Mean Serum Alanine Aminotransferase Research Articles

Safety of Intermittent Pringle Maneuver Cumulative Time Exceeding 120 Minutes in Liver Resection

We retrospectively compared the short-term outcome of a consecutive cohort of patients who underwent hepatectomy with intermittent clamping ranging between 60 and 120 minutes with those having a clamping time exceeding 120 minutes. Intermittent Pringle maneuver is widely used to minimize blood loss during hepatectomy, without an established time limit. However, many authors claim it is dangerous for patient outcome. Among 426 consecutive patients who underwent hepatectomy, we retrospectively selected 189 whose intermittent clamping time exceeded 60 minutes: 117 of these had intermittent Pringle maneuver lasting less than 120 minutes (group 1) and 72 clamping time exceeded 120 minutes (group 2). Groups were homogeneous for demographics, preoperative laboratory tests, background liver, and type of tumors. Operation length, and number of lesions removed, was significantly higher in group 2. Conversely, the two groups experienced similar amount of blood loss, rate of blood transfusions, overall and major morbidity, and 30- and 90-day postoperative mortality. In particular, in group 2 there was no mortality at all. Mean serum total bilirubin and alanine aminotransferase level on seventh pod resulted significantly higher in group 2, conversely mean aspartate aminotransferase, cholinesterases, and prothrombin time not differed in 2 groups. This study shows that hepatectomies done with intermittent clamping exceeding 120 minutes are as safe as those performed with shorter one despite more complex tumor presentations. This seems encouraging the diffusion of procedures done in 1 stage for extensive liver diseases despite the prolonged clamping time.

Baseline CD4+ T lymphocyte cell counts, hepatitis B and C viruses seropositivity in adults with Human Immunodeficiency Virus infection at a tertiary hospital in Nigeria

Ekiti State of Nigeria is known to have the lowest prevalence of HIV in Nigeria. University Teaching Hospital (UTH), Ado Ekiti was recently upgraded to serve as one of the three centres for HIV/AIDS referral, diagnosis and treatment in Ekiti State. We evaluated the baseline immunologic and biochemical parameters of patients presenting at the ART clinic of University Teaching Hospital, Ado Ekiti, Ekiti State. All HIV seropositive patients not yet on antiretroviral therapy, who presented at the ART Clinic within the study period had at the first visit to the clinic, their blood sample taken for CD4 cell counts estimation, HBsAg and anti- HCV screening, ALT, AST as well as hemoglobin estimation as part of the routine workup to assess their disease health status and need for antiretroviral therapy. Statistical significance was taken as p< 0.05. A total of 273 patients comprising 79 (28.9%) males and 194 (71.1%) females were included in the study (F:M = 2.46: 1). The mean age of the study population was 36.21 ± 10.20 years with mean age of males (39.52 ± 9.95 years) significantly higher than females (34.88 ± 10.02; p=0.001). The overall prevalence of HBsAg in the study population was 6.6% with a sex specific prevalence of 8.1% and 6% for males and females, respectively. No statistically significance difference in the mean serum alanine transaminase, serum aspartate transaminase, hemoglobin and CD4+ T- Lymphocytes cell count of those who had HBsAg negative status compared to those who had HBsAg positive status. Two (0.7%) of the patients had positive serum anti HCV antibodies. The CD4+ T- Lymphocytes cell count ranged between 5 - 1050 cells/µl with a mean of 286.19 ± 233.31 cells/µl. The majority of patients (71.8%) had a CD4+ T- Lymphocytes cell count < 350 cells/µl. At the time of presentation, majority of our patients had a CD4+ T- Lymphocytes cell count less than 350 cells/µl consistent with significant immune-suppression. More sustained and vigorous awareness campaigns still need to be done in Ekiti State to diagnose this disease early. There is also a need to accelerate the integration of hepatitis B virus screening and treatment programme into HIV/AIDS programme because of the morbidity and mortality implication of HBV and HIV co-infection.

A Common Variant in the PNPLA3 Gene is a Risk Factor for Non-Alcoholic Fatty Liver Disease in Obese Taiwanese Children

To test the hypothesis that the presence of the PNPLA3 rs738409 G allele would increase the susceptibility of non-alcoholic fatty liver disease (NAFLD) in obese Taiwanese children. A total of 520 obese children aged 6-18 years were recruited. Their PNPLA3 rs738409 genotypes-CC, CG, or GG-were detected by the 5'-nuclease assay. The effects of the PNPLA3 rs738409 G allele on pediatric NAFLD were evaluated based on liver ultrasonography findings and mean serum alanine aminotransferase levels in these children. NAFLD was present in 19.6% of the obese children. In comparison to the subjects with CC alleles, the risk of NAFLD was increased by 2.96-fold (95% CI, 1.57 to 5.59, P = .0008) in the subjects with CG alleles and by 5.84-fold (95% CI, 2.59 to 13.16; P < .0001) in those with GG alleles. Variant PNPLA3 rs738409 genotypes were associated with increases in mean serum alanine aminotransferase level of 4.77 IU/L (P = .0435) in subjects with CG alleles and of 10.86 IU/L (P < .0001) in those with GG alleles compared with subjects with CC alleles. The variant PNPLA3 rs738409 genotypes increased the risk of NAFLD in our population of obese Taiwanese children. The effect of the G allele on pediatric NAFLD followed a dominant genetic model.

Association between serum uric acid level and chronic liver disease in the United States†

Elevated serum uric acid (UA) levels strongly reflect and may even cause oxidative stress, insulin resistance, and metabolic syndrome, which are risk factors for the progression of liver disease. We sought to determine whether serum UA levels are associated with the development of cirrhosis or the presence of elevated serum liver enzymes. We used cohort data from the first National Health and Nutrition Examination Survey (NHANES I) to determine whether the baseline serum UA level was associated with the incidence of hospitalization or death due to cirrhosis among 5518 participants during a mean follow-up of 12.9 years (range = 4-21 years) after the exclusion of the first 4 years of follow-up. We also used cross-sectional data from NHANES 1988-1994 (n = 10,993) and NHANES 1999-2006 (n = 6186) to determine whether the serum UA level was associated with elevated serum alanine aminotransferase (ALT) or gamma-glutamyl transferase (GGT), two markers of hepatic necroinflammation. Compared to persons in the lower third of the distribution of serum UA (<4.8 mg/dL), those in the top third (>6 mg/dL) had a higher risk of cirrhosis-related hospitalization or death [adjusted hazard ratio (AHR) = 2.8, 95% confidence interval (CI) =1.3-5.7], whereas the risk was not substantially increased in persons within the middle third (serum UA level = 2.6-4.8 mg/dL, AHR = 1.3, 95% CI = 0.6-2.7). A higher serum UA level was associated with greater mean serum ALT and GGT levels and a greater probability of elevated serum ALT and GGT. The serum UA level is associated with the development of cirrhosis and the presence of elevated serum liver enzymes after adjustments for important causes and risk factors of chronic liver disease.

Relationship Between Blood Alcohol Concentration and Hepatic Enzymes in an Emergency Department

Objective Hepatic enzymes can be used as a predictor of hepatic injury. The present study investigated the relationship between blood alcohol concentration (BAC) and hepatic enzymes in patients intoxicated with ethanol at an emergency department (ED). Materials and Methods To determine whether BAC is an independent predictor of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, we retrospectively reviewed the medical data for patients who were intoxicated and whose BAC and hepatic enzyme levels were measured. Patients who had hepatitis caused by viruses or traumatic hepatic injury, as well as patients with a normal BAC, were excluded. Results Of the 1432 patients, 298 were female and 1134 were male. The average age of males was 41.4 ± 11.7 years and that of females was 35.6 ± 11.8 years. Mean serum AST and ALT levels were 78 ± 88 IU/L and 51 ± 67 IU/L in males, while those in females were 63 ± 110 IU/L and 40 ± 83 IU/L, respectively. Mean BACs were 199.6 ± 99.0 mg/dL for males and 175.1 ± 101.1 mg/dL for females. Log BAC had a high positive correlation with log ALT ( r = 0.208; p < 0.001) and log AST ( r = 0.086; p = 0.001) when BAC was above 50 mg/dL (0.05%). Multivariate linear regression showed that BAC was an independent predictor of AST and ALT ( r 2 = 0.057 and 0.056, respectively). Conclusion The high correlation of BAC with serum AST and ALT levels in patients intoxicated with ethanol when their BAC was above 50 mg/dL can be used to predict serum AST and ALT levels. However, a high BAC only appears to be associated with a slight elevation in hepatic enzymes. Therefore, in patients with acute alcohol intoxication at the ED, an elevation in AST and ALT levels should be considered as a result of hepatic injury rather than an effect of alcohol.

Lack of correlation between serum alanine amino transferrase and abdominal ultrasound in the diagnosis non alcoholic fatty liver disease in type 2 diabetes

Non alcoholic fatty liver disease (NAFLD) and type II diabetes (DM II) are increasingly recognized. Screening of DM II patients for NAFLD includes serum alanine amino transferase (ALT) and abdominal ultrasound (US). A retrospective cohort study was used to examine the sensitivity of serum ALT in the diagnosis of NAFLD in type 2 DM patients when compared to abdominal ultrasound and to determine the predictive factors of serum ALT in type 2 DM patients. Patient's age, sex, and history of hypertension (HTN), hyperlipidemia, height and weight were obtained from type 2 DM patients attending Out-patient Clinics. The body mass index (BMI) was also measured. Then retrospectively, we collected results of liver function tests, fasting lipids and abdominal US. Out of the 72 patients (30 males, 42 females; mean age: 58.49), 38.9% had hyperlipidemia, 59.7 % had HNT. The mean BMI was 29.97. Females were more obese and morbidly obese compared to males (p  0.001). 69 patients had normal serum ALT. Mean serum ALT for males was 39.29 U/L (95% CI 33.5-45.07) and the value for females was 30.9U/L (95% CI 33.55-36.2). The difference between the values in male and females was statistically significant (p  0.033). The serum ALT in type 2 DM obese and morbidly obese patients was significantly (p  0.034) higher than that of normal and overweight patients. 55.6% had NAFLD by US. ALT was not different in patients with US diagnosed NFLD from those without. HTN significantly increased the risk for NAFLD (p  0.018). In conclusion, serum ALT correlates poorly with abdominal US in the diagnosis of NAFLD in type 2 diabetic patients. Sex and BMI significantly influence serum ALT in type 2 DM patients.

A Reliable Screening Test to Predict Liver Injury in Pediatric Blunt Torso Trauma

We determined the validity of serumaspartate aminotransferase (AST) and alanine aminotransferase(ALT) as screening tests in the identificationof liver injuries in pediatric torso trauma patients. We conducted a retrospective study inpediatric patients < 17 years of age who sustainedblunt trauma and were admitted to an urban traumacenter during a 39-month period. The serum AST andALT levels, injury severity scores (ISS), lengths of hospitaland intensive care unit stays, laparotomy andvascular embolization requirement, mortality rate, andconcomitant injuries were compared betweenpatients with and without liver injury. Of the 40 patients reviewed, 16 patients hadliver injuries. The mean serum AST and ALT levels weremarkedly higher in the liver injury (LI) group than inthe non-liver injury (NLI) group (773.4 IU/l ± 781.3 [SD]and 613.6 IU/l ± 640.0 [SD], respectively, and (67.2IU/l ± 63.2 [SD] and 55.5 IU/l ± 62.6 [SD], respectively;p < 0.01). One of the 16 LI patients and 20 of the 24 NLIpatients had AST levels < 200 IU/l or ALT levels < 125IU/l. The sensitivity, specificity, and positive and negativepredictive values were 94, 83, 79, and 95%,respectively. A serum AST > 200 IU/l or an ALT> 125 IU/l are strong predictors of liver injury in childrensustaining blunt torso trauma. We recommend theroutine use of serum transaminase levels as screeningtests in hemodynamically stable patients.

Hepcidin in acute iron toxicity

Background Hepcidin regulates extracellular iron concentration by inhibiting iron release from macrophages and preventing iron absorption in the intestine. Our objective was to evaluate the expression of hepcidin in the liver in acute iron poisoning in a rat model. Methods Male Wistar rats were assigned to group 1, who received 750 mg/kg elemental iron (LD 50) by gavage, and group 2 (control), who received distilled water. Iron concentrations and liver transaminases were measured in the serum. Hepcidin messenger RNA levels were measured in the liver. Results Mean serum iron levels, aspartate aminotransferase, alanine aminotransferase, and uric acid were significantly higher in group 1 compared to group 2 ( P < .0001, P = .01, P < .0001, and P = 0.0001, respectively). Hepcidin messenger RNA levels in the liver were significantly higher in the study group ( P = .005). Conclusions In acute iron intoxication, hepcidin expression in the liver significantly increased. Further studies are needed to determine whether hepcidin levels correlate with the severity of the intoxication.

Iron reduction in chronic hepatitis C by repeated phlebotomy: A study using a less aggressive protocol

Background: Iron accumulation is common in chronic hepatitis C (CHC), and iron depletion through phlebotomy may serve as a kind of alternative therapy for CHC patients (pts) who are unsuited for interferon plus ribavirin treatment. Aim: To acquire experience with this therapeutic modality using a novel phlebotomy protocol which is less aggressive than those described earlier. Subjects: 27 CHC pts (17 men, 10 women; age: 37 to 68 ys) with pathological serum alanine aminotransferase (ALT) levels and a transferrin saturation (TFS) of &gt;25%. They were nonresponder or intolerant to or on a waiting list for interferon-ribavirin therapy. None of them had hemochromatosis. Methods: The pts underwent 400ml phlebotomy monthly until an iron deficiency (TFS &lt;20%) was achieved, and thereafter less frequently in order to keep the iron saturation around 10% with acceptable hematocrit levels. They were treated for 6 months and laboratory tests were performed every 3 months. A more than 50% decrease in serum ALT was considered a good biochemical response. The circulating levels of tumor necrosis factor-alpha (TNF-α; a major proinflammatory cytokine contributing to hepatic necroinflammation) and procollagen III N-terminal peptide (PIIINP; a marker of fibrogenesis) were also determined. Results: The phlebotomy protocol was well tolerated by the pts, and led to significant (p&lt;0.05) decreases in the mean serum ALT and gamma-glutamyltransferase activities, serum iron concentration and TFS. Moreover, it did not hamper subsequent use of interferon + ribavirin. Treatment for 6 months led to statistically significant (P&lt;0.05) decrease in the mean serum ALT activity (from 176±108 to 83.1±55.6 IU/L). A good therapeutic response was associated with significant decreases in the circulating concentrations of TNF-α and PIIINP, too. Conclusion: This study indicates that iron depletion by this well-tolerable phlebotomy protocol may exert a beneficial effect on hepatic necroinflammation and fibrogenesis and can lead to a substantial biochemical improvement in a part of pts with CHC.

Hepatocellular enzyme glutathione S‐transferase alpha and intrahepatic cholestasis of pregnancy

To evaluate and compare plasma glutathione S-transferase alpha (GSTA) concentrations in the third trimester of pregnancy in patients with intrahepatic cholestasis of pregnancy (ICP) and in healthy pregnant women. Non-randomized clinical study. Maternity unit and Department of Clinical Chemistry, Turku University Central Hospital, Turku, Finland. Twenty-seven women with ICP and 49 healthy pregnant women. GSTA concentrations were assessed in plasma samples in the third trimester of pregnancy using an enzyme-linked immunoassay (HEPKIT Alpha, Biotrin, Sinsheim-Reihen, Germany). Plasma GSTA, serum alanine and bile acid concentrations were compared between study and control group. Correlation between plasma GSTA levels and serum alanine aminotransferase and bile acid levels in the ICP patients were tested by Spearman correlation coefficients. Main perinatal outcome was compared between the groups. GSTA concentration in the control group was 1.62 microg/l (range: 0.25-6.1). In the ICP patients, the mean plasma GSTA concentration was 51.0 microg/l (range: 2.1-183.5), the mean serum alanine aminotransferase concentration was 145.70 U/l (range: 6-393) and the mean bile acid concentration was 19.2 micromol/l (range: 3-63). There was a statistically significant correlation in ICP patients between plasma GSTA concentration and serum alanine aminotransferase concentration (r=0.694, p=0.0001), but not with serum bile acid concentration. Nor was there any statistically significant correlation between gestational weeks and plasma GSTA concentration in the study group. Plasma GSTA measurements may provide a more sensitive and specific diagnostic tool for diagnosis of ICP than the evaluation of transaminases or bile acid concentrations alone. Further studies are needed to evaluate the role of GSTA in the follow-up of patients with ICP and its prognostic value for threatening fetal distress in patients with ICP.

Placebo in Nonalcoholic Steatohepatitis: Insight Into Natural History and Implications for Future Clinical Trials

Changes in biochemical and histologic parameters related to nonalcoholic steatohepatitis (NASH) in placebo-treated patients may provide an insight into the natural history and help in defining treatment end points in NASH. The aim of our study was to assess the biochemical and histologic changes seen in the placebo arm of the randomized, placebo-controlled trials in adult patients with NASH. Medline was searched (through May 2008) for studies published in the English language. Randomized, placebo-controlled trials of at least 6 months' duration in patients with NASH that provided biochemical and/or histologic data of the placebo arm were included. One investigator performed the literature search and data extraction. Two investigators independently confirmed that the studies met prespecified criteria. Pooled estimates of biochemical and histologic parameters associated with NASH were calculated. Five randomized controlled trials met the predefined criteria and included 162 placebo-treated and 189 active-treatment patients. The mean serum alanine and aspartate aminotransferase levels decreased on placebo. A 1-point improvement in steatosis, ballooning degeneration, lobular inflammation, NASH fibrosis, and combined inflammation scores was seen in 31%, 15%, 33%, 22%, and 32% of patients, respectively. A 2-point improvement in NASH histologic scores is rarely seen. Serum alanine aminotransferase levels may decrease on placebo and is not a reliable measure of treatment response. Although a 1-point improvement is seen in a third of patients, a 2-point improvement in histologic parameters is rarely seen in the placebo arm and may be more reliable in assessing treatment response. These data may have important implications in designing future clinical trials in NASH.

A nutrient mixture suppresses carbon tetrachloride–induced acute hepatic toxicity in ICR mice

We examined the effect of a nutrient mixture (NM) that contains lysine, proline, ascorbic acid, and green tea extract in mice treated with carbon tetrachloride (CCl4), a model of liver injury in which free radical, oxidative stress, and cytokine production are closely linked. Seven-week-old male Imprinting Control Region (ICR) mice were divided into four groups (A-D) of five animals each. Groups A and C mice were fed a regular diet for 2 weeks, whereas groups B and D mice were supplemented with 0.5% NM (w/w) during that period. Groups A and B received corn oil i.p., whereas groups C and D received CCl4 (25 microL/kg, in corn oil, i.p.). All animals were killed 24 h after CCl4 administration, serum was collected to assess liver and kidney functions, and livers and kidneys were excised for histology. Mean serum aspartate aminotransferase and alanine aminotransferase were comparable in groups A and B, increased markedly in group C, and significantly lowered in group D compared with group C. CCl4 had no significant effect on renal markers (blood urea nitrogen [BUN], creatinine, and BUN/creatinine ratio). CCl4 administration caused an intense degree of liver necrosis that was less severe in the NM fed group D. These results indicate that NM could be a useful supplement in preventing acute chemical-induced liver toxicity.

A pilot study of pharmacokinetically guided dosing of oral methotrexate in the initial phase of psoriasis treatment

Clinical studies of low-dose oral methotrexate (MTX) in the treatment of psoriasis and rheumatoid arthritis document a large interpatient variability in the pharmacokinetics of MTX, including its polyglutamates (MTXPGs) in erythrocytes (RBC). This can be a factor contributing to the variability of therapeutic and toxic effects. This pilot trial aimed to investigate the MTXPG concentrations in RBC as well as their relation to therapeutic and adverse effects during the initial 4 months of pharmacokinetically guided therapy with a divided-dose schedule (three doses of MTX separated by 12-h intervals once a week). Sixteen psoriatic patients (4 men and 12 women; mean age, 53 years; range, 28-69 years) with moderate-to-severe chronic plaque psoriasis [mean Psoriasis Area and Severity Index (PASI) = 24; range, 9-42] were enrolled in the study. Concentrations of plasma MTX and that of MTXPGs in RBC were assayed using liquid chromatography methods. The area under the concentration-time curve of plasma MTX in the interval 0-8 h post-dose (AUC(0-8 h)) was measured after a test bolus dose of 10 mg, and the starting weekly dose was individualized in order to achieve the target AUC(0-8 h) of 1800 nmol.h/L. The PASI, biochemistry, and haematology tests and MTXPGs levels in RBC were evaluated at baseline and at 4-week intervals. The AUC(0-8 h )achieved 1360 +/- 425 nmol.h/L (mean +/- SD: range, 778-2400 nmol.h/L). The mean (range) of individualized doses was 14.5 mg/week (7.5-22.5 mg). The mean (SD) steady-state concentration of total MTXPGs observed between days 85 to 110 reached 113 (34.6) nmol/L (range, 66.1-174 nmol/L). The PASI decreased from 24.0 +/- 8.0 (mean +/- SD) at baseline to 8.0 +/- 6.1 at day 110 (P < 0.001). Thirteen patients (87%) achieved a greater than 50% improvement in baseline PASI, and seven (47%) experienced a greater than 75% improvement. There was no relationship between the percent improvement from baseline PASI and the steady-state concentration of MTXPGs in RBC. All patients tolerated MTX well. Throughout the study period, there was a continuous increasing trend in the geometric mean values of the mean corpuscular volume from 92.6 to 96.4 fL (P < 0.001) and of plasma homocysteine from 9.5 to 12.3 micromol/L (P < 0.005). The geometric mean serum alanine aminotransferase (ALT) activity slightly increased from 0.49 to 0.80 microkat/L (P < 0.05). However, only two patients had the ALT activity transiently elevated above twice the upper limit of normal. Results of this pilot trial show that the steady-state levels of MTXPGs in RBC vary less than threefold between patients and did not correlate with the change in PASI observed after 4 months of therapy with an individualised weekly dose of MTX. Whether pharmacokinetically guided dosing can improve the results of psoriasis therapy with MTX should be prospectively tested in large controlled studies.

Hyper-CK-emia in Pediatric Celiac Disease

Hyper-transaminasemia (HT) is a well-known laboratory sign of celiac disease (CD); however, hyper-creatine phosphokinase (CK)-emia (HCK) is not so familiar. As there are reported cases of myopathy associated CD in the literature, we aimed to investigate serum CK levels of children with CD. Newly diagnosed 126 children were included. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and CK levels were determined. Mean age was 8.7+/-4.4 years (11 mo to 18 y). Of patients, 77 (61.1%) had classic form, 49 (38.9%) had atypical form. Elevated levels of AST, ALT, and CK, respectively, were found in 65 (51.6%), 45 (35.7%), and 50 (39.7%) patients. Isolated HCK was detected in 9 (7.1%) patients. AST, ALT, and CK were all elevated in 29 (23.0%) children. Mean serum AST, ALT, and CK levels were found as 56.1+/-53.7 U/L (11 to 403), 44.7+/-44.0 U/L (7 to 290), and 258.0+/-686.5 U/L (36 to 5956), respectively. In 95 (75.4%) children, AST/ALT value was greater than 1, and in 19 (15.1%) it was greater than 2. We found positive correlations with the level of CK and AST, and ALT (P=0.01). CK level was inversely correlated with hemoglobin and cholesterol levels (P=0.013 and 0.007). In conclusion, this is the first study, which determined elevated serum levels of CK in CD and demonstrated that HCK is as common as HT in children with CD. We emphasize that HT seen in CD is not necessarily a sign of liver injury, but may also be due to myopathy.

The Effect of Acetaminophen on the International Normalized Ratio in Patients Stabilized on Warfarin Therapy

To determine whether an interaction exists between acetaminophen and warfarin that alters the international normalized ratio (INR). Prospective, randomized, double-blind, placebo-controlled trial. Anticoagulation clinic at a Veterans Affairs Medical Center. Thirty-six adult patients receiving warfarin with stable INRs, defined as two consecutive INRs at least 3 weeks apart that were within the therapeutic range. Patients were randomly assigned to receive acetaminophen 1 g twice/day along with matching placebo twice/day (12 patients), acetaminophen 1 g 4 times/day (12 patients), or matching placebo 4 times/day (12 patients) for 4 weeks. The primary end point was the difference in mean INR between groups at weekly intervals. Secondary end points were the percentages of patients in each group with supratherapeutic (INR > or = 0.3 above the upper limit of their therapeutic range) or subtherapeutic (INR > or = 0.2 or 0.3 below the lower limit of their respective therapeutic range of 2.0-3.0 or 2.5-3.5) INRs, and the difference in mean serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels between groups at biweekly intervals. Slow enrollment and a preliminary observation that 15 patients experienced an elevated INR prompted early termination of the study. At week 2, the group receiving acetaminophen 2 g/day had a significantly higher mean INR versus the placebo group (p=0.01). At weeks 1, 2, and 3, the acetaminophen 4-g/day group had significantly higher mean INRs compared with those in the placebo group (p=0.04, p=0.01, p=0.01, respectively). In addition, 13 (54%) of 24 patients in the acetaminophen groups combined exceeded the upper limit of their therapeutic range by 0.3 or greater compared with only 2 (17%) of 12 patients in the placebo group. No statistically significant differences in serum ALT or AST levels between either acetaminophen group versus the placebo group were found at week 4; however, there was a statistically significant increase in mean ALT level at week 2 in the acetaminophen 4-g/day group versus the placebo group. These findings support the existence of a clinically significant interaction between warfarin and daily use of acetaminophen 2-4 g, necessitating close monitoring of patients who receive this drug combination. Whether this interaction occurs when acetaminophen is taken in lower doses or is used sporadically requires further study.

The association between non‐alcoholic fatty liver disease and insulin resistance in 20 obese children and adolescents

To investigate whether there are correlations between non-alcoholic fatty liver disease (NAFLD) and insulin resistance in obese children. For the first time, we present clinical data of 20 obese children with NAFLD, including an oral glucose tolerance test. Twenty obese children were diagnosed as having NAFLD by abdominal ultrasonography. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (gamma-GT) were reported. Insulin sensitivity was evaluated by oral glucose tolerance test, oral glucose insulin sensitivity (OGIS) and homeostasis is model assessment (HOMA) index. All parameters were compared to 20 obese age- and sex-matched patients without NAFLD. With 81% the prevalence of insulin resistance according to HOMA or OGIS criteria was high in the NAFLD-patients compared to the other group with 63%. Statistically significant differences between both groups were found for mean serum ALT levels, mean glucose levels after 30, 60 and 90 minutes and mean insulin levels after 60 minutes of the glucose tolerance test. The high prevalence of insulin resistance we found in children with NAFLD confirms the suggestion that there may be an association between insulin resistance and NAFLD in obese children and indicates that markers of insulin sensitivity could be useful screening parameters for NAFLD.

Effect of iron reduction by phlebotomy in Japanese patients with nonalcoholic steatohepatitis: A pilot study☆

Increased hepatic iron deposition may play a role in the pathogenesis of nonalcoholic steatohepatitis (NASH). This study aimed to test whether iron removal by phlebotomy improves serum transaminase activities in patients with NASH. Eleven patients (six males and five females) with biopsy-proven NASH underwent phlebotomy biweekly until they reached near-iron deficiency (NID) (serum ferritin concentration lower than or equal to 30ng/ml). Nine patients completed this study. Serum ferritin levels in these patients fell from 563+/-322 to 18+/-9ng/ml (p=0.001). The treatment reduced mean serum alanine aminotransferase (ALT) activity from 126+/-47 to 56+/-17IU/l (p=0.002). Their weight did not change significantly throughout the study period. Although two patients withdrew from the study, none was affected by any side effects of repeated phlebotomy that required discontinuing the treatment. In conclusion, this pilot study suggests that iron reduction therapy by phlebotomy will be one of the promising therapies for NASH.

Effects of bezafibrate in patients with chronic hepatitis C virus infection: combination with interferon and ribavirin

An association of hepatitis C virus (HCV) with low-density lipoproteins (LDL) in serum of patients with chronic hepatitis C (CHC) has been suggested. We conducted a prospective study in CHC patients complicated with hyperlipidaemia, to examine whether bezafibrate, which is commonly used for treatment of hyperlipidaemia, reduces serum HCV-RNA titre and improves liver dysfunction. Fifteen patients received daily oral bezafibrate treatment (400 mg/day) for 8 weeks, and its effects on serum lipids, transaminases, HCV-RNA titres, and HCV-RNA titres bound to LDL were evaluated. Fifteen untreated patients with CHC and hyperlipidaemia were used as controls. The mean serum alanine aminotransferase levels and HCV-RNA titres significantly decreased at the end of bezafibrate therapy in the treated group (105 +/- 34 to 80 +/- 32 IU/L, P = 0.02 and 2.23 +/- 2.71 to 1.78 +/- 2.38 x 10(7) copies/mL, P < 0.01 respectively), but no changes were observed in the control group. Serum HCV-RNA titres bound to LDL, as quantified by immunoprecipitation using anti-LDL antibody, also decreased in all 15 treated patients [5.55 +/- 6.59 to 1.07 +/- 1.58 x 10(6) copies/ml, P < 0.01 (mean reduction rate was -78.5 +/- 17.0%)]. Sucrose density-gradient ultracentrifugation study revealed that HCV-RNA-decreased density fractions after the bezafibrate were identical to LDL-density fractions (1.015-1.062 g/mL). Eight CHC patients were treated with bezafibrate, interferon, and ribavirin triple therapy for 32 weeks, and four patients achieved sustained virological response to therapy. This pilot study provides further evidence of an association between HCV and LDL in serum and suggests the potential usefulness of bezafibrate as an anti-HCV reagent for the treatment of CHC patients.

Effects of Indomethacin on Viral Replication Markers in Asymptomatic Carriers of Hepatitis B: A Randomized, Placebo-Controlled Trial

Previous studies have suggested some benefits of nonsteroidal antiinflammatory drugs (NSAIDs) use in patients with chronic viral hepatitis. We evaluated potential effects of indomethacin in asymptomatic carriers of hepatitis B surface antigen (HBsAg). Randomized, placebo-controlled, double-masked clinical trial. One hundred and twelve patients who were confirmed to be HBsAg carriers for at least 6 months and had normal liver function tests, normal abdominal sonography, and no sign of cirrhosis were randomly assigned into two groups. One group (56 participants, mean age (+/-SD) 31.7 (+/-9.6) yr, 29 male, mean serum alanine aminotransferase (ALT) (+/-SD) 24.9 (+/-9.2)) received indomethacin capsules (25 mg) three times daily and the other group (56 participants, mean age (+/-SD) 33.8 (+/-10.2) yr, 33 male, mean serum ALT (+/-SD) 24.5 (+/-8.7)) took placebo capsules with identical package and appearance. All participants were under treatment for 6 months and were followed 3 months thereafter. Statistical analyses were performed both by intention-to-treat and on-treatment methods. Nine participants in the indomethacin group (16%) and 8 in the placebo group (14%) did not complete the trial. HBsAg seroconversion did not differ by treatment group (2 subjects in each group became seronegative). Hepatitis B virus DNA (HBV-DNA) became negative in sera of 7 participants in the indomethacin group but only in 1 in the placebo group (intention-to-treat p= 0.06; on-treatment p= 0.03). Seroconversion of HBeAg to anti-HBe occurred only in 5 participants in the indomethacin group (intention-to-treat p= 0.06; on-treatment p= 0.03). Adverse events included one case of hepatotoxicity and two cases of gastritis in the indomethacin group and one suspected gastritis in the placebo group. We suggest use of indomethacin only in the subgroup of asymptomatic HBsAg carriers who have detectable HBV-DNA or HBeAg in their sera.

Interferon sensitivity‐determining region of nonstructural region 5A of hepatitis C virus genotype 1b correlates with serum alanine aminotransferase levels in chronic infection

The mutations in the interferon (IFN) sensitivity-determining region (ISDR) of nonstructural region 5A (NS5A) of hepatitis C virus (HCV) have been correlated with response to IFN therapy. NS5A appears to disrupt a host antiviral pathway that plays a role in suppressing virus replication and protects hepatocytes from apoptosis. We assessed whether ISDR correlates with viral load and serum alanine aminotransferase (ALT) levels. Serum viral load and ALT levels were prospectively measured bimonthly by HCV core protein assay and monthly, respectively, for 22 months in 87 patients chronically infected with HCV genotype 1b. ISDR of HCV was directly sequenced from the products of reverse transcription and polymerase chain reaction of HCV RNA. Five patients had four or more substitutions (mutant type), 33 had 1-3 (intermediate type), and 49 had no substitutions (wild type) in ISDR. The numbers of substitutions in ISDR were inversely correlated with mean viral load over a 22-month period (r = 0.292, P = 0.0060) and directly with mean serum ALT levels (r = 0.360, P = 0.0006). The numbers of substitutions in ISDR was significantly larger in the patients with changes of viral load more than fivefold during the 22 months (1.4 +/- 2.4) than in those without changes (0.6 +/- 0.8) (P = 0.0188). The present study demonstrates that the patients with more substitutions in ISDR had significantly higher serum ALT levels and smaller viral load. These results suggest that NS5A with more substitutions in ISDR may lose the ability to block host antiviral pathways and to protect hepatocytes from apoptosis.