Serum Liver Enzyme Concentrations Research Articles

Nonalcoholic fatty liver disease in adult hypopituitary patients with GH deficiency and the impact of GH replacement therapy

Liver dysfunction in adult hypopituitary patients with GH deficiency (GHD) has been reported and an increased prevalence of nonalcoholic fatty liver disease (NAFLD) has been suggested. The objective of the present study was to elucidate the pathophysiology of the liver in adult hypopituitary patients with GHD. We recruited 69 consecutive Japanese adult hypopituitary patients with GHD and examined the prevalence of NAFLD by ultrasonography and nonalcoholic steatohepatitis (NASH) by liver biopsy. Patients had been given routine replacement therapy except for GH. We compared these patients with healthy age-, gender-, and BMI-matched controls. We further analyzed the effect of GH replacement therapy on liver function, inflammation and fibrotic markers, and histological changes. The prevalence of NAFLD in hypopituitary patients with GHD was significantly higher than in controls (77 vs 12%, P<0.001). Of 16 patients assessed by liver biopsy, 14 (21%) patients were diagnosed with NASH. GH replacement therapy significantly reduced serum liver enzyme concentrations in the patients and improved the histological changes in the liver concomitant with reduction in fibrotic marker concentrations in patients with NASH. Adult hypopituitary patients with GHD demonstrated a high NAFLD prevalence. The effect of GH replacement therapy suggests that the NAFLD is predominantly attributable to GHD.

Non-alcoholic and alcoholic Fatty Liver Disease - two Diseases of Affluence associated with the Metabolic Syndrome and Type 2 Diabetes: the FIN-D2D Survey

BackgroundNon-alcoholic fatty liver disease (NAFLD) is known to be associated with the metabolic syndrome (MetS) and abnormal glucose tolerance. Whether alcoholic fatty liver disease (AFLD) is associated with similar metabolic abnormalities has not been examined in a population-based study. We aimed at assessing the prevalences of NAFLD and AFLD, and to examine to what extent these conditions are associated with MetS and abnormal glucose tolerance.MethodsThe cohort included 2766 Finnish subjects (45-74 years) from the population-based FIN-D2D survey. Features of insulin resistance, components of the MetS, glucose tolerance status by oral glucose tolerance test, serum liver enzyme concentrations, and daily alcohol consumption were assessed.ResultsSubjects with NAFLD and AFLD were equally obese and had similar fasting and insulin concentrations. The prevalences of NAFLD and AFLD were 21% (95% CI: 19%-22%) and 7% (95% CI: 6%-8%). The MetS was slightly more prevalent in AFLD (73%) than in NAFLD (70%, p = 0.028), and type 2 diabetes was similarly prevalent in NAFLD and AFLD (24-25%). The MetS and type 2 diabetes were more prevalent in subjects with NAFLD or AFLD compared to subjects with normal LFTs (53% and 14%, p < 0.0001 for both).Discussion and conclusionIn Finnish middle-aged population, the prevalence of NAFLD is 3-fold higher than that of AFLD. The prevalences of MetS and type 2 diabetes are, however, significantly increased in both NAFLD and AFLD compared to subjects with normal LFTs. Subjects with AFLD are thus similarly metabolically unhealthy as subjects with NAFLD.

Prevalence and Predictors of Abnormal Liver Enzymes in Young Women with Anorexia Nervosa

To determine the prevalence and predictors of abnormal liver enzyme levels in ambulatory young women with anorexia nervosa (AN). In this cross-sectional study of 53 females with AN, serum concentrations of liver enzymes and hormones were measured. Anthropometric, dietary, and body composition information was collected. Correlational analyses were performed between liver enzyme concentrations and these variables. Elevated alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT) levels were found in 14 subjects (26%) and 5 subjects (9%), respectively. ALT and GGT were inversely correlated with body mass index (r = -0.27 to -0.30, P < .049) and percentage body fat (r = -0.36 to -0.47, P < .007) but showed no relationship with lean body mass. Subjects with percentage body fat < 18% had higher ALT levels than those above this threshold (median 26.5 vs 18.0 U/L, P = .01). Liver enzyme concentrations did not correlate with dietary variables, except for GGT and percentage of calories from protein (r = 0.28, P = .04). Serum ALT and GGT concentrations are inversely related to adiposity in young women with AN. Future studies are needed to determine whether these liver enzyme elevations signify unrecognized, clinically relevant liver disease.

Impact of Intravenous Administration of Voriconazole in Critically Ill Patients with Impaired Renal Function

The administration of voriconazole by the intravenous (i.v.) route in patients with moderate or severe renal failure is limited because of potential toxic effects of the accumulation of the solvent vehicle sulphobutylether beta cyclodextrin sodium. This study aimed to assess the impact of intravenous voriconazole administration on renal and liver function in critically ill patients with impaired renal function treated with this antifungal drug. The study population consisted of a retrospective cohort of patients admitted to medical-surgical intensive care units (ICUs) who were treated with i.v. voriconazole for more than 3 days. Patients with impaired renal function were those with serum creatinine concentration >1.5 mg/dL, creatinine clearance <50 mL/min, or under any extrarenal depuration procedure. Renal damage was defined as an increase of at least ≥2 times initial serum creatinine level or starting of an extrarenal depuration procedure during voriconazole therapy. Liver damage was defined as an increase of ≥4 times the initial serum concentration of liver enzymes, or ≥2 times in patients with previous impaired liver function. A total of 69 patients was included in the study of which 26 (37.7%) had impaired renal function at the beginning of voriconazole treatment (serum creatinine >2.5 mg/dL in 10 patients). Mean (SD) duration of voriconazole treatment was 13.0 (9.5) days in patients with normal renal function and 11.2 (6.3) days in those with altered renal function. Renal damage during voriconazole therapy occurred in 13 (30.2%) patients with initial normal renal function and in 4 (15.4%) in patients with impaired renal function (P = 0.257). Liver damage during treatment with voriconazole was observed in 12 (27.9%) patients with normal initial renal function and in 3 (11.5%) patients with impaired renal function (P = 0.281). Renal failure developing during voriconazole treatment was associated with a significantly higher mortality rate (82.4% vs. 44.%, P= 0.01), except in the subgroup of patients with altered renal function before starting i.v. voriconazole (60% vs. 75%, P = 0.385). The use of i.v. voriconazole in ICU patients with pretreatment impaired renal function was not associated with renal or liver damage nor with an increase in ICU mortality.

Semimechanistic pharmacokinetic/pharmacodynamic model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET-743) treatment

Reversible transient elevations in transaminases have been observed after trabectedin administration. A semimechanistic pharmacokinetic and pharmacodynamic (PKPD) model was developed to evaluate the time course of alanine aminotransferase (ALT) elevation, tolerance development, and the hepatoprotective effect of dexamethasone on trabectedin-induced transient transaminitis following different dosing schedules in cancer patients. Trabectedin was administered to 711 patients as monotherapy (dose range: 0.024-1.8 mg/m(2)) as 1-, 3-, or 24-h infusions every 21 days; 1- or 3-h infusions on days 1, 8, and 15 every 28 days; or 1-h infusions daily for five consecutive days every 21 days. Population PKPD modeling was performed with covariate evaluation [dexamethasone use (469/711 pt), ECOG performance status scores (89.7% pts <or= 1), and body weight (36-122 kg)] on PD parameters, followed by model validation. Simulations assessed the influence of dosing regimen and selected patient factors on the time course of ALT and the effectiveness of the dose reduction strategy. A precursor-dependent PKPD model described the temporal relationship between ALT elevation and trabectedin concentrations, where the transfer process of ALT from hepatocytes to plasma is stimulated by trabectedin plasma concentrations. Overall, 66% of patients had transaminitis. Mean predicted (%SEM) baseline ALT (ALT(o)) and t (1/2) in plasma were 31.5 (5.1) IU/L and 1.5 days, respectively. The magnitude of the trabectedin stimulation of the ALT transfer rate from hepatocytes to plasma was 11.4% per 100 pg/mL of trabectedin plasma concentration. Dexamethasone decreased the rate of trabectedin-induced ALT release from hepatocyte by 63% (P < 0.001). Model evaluation showed that the model predicted incidence of grade 3/4 transaminase elevation was similar to the observed values. Simulations showed that severity of ALT elevation was dose- and schedule-dependent. The dose reduction strategy decreased the incidence of grade >or=3 toxicity by 13 and 39% following two and four cycles of therapy, respectively. A PKPD model quantifying the hepatoprotective effect of dexamethasone on transient and reversible transaminitis following trabectedin treatment has been developed. The model predicts that co-administration of dexamethasone and the suggested dose reduction strategy based on the serum concentration of liver enzymes will enhance the safe use of trabectedin in the clinic.

Monitoring Abnormal Laboratory Values as Antecedents to Drug-Induced Injury

Clinical abnormalities associated with drug therapy may lead to injury if untreated. Detection of preceding drug-related hazardous conditions (DRHCs) may provide the opportunity to prevent injury. This study evaluated the frequency of abnormal laboratory values attributed to the effect of drugs. A total of 590 patients consecutively admitted to a surgical intensive care unit during a 3-month period were prospectively studied. Serum electrolyte, platelet, creatinine, glucose, magnesium, and liver enzyme concentrations were classified as either normal or abnormal using standard criteria. DRHCs were abnormal laboratory results determined to be caused by drugs. DRHCs were detected in 16.4% of patients, reflecting a rate of 47 events per 1,000 patient days. 66%, 22%, and 12% of DRHCs were categorized as either definite, probable, or possible, respectively. In 97% of suspected DRHCs, clinicians responded by ordering additional laboratory tests or changing drug regimens. Monitoring laboratory values and assessing the association to medications may reduce the risk of injury consequent to adverse drug events.

Adiponectin, hepatocellular dysfunction and insulin sensitivity.

Insulin resistance plays a major aetiological role in the development of fatty liver disease. Because adiponectin is a hepatic insulin sensitizer and also an inhibitor of tumour necrosis factor, a cytokine known to induce insulin resistance and liver damage, we wished to study whether low circulating adiponectin would be associated with higher serum concentrations of liver enzymes in healthy subjects. Cross-sectional, population-based study dealing with diabetes prevalence in northern Spain. Two hundred and fifty-seven apparently healthy Caucasian subjects consecutively enrolled in the study. Adiponectin serum levels were measured by enzyme-linked immunosorbent assay (ELISA), liver function tests (LFTs) by colourimetry and insulin resistance by the homeostasis model of assessment (HOMA value). Adiponectin levels were negatively correlated with alanine aminotransferase (ALT) and gamma-glutamyltranspeptidase (GGT), before and after adjustment for sex, age, body mass index (BMI) and insulin resistance (ALT; r = -0.32, P < 0.001; adjusted: r = -0.13, P = 0.033; GGT; r = -0.31, P < 0.001; adjusted: r = -0.16, P = 0.011). Additionally, adiponectin correlated with alkaline phosphate (ALKP) only after adjusting for the same confounding variables (r =-0.10, P = 0.098; adjusted: r = -0.14, P = 0.031). A general linear model, adjusting for age, sex and BMI, was constructed to predict the decrease in circulating adiponectin for each LFT value (i.e. ALT, GGT and ALKP) above the median. Beyond one LFT value above the median, serum adiponectin decreased by -0.97 mg/l (95% CI -1.46 to -0.48). In multiple regression analysis, sex, BMI and adiponectin, but not insulin resistance, predicted serum concentrations of both ALT and GGT, explaining 19% and 14% of their variance, respectively. Age, BMI and adiponectin, but not sex or insulin resistance, explained 20% of ALKP variance. Adiponectin levels are associated in healthy humans with plasma concentrations of various liver function tests. The contributions of adiponectin to maintaining liver integrity through the regulation of both insulin sensitivity and/or the inflammatory response merit further studies.

Protective effect of FK506 and thromboxane synthase inhibitor on ischemia-reperfusion injury in non-heart-beating donor in rat orthotopic liver transplantation.

The study investigated the possibility of pharmacologically modulating hepatic allograft function from non-heart-beating donors (NHBDs) using male Lewis rats. The donors were divided into 4 groups: Group 1 in which the vehicle was administered, Group 2 in which FK506 (tacrolimus; a powerful immunosuppressive agent) was administered, Group 3 in which OKY046 (a specific thromboxane synthetase inhibitor) was administered and Group 4 in which FK506 and OKY046 were administered. The recipients received orthotopic liver transplantation. The survival rates differed significantly between the recipients that had received liver transplantation from Groups 1 and 4. The serum liver enzyme and inflammatory cytokine concentrations of the recipients which had received liver transplantation from Groups 2, 3 and 4 were significantly lower than those of the recipients that had received liver transplantation from Group 1. Although there was no significant difference, all parameters were better in the recipients that had received transplantation from Group 4 than those that had received transplantation from Groups 2 and 3. The action mechanisms of FK506 and OKY046 are completely different. Therefore, concomitant use of FK506 and OKY046 might have additive effects on liver transplantation from NHBDs. In conclusion, we demonstrated that pretreatment of NHBDs using FK506 and OKY046 ameliorated graft viability.

Superior mesenteric arteriovenous fistula causing massive hematemesis

Surgery 2003;134:102-4.

Hormone replacement therapy may improve hepatic function in women with Turner's syndrome.

Women with Turner's syndrome (TS) have recently been shown to be at an increased risk of developing chronic liver disease. There has been some concern that oestrogen replacement therapy may exacerbate hepatic dysfunction. The aim of this study was to assess hepatic function in women with TS and to determine the effect of oral oestradiol valerate on liver enzymes. A retrospective review of liver enzymes of 80 women with TS, followed by a prospective study looking at serum liver enzyme concentrations in 20 women with TS following 3 months on and off hormone replacement therapy (HRT) (oestradiol valerate, 2 mg/levonorgestril 75 microg). Liver enzymes (gamma glutamyl transferase, aspartate transaminase and alkaline phosphatase), albumin and bilirubin were measured on and off HRT. Viral hepatitis serology and liver autoantibodies were tested in patients with abnormal liver function. Thirty-five out of 80 women (44%) had elevated serum liver enzyme concentrations. Two women (2.5%) had a mildly raised serum bilirubin, but protein synthesis was normal in all subjects. HRT resulted in a significant fall in all liver enzymes (P < 0.05) but did not affect serum protein concentrations Women with Turner's syndrome often have elevated liver enzymes. Oestrogen/progestagen therapy using oestradiol valerate improves liver function in this group of patients. The mechanisms behind this are unclear.

Short-term effects of statin therapy in patients with hyperlipoproteinemia after liver transplantation: results of a randomized cross-over trial

Background/Aims : Hyperlipoproteinemia is frequent following liver transplantation and may lead to atherosclerosis. Lipid-lowering agents may be useful, but could interfere with the function of the transplanted organ and with immunosuppression. We therefore evaluated in a prospective, randomized, open-labeled cross-over trial the effect of two frequently used 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (pravastatin 10 mg d −1 and cerivastatin 0.1 mg d −1) in hyperlipoproteinemic patients after liver transplantation. Methods : Sixteen patients (6.3±2.0 years post-transplantation, cyclosporine n =11, tacrolimus n =5) with hyperlipoproteinemia (cholesterol 246±42, triglycerides 191±87, low-density lipoprotein (LDL)-cholesterol 161±35, high-density lipoprotein (HDL)-cholesterol 44±11 mg dl −1) were included. Treatment periods of 6 weeks were separated by a 4-week washout period. Results : Both medications were tolerated well, no effects on serum concentrations of liver enzymes or immunosuppressive agents were observed. Cerivastatin and pravastatin decreased ( P <0.001) cholesterol by 21±10% and 15±10%, LDL-cholesterol by 27±14% and 17±15%, respectively, while triglyceride and HDL-cholesterol concentrations did not change significantly. LDL/HDL-cholesterol markedly improved ( P <0.001) by 29±16% (cerivastatin) and 16±16% (pravastatin). Cerivastatin was more potent than pravastatin in patients receiving cyclosporine A, while there was no significant difference in patients receiving tacrolimus. Conclusions : Low-dose cerivastatin and pravastatin significantly improve lipid profiles following liver transplantation without affecting liver function or immunosuppression.

Liver enzyme abnormalities in gram-negative bacteremia of premature infants.

Hyperbilirubinemia and liver enzyme abnormalities are commonly observed in sepsis. However, the frequency in premature neonates and the specific relation to gram-negative bacteria are not known. Charts of all preterm infants who had positive blood cultures for either gram-negative bacteria or coagulase-negative staphylococci were reviewed. Neonates with gram-negative bacteremia (n = 54) were compared with neonates with coagulase-negative staphylococcal bacteremia (n = 31). In addition infants with gram-negative bacteremia and elevated liver enzymes (n = 25) were compared with infants with gram-negative bacteremia and normal liver enzymes (n = 29). Liver enzyme abnormalities accompanied 46.3% (25 of 54) of gram-negative bacteremia and 12.9% (4 of 31) of episodes of coagulase-negative staphylococcal bacteremia (P = 0.002). Serum concentrations of liver enzymes were significantly higher in infants with gram-negative bacteremia than in those with coagulase-negative staphylococcal bacteremia (P < 0.0001), but no difference in alkaline phosphatase serum values was observed. Infants with gram-negative bacteremia and elevated liver enzymes were not fed for a longer period than infants with gram-negative bacteremia and normal liver enzymes (7.3 +/- 6.3 days vs. 4.0 +/- 4.3 days, P = 0.03), and this was accompanied by significant conjugated hyperbilirubinemia (P < 0.0001). Ventilation, total parenteral nutrition and medications were not responsible for the observed differences. Klebsiella pneumoniae bacteremia was commonly associated with elevated liver enzymes (12 of 18), whereas none of the infants with Pseudomonas aeruginosa bacteremia had elevated liver enzymes. Gram-negative bacteremia is commonly associated with cholestasis in premature neonates. Liver enzyme abnormalities are more common than elevated conjugated bilirubin, not all gram-negative bacteria have the same effect and the lack of enteral feeding seems to play a more significant role than the administration of parenteral nutrition.

Serum liver enzymes in Turner syndrome.

Increased serum concentrations of liver enzymes are sometimes observed, in the absence of clinical symptoms of liver disease, in patients with Turner syndrome. The purpose of this study was to evaluate, in our Turner patients, serum liver enzyme levels and to find a cause for their increase. In 70 Turner patients, serum AST, ALT, GGT levels were evaluated every 6 months during a period of 0. 8-21.9 years. In patients in whom increased values of liver enzymes were found, serological markers for infectious hepatitis, serum hepatitis C virus RNA and virus genotype, IgG and IgA antibodies to gliadin and endomysium, coeruloplasmin, copper, alpha(1)-antitrypsin, total proteins and electrophoresis, IgG, IgA, IgM, fibrinogen, prothrombin, alkaline phosphatase, creatine kinase and total and direct bilirubin were also determined. Antinuclear, anti-smooth muscle and anti-liver-kidney microsome antibodies together with antithyroglobulin and anti-thyroid peroxidase antibodies were determined in all patients and in 166 age-matched female controls. In 22 patients, increased liver enzymes were observed, not related to karyotype. Follow-up showed that the hepatic disorder did not worsen with the time. Serological markers of hepatitis C virus were positive in three patients. When the serum liver enzyme increase was first observed in the other 19 patients with high enzyme levels (group A), 14 patients had never been submitted to hormonal treatment, 4 were on oestrogen/gestagen treatment and 1 was being treated with both growth hormone and oestrogen. Coeliac disease, alpha(1)-antitrypsin deficiency and Wilson disease were ruled out by appropriate investigations. In 8/19 group A patients, antinuclear and/or anti-smooth muscle antibodies were present versus 6/48 of patients with normal liver enzymes (group B). Thyroid antibodies were found in 8/19 patients in group A and in 13/48 in group B. Weight excess SDS was significantly higher in Turner girls with liver enzyme increase. Ultrasonography, performed in 17 patients of group A, showed mild hepatomegaly in 4 and increased echogenicity with fatty infiltration in 6. Hepatic abnormalities in Turner syndrome are not progressive. Oestrogen should not be considered the main cause of increased liver enzymes in Turner syndrome since most of our patients with this finding had not been previously treated with oestrogens. An auto-immune pathogenesis might be considered in some cases, whereas the association with weight excess seems the most frequent cause of liver disorder in Turner syndrome.

Factors associated with osteonecrosis in the femoral head in chronic alcoholism.

While alcohol abuse is a possible etiologic factor in osteonecrosis in the femoral head (ON), the relationship between alcoholic liver dysfunction and ON is uncertain. Among 336 patients with alcoholic liver dysfunction who had radiographic examination of the hip at two hospitals for alcohol abuse treatment in southern Japan, the records for 291 men and 1 woman (mean age, 47.8 years; range, 24 to 72 years) had adequate information available concerning daily and cumulative alcohol intake, duration of intake, serum concentrations of liver enzymes, and platelet count. These variables were investigated for any correlation between the 8 patients with radiographic evidence of ON and the 284 without. Liver biopsy was performed in 223 patients. Except for alanine aminotransferase, liver enzyme concentrations were significantly lower in patients with ON than in those without. Histologically, 2 patients with ON were diagnosed with cirrhosis; 1 with pre-cirrhotic changes; and 2 with fibrosis. These results suggested that ON occurred in the late stages of liver disease when serum enzyme concentrations had returned to normal or were only mildly elevated.

Cure of Helicobacter pylori infection and healing of duodenal ulcer: comparison of pantoprazole-based one-week modified triple therapy versus two-week dual therapy

Objective: Eradication of Helicobacter pylori ( H. pylori) is recommended as the first-line therapeutic concept for reliable long-term prevention of duodenal ulcer (DU) relapse. Current treatment regimens vary in efficacy, complexity, and compliance. To assess the efficacy of pantoprazole in H. pylori eradication in parallel groups of patients using two eradication regimens. Methods: Patients, (18–85 yr old; intention-to-treat, n = 286) with proven DU, positive rapid urease test (biopsy), and 13C-urea breath test (UBT) were included in a prospective, randomized, multicenter study. Modified triple therapy consisted of 40 mg pantoprazole b.i.d., 500 mg clarithromycin t.i.d., and 500 mg metronidazole t.i.d. for 7 days (PCM therapy); dual therapy consisted of 40 mg pantoprazole b.i.d. and 500 mg clarithromycin t.i.d. for 14 days (PC therapy). In both groups 40 mg pantoprazole o.d. was given until day 28 when healing of DU was evaluated endoscopically; H. pylori status was assessed by UBT on day 56. Results: H. pylori eradication rate was 95% in PCM versus 60% in PC therapy groups (per-protocol population, p < 0.001), and 82% in PCM versus 50% in PC therapy in the intention-to-treat patient population ( p < 0.001). The DU healing rate was 98% in the PCM and 95% in the PC therapy groups (per-protocol population). Both regimens were similarly well tolerated. Adverse events in both regimens included taste disturbance, diarrhea, and increased serum concentration of liver enzymes, at an incidence of < 10%. Conclusions: Compared to 2-wk PC therapy (pantoprazole and clarithromycin), the 1-wk PCM therapy (pantoprazole, clarithromycin, and metronidazole) is a significantly superior and highly promising strategy for eradication of H. pylori.

Liver and renal function after repeated sevoflurane or isoflurane anaesthesia.

To compare retrospectively liver and renal function after repeated exposure (twice) to sevoflurane or isoflurane. Sixty patients were studied for liver and renal function after repeated exposure within 30 to 180 days to sevoflurane (30 patients) or isoflurane (30 patients). Serum concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBil), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GTP), blood urea nitrogen (BUN) and creatinine (Cr) were measured before and, 1, 3, 7, and 14 days after surgery. Qualitative analyses of urinary protein and glucose were done 1, 3, and 7 days after surgery. The number of patients with abnormal values in AST, ALT and GTP was larger in the isoflurane than in the sevoflurane group. BUN and Cr were within normal range after anaesthesia in either group. Renal excretion of protein and glucose increased one and three days after anaesthesia with no difference between the anaesthetics. None of the variables showed differences between the first and second anaesthesia after either anaesthetic. Repeat exposure to sevoflurane or isoflurane within 30 to 180 days had no additional risk of increasing serum concentration of liver enzymes or increasing urinary excretion of protein and glucose compared with the first exposure to the same anaesthetic.

Augmentation of Mitochondrial Reduced Glutathione by S-Adenosyl-L-Methionine Administration in Ischemia-Reperfusion Injury of the Rat Steatotic Liver Induced by Choline-Methionine-Deficient Diet

We examined whether warm ischemia-reperfusion (I/R) damage of the rat steatotic liver can be reduced by administration of S-adenosyl-L-methionine (SAMe). We examined the effect of SAMe on the mitochondrial reduced-glutathione (GSH) pool. Sixty minutes of partial left lobar vascular clamping followed by 2 h of reperfusion were employed for a model of hepatic warm ischemia. Either 5% dextrose or SAMe was injected intraperitoneally 2 h before I/R in steatotic rats (S-D5% or S-SAMe group). Serum liver enzyme concentrations 2 h after reperfusion were significantly lower in the S-SAMe group than in the S-D5% group. The cytosolic and mitochondrial GSH concentrations after I/R were significantly higher in the S-SAMe group than in the S-D5% group (p < 0.05). The cytosolic and mitochondrial oxidized-glutathione/GSH ratios after I/R were significantly greater in the S-D5% group than in the S-SAMe group (p < 0.01). The adenosine triphosphate concentration was higher in the S-SAMe group than in the S-D5% group (p = 0.0515). These results show that hepatocellular and mitochondrial oxidative stress after I/R in the steatotic liver can be reduced by administration of SAMe. The results also show that mitochondrial function and hepatocellular integrity can be restored by administration of SAMe in steatotic rats.

Efficacy of taxol in the orpk mouse model of polycystic kidney disease.

Polycystic kidney disease (PKD) a is common disease in the human population that can lead to renal failure and death. Taxol has recently been reported to be of therapeutic benefit in the cpk mouse model of PKD. To determine whether these results also apply to other models of PKD, we studied the effects of taxol treatment on the development of renal cysts and biliary hyperplasia/dysplasia/fibrosis in the orpk mouse mutant, a unique murine model for human autosomal recessive PKD. We report no significant differences between the treatment and control groups with respect to weight gain, survival, urine to serum osmolality ratio, and serum concentration of liver enzymes. Moreover, renal cystic development was not affected by taxol treatment in the orpk mutant animals. This was confirmed by lectin staining and morphometric analysis of the renal cysts, which indicated no significant differences between treatment groups. Therefore, while taxol has a positive effect on the cystic kidney disease in cpk mutant mice, this effect is not applicable to all forms of PKD.

Acarbose-induced acute severe hepatotoxicity

Acarbose, a complex oligosaccharide produced by fermentation of Actinoplanes utahensis, has been available in Europe for several years, and has recently been approved by the US Food and Drug Administration for treatment of noninsulin-dependent diabetes mellitus (NIDDM). Oral acarbose competitively and reversibly inhibits the small intestine brush-border alpha-glucosidases, which results in delayed carbohydrate breakdown and thus a dose-dependent reduction in postprandial hyperglycaemia and hyperinsulinaemia. Since systemic absorption of acarbose itself is limited to about 1% of the dose, gastrointestinal disturbances are the most frequently observed adverse effects. In addition, mild symptomless increase in aminotransferase activity has only occasionally been reported without associated changes in other hepatic function tests. As far as we are aware only one suspected case of clinically significant acarbose-induced hepatotoxicity has been reported in English-language publications. We describe a patient who developed severe liver injury while on acarbose. A 40-year-old woman was admitted in January, 1995, because of vomiting, abdominal pain, and jaundice. 5 years earlier she had started 25 mg intramuscular fluphenazine decanoate (once monthly) for schizophrenia, with good control of the disease. Although she was a mild wine drinker, her liver function tests, prothrombin time, and abdominal ultrasonography done in July, 1994, were normal. The patient had NIDDM and had been receiving glibenclamide 10 mg day for the past year, without adequate glycaemic control. 2 months before admission, acarbose (100 mg every 8 h) had been added to the treatment, which improved her metabolic condition. Physical examination was unremarkable apart from jaundice, hepatomegaly, and abdominal tenderness. Her aspartate aminotransferase (AST) concentration was 1938 IU/L, alanine aminotransferase (ALT) 2350 IU/L, alkaline phosphatase 325 IU/L, and total bilirubin 188 μmol/L (conjugated bilirubin, 171 μmol/L). Prothrombin time was mildly decreased. Abdominal ultrasonography showed only hepatomegaly. Results of serological tests for viral and non-viral infectious hepatitis, iron and copper studies, and tests for autoantibodies were normal or negative. Acarbose was discontinued, but fluphenazine and glibenclamide were maintained. 2·5 months later AST had fallen to 50 IU/L, and ALT to 69 IU/L. 10 months after admission all laboratory values had returned to normal (AST 20 IU/L; ALT 25 IU/L). Acarbose was reinstituted (50 mg thrice daily) with the patient’s informed consent and under intensive clinical surveillance. Her serum liver enzyme concentrations rose again after a week, reaching a peak 1 month later (AST 37 IU/L; ALT 87 IU/L). Acarbose was stopped, and her liver enzyme values were within the normal range 1 month and 4 months later. Various factors, such as the temporal relation between the initiation of acarbose and the onset of the liver injury, in addition to the effects of the discontinuation and resumption of the drug, are highly suggestive of acarbose-induced acute hepatotoxicity (probably of idiosyncratic type). Monitoring of serum aminotransferase activity during acarbose treatment may be warranted to avert this unpredictable but potentially severe complication.

Effects of serotonin reuptake inhibitors on hemostasis.

To examine the hematologic safety profile of the selective serotonin reuptake inhibitors (SSRIs), with particular emphasis on the effects of these drugs on platelet aggregation. Platelet aggregation studies were undertaken at baseline, and repeated 2 and 4 weeks after the initiation of treatment with an SSRI. Other investigations undertaken included analysis of serum electrolyte and liver enzyme concentrations, complete blood count, and coagulation studies. Patients were also assessed for clinical signs of bleeding. Eight patients (7 treated with fluoxetine, 1 with paroxetine) completed the study protocol. Repeated ANOVA revealed no abnormalities in platelet aggregation, hematopoiesis, or coagulation profile. No patient developed clinical signs of abnormal hemostasis during the study period. A statistically significant elevation in the mean serum bilirubin concentration was detected, but this was not of clinical significance. Although the SSRIs may cause abnormal hemostasis, this effect is probably rare. Another possibility is that abnormal hemostasis is more likely to occur when high doses of SSRIs are administered.