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Background & Aims: We investigated the efficacy and safety of simeprevir plus daclatasvir in treatment-naïve patients with chronic, genotype 1b hepatitis C virus infection and advanced liver disease, excluding patients with pre-defined NS5A resistance-associated substitutions. Methods: This phase II, open-label, single-arm, multicentre study included patients aged≥18years with advanced fibrosis or compensated cirrhosis (METAVIR F3/4). Patients with NS5A-Y93H or L31M/V resistance-associated substitutions at screening were excluded. Simeprevir (150mg)+daclatasvir (60mg) once daily was administered for 12 or 24weeks; treatment could be extended to 24 weeks prior to or at the Week 12 visit. Primary efficacy endpoint was sustained virological response 12weeks after the end of treatment. Results: A total of 106 patients were treated; 27% patients were aged >65years, 39% had cirrhosis, 53% had estimated glomerular filtration rate 30-89mL/min, 14% had diabetes, and 38% had arterial hypertension. Overall, 42/106 received 12weeks of treatment and 64/106 received 24weeks of treatment. Ninety-seven (92%) patients achieved a sustained virological response 12 weeks after the end of treatment. The reasons for failure were viral breakthrough (n=7) at weeks 4-16, early treatment discontinuation (n=1) and viral relapse (n=1). Seventy-four (70%) patients had ≥1 adverse event during treatment, including six (6%) patients with ≥1 serious adverse event. Three (3%) patients discontinued treatment owing to adverse events. Conclusions: Simeprevir+daclatasvir demonstrated strong antiviral activity and was well-tolerated in patients with hepatitis C virus genotype 1b infection, advanced liver disease and a high prevalence of comorbidities. However, viral breakthrough occurred in seven patients, making this regimen unsatisfactory.

Although multiple HCV prevalence studies were recently performed in the general population from Belgium, they suffer from a lack of geographical representativeness, an insufficient number of participants or a lack of inclusion of high prevalence groups. The aim of this study is to provide robust information on the HCV burden.Recently performed HCV prevalence studies in the general, adult population were included in this study, based on well-defined selection criteria. A meta-analysis was performed to estimate the seroprevalence, the prevalence of participants with viremia and the prevalence estimation for people with viremia which were unaware of their status.Eight studies fulfilled the criteria for inclusion of the quantitative prevalence estimation. Based on the meta-analysis on these 8 studies, we estimated an HCV seroprevalence of 1.01% [95% CI : 0.66-1.42%], representing a total of 90,722 adult, HCV seropositives of which 64,412 individuals (0.71%) were confirmed seropositive. Based on the RNA presence, an estimated viremic prevalence of 0.33% [95% CI : 0.21-0.47 %] was determined, corresponding with 29,642 individuals. This is 46,0% of the true HCV seropositive residents. Further, based on the availability of patient information in 5 out of the 8 studies, a prevalence of 0.18% [95% CI : 0.07-0.33] representing 16,168 individuals from the adult Belgian population are unaware of their HCV status.We believe that the quantitative measurement by the meta-analysis will be more reliable for their use in the design of a screening strategy or in the development of prevention campaigns as compared to the prevalence estimations performed at local level.

Background: Mucin-producing hepatic cystic neoplasms (MHCN) are uncommon and potentially malignant. Methods: Nine MHCN were encountered in our centre for over 32 years. Patients’ clinical, biological, radiological and pathological features were reviewed. Lesions were classified into Mucinous Cystic Neoplasms (MCN) and Intraductal Papillary Neoplasms of the Bile duct (IPNB) (WHO 2010 classification). Results: Five MCN and 4 IPNB were reviewed. Serum and intracystic tumour markers were insufficient to diagnose malignancy. Complications were encountered in five out of nine patients (56%), mean symptom duration was 26 months (range: 1–132). Three patients were mismanaged pre-referral. Radiological features enabled preoperative diagnosis in eight out of nine patients (89%). Greater tumour size, unilocular lesion and mural nodularity indicated malignancy. Radical tumour excision was achieved in eight patients. One IPNB patient was misdiagnosed and underwent unroofing. For 103 months median follow-up, five out of six patients with benign tumours were alive and disease-free, whereas the misdiagnosed IPNB recurred with fatal malignant transformation seven years later. Among the three patients with malignancies (median follow-up: 77 months), two IPNB died, one from cancer recurrence and one from unrelated causes, whereas the malignant MCN was alive and disease-free. Conclusions: Appropriate MHCN diagnosis is crucial, yet it is often misdiagnosed and mismanaged. The prognosis after complete excision is favourable

PROPHESYS was a prospective, international cohort study of monoinfected, treatment-naive chronic hepatitis C patients treated with a combination of peginterferon alfa-2a or alfa-2b and ribavirin.It included worldwide 7,163 patients from 19 countries (including 384 patients from Belgium alone) and demonstrated that sustained virologic response rates in the real world were similar to those achieved in well-controlled clinical trials. The objective of this sub-analysis was to present an overview of the baseline characteristics, anti-hepatitis C drug treatment, and virologic responses of the patients treated in Belgium, infected with HCV genotype 1, 2, 3, or 4, and administered pegin-terferon alfa-2a. Moreover, the impact of ribavirin dosage on the response to treatment was studied.356 patients were included in this sub-analysis. All variables were summarized using descriptive statistics.Compared to the published data of the whole study population (1), the Belgian data presented some significant differences in terms of genotype distribution and response to treatment (e.g. lower prevalence of HCV genotype 1 infection, lower virologic response rates in HCV genotype 2 patients). Deviations from existing recommendations were identified (e.g. higher dose of ribavirin in HCV genotype 2 or 3 patients). Patients who received less than 80% of the target dose of ribavirin experienced a significantly weaker response to treatment.This sub-analysis provided an interesting profile of the Belgian experience in the treatment of chronic hepatitis C.

OBJECTIVE: The main objective of this study was to evaluate the effect of switching from parenteral to enteral feeding on liver blood flow and propofol steady-state blood concentrations in patients in the intensive care unit (ICU). DESIGN AND PATIENTS: Steady-state blood concentrations of propofol were measured in eight ICU patients before (on days D -3, D -2, and D -1) and after (on days D + 1, D + 2, and D + 3) switching from parenteral to enteral feeding (on day DO). All patients received a continuous intravenous infusion of propofol (4.5 mg x kg(-1) x h(-1)) from several days before the start of the study, continuing throughout the experimental period. Hepatic blood flow was estimated by measuring steady-state D-sorbitol hepatic clearance. RESULTS: Hepatic blood flow was high and was not affected by switching from parenteral to enteral feeding: 33 +/- 8 ml x min(-1) x kg(-1) (mean +/- SD) and 33 +/- 10 ml min(-1) x kg(-1) on D -3 and D -1, respectively, as compared to 37 +/- 11 ml x min(-1) kg(-1) and 34 +/- 8 ml x min(-1) x kg(-1) on days D + 1 and D + 3, respectively. Systemic clearance of propofol was much higher than liver blood flow with average values on the six observation days ranging from 74.0 to 81.2 ml x min(-1) x kg(-1) and was not affected by switching from parenteral to enteral feeding. CONCLUSIONS: Liver blood flow and systemic clearance of propofol were not affected by switching from parenteral to enteral feeding in the eight ICU patients studied. Extrahepatic clearance accounted for at least two thirds of the overall systemic clearance of propofol.

Radiation-induced liver disease is recorded as a form of veno-occlusive disease. Its pathogenesis remains unclear even if the initial injury likely occurs in the endothelial cells of central veins. The aim of our study was to investigate liver morphological features in relation to alpha-isoform of smooth muscle actin expression in hepatic stellate cells in six patients treated by localized radiotherapy on the biliopancreatic area. Within the month after completion of treatment, an activation of hepatic stellate cells strictly confined to irradiated areas and coinciding with congestive changes was observed. At a later stage, collagen deposition gradually increased, replacing the congestive and destroyed areas. This new fibrotic tissue also contained numerous alpha-smooth muscle positive cells. Our data suggest that early hepatic stellate cells activation coinciding with congestive changes plays an important role in radiation liver injury and ensuing fibrosis.

OBJECTIVE: The aim of our prospective study was to compare the values of ferumoxides-enhanced gradient-echo and T2-weighted spin-echo MR imaging for the detection and segmental location of malignant hepatic tumors. SUBJECTS AND METHODS: Eighteen patients underwent ferumoxides-enhanced T2 weighted spin-echo and steady-state gradient-echo imaging before surgery. Intraoperative sonography was used as the reference examination and showed 28 malignant tumors involving 39 of the 144 hepatic segments. The MR images were reviewed independently by two observers who recorded the number of tumors and their segmental location. The results of the segmental location were subjected to receiver-operating-characteristic analysis. Tumor-liver, vessel-liver, and tumor-vessel contrast-to-noise ratios were calculated. RESULTS: Detection on the gradient-echo images did not differ significantly from that on the T2-weighted spin-echo MR images (observers A and B detected 23 and 24 tumors, respectively, on the gradient-echo images; the two observers each detected 22 tumors on the T2-weighted spin-echo images). Segmental localization was significantly better on the gradient-echo images than on the T2-weighted spin-echo images (mean area under the receiver-operating-characteristic curve: 0.974 versus 0.895 for observer A and 0.962 versus 0.906 for observer B, p = .024). The highest contrast-to-noise ratios for vessel to liver and tumor to vessel were obtained on the gradient-echo images and the highest tumor-liver contrast-to-noise ratio was obtained on the T2-weighted spin-echo images. CONCLUSION: In our study, ferumoxides-enhanced gradient-echo imaging was as accurate as T2-weighted spin-echo imaging for revealing malignant hepatic tumors and was superior for showing their segmental location.

The combination of Pegylated (PEG)interferon alpha-2b and ribavirin is considered to be the standard treatment for naïve chronic hepatitis C patients. Study aims are to evaluate the differences between standard interferon and PEG-interferon by conducting a multi-centre, controlled randomized trial comparing 3 groups. Group A : daily interferon alfa-2b at a dose of 4 MIU + ribavirin, Group B : PEG-interferon alfa-2b at a dose of 100 mcg/week + ribavirin; Group C: interferon alfa-2b at a dose of 3 MIU TIW + ribavirinMulticentrer, open label study including naïve chronic Hepatitis C Virus patients randomised in three groups with a ratio of 2:2:1. Group A: daily interferon alpha-2b (4 MIU s.c. for patients65 kg or 0.06 MIU/kg65 kg) and ribavirin, group B: PEG-interferon alpha-2b (100 microg s.c. weekly for patients65 kg or 1.5 microg/kg weekly for patients65 kg) and ribavirin and group C (reference arm) : interferon alpha-2b (3MIU s.c. TWI) and ribavirin. The duration of the treatment was 48 weeks for all 3 groups, with a 6 month follow-up period. 336 patients were enrolled in the study and included in the intention-to-treat analysis; 78 never started treatment (35 in group A, 28 in group B and 15 in group C): 101 in group A, 98 in group B and 59 in group C.Demographic data, PCR results and reasons for early withdrawal have been statistically analysed. At baseline, the 3 groups did not show any statistical difference regarding age, gender, race, genotypes and METAVIR score. At week 24 on treatment, HCV ribonucleic acid RNA was undetectable in 87% in group A, in 79% in group B and in 69% in group C. At the end of treatment, 73% 74% and 58% respectively, had a negative PCR result. At week 24 of follow-up, these results were 71%, 64% and 48%, respectively. When comparing the efficacy of the daily interferon (+ ribavirin) and the PEG-interferon (+ ribavirin) regimen, no statistical difference was found (p = 0.32). In group A, 38% of drop-outs were due to adverse events compared to 37% in group B and 58% in group C. No statistical differences were observed regarding safety.Daily weight based interferon alpha-2b dosing and PEG interferon alpha-2b weighed based dosing once weekly both in combination with Ribavirin offer the same efficacy and safety rates.

The case of a patient with large hepatic calcifications along the portal vascular network caused by long-standing portal vein thrombosis is presented. These calcifications appeared in extended portal thrombosis and were confirmed in follow-up for a surgical portocaval shunt related to portal hypertension. The differential diagnosis should distinguish these from hyperechoic patterns observed along the periportal vascular network, including intraductal biliary stones, portal venous gas, gas in the biliary tract, biliary comet tail artifacts, periportal fibrosis in parasitosis, and calcifications of the hepatic arteries.

The authors present the results of a single centre study of 587 liver transplants performed in 522 adults during the period 1984-2002. Results have improved significantly over time due to better pre-, peri- and post-transplant care. One, five, ten and fifteen year actuarial survivals for the whole patient group are 81.2; 69.8; 58.9 and 51.2%. The high incidence of de novo tumors (12.3%), of cardiovascular diseases (7.5%) and of end-stage renal function (3.6%) should be further incentives to tailor the immunosuppression to the individual patient and to direct the attention of the transplant physician to the long-term quality of life of the liver recipient.

The number of adult patients on the liver transplantation waiting lists is growing steadily. Adult living related liver transplantation (LRLT) represents the ultimate means to expand the donor pool. The success of this model of "small for size" grafting relies on strict donor and recipient selection. The choice of the graft (2 left and 4 right hepatectomies) was made on the minimal ratio between estimated graft and recipient body weights (0.8-1%), necessary to meet the recipient's metabolic demands. Our experience with six adults is reported. Donor morbidity was minimal (one wound infection); there was no mortality. Four (66%) recipients are doing well, two died of infectious complications. All recipients had a complicated post-transplant course. Due to its complexity, both in donor and recipient, LRLT should only be developed very carefully in experienced liver transplant centers.

Cytochrome P-450 3A enzymes belong to the most abundant subfamily of the cytochrome P-450 system. They are predominantly found in the liver where they metabolize numerous drugs and endogenous substances such as oestrogens. However, they are also expressed by normal and tumoural extrahepatic tissues. Accordingly, immunolocalization was assessed in malignant breast tumours (n=32) and normal counterparts, by using a monoclonal antibody that recognizes all human CYP3A proteins. We investigated a potential relation between expression of CYP3A protein expression, the degree of tumour differentiation assessed by the histological grade and the proliferation index assessed by Ki-67 immunostaining. Immunodetection of CYP3A was observed in 27 of the 32 tumours analyzed (84%). A focal staining was also observed in the adjacent normal breast tissue in 33% of the samples, but expression was always fainter than in tumours. A significant negative association was found between CYP3A and the proliferation index, but there was no relation with receptor status or tumour differentiation. While CYP3A protein expression can be found in normal breast tissues, these data highlight higher and more frequent CYP3A in malignant breast cells. Such expression in malignant breast cells appears inversely related to the proliferation index whereas no relation is found with tumour differentiation.

Most series that report the results of surgical treatment for congenital liver cysts focus more on the technical aspects of the operation than on the late outcome of these patients. In this paper, we emphasize the importance of appropriate patient selection and adequate surgical technique for successful long-term outcome.Twenty-four consecutive patients with congenital liver cysts were selected for surgical treatment. According to our own classification, 13 patients had simple liver cysts, nine had multicystic liver disease, and two had type I polycystic liver disease. All of these patients were treated by the fenestration technique. An open approach was used for five patients (group 1) treated between 1984 and 1990. In 19 patients (group 2) treated since 1991, a laparoscopic approach was used. The incidence of complicated liver cysts was 40% in group 1 and 68% in group 2.There were no treatment-related deaths in this series. The mean postoperative hospital stay was significantly shorter for patients who underwent successful laparoscopic fenestration (p0.05). In the open group (group 1), there were no postoperative complications, and all patients were alive and free of symptoms during a mean follow-up of 130 months, without any sign of cyst recurrence. In the laparoscopic group (group 2), four patients were converted to open surgery. One of these patients had an inaccessible posterior cyst; another had bile within the cystic cavity. A further two cases had complicated liver cysts with an uncertain diagnosis between congenital and neoplastic cysts. Four patients (21%) developed peri- or postoperative complications. During a mean follow-up time of 38.5 months, none of the patients with simple liver cysts incurred late symptoms or signs of cyst recurrence. In the six patients with multicystic liver disease, one developed disease-related cyst progression (17%) and required reoperation. One of the two patients with type I polycystic liver disease (50%) developed asymptomatic disease-related cyst progression.When patients are carefully selected and a proper surgical technique is employed, excellent long-term results with a low morbidity rate can be achieved in patients with congenital liver cysts. Patients with multicystic liver disease or type I polycystic liver disease are more prone to late cyst recurrence. A tailored approach is thus indicated for patients with congenital liver cystic disease. However, the laparoscopic approach appears to be the gold standard for the treatment of highly symptomatic or complicated simple liver cysts.

The purpose of this study was to compare in the same patients tailored and fixed scanning delays during gadolinium-enhanced arterial-phase magnetic resonance imaging of hypervascular liver tumors. Tailored scanning delays were obtained with automated region of interest threshold triggering. A delay of 23 seconds between the start of contrast material injection and imaging was used for fixed delay examinations. Quantitative and qualitative evaluation was performed in 21 patients with normal cardiac function referred for MR assessment of hypervascular liver tumors. In the tailored examinations, the median time delay between the start of contrast material injection and the start of magnetic resonance imaging was 21 seconds (range, 18-34 seconds). The median tumor-to-liver contrast during tailored examinations was 19.1 versus 14.7 during fixed delay examinations. This difference, however, was not significant. Similarly, the enhancement in the aorta, the portal vein, the liver, and the tumor did not differ significantly between examinations performed with tailored and fixed delays. It is concluded that in our group of patients with hypervascular liver tumors and normal cardiac function, no significant improvement in tumor-to-liver contrast and enhancement during the arterial phase was found when gadolinium-enhanced magnetic resonance imaging was performed with a tailored scanning delay rather than with a fixed delay.

We report the case of a female patient with rheumatoid arthritis who developed acute cytolytic hepatitis due to meloxicam. Recently introduced in Belgium, meloxicam is the first nonsteroidal antiinflammatory drug with selective action on the inducible form of cyclooxygenase 2. The acute cytolytic hepatitis occurred rapidly after meloxicam administration and was associated with the development of antinuclear antibodies suggesting a hypersensitivity mechanism. This first case of meloxicam related liver toxicity demonstrates the potential of this drug to induce hepatic damage.

Recently, ultrasound-guided percutaneous acetic acid injection has been proposed in the treatment of hepatocellular carcinoma as an alternative to percutaneous ethanol injection. We report the case of severe renal failure requiring haemodialysis which occurred in a patient with 4 cm hepatocellular carcinoma treated adequately by high dose percutaneous acetic acid injection. The risk of such a serious side effect, likely related to a direct toxic effect of acetic acid, should be of concern when considering percutaneous treatment of hepatocellular carcinoma. Acute renal failure has been reported as a complication of acetic acid poisoning, but to our knowledge, we report here the first case of acute renal failure following high dose percutaneous acetic acid injection.

Serum alanine aminotransferase (ALT) level is the most common screening test as part of a routine evaluation of liver damage. In order to determine the factors influencing this liver function test in normal subjects, the relationship between ALT level and gender, age and body mass index (BMI) was studied in a large population of healthy blood donors.This population included 9,420 volunteer blood donors (4,488 men and 4,932 women aged from 18 to 70 years) selected on the basis of negative answers to a detailed medical questionnaire including past medical history, drug and alcohol consumption, on the absence of clinical signs of liver disease, on the negativity of serological testing for hepatitis B and C virus and HIV.In the overall population, the mean serum ALT value was 21.8 I.U./L and the mean BMI was 24.4 kg/m2. There was a positive significant correlation between serum ALT level and BMI (Pearson r = 0.54; p0.001) and between ALT and age (Pearson r = 0.25; p0.001). A major sex-difference in ALT value was observed, the mean ALT value being higher in men than in women (26.8 +/- 13.6 vs. 17.2 +/- 8.1 I.U./L, p0.0001). In both sexes, ALT level was significantly correlated with BMI (Pearson r = 0.45 in men and r = 0.37 in women; p0.001). In women a consistent rise in BMI and ALT value with increasing age was observed whereas in men BMI and ALT level only increased with age up to the fifth decade.There was a significant positive correlation between ALT and BMI regardless the gender in a population of healthy volunteer blood donors. Moreover, at the same age and the same BMI, ALT was significantly lower in women than in men suggesting that the normal range for ALT value should be adjusted for gender. So gender and BMI have to be considered in the interpretation of ALT values.

The phenytoin hydroxylation index was studied in 122 unrelated Caucasian volunteers. Following a 100 mg oral dose of phenytoin, phenytoin and hydroxyphenytoin were measured in urine from 0-32 hr after administration. As phenytoin was not found in all urine collections, a phenytoin hydroxylation index was expressed as follows: Phenytoin hydroxylation index = amount of phenytoin administered/0-32 hr urinary output of hydroxyphenytoin. Phenytoin hydroxylation index values appear to be bimodally distributed, 92% of the population showing a mean (+/- S.E.M.) value of 0.639 +/- 0.099 and 8% a mean (+/- S.E.M.) value of 1.001 +/- 0.180 (log10 values). These results are in favour of the existence of a phenytoin genetic polymorphism. Since misuse of urinary metabolite excretion data in drug metabolism studies is a well-known phenomenon, our data emphasize the need for future population studies on phenytoin pharmacokinetics as well as on CYP2C9 genotyping before concluding about existence of a phenytoin genetic polymorphism.

Hepatobiliary cystadenoma and cystadenocarcinoma are rare tumors of the liver. The differential diagnosis of cystadenoma includes other cystic neoplasms, nonneoplastic cysts, and even on some occasions parasitic liver involvement. It has been suggested that elevated serum level of the tumor marker CA 19-9 may be of value in distinguishing between cystadenoma with ovarian stroma and hydatid disease. We report the unique case of a male patient with a hepatobiliary cystadenocarcinoma without ovarian stroma of prolonged evolution characterized by a normal CA 19-9 serum level, low cyst fluid CA 19-9, and a very weak CA 19-9 expression on cyst epithelium.

We report our experience based on 500 transjugular liver biopsies, a safe procedure even in high risk patients. Transjugular liver biopsies represents one third of all liver biopsies performed in our Hepato-Gastroenterology units. Liver specimen was adequate to evaluate liver architecture in 87.6% of patients in whom a minimal size of 7.6 mm of the liver core was found suitable for this purpose. The size of the liver specimen negatively correlated with the increase in hepatic venous pressure gradient (p0.0001). The liver biopsy was unsuccessful in 3.6% of patients. Hepatic capsular perforation occurred in 3.4% of patients but remained invariably asymptomatic.

A peculiar abnormal biliary tract consisting in a double common bile duct, one with a normal drainage into the duodenum and the other providing from the left lobe with an ectopic drainage into the stomach is described. For the first time, this anomaly was discovered by endoscopic retrograde cholangiopancreatography (E.R.C.P.). In the literature, only twelve other cases of abnormal drainage into the stomach are described. This could be related to a random subdivision of the hepatic diverticulum during the first weeks of embryogenesis.

Interferons exhibit antiviral and immunomodulatory properties. Antiviral effects appear mainly mediated via 2'5' oligoadenylate synthetase and protein kinase proteins which inhibit viral components synthesis. Interferons also influence the immune system through various mechanism among whom an increased expression of HLA class I antigens on hepatocyte plasma membrane and the promotion of natural killer cell activity leading to the clearance of infected hepatocytes. We report the results of various alpha interferon therapeutic regimens in 60 patients with chronic hepatitis C. In our series, 20 patients (33%) achieved a complete response but 78% of them relapsed after therapy withdrawal. Predictors of good response include young age, low serum ALT levels and mild liver injury. On the contrary, cirrhosis is associated with a poorer response.

Viral infections after liver transplantation represent a major cause of morbidity and mortality. These agents may be introduced into the patient through the allograft, infusion of blood, blood products, and intravenous lines... Reactivation of latent viruses related to immunosuppression is also frequently observed after liver transplantation. Finally, a persistent infection due to hepatitis B, C or D viruses frequently occurs after liver transplantation and still presents serious problems when evaluating the therapeutic benefits of liver grafting. In this review, the clinical, biochemical, and histological characteristics of most frequent viral pathogens observed after liver transplantation are described. Particular features of each of these viruses are underlined.

Vascular gastric lesions are a rare cause of chronic gastric bleeding. We report the case of a 70-year old woman with primary biliary cirrhosis, CREST syndrome and vascular gastric lesions corresponding to watermelon stomach. Oestrogen-progesterone treatment successfully controlled recurrent blood loss.

1. The effects of nilutamide (an anti-androgen with a hydantoin moiety) on the 4-hydroxylation of mephenytoin were studied in rat liver microsomes. Nilutamide, at a concentration expected in human liver (100 microM) during prolonged administration of nilutamide, inhibited by 40% mephenytoin (0.3 mM) 4-hydroxylase activity in liver microsomes from untreated male rats, but not in microsomes from untreated female rats, or in microsomes from dexamethasone-treated male or female rats. 2. Administration to male rats of nilutamide, in doses (20 mg/kg i.p. twice daily) known to reproduce plasma concentrations observed in human therapeutics, decreased by 60% the 24 h urinary excretion of 4-hydroxymephenytoin after administration of mephenytoin (15 mg/kg oral). 3. Nilutamide (100 microM) markedly inhibited mephenytoin 4-hydroxylase activity in human liver microsomes. Inhibition kinetics were consistent with mixed inhibition. It is concluded that nilutamide inhibits mephenytoin 4-hydroxylase activity in untreated male rats and in human liver microsomes. It is suggested that inhibition is likely to occur in vivo in humans receiving therapeutic doses of nilutamide.

This article summarizes our present knowledge concerning drug-induced cholestasis by lesions of the bile ducts. Acute or chronic ductular and ductal cholestasis are induced by a few drugs. The acute form may mimic viral hepatitis or biliary tract obstruction. The outcome is generally good. The mechanism may be immunoallergic. The clinical presentation of the chronic form resembles that of primary biliary cirrhosis or sclerosing cholangitis. Its prognosis is generally good and characterized by a complete recovery. However, an evolution to biliary cirrhosis is sometimes possible. The mechanism could also be immunoallergic. Extrahepatic cholestasis is frequently observed after intra-arterial infusion of floxuridine. The prognosis is generally poor. The mechanism of this sclerosing cholangitis may be ischaemic.

Four patients developed acute hepatitis after receiving Atrium, an association of phenobarbital, febarbamate and difebarbomate, for the treatment of tremor or for the prevention of alcohol withdrawal symptoms. Hepatitis occurred 1 to 3 months after treatment. Asthenia was the unique clinical manifestation. Marked increase in serum aminotransferases and gamma-glutamyltranspeptidase levels were the main biological features. Histological examination showed liver cell necrosis in two cases, prominent in the centrolobular area in one case. There was no case of hepatic failure. Atrium withdrawal was followed by complete recovery within 6 to 12 weeks. The mechanism of Atrium hepatotoxicity remains unknown.

A retrospective comparison of urinary excretion of norepinephrine, epinephrine, dopamine and/or their acidic metabolites, HVA and VMA, in 36 children with neuroblastoma versus 360 hospitalized children without neuroblastoma showed a sensibility of 72% and a specificity of 98% for HVA and 80% and 97% for VMA respectively. Consequently, the sensibilities and specificities of these 2 determinations confirm their useful purpose for the biochemical diagnosis of neuroblastoma in preference to the determinations of norepinephrine, epinephrine and dopamine.

The effect of enzyme induction by rifampicin and phenobarbital and enzyme inhibition by cimetidine on the hepatic mixed-function monooxygenase (MFO) was investigated in 11 non-smokers, healthy male volunteers. Five were classified as extensive metabolizers (EM) of debrisoquine and 6 as poor metabolizers (PM). Rifampicin (600 mg/day), phenobarbital (100 mg/day) and cimetidine (1.2 g/day) were given for 8, 14 and 4 days, respectively. In PM on rifampicin, the debrisoquine metabolic ratio (MR) was significantly reduced, even reaching a value less than 12.6 in 2 subjects but on phenobarbital and cimetidine, the MR was not significantly modified. In PM on rifampicin and phenobarbital, the urinary excretion of 6 beta-hydroxycortisol was significantly enhanced but not in EM on these drugs. In both groups on cimetidine, salivary antipyrine half-life was lengthened and on rifampicin, it was shortened. In EM and PM on cimetidine, the total oral clearance of antipyrine was lowered but on rifampicin it was solely increased in PM. Regarding the metabolic clearance to the three main urinary antipyrine metabolites, that of norantipyrine (NORA) was significantly increased in PM on rifampicin. In PM on cimetidine, the metabolic clearance of NORA and hydroxymethylantipyrine (HMA) was reduced but in EM that of hydroxyantipyrine was additionally decreased. In PM on rifampicin, the induction of the hepatic mixed-function oxidase system, assessed by the urinary excretion of 6 beta-hydroxycortisol, the salivary antipyrine half-life and total oral clearance and the metabolic clearance of urinary NORA, were shown. On the other hand in PM, cimetidine, a probe drug used for inhibition of the MFO system, made it impossible to distinguish PM from EM.