetate (LA) induced biochemical alterations in the rats. It is proposed that taurine antioxidant (TA) decreased the alterations in the biochemical parameters partly through its antioxidant, hepatoprotective and nephroprotective properties. It is concluded that taurine is a useful prophylactic agent against biochemical toxicity in individuals that are constantly co-exposed to chlorpyrifos and lead in the environment.   Key words: Taurine, chlorpyrifos, lead, oxidative stress, biochemical effects.

Cardiorespiratory Fitness, Waist Circumference, and Alanine Aminotransferase in Youth

Nonalcoholic fatty liver disease (NAFLD) is considered the liver component of the metabolic syndrome and is strongly associated with cardiometabolic diseases. In adults, cardiorespiratory fitness (CRF) is inversely associated with alanine aminotransferase (ALT), a blood biomarker for NAFLD. However, information regarding these associations is scarce for youth. The objective of this study is to examine associations between CRF, waist circumference, and ALT in youth. Data were obtained from youth (n = 2844, 12-19 yr) in the National Health and Nutrition Examination Survey 2001-2004. CRF was dichotomized into youth FITNESSGRAM categories of "low" and "adequate" CRF. Logistic and quantile regression were used for a comprehensive analysis of associations, and variables with previously reported associations with ALT were a priori included in the models. Results from logistic regression suggested that youth with low CRF had 1.5 times the odds of having an ALT >30 than youth with adequate CRF, although the association was not statistically significant (P = 0.09). However, quantile regression demonstrated that youth with low CRF had statistically significantly higher ALT (+1.04, +1.05, and +2.57 U·L) at the upper end of the ALT distribution (80th, 85th, and 90th percentiles, respectively) than youth with adequate CRF. For every 1-cm increase in waist circumference, the odds of having an ALT >30 increased by 1.06 (P < 0.001), and the strength of this association increased across the ALT distribution. Future studies should examine whether interventions to improve CRF can decrease hepatic fat and liver enzyme concentrations in youth with ALT ≥80th percentile or in youth diagnosed with NAFLD.

Study of Liver Function Tests and Renal Function Tests in diabetic type II patients

In individuals who have diabetes type 2, they are a higher incidence of liver function test abnormalities than individuals who do not have diabetes. The most common liver function tests ( LFTs) include the serum aminotransferases, alkaline phosphatase, bilirubin, albumin, and prothrombin time. Aminotransferases, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), measure the concentration of intracellular hepatic enzymes that have leaked into the circulation and serve as a marker of hepatocyte injury. The study was done on (55) blood samples which divided in two groups: first group was (40) the patients (diabetic typeII ) (25 females &15 males) and the second was (15) the control group which( 8 females &7 males) , glucose , Urea, Creatinine, Alkaline phosphates ,ALT and AST were measured in these groups. there is no significant difference between females and males in controls and patients, there is significant difference between the controls group and the patients and the correlation between the glucose and biochemical parameters in female patients was glucose levels were positive significant correlated with Creatinine, Alkaline phosphate, ALT and AST, but non- significant with Urea, but In males the correlation between the glucose and all biochemical parameters even Urea. As conclusions there is relationship between the glucose and biochemical parameters above .

γ-Glutamyl transferase

The incidence of metabolic syndrome has increased in Mexico and nonalcoholic fatty liver disease (NAFLD) is a common complication. The authors aimed to evaluate the role of hepatic enzymes as biomarkers for NAFLD in patients presenting metabolic syndrome. We studied 193 nondiabetic individuals with metabolic syndrome identified from a population-based cross-sectional survey. To identify NAFLD, real-time gray-scale abdominal ultrasound was performed, and the right, left, and caudate hepatic lobules were observed to assess the size, echogenicity, and borders of the liver. All individuals answered a questionnaire for risk factors, and anthropometric measures and blood pressure were obtained. The concentration of hepatic enzymes and insulin in blood was measured and the Homeostatic Model Assessment index was calculated. A total of 160 individuals were identified as presenting NAFLD (82.9%). Body weight, BMI, and the waist-hip ratio increased as a direct result of the presence and severity of fatty liver. A similar situation was observed in the levels of triglyceride and hepatic enzymes aspartate aminotransferase and γ-glutamyltransferase (GGT), basal insulin level, and the Homeostatic Model Assessment index. In a multivariate model, the variables associated with the occurrence of NAFLD were sex, triglyceride and GGT levels, and obesity. The main factors that predict the occurrence of NAFLD are levels of triglyceride and GGT in the blood, as well as obesity. The accumulation of fat in the liver, in addition to increased oxidation and oxidative stress at the hepatic level, may be the mechanisms through which these factors increase the risk of NAFLD.

Evaluation of short-term safety and efficacy of HMG-CoA reductase inhibitors in hypercholesterolemic patients with elevated serum alanine transaminase concentrations: PITCH study (PITavastatin versus atorvastatin to evaluate the effect on patients with hypercholesterolemia and mild to moderate hepatic damage)

We evaluated the safety and efficacy of the 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and pitavastatin in patients with mild-to-moderate increased levels of hepatic enzymes. In this 12-week, prospective, randomized, open-label, active drug-controlled, and dose-titration study, 189 subjects with elevated low-density lipoprotein cholesterol (≥3.36 mmol/L) and alanine transaminase (ALT; ×1.25≥ and ≤×2.5 ULN; 50-100 IU/L) concentrations, but nonalcoholic and serologically negative for viral hepatitis markers at screening, were randomized to 12 weeks of treatment with pitavastatin 2-4 mg/day (PITA, n= 97) or atorvastatin 10-20 mg/day (ATOR, n= 92). Pitavastatin and atorvastatin equally reduced low-density lipoprotein cholesterol concentrations (-34.6 ± 16.0% and -38.1 ± 16.2%, respectively, P < .0001 each by analysis of variance). Seven (n= 4 PITA, n= 3 ATOR) and 10 (n= 5 PITA, n= 5 ATOR) patients experienced episodes of ALT >100 IU/L at weeks 4 and 12, respectively, with one patient in each group excluded because of severe ALT elevation >3× ULN (>120 IU/L) at week 4. The 135 patients with persistently increased ALT concentrations at screening and randomization showed significant reductions in ALT after 12 weeks of treatment with PITA (n= 68, -8.4%) or ATOR (n= 67, -8.9%; P < .05, analysis of variance). Serial nonenhanced computed tomography in 38 subjects (n= 18 PITA, n= 20 ATOR) showed that both statins reduced the severity of hepatic steatosis, especially in subjects with clear hepatic steatosis at baseline (n= 9 PITA, n= 10 ATOR). Statin treatment of another 38 subjects with spontaneous normalization of ALT at randomization had little effect on ALT levels but did not induce severe ALT elevation (>100 IU/L). Conventional doses of pitavastatin and atorvastatin effectively and safely reduce elevated hepatic enzyme concentrations.

Apixaban versus enoxaparin in patients with total knee arthroplasty

It was the objective of this study to systematically compare the effects of apixaban versus enoxaparin in patients following total knee arthroplasty (TKA). A systematic search of Medline, EMBASE, Cochrane Central Register of Controlled Trials was conducted. Eligible studies were prospective, randomised control trials (RCT) of apixaban therapy, comparing with enoxaparin, in patients who have a high risk of venous thromboembolism (VTE) after TKA. Three RCTs involving 7,337 individuals were identified, of whom 4,057 were treated with apixaban 2.5 mg once daily, and 3280 were subcutaneous enoxaparin (40 mg once-daily or 30 mg twice-daily). Meta-analysis demonstrated the odds ratio (OR) for the composite of major VTE (proximal deep-vein thrombosis and pulmonary embolism) for apixaban versus enoxaparin was 0.47 (95% confidence interval [CI]: 0.27 to 0.82, 0.6% vs. 1.2%) and 2.09 (95%CI: 0.99 to 4.45, 0.6% vs. 0.3%), respectively. All-cause mortality occurred in 0.2% of the apixaban group versus 0.09% of the enoxaparin group (OR=1.74; 95%CI, 0.51 to 5.95). With respect to safety outcomes, apixaban was associated with a lower major bleeding rate than enoxaparin (OR=0.55, 95%CI: 0.32 to 0.96). No significant differences were detected between two strategies in other endpoints of safety profile analysed: clinically relevant non-major bleeding, raised hepatic transaminase enzyme or bilirubin concentrations and arterial thromboembolic events. In conclusion, apixaban is non-inferior to subcutaneous enoxaparin when used for the same duration, with considerable advantage regarding safety profile of major bleeding after TKA.

Glucagon increases hepatic mRNA concentrations of ureagenic and gluconeogenic enzymes in early-lactation dairy cows

Exogenous glucagon increases hepatic glucose synthesis in part by increasing hepatic extraction of amino acids from blood for conversion to glucose. To examine the role of glucagon in orchestrating gene expression of gluconeogenic and ureagenic enzymes, we determined the mRNA concentrations of key hepatic ureagenic and gluconeogenic enzymes at d 11, 15, and 22 postpartum in multiparous Holstein cows that received 0 or 5mg of glucagon in 60mL of saline by subcutaneous injection every 8h for 14 d starting on d 8 postpartum. On d 11 postpartum, glucagon increased the hepatic mRNA concentrations for all measured ureagenic enzymes (carbamoylphosphate synthetase I, ornithine transcarbamylase, and argininosuccinate synthetase) and gluconeogenic enzymes (pyruvate carboxylase and cytosolic and mitochondrial forms of phosphoenolpyruvate carboxykinase) and increased or tended to increase mRNA concentrations of gluconeogenic enzymes on d 15 postpartum but not on d 22. The effect of glucagon to increase mRNA concentrations of ureagenic and gluconeogenic enzymes was limited to times when concentrations of plasma insulin were not increased. Our results suggest that hepatic gene expression of key ureagenic and gluconeogenic enzymes in early-lactation dairy cows is responsive to hormonal regulation by glucagon.

Mirazid shows insignificant activity against ovine fascioliasis

In a recent study, the fasciolicidal activity of Mirazid (a myrrh-derived drug) and its effect on the function and histopathology of host liver were investigated in Egyptian sheep, with triclabendazole (TCBZ) used as the positive control. Sheep were infected with metacercariae (150/animal) and treated 3 months later, either with Mirazid (10 mg/kg/day for six consecutive days) or TCBZ (a single dose of 10 mg/kg), or left untreated, as controls. When the animals were killed 4 weeks after the end of treatment, no Fasciola flukes or eggs could be found in the animals given TCBZ but the number of flukes found in the Mirazid-treated animals was only 6% lower than that recorded in the untreated sheep (a statistically insignificant difference). In terms of their Fasciola egg loads, serum concentrations of hepatic enzymes and hepatic histopathological changes, the Mirazid-treated sheep appeared very similar to the untreated, infected animals. The TCBZ-treated animals, in contrast, showed remarkably little evidence of hepatic pathology. It therefore appears that, in the treatment of ovine fascioliasis, at least some batches of Mirazid have little, if any, value.

Metabolically healthy but obese individuals: relationship with hepatic enzymes

The purpose of this study was to investigate the level of plasma hepatic enzymes in obese women displaying the metabolically healthy but obese (MHO) phenotype. We studied 104 obese, sedentary, postmenopausal women. Subjects were classified as MHO or at risk based on insulin sensitivity as assessed with the oral glucose tolerance test–derived Matsuda index. Subjects were divided into quartiles according to insulin sensitivity values. Subjects in the upper quartile were categorized as MHO, whereas subjects in the lower 3 quartiles represented at-risk subjects. Outcome measures were hepatic enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, and γ-glutamyltransferase [GGT]], high-density lipoprotein cholesterol, triglycerides, triglycerides to high-density lipoprotein cholesterol ratio, apolipoprotein B, fatty liver index, body composition (dual-energy x-ray absorptiometry), and visceral adipose tissue (computed tomography). The MHO individuals had significantly lower concentrations of ALT, AST, and GGT as well as a lower fatty liver index compared with at-risk subjects ( P < .05). In addition, lean body mass index and visceral adipose tissue were significantly lower in MHO individuals ( P < .05). Moreover, stepwise regression analysis showed that ALT explained 17.9% of the variation in insulin sensitivity in our cohort, which accounted for the greatest source of unique variance. Results of the present study indicate that postmenopausal women displaying the MHO phenotype present favorable levels of ALT, AST, and GGT. Lower concentrations of hepatic enzymes, in particular, lower circulating ALT levels, in MHO individuals may reflect lower hepatic insulin resistance and lower liver fat content; and this could be involved, at least in part, in the protective profile of MHO individuals.

Inflammation, hepatic enzymes and resistance training in individuals with metabolic risk factors

Increases in inflammatory markers, hepatic enzymes and physical inactivity are associated with the development of the metabolic syndrome (MetS). We examined whether inflammatory markers and hepatic enzymes are correlated with traditional risk factors for MetS and studied the effects of resistance training (RT) on these emerging risk factors in individuals with a high number of metabolic risk factors (HiMF, 2.9 +/- 0.8) and those with a low number of metabolic risk factors (LoMF, 0.5 +/- 0.5). Twenty-eight men and 27 women aged 50.8 +/- 6.5 years (mean +/- sd) participated in the study. Participants were randomized to four groups, HiMF training (HiMFT), HiMF control (HiMFC), LoMF training (LoMFT) and LoMF control (LoMFC). Before and after 10 weeks of RT [3 days/week, seven exercises, three sets with intensity gradually increased from 40-50% of one repetition maximum (1RM) to 75-85% of 1RM], blood samples were obtained for the measurement of pro-inflammatory cytokines, C-reactive protein (CRP), gamma-glutamyltransferase (GGT) and alanine aminotransferase (ALT). At baseline, HiMF had higher interleukin-6 (33.9%), CRP (57.1%), GGT (45.2%) and ALT (40.6%) levels, compared with LoMF (all P < 0.05). CRP, GGT and ALT correlated with the number of risk factors (r = 0.48, 0.51 and 0.57, respectively, all P < 0.01) and with other anthropometric and clinical measures (r range from 0.26 to 0.60, P < 0.05). RT did not significantly alter inflammatory markers or hepatic enzymes (all P > 0.05). HiMF was associated with increased inflammatory markers and hepatic enzyme concentrations. RT did not reduce inflammatory markers and hepatic enzymes in individuals with HiMF.

Hepatic Enzymes are Associated with components of Metabolic Syndrome and Elevated ALT, GGT Predicts the Incidence of Metabolic syndrome

Recently, several population based studies have suggested concentrations of hepatic enzymes are more than the meaning of marker for liver disease and are associated with increase in the risk of car...

Outbreaks of Renal Failure Associated with Melamine and Cyanuric Acid in Dogs and Cats in 2004 and 2007

Sixteen animals affected in 2 outbreaks of pet food-associated renal failure (2 dogs in 2004; 10 cats and 4 dogs in 2007) were evaluated for histopathologic, toxicologic, and clinicopathologic changes. All 16 animals had clinical and laboratory evidence of uremia, including anorexia, vomiting, lethargy, polyuria, azotemia, and hyperphosphatemia. Where measured, serum hepatic enzyme concentrations were normal in animals from both outbreaks. All animals died or were euthanized because of severe uremia. Distal tubular lesions were present in all 16 animals, and unique polarizable crystals with striations were present in distal tubules or collecting ducts in all animals. The proximal tubules were largely unaffected. Crystals and histologic appearance were identical in both outbreaks. A chronic pattern of histologic change, characterized by interstitial fibrosis and inflammation, was observed in some affected animals. Melamine and cyanuric acid were present in renal tissue from both outbreaks. These results indicate that the pet food-associated renal failure outbreaks in 2004 and 2007 share identical clinical, histologic, and toxicologic findings, providing compelling evidence that they share the same causation.

Hypoxic Hepatopathy: Pathophysiology and Prognosis

Dramatic transient elevation in serum concentrations of hepatic enzymes occurs in some patients following a hypo-perfusion state. This entity is variously termed "shock liver" or "ischemic hepatitis", since the pathogenesis is considered to be ischemia. However, hypotension or shock is not always present. We analyzed the medical records of 293 patients (322 episodes) who had a hypoxic state and were admitted to the critical care units of two general hospitals over a 13-year period. Hepatic injury was identified in about 1% of patients in critical care admissions. In addition to hypotension, the causes for hepatic injury were a low flow state secondary to congestive heart failure and hypoxia from sepsis or respiratory failure and hypoxemia from a variety of etiologies. These values were mostly normalized within several days when the hypoxic etiology was corrected and a serious co-morbid state did not intervene. Marked elevation of hepatic enzymes can be identified not only in patients with hypotension, but also in normotensive patients in hypoxic state. Thus, the condition is appropriately termed hypoxic hepatopathy.

Effect of hyperbaric oxygen on cold storage of the liver in rats

The depletion of biochemical energy stores during prolonged cold storage is one of the most critical events of cold ischemia-reperfusion (CI/R) injury. The aim of this study was to evaluate the effect of hyperbaric oxygen (HBO) treatment on CI/R injury. Livers were harvested from male Wistar rats and stored for 24 h at 4 degrees C in University of Wisconsin solution (Group 1). Others were additionally treated with HBO during the preservation period (Group 2). At the end of the 24 h cold preservation, the concentrations of hepatic enzymes and lipid peroxidation (LPO) in the effluent and the hepatic adenosine triphosphate (ATP) levels were measured. After preservation, the livers were reperfused for 90 min with an oxygenated Krebs-Henseleit bicarbonate buffer. Perfusate samples were obtained serially, and portal flow rates were also recorded. In group 2, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and LPO into the effluent at the end of preservation were decreased and the depletion of ATP was prevented (P<0.05). After reperfusion, the portal flow was significantly improved in group 2 (P<0.05). The time-dependent increase of alanine aminotransferase levels (ALT) observed in group 1 was suppressed significantly in group 2, and total bile production during 90 min of reperfusion was significantly greater in group 2 (P<0.05). The structure of the livers in group 2 was significantly well maintained, and the liver weight change ratio was significantly greater in group 1 (P<0.05). HBO treatment during cold storage seems to prevent hepatic ischemic injury and have protective effects against CI/R injury by attenuating the depletion of energy stores.

Potential drug—Drug interaction between interferon alfa-2b and gemfibrozil in a patient with malignant melanoma

Background: In the United States, patients withhigh-risk stage II or III melanoma are often treated with adjuvant interferon (IFN) therapy for 1 year after surgery. Adverse events associated with IFN alfa-2b use are primarily constitutional symptoms. However, hypertriglyceridemia requiring treatment has been reported. Objective: The aim of this report was to describe apotential drug—drug interaction between IFN alfa-2b and gemfibrozil in a patient with malignant melanoma. The possible mechanism of this potential interaction was examined. Methods: This report presents the case of a 43-year-oldmale patient weighing 101 kg with newly diagnosed stage III melanoma of the left arm, with metastasis to the supraclavicular node. The patient presented to the University of California Irvine Medical Center, Orange, California with severe gastrointestinal (GI) symptoms and elevated hepatic enzyme concentrations at week 48 of 104 of adjuvant treatment of malignant melanoma (IFN alfa 11 MU SC TIW in combination with the investigational melanoma vaccine melanoma theraccine 1.25 mL [I mL lysate + 0.25 mL vaccine adjuvant] given SC at weeks 1, 2, 3, 4, 8, 16, 24, 32, 40, and 48 and then every 8 weeks until week 104), and IFN-induced hypertriglyceridemia (gemfibrozil 600 mg PO BID). The patient had no history of cardiovascular or GI disease and was not receiving any concomitant medication. The possible mechanism of this potential IFN alfa-gemfibrozil interaction as related to the cytochrome P450 (CYP) enzyme system was assessed. Results: In this case of a possible drug-drug interactionbetween IFN alfa 11 MU TIW and gemfibrozil 600 mg BID in a patient undergoing treatment for IFN-induced hypertriglyceridemia, the Naranjo Adverse Drug Reactions (ADR) Probability Scale score was 7 (ie, ADR possibly related to treatment). Conclusions: Both IFN and gemfibrozil inhibitthe activity of the hepatic enzymes CYP1A2 and CYP2C19. A possible drug-drug interaction between IFN alfa 11 MU TIW and gemfibrozil 600 mg BID was reported in a patient undergoing treatment for IFN-induced hypertriglyceridemia.

Hepatobiliary Neuroendocrine Carcinoma in Cats: A Clinicopathologic, Immunohistochemical, and Ultrastructural Study of 17 Cases

Hepatobiliary neuroendocrine carcinoma was diagnosed in 17 cats in a period of 10 years. Seven tumors were of intrahepatic origin, one of which was a composite containing components of epithelial and neuroendocrine carcinoma. Nine tumors were of extrahepatic origin, and one tumor was located in the gall-bladder. The cats were adult and geriatric, and the male : female ratio varied according to tumor group. Hepatomegaly, anorexia, weight loss, and vomiting were the most common clinical signs observed in the cats with hepatic neuroendocrine carcinoma. The cats with extrahepatic neuroendocrine carcinoma showed these signs plus icterus (5/9) and high concentrations of hepatic enzymes. Histologically, the hepatic neuroendocrine carcinomas had two patterns, one with acinar structures separated by vascular stroma lined by cuboidal or columnar cells and the other solid with groups of anaplastic cells separated by vascular stroma. The composite tumor consisted of both bile duct carcinoma and neuroendocrine carcinoma. The extrahepatic neuroendocrine carcinomas and the gallbladder neuroendocrine carcinoma were characterized by solid sheets or groups of round to oval cells with vascular or fibrovascular stroma. Immunohistochemical examination of 10 of the neuroendocrine carcinomas revealed that all 10 stained with neuron-specific enolase; one bile duct carcinoma and the gallbladder carcinoma stained with chromogranin; four of five bile duct carcinomas and the gall bladder carcinoma stained with synaptophysin; and one bile duct carcinoma stained with gastrin. One cat with hepatic carcinoma had duodenal ulcer; in this cat, ultrastructural studies showed neurosecretory granules leading to the diagnosis of Zollinger-Ellison syndrome. In four cats in which necropsy was permitted, carcinomatosis (4/4), lymph nodes (4/4), lungs (2/4), and intestines (1/4) were the metastatic sites. Fourteen of the 17 cats were euthanatized during or immediately after surgery.

Fatal colchicine poisoning by accidental ingestion of meadow saffron-case report

A 62-year-old male died of colchicine poisoning after accidental ingestion of Colchicum autumnale (meadow saffron). He ate a salad of plant with green leaves regarded as wild garlic ( Allium ursinum). A few hours later he developed symptoms of gastroenteritis and was admitted to hospital. In spite of gastric lavage, activated charcoal and supportive measures, multi-organ system failure developed over the next two days. Laboratory analysis showed highly elevated blood concentrations of hepatic enzymes, creatine kinase, lactate dehydrogenase and blood urea nitrogen, as well as leukocytopenia and thrombocytopenia. Mechanical ventilation, dopamine, noradrenaline, crystalloid solutions and fresh frozen plasma were applied but despite treatment the patient died five days after the ingestion. Post-mortem examination revealed hepatic centrilobular necrosis, nephrotoxic acute tubular necrosis, petechial bleeding in fatty tissue, blunt and shortened intestinal villi and cerebral toxic edema. Botanical identification of incriminated plant gave Colchicum autumnale which confirmed colchicine poisoning. Although the accidental ingestion of Colchicum autumnale is rare and to our knowledge only five such cases have been described in detail, this is the second fatal case in Croatia described in the last 3 years.

Efficacy of preconditioning with N-acetylcysteine against reperfusion injury after prolonged cold ischaemia in rats liver in which glutathione had been reduced by buthionine sulphoximine.

To investigate the ability of N-acetylcysteine (NAC) to prevent cold ischaemic-reperfusion injury and improve hepatic integrity in a glutathione-depleted condition. Open laboratory study. University hospitals, Japan and France. 40 male Wistar rats. To produce a glutathione-depleted liver, buthionine sulphoximine (BSO) was injected intraperitoneally 2 hours before either NAC or 5% dextrose was infused 15 minutes before the liver was harvested. We used an isolated perfused rat liver model that had undergone prolonged hypothermic ischaemia, cold-storage for 48 hours and reperfusion for 120 minutes. Concentrations of hepatic enzymes released into samples of perfusate, concentration of adenosine triphosphate in liver tissue, concentrations of reduced and oxidized glutathione in perfusate, and bile production. The concentrations of the hepatocellular enzymes and oxidised glutathione in the perfusate samples were significantly reduced in the NAC group compared with the 5% dextrose group. Bile production improved significantly in the NAC group compared with the 5% dextrose group. The concentration of reduced glutathione in liver tissue was not increased by NAC. In a glutathione-depleted liver NAC prevented hepatic injury and improved liver integrity after a cold ischaemic-reperfusion injury, by acting not as a substrate for glutathione synthesis but as a direct free radical scavenger.

Abnormalities in liver enzymes during simultaneous therapy with itraconazole and amphotericin B in leukaemic patients

Sir, Systemic mycoses, such as invasive aspergillosis, are usually treated with antifungal drugs such as iv amphotericin B or itraconazole capsules. The plasma concentrations of itraconazole observed in patients are sometimes much higher than the minimal therapeutic level (1000 ng/mL), and the potential hepatic toxicity of the drug needs to be evaluated. A retrospective study on the effect of itraconazole on liver enzyme levels was conducted after checking bioavailability by plasma assays. Twenty patients, hospitalized between 1 January 1993 and 1 February 1998 were studied. Fourteen had leukaemia, four chronic respiratory insufficiency and one cystic fibrosis, while one had a lung transplant, all complicated by fungal ‘infections’ (12 definitely or probably had invasive aspergillosis, seven were colonized with an Aspergillus sp. and one had Scedosporium sp. sinusitis). Inclusion criteria were: a curative treatment by itraconazole followed by at least one serum concentration (out of three to six assays) 2500 ng/mL of unchanged itraconazole and of its active metabolite (total 5000 equivalent ng/mL). Patients with known hepatic illness before the start of itraconazole therapy, and those with a history of alcohol abuse, were excluded. Patients were treated for 44–455 days (median 143 days with itraconazole 200–600 mg/day (900 mg/day in two patients for 8 days). Twelve patients, all with leukaemia, received itraconazole and amphotericin B for 10–54 days (median 28 days). None of these patients received a bone marrow transplant. No disorders were observed in eight patients, even during the period of high plasma itraconazole concentration. One patient with liver dysfunction presented with cholecystitis at the onset of itraconazole therapy, which was resolved by surgery, but no subsequent hepatic disorders were seen. The 11 other patients, all with leukaemia, had increases in -glutamyltranspeptidase ( GT) and alkaline phosphatase (AP) (median value of 6.5 and 2.5 higher than the normal limit). In nine of these patients, ALT levels were also increased. In three patients such abnormalities were only seen during the period of high plasma itraconazole concentration, with a decrease following a decrease of itraconazole treatment. Different co-drugs were given to these 11 patients and their possible interactions were analysed by a causality assessment. Amphotericin B was the only drug administered, in addition to itraconazole, to all these 11 patients with hepatic disorders. Another leukaemic patient was also treated with itraconazole and amphotericin B, with no hepatic disorders. For the 12 patients treated with itraconazole and amphotericin B, the GT, AP and ALT concentrations were measured at three times: (i) before the beginning of antifungal therapy (period A), during administration of amphotericin B plus itraconazole (and within 21 days after amphotericin B treatment was ended, a time corresponding to seven halflives of the drug) (period B) and 2 months after the end of amphotericin B treatment (period C) (Figure). For each patient, hepatic enzyme concentrations were greatest during period B (Friedman test: P 0.001 for GT and AP, P 0.0015 for ALT). In seven patients, these abnormalities disappeared when amphotericin B was discontinued, although itraconazole therapy was continued. In three other patients, hepatic enzyme abnormalities were observed 5–19 days after the end of amphotericin B therapy. For one patient, the data for period C were not available. A significant increase in hepatic enzyme values, in 11 (92%) out of 12 leukaemic patients was seen. This increase appeared not to be related to the period of high plasma itraconazole concentration for eight of the patients but it was observed during simultaneous treatment with itraconazole plus amphotericin B or a few days after amphotericin B treatment ended.