Elevated Serum Transaminase Levels Research Articles

CLINICAL LABORATORY, VIROLOGIC, AND PATHOLOGIC CHANGES IN HAMSTERS EXPERIMENTALLY INFECTED WITH PIRITAL VIRUS (ARENAVIRIDAE): A RODENT MODEL OF LASSA FEVER

The clinical laboratory, virologic, and pathologic changes occurring in hamsters after infection with Pirital virus (Arenaviridae) are described. Pirital virus infection in the hamsters was characterized by high titered viremia, leukocytosis, coagulopathy, pulmonary hemorrhage and edema, hepatocellular and splenic necrosis, and marked elevation of serum transaminase levels. All of the animals died within 9 days. The clinical and histopathological findings in the Pirital virus-infected hamsters were very similar to those reported in severe human cases of Lassa fever, suggesting that this new animal model could serve as a low-cost and relatively safe alternative for studying the pathogenesis and therapy of Lassa fever.

Hipertransaminasemia como manifestación del síndrome de Shwachman-Diamond

Shwachman-Diamond syndrome (SDS) is the second most common cause of congenital exocrine pancreatic insufficiency after cystic fibrosis. SDS is an autosomal recessive multisystemic disorder, with wide heterogenicity in its clinical characteristics. The central features of this syndrome are pancreatic exocrine and bone marrow dysfunction (mainly neutropenia). Other features are skeletal abnormalities, hepatomegaly, elevation of serum aminotransferase levels, short stature and frequent infections. We present two patients who were referred to us because of persistent hypertransaminasemia. In both patients, liver function returned to normal and pancreatic function improved. Both patients showed several neutropenic episodes but no bone disorders, which does not exclude the diagnosis.

Delayed amnesic syndrome after riluzole autointoxication in Huntington disease

No treatment has been shown effective in slowing Huntington disease (HD). However, the anti-glutamatergic agent riluzole has been shown to reduce chorea.1,2 Therefore, trials have been performed to study the effect of riluzole on progression of HD. In the European Huntington’s Disease Initiative (EHDI) trial, patients were treated with 50 mg of riluzole (or placebo) BID. Side effects included general asthenia, nausea, and elevated serum transaminase levels. Less frequently, abdominal discomfort, dizziness, headaches, acute hepatitis, and neutropenia were noted.1,3 Little is known about the effects of riluzole overdose; both methemoglobinemia and an amnesic syndrome have been reported only once each.4,5 We present a woman who developed an amnesic syndrome 4 days after ingestion of 3 g of riluzole. A 44-year-old woman who had been diagnosed with HD in 2000 presented at the emergency room in March 2003 after ingestion of 60 tablets of study medication (riluzole, after …

Normal Serum Aminotransferase Levels and the Metabolic Syndrome: Korean National Health and Nutrition Examination Surveys

Increasing evidence suggests an association between elevated serum aminotransferase level and the metabolic syndrome. However, the significance of relatively low levels of aminotransferase in relation to the metabolic syndrome has not been fully investigated in the general population. We investigated the association between serum amiontransferase level and the metabolic syndrome using data from a nationwide survey in Korea. We measured serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and metabolic conditions among 9771 participants aged 20 or more in the 1998 and 2001 Korean National Health and Nutrition Examination Surveys. Metabolic syndrome was defined according to NCEP-ATP III criteria with a modified waist circumference cutoff (men > 90 cm; women > 80 cm). Serum aminotransferase level, even within normal range, was associated with the metabolic syndrome independent of age, body mass index, waist circumference, smoking, and alcohol intake. Compared with the lowest level (< 20 IU/L), the adjusted odds ratios (95% CI) for an AST level of 20-29, 30-39, 40-49 and ≥ 50 IU/L were 1.10 (0.85-1.42), 1.37 (1.02-1.83), 1.62 (1.08-2.43), and 2.25 (1.47-3.44) in men, and 1.18 (0.99-1.41), 1.43 (1.29-1.83), 1.71 (1.09-2.68), and 2.14 (1.20-3.80) in women, respectively. Corresponding odds ratios for ALT levels were 1.27 (0.99-1.63), 1.69 (1.28-2.23), 2.17 (1.58-2.99), and 2.65 (1.96-3.58) in men, and 1.44 (1.22-1.70), 1.65 (1.26-2.15), 2.94 (1.93-4.47), and 2.25 (1.54-3.30) in women, respectively. In conclusion, elevated serum aminotransferase levels, even in the normal to near normal range, are associated with features of the metabolic syndrome.

S-Adenosyl-l-methionine Attenuates Hepatotoxicity Induced by Agonistic Jo2 Fas Antibody following CYP2E1 Induction in Mice

S-Adenosyl-l-methionine (SAM) has been shown to be hepatoprotective against many toxic agents. Its possible effectiveness in protecting against CYP2E1-dependent toxicity is not known. We recently reported that treatment of mice with pyrazole to induce CYP2E1 increased hepatotoxicity produced by Fas agonistic Jo2 antibody. The current study was designed to investigate the effect of exogenous administration of SAM on the synergistic hepatotoxicity produced by Fas agonistic Jo2 antibody plus CYP2E1 following pyrazole pretreatment in C57BL/6 mice. Suboptimal administration of Jo2 Fas antibody combined with pyrazole pretreatment caused severe hepatotoxicity as determined by elevations in serum transaminase levels and histopathology. Exogenous administration of SAM (50 mg i.p./kg body weight every 12 h for 3 days) significantly decreased serum transaminases and ameliorated morphological changes of the liver. Addition of SAM elevated hepatic SAM and total reduced glutathione levels and inhibited CYP2E1 activity. SAM also lowered the elevated oxidative stress (lipid peroxidation, protein carbonyls, and superoxide production) and nitrosative stress (induction of inducible nitric-oxide synthase and 3-nitrotyrosine adducts) and increases in caspase-8 and -3 activation produced by the pyrazole plus Jo2 treatment. SAM did not prevent the increase in serum TNF-alpha levels or the decrease in catalase activity in this model. These results indicate that SAM can have an important hepatoprotective role as an effective reagent against Fas plus CYP2E1-induced hepatotoxicity by lowering oxidative and nitrosative stress.

Laparoscopic radiofrequency ablation of hepatic cavernous hemangioma

Radiofrequency ablation (RFA), currently used extensively for liver tumors, also has been applied successfully to hepatic cavernous hemangioma (HCH) percutaneously. The aim of this study was to assess the feasibility, safety, and efficacy of laparoscopic RFA for patients with HCHs. Between March 2001 and March 2004, 27 patients with symptomatic and rapid-growth lesions were treated by laparoscopic RFA using the RF-2000 generator system. The treatment-related complications were observed. All the patients were followed up with helical computed tomography scans and ultrasonography at regular intervals to assess the therapeutic efficacy of laparoscopic RFA. This study assessed 9 men and 18 women with a mean age of 41.6 +/- 8.3 years. Three additional intrahepatic lesions missed preoperatively were found in three patients on intraoperative ultrasound. A total of 27 patients with 50 liver lesions were treated successfully with laparoscopic RFA. The mean maximum tumor diameter was 5.5 +/- 2.0 cm. The mean length of time for RFA per lesion was 20.7 +/- 11.9 min, and the mean blood loss was 134.4 +/- 88.9 ml. Laparoscopic cholecystectomy was performed simultaneously for gallstones in 13 patients and for abutting of gallbladder from hemangioma in 2 patients. In addition, 3 patients also had a laparoscopic deroofing of simple hepatic cysts. Although postoperative low-grade fever and transient elevation of serum transaminase levels were observed in 13 patients, there were no complications related to laparoscopic RFA. During a median follow-up period of 21 months (range, 12-42 months), complete lesion necrosis was achieved for all the patients. Laparoscopic RFA therapy is a safe, feasible, and effective treatment option for patients with symptomatic and rapid-growth HCHs located on the surface of the liver or adjacent to the gallbladder. Intraoperative ultrasonography is a useful adjunct for detecting additional liver lesions and offering more accurate targeting for RFA.

The efficacy of two different lipid‐based amphotericin B in neonatal Candida septicemia

Fungal sepsis is becoming more frequent in neonatal intensive care units (NICU) and has a high mortality rate due to the invasive nature of the disease and to the insufficiency of low doses and high incidence of renal problems with effective doses of amphotericin B. New generation lipid formulated amphotericin B preparations may be more efficient because they are less toxic to be applied in target doses. However, there is limited experience in neonates and preterm infants. The charts of 917 patients admitted to NICU between 2001 and 2003 were reviewed and the data of 21 patients with systemic Candida infection, requiring different amphotericin B therapy, were analyzed. Infants with fungal septicemia were treated with amphotericin B lipid complex (Abelcet)(n = 10) and liposomal amphotericin B (AmBisome)(n = 9) for a mean duration of 21 and 18 days. The mean gestational age of the patients was 30.9 +/- 4.2 weeks and mean birth weight was 1536 +/- 714 g. Two patients in the Abelcet group and one patient in the AmBisome group died during therapy. Fungal eradication was achieved in 16 surviving infants and mean eradication time was 8.1 +/- 2.6 days and mean duration of therapy was 19.2 +/- 4.1 days. Mortality rates related to treatment failure were similar being 20% in the Abelcet group and 11% in the AmBisome group. No patient showed severe side-effects from the antifungal therapy; the incidence of minimal side-effects were similar in both groups and they were elevated serum transaminase levels in six patients, increased serum creatinine in one patient and hypokalemia in one patient. Both preparations have the same benefits for the treatment of neonatal fungal sepsis and they can be used safely in neonates including very low birth weight infants. However, the clinician must keep in mind the cost of treatment.

Direct Thrombin Inhibitors for Treatment of Heparin Induced Thrombocytopenia, Deep Vein Thrombosis and Atrial Fibrillation

Thrombin is a central enzyme in hemostasis, exerting potent procoagulant effects and activating platelets. Recently, several small molecule direct thrombin inhibitors (DTI's) with important clinical applications have been developed. Both lepirudin and argatroban are effective in treatment of heparin-induced thrombocytopenia resulting in rapid normalization of platelet counts and a reduction in thrombotic events. Because of differences in clearance mechanisms, argatroban is preferable in patients with renal insufficiency and lepirudin if there is hepatic impairment. DTI's have also been evaluated in treatment of venous thromboembolism. Small studies with recombinant hirudin have shown promise. Ximelagatran is a new DTI in late-stage clinical trials with advantages for treatment of venous thromboembolism including oral administration and fixed dosing, making it convenient for long-term treatment. A Phase III trial demonstrated that ximelagatran was superior to placebo for preventing recurrent thrombosis in patients who had undergone six months of standard anticoagulant therapy for venous thromboembolism. Another large trial compared ximelagatran to standard treatment with enoxaparin and warfarin for treatment of symptomatic deep vein thrombosis in a Phase III trial of 2,528 patients. The results showed that ximelagatran administered twice daily was as effective as standard treatment in preventing recurrence with no increase in bleeding complications. Ximelagatran has also been evaluated in two Phase III trials in patients with atrial fibrillation. The primary analysis of both showed that ximelagatran was non-inferior to warfarin for preventing stroke and other embolic events with no increase in bleeding complications. Unexpectedly, elevated serum transaminase levels were observed in 5-10% of patients receiving ximelagatran for over 1 month, and routine monitoring may be necessary. The introduction of DTIs represents an important advance in treatment of heparin-induced thrombocytopenia. The oral direct thrombin inhibitor, ximelagatran, shows promise in providing simplified, effective therapy for venous thromboembolism and atrial fibrillation.

Elevated Serum Aminotransferase Level as a Predictor of Intracerebral Hemorrhage

Serum aminotransferase levels are known to be associated with cardiovascular risk factors, but the relation with stroke incidence is not well known. We investigated the relation between serum aminotransferase levels and the incidence of stroke. We measured serum aspartate and alanine aminotransferase levels and traditional cardiovascular risk factors in 108 464 Korean men, aged 35 to 59 years, in 1990 and 1992. Serum aminotransferase levels were classified into 3 categories (<35, 35 to 69, and > or =70 IU/L). The outcomes were hospital admissions and deaths from stroke subtypes (ischemic stroke, intracerebral hemorrhage [ICH], and subarachnoid hemorrhage [SAH]) from 1993 to 2002. During the 10 years, 1728 ischemic, 1051 hemorrhagic (718 ICH and 222 SAH), and 243 unspecified stroke events occurred. After adjustment for age and other traditional risk factors and according to Cox proportional-hazards models, serum aminotransferase level had an independent positive associations with ICH. However, ischemic stroke and SAH were not associated with aminotransferase levels. Compared with the level <35 IU/L, the adjusted relative risks (95% confidence interval) of ICH for an aspartate aminotransferase level of 35 to 69 and > or =70 IU/L were 1.49 (1.21 to 1.83) and 4.21 (3.06 to 5.77), respectively. The corresponding risks for alanine aminotransferase were 1.34 (1.09 to 1.65) and 2.89 (2.09 to 4.01), respectively. These associations were consistent regardless of the level of obesity, blood pressure, fasting glucose, alcohol intake, and follow-up length. These findings suggest that an elevated aminotransferase level is a predictor of ICH. The biologic significance of aminotransferase level for the development of ICH merits further study.

Typhoid fever and typhoid hepatitis in Taiwan

The annual incidence of typhoid fever in Taiwan was 2.1-3.6 cases per 1,000,000 population from 1995 to 2002. More than 80% of 45 patients with typhoid fever treated at National Taiwan University Hospital from 1996 to 2002 had elevated serum aminotransferase levels at presentation. Ten of these patients were treated during an outbreak in Taipei County in 2002, and seven of them who did not have pre-existing liver disease developed hepatitis, which was unrelated to other aetiologies. All Salmonella typhi isolates were susceptible to extended-spectrum cephalosporins and fluoroquinolones. Multidrug resistance (intermediate resistance to ampicillin, trimethoprim-sulphamethoxazole, and chloramphenicol) was found in one (2.5%) of the 40 isolates studied. Pulsed-field gel electrophoresis analysis demonstrated a high genetic diversity among S. typhi isolates and identified a novel clone associated with the 2002 outbreak. Physicians should be alert to the possibility of typhoid fever when patients, without other gastrointestinal symptoms, present with sustained fever and hepatitis.

Gabexate mesilate, a synthetic protease inhibitor, attenuates carbon tetrachloride-induced liver injury in rats

Gabexate mesilate, a synthetic protease inhibitor, is used to treat acute pancreatitis and disseminated intravascular coagulation because it inhibits various serine proteases; however, whether gabexate mesilate prevents acute liver failure has not yet been studied. The aim of the present study was to investigate the effect of gabexate mesilate in carbon tetrachloride (CCl4)-induced liver injury in rats. Acute hepatic failure was induced by administration of CCl4 intragastrically to male Sprague-Dawley rats. The effects of gabexate mesilate were examined in terms of serum transaminase levels, liver histology, and the prognosis of rats. Gabexate mesilate treatment significantly decreased the elevation of serum transaminase levels and improved liver histology 24 h after the administration of CCl4 (0.2 ml/100 g rat weight). Plasma tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) decreased significantly in the gabexate mesilate-treated rats compared with saline-treated rats. Gabexate mesilate treatment also significantly improved survival rate after a lethal dose of CCl4 (0.5 ml/100 g rat weight) from 0% to 20%. Gabexate mesilate treatment attenuated CCl4-induced liver injury via a suppression of proinflammatory cytokine production. In addition, these investigations suggest that gabexate mesilate treatment may provide therapeutic strategies for human acute liver failure.

Adverse Events and Treatment Completion for Latent Tuberculosis in Jail Inmates and Homeless Persons&lt;xref rid="AFF1"&gt;&lt;sup&gt;*&lt;/sup&gt;&lt;/xref&gt;

Recently, a short-course treatment using 60 daily doses of rifampin and pyrazinamide was recommended for latent tuberculosis (TB) infection (LTBI). To determine the acceptability, tolerability, and completion of treatment. Observational cohort study. Five county jails and TB outreach clinics for homeless populations in three cities. Study staff enrolled 1,211 patients (844 inmates and 367 homeless persons). Sites used 60 daily doses of rifampin and pyrazinamide, an approved treatment regimen for LTBI. Types and frequency of drug-related adverse events and outcomes of treatment. Prior to treatment, 25 of 1,178 patients (2.1%) had a serum aminotransferase measurement at least 2.5 times the upper limit of normal. Patients who reported excess alcohol use in the past 12 months were more likely than other patients to have an elevated pretreatment serum aminotransferase level (odds ratio, 2.1; 95% confidence interval, 1.1 to 6.1; p = 0.03). Treatment was stopped in 66 of 162 patients (13.4%) who had a drug-related adverse event. Among 715 patients who had serum aminotransferase measured during treatment, 43 patients (6.0%) had an elevation > 5 times the upper limits of normal, including one patient who died of liver failure attributed to treatment. In multivariate analyses, increasing age, an abnormal baseline aspartate aminotransferase level, and unemployment within the past 24 months were independent risk factors for hepatotoxicity. Completion rates were similar in jail inmates (47.5%) and homeless persons (43.6%). This study detected the first treatment-associated fatality with the rifampin and pyrazinamide regimen, prompting surveillance that detected unacceptable levels of hepatotoxicity and retraction of recommendations for its routine use. Completion rates for LTBI treatment using a short-course regimen exceeds historical rates using isoniazid. Efforts to identify an effective short-course treatment for LTBI should be given a high priority.

Adverse Events and Treatment Completion for Latent Tuberculosis in Jail Inmates and Homeless Persons

Background : Recently, a short-course treatment using 60 daily doses of rifampin and pyrazinamide was recommended for latent tuberculosis (TB) infection (LTBI) Study objectives : To determine the acceptability, tolerability, and completion of treatment Design : Observational cohort study Setting : Five county jails and TB outreach clinics for homeless populations in three cities Patients : Study staff enrolled 1,211 patients (844 inmates and 367 homeless persons) Interventions : Sites used 60 daily doses of rifampin and pyrazinamide, an approved treatment regimen for LTBI Measurements : Types and frequency of drug-related adverse events and outcomes of treatment Results : Prior to treatment, 25 of 1,178 patients (2.1%) had a serum aminotransferase measurement at least 2.5 times the upper limit of normal. Patients who reported excess alcohol use in the past 12 months were more likely than other patients to have an elevated pretreatment serum aminotransferase level (odds ratio, 2.1; 95% confidence interval, 1.1 to 6.1; p = 0.03). Treatment was stopped in 66 of 162 patients (13.4%) who had a drug-related adverse event. Among 715 patients who had serum aminotransferase measured during treatment, 43 patients (6.0%) had an elevation > 5 times the upper limits of normal, including one patient who died of liver failure attributed to treatment. In multivariate analyses, increasing age, an abnormal baseline aspartate aminotransferase level, and unemployment within the past 24 months were independent risk factors for hepatotoxicity. Completion rates were similar in jail inmates (47.5%) and homeless persons (43.6%) Conclusions : This study detected the first treatment-associated fatality with the rifampin and pyrazinamide regimen, prompting surveillance that detected unacceptable levels of hepatotoxicity and retraction of recommendations for its routine use. Completion rates for LTBI treatment using a short-course regimen exceeds historical rates using isoniazid. Efforts to identify an effective short-course treatment for LTBI should be given a high priority

Steatohepatitis develops rapidly in transgenic mice overexpressingAbcb11and fed a methionine-choline-deficient diet

Nonalcoholic fatty liver disease is the most common reason for abnormal liver chemistries in the United States. The factors that lead from benign steatosis to nonalcoholic steatohepatitis are poorly understood. Transthyretin-Abcb11 (TTR-Abcb11) transgenic mice overexpress the bile salt transporter Abcb11 and hypersecrete biliary lipids. Thus the aim of this study is to employ feeding of the methionine-choline-deficient (MCD) diet to TTR-Abcb11 transgenic mice to further determine the mechanisms responsible for the development of steatohepatitis. FVB/NJ and TTR-Abcb11 mice were fed control or MCD diets for up to 30 days. Serum aminotransferase levels, serum and hepatic triglyceride content, cytokines, markers of oxidative stress, and expression of selective genes were examined. MCD diet-fed TTR-Abcb11, but not wild-type, mice have elevated serum aminotransferase levels when compared after 7 days. They also have significantly lower hepatic triglyceride levels at all time points studied. After 14 days on the MCD diet, TTR-Abcb11 mice have 3-fold increases in TNF-alpha mRNA and 3.9-fold increases in IL-6 mRNA compared with FVB/NJ mice. TTR-Abcb11 mice also had a greater increase in cytochrome P-450 2E1 expression. A greater decrease in sterol regulatory element binding protein-1c and fatty acid synthase mRNA expression was also seen in TTR-Abcb11 compared with wild-type mice fed an MCD diet. They also have enhanced TNF-alpha, IL-6, and cytochrome P-450 2E1 expression. We conclude that TTR-Abcb11 mice develop a more rapid hepatitis with less steatosis.

Is adiponectin level a predictor of nonalcoholic fatty liver disease in nondiabetic male patients?

Adiponectin is a hepatic insulin sensitizer and also an inhibitor of tumor necrosis factor. We studied its levels in nondiabetic patients with nonalcoholic fatty liver disease (NAFLD) and compared with control group. Thirty-five patients who had elevated serum aminotransferase levels with bright liver and 34 healthy volunteers without liver disease were evaluated. Age, gender and body mass index (BMI) were recorded. Fasting plasma glucose, insulin, adiponectin, proinsulin and lipid profile were measured. A standard oral glucose tolerance test (OGTT) with insulin response was performed and the index of insulin resistance was calculated according to the homeostasis model assessment (HOMA) method. According to the OGTT results, none of the participants had diabetes. Serum adiponectin levels were statistically significantly lower in patients with NAFLD than in control group (8.14+/-3.4 microg/mL vs 12.4+/-9.4 microg/mL, respectively, P<0.01). A statistically significant correlation was found between adiponectin and BMI (r : -0.33, P<0.01), HOMA (r : -0.26, P<0.05), proinsulin (r : -0.32, P<0.01), AST (r : -0.25, P<0.05), ALT (r : -0.26, P<0.05) or GGT (r : -0.22, P<0.05). In multiple regression analysis models, adiponectin levels were the only predictor of NAFLD in males, whereas in female group it was the BMI. Low adiponectin level might be a predictor of NAFLD especially in male nondiabetics.

Syphilitic Hepatitis in HIV-Infected Patients: A Report of 7 Cases and Review of the Literature

A recent resurgence of primary and secondary syphilis has been observed in certain population groups, particularly among persons infected with human immunodeficiency virus (HIV). Liver involvement is an infrequently recognized complication of early syphilis, with no previous reports among HIV-infected patients. We describe 7 cases of syphilitic hepatitis in HIV-positive individuals and review the literature. At our institutions, all patients presented with a rash consistent with secondary syphilis. Each case was characterized by a conspicuous increase in serum alkaline phosphatase level (mean level +/- standard deviation, 905 +/- 523.6 IU/L) and milder elevations in serum transaminase levels. The mean CD4+ absolute T cell count was 317 cells/mm3, and the median rapid plasma reagin (RPR) titer was 1 : 128. There was a significant correlation between higher CD4+ cell counts and the RPR titers (R=0.93; P=.002). Symptomatic resolution and biochemical improvement, particularly a significant decrease in serum alkaline phosphatase levels (P=.02), occurred following antibiotic therapy. Hepatic dysfunction is not uncommon in HIV-infected persons and is attributable to multiple causes. In the appropriate clinical setting, syphilitic hepatitis is an easily diagnosed and reversible etiology of liver dysfunction. The recognition of this entity will prevent unnecessary evaluation of abnormal liver enzyme levels in HIV-positive patients.

Adverse drug reactions due to prolonged antibiotic therapy for malignant external otitis

Background Malignant external otitis (MEO) is a life-threatening infection requiring prolonged antibiotic therapy. Adverse drug reactions (ADR) occur frequently in patients treated with long-term antibiotics, often limiting treatment effectiveness. We attempted to identify and categorize the frequency and type of ADR in patients undergoing treatment for MEO in an attempt to improve overall treatment of individuals with this disorder. Methods Twenty-one patients with MEO who were treated during a 10-year period at our institution were identified retrospectively. Records were reviewed to determine demographic and clinical information as well as laboratory data. Results Overall, ADR occurred in six individuals (26.8%). Of the 15 patients who received ciprofloxacin therapy, none experienced ADR. In contrast, six of the nine patients who were treated with β-lactam antibiotics experienced ADR including urticaria, elevated serum transaminase levels and neutropenia. Conclusions Prolonged antibiotic therapy for MEO with β-lactam antibiotics is more likely to be complicated by ADR and requires careful monitoring.

Tetrathiomolybdate therapy protects against concanavalin a and carbon tetrachloride hepatic damage in mice.

Tetrathiomolybdate, an anticopper drug, has been shown to protect mice against pulmonary fibrosis from bleomycin. Our hypothesis is that it does so by inhibiting fibrosis-inducing cytokines. Indeed, we have good evidence, not yet published, that tetrathiomolybdate inhibits pulmonary levels of transforming growth factor-beta and tumor necrosis factor-alpha expression in these bleomycin experiments. Herein, we evaluate tetrathiomolybdate's effectiveness in mitigating hepatitis and fibrosis in mice from the hepatotoxins, concanavalin A and carbon tetrachloride, and its inhibition of cytokines as a possible mechanism. In short-term experiments, concanavalin A elevated serum amino leucine transferase levels several fold, and tetrathiomolybdate completely prevented this increase. In additional experiments, tetrathiomolybdate therapy reversed the elevated serum transaminase levels despite continued concanavalin A injections, with nearly significant serum interleukin-1beta inhibition. Concanavalin A given for 12 weeks produced mild fibrosis, whereas concomitant tetrathiomolybdate treatment resulted in normal histology. Carbon tetrachloride given for 12 weeks resulted in very high serum amino leucine transferase levels, high serum transforming growth factor-beta levels, cirrhosis as seen histologically, and increase in liver hydroxyproline, a measure of fibrosis. Concomitant tetrathiomolybdate partially and significantly protected against increases in amino leucine transferase and transforming growth factor-beta, fully protected against the increase in hydroxyproline, and resulted in normal histology. In conclusion, tetrathiomolybdate protects against the hepatitis and fibrosis produced by these hepatotoxins, probably by inhibiting the excessive increase in inflammatory and fibrotic cytokines.

Hepatitis C screening practices among private practitioners: impact of an information campaign

A campaign designed to enhance screening for hepatitis C virus infection (HCV) by private practitioners was conducted in the Lyon area from April 2000 to March 2001. The target population for screening was composed of individuals with active/previous intravenous drug abuse habits or had received blood products before 1991 or who presented elevated serum transaminase levels. The objectives of the present study were to validate the campaign's organization and its impact on screening practices. The impact of the campaign was estimated from the number of prescribed and performed HCV screening and confirmation tests, the number of physicians who prescribed HCV screening tests, and the number of HCV screening tests prescribed by each physician. Indicators/practices observed during the 12-month campaign were compared with the same indicators/practices observed during the 12-month period preceding the campaign. During the campaign, 15952 HCV serology tests were prescribed by 1798 of the 3052 physicians (58.9%) practising in the Lyon area. Among physicians who prescribed serology, 11.4% of the general practitioners and 10.9% of the specialists prescribed HCV serology tests for the first time during the campaign. Prescriptions for HCV serology increased significantly between the two calendar periods (+15.6%, epsilon = 17.7), similarly for general practitioners and specialists. The number of general practitioners who prescribed more than five serology tests per year increased 15.3% while the number of general practitioners who did not prescribe serology tests decreased 9.7% (P = 0.02). More HCV-positive patients were detected during the campaign (276 patients) than during the previous period (231 patients) [epsilon = 2.8]. When provided with pertinent information and training adapted to their medical practice, private practitioners become actively involved in screening for HCV infection.

P0032 PP CLINICAL AND MOLECULAR ANALYSIS OF SEVENTEEN JAPANESE PATIENTS WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS

Introduction: Progressive familial intrahepatic cholestasis (PFIC) type 1 and type 2, characterized by normal serum gamma-glutamyltransferase levels, are caused by defects in FIC1 and BSEP, respectively. Previous reports showed that PFIC type 1 patients had bland intracanalicular cholestasis, whereas non-type 1 patients were marked by non-specific giant cell hepatitis with moderately to markedly elevated serum transaminase levels. However, there has been only one study comparing the clinical features of these two genotypes on the basis of a molecular diagnosis. To investigate the occurrence of genetic mutations and clinical differences between the two genotypes, we performed mutational analysis in FIC1 and BSEP genes in patients with PFIC phenotypes and normal gamma-glutamyltransferase activities. Methods: The coding region and exonintron boundaries of the FIC1 and BSEP gene were sequenced in 17 unrelated Japanese PFIC patients with normal serum gamma-glutamyltransferase activities. All patients were Japanese, from various parts of the country. The following clinical data were collected: age at onset, clinical signs of cholestasis, serum alanine aminotransferase (ALT) levels, liver histology, growth, and therapy including liver transplantation. Results: All patients had novel disease-causing mutations in FIC1 or BSEP. Of the 17 patients, 13 carried FIC1 mutations (5 homozygotes, 7 compound heterozygotes, 1 heterozygote), and 4 carried BSEP mutations (1 homozygote, 2 compound heterozygotes, 1 heterozygote). FIC1 mutations included 8 missense mutations, 2 nonsense mutations, 2 insertions, 1 deletion and 3 splicing mutations. BSEP mutations consisted of 5 missense mutations and 1 exon skipping. There were overlap in ALT levels between PFIC type 1 and PFIC type 2 patients, and other clinicopathological features were insufficient to differentiate between the two genotypes. However, complications such as intractable diarrhea or severe liver steatosis occurred after transplantation in 12 of the 13 patients with type 1, while they never occurred in the type 2 patients. Conclusion: PFIC type 1 is the major type in Japan, and frequently causes severe complications such as intractable diarrhea and liver steatosis after liver transplantation. For predicting these unfavorable complications, genetic diagnosis is needed for case of PFIC before liver transplantation, because it is impossible to distinguish between PFIC type 1 and PFIC type 2 by clinical findings exclusively.