Biomedical subjects
Publications and source records attributed to C Buffet.
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Interferon-alpha (IFN) monotherapy results in sustained virological clearance in a minority of patients with chronic hepatitis C. The aim of this study was to assess the effect of a reinforced regimen combining ribavirin and high-dose IFN for 48 weeks compared with a nonreinforced regimen combining a standard IFN regimen and ribavirin for 24 weeks in nonresponders with chronic hepatitis C. A total of 231 patients with chronic hepatitis C and previous nonresponse to IFN monotherapy were randomized. The reinforced group (n = 114) received IFN-2b 6 million units (MU) thrice weekly (TIW) and ribavirin for 48 weeks, and the nonreinforced group (n = 117) received IFN-2b 3 MU TIW and ribavirin for 24 weeks. The main outcome measure was a sustained virological response, defined as negative serum hepatitis C virus (HCV)-RNA 24 weeks following the end of treatment. This endpoint was determined in 98 patients of the reinforced group and 105 patients of the nonreinforced group. At the end of follow-up, a sustained virological response was observed in 29 of the 98 patients (29.6%) in the reinforced group vs 16 of the 105 patients (15.2%) in the nonreinforced group (P = 0.014). In multivariate analysis, factors associated with a sustained virological response were treated with a reinforced regimen [odds ratio (OR) 2.9; P = 0.06] and genotype 2 or 3 (OR 8.8; P < 0.0002). A total of 160 patients had paired biopsies before and after treatment. Histological activity improvement was observed in 32 of 80 patients (40%) and fibrosis worsening in 26 of 80 patients (33%) in the reinforced group vs 13 of 80 (16%) and 19 of 80 (24%) in the nonreinforced group (P = 0.30 and 0.20, respectively). Hence in nonresponders, a high-dose 48-week regimen of IFN and ribavirin combination was more effective than a regimen with interferon at lower dose and ribavirin for 24 weeks only.
An exceptional cause of obstructive jaundice is reported in the present case. A 51-year-old woman progressively developed jaundice with pruritus, and abdominal ultrasonography revealed dilated intra- and extrahepatic bile ducts. Endoscopic retrograde cholangiography and endoscopic ultrasonography showed a tumor in the distal common bile duct, but failed to determine the nature of the lesion, and the patient underwent a pancreaticoduodenectomy. The final diagnosis was an inflammatory pseudotumor of the common bile duct. Inflammatory pseudotumors are uncommon, without evident pathogenesis, and are described in many organs. The localization in the common bile duct is exceptional. The prognosis is good, and a more conservative approach is possible if the diagnosis is certain before surgery.
BACKGROUND: Liver cirrhosis may lead to hepatocellular carcinoma (HCC), regardless of its cause. Genetic and/or environmental factors may modulate the risk of HCC. Mutations in the HFE gene are responsible for genetic haemochromatosis, a condition known to be associated with liver cirrhosis, HCC, or both. It has recently been suggested that the C282Y HFE gene mutation may be more frequent in patients with HCC that have developed in the non-cirrhotic liver than in the general population. Whether or not HFE gene mutations are associated with an increased risk of HCC in patients with cirrhosis is unknown. AIM: To assess the prevalence of HFE gene mutations in cirrhotic patients with and without HCC. PATIENTS AND METHODS: A total of 133 consecutive cirrhotic patients with HCC were prospectively studied for the presence of C282Y and H63D mutations. The control group consisted of 100 cirrhotic patients without HCC. We used restriction enzyme digestion of polymerase chain reaction amplified genomic DNA for determination of HFE genotypes. Iron loading was assessed on non- tumoral liver biopsy samples from 89 patients with HCC and 73 patients without HCC. RESULTS: The prevalence of C282Y heterozygotes was similar in patients with and without HCC (5% v 4%, respectively; p=0.65) and did not differ from that expected in the general population. None of the HCC patients was found to be homozygous for C282Y or H63D, nor compound heterozygous. The prevalence of H63D heterozygotes was similar in patients with and without HCC (31% v 38%, respectively; p=0.25). No relation was detected between HFE genotypes and hepatic iron loading in patients with or without HCC. CONCLUSION: C282Y and H63D mutations do not appear to be associated with an increased risk of HCC in patients with cirrhosis.
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AIMS: The hepatic venous pressure gradient is a major prognostic factor in portal hypertension but its measurement is complex and requires invasive angiography. This study investigated the relationship between the hepatic venous pressure gradient and a number of Doppler measurements, including the arterial acceleration index. METHOD: We measured the hepatic venous pressure gradient in 50 fasting patients at hepatic venography. Immediately afterwards, a duplex sonographic examination of the liver was performed at which multiple measurements and indices of the venous and arterial hepatic vasculature were made. RESULTS: Hepatic arterial acceleration was correlated directly with the hepatic venous pressure gradient (r=0.83, P<0.0001) and with the Child-Pugh score (r=0.63, P<0.0001). An acceleration index cut-off value of 1m.s(-2) provided a positive predictive value of 95%, a sensitivity of 65% and a specificity of 95% for detecting patients with severe portal hypertension (hepatic venous pressure gradient>12 mmHg). A correlation between the hepatic venous pressure gradient and the congestion index of the portal vein velocity (r=0.45,P=0.01) and portal vein velocity (r=0.40,P=0.044), was also noted. CONCLUSION: Measuring the hepatic arterial acceleration index may help in the non-invasive evaluation of portal hypertension.
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C18 Empore 96-well extraction disc plates have been employed for the analysis of three drugs with different polarities in plasma in conjunction with HPLC-UV, rufinamide, ICL670 and an anticonvulsant agent (AA1) in an early stage of development. With the most polar compound (AA1), ion-pair extraction at pH 12 was applied. The method developed for the assay of AA1 in plasma was applied to its determination in brain using an Oasis HLB plate following homogenisation in a pH 7.4 buffer and protein precipitation with NaOH-ZnSO4, thereby saving time for method development. Protein precipitation in the 96-well format with filtration of the precipitate was applied to the determination of ICL670, a highly protein-bound compound (>99.5%), with a good recovery (78%). Reversed-phase chromatography was applied using a short 5 cm column packed with 3 microm particles for the determination of ICL670 and AA1 and two parallel columns (15 cm long) for the determination of rufinamide. The methods were used routinely, one plate per analysis day being processed, resulting in increase in sample throughput and saving in solvents.
UNLABELLED: CHRONIC INFECTION AND CIRRHOSIS: In France, the prevalence of hepatitis C virus (HCV) infection reaches an estimated 1% of the general population. Careful management is required since about 75% of all infected subjects will develop chronic liver disease with the risk of progression to cirrhosis. The major improvements in the efficacy of treatments developed over the last decade should help reduce the incidence of cirrhosis-related complications. PRACTICAL STEPS: A liver biopsy should be performed in all HCV-positive patients in order to study the histological impact. An antiviral treatment should be prescribed for patients free of decompensated cirrhosis or contraindications who have moderate to severe histological lesions. STANDARD TREATMENT: Alpha-interferon (3 MU three times a week) in combination with ribavirin (1000-1200 mg/d) should be given for 6 to 12 months. Resent publications have reported promising results with pegylated interferon which would be more effective and only require one injection per week. This new interferon, given in association with ribavirin, will undoubtedly shortly become the gold standard treatment for patients with chronic hepatitis C, particularly those infected with treatment-resistant geno-types.
INTERFERON ALPHA AND LAMIVUDINE: Chronic hepatitis B is currently treated with interferon alpha and lamivudine. Lamivudine (marketed under the name Zeffix in France) is given in oral preparations and is excreted in the urine. It is rapidly effective against virus replication since, after a one-month treatment, hepatitis B DNA levels are negative in most of the treated patients. After 12 months, there is an improvement in liver histology. ADVANTAGES AND DISADVANTAGES: The probability of effective treatment is greatest for patients with highly elevated transaminase levels and low hepatitis B DNA levels prior to treatment. Another advantage of lamivudine is the extremely low rate of side effects. The risk of a rebound in viral replication after withdrawal is a drawback together with the possible development of viral mutations of the polymerase gene, particularly after more than one year of treatment. INDICATIONS: Lamivudine can be prescribed for patients with a contraindication or non-responsive to alpha interferon: liver transplantation candidates, organ graft recipients. For other cases, alpha interferon is the first line treatment of choice. If lamivudine is used too early, there is a risk the patients could no longer be transplanted after the development of mutations and major aggravation of liver function. Future perspectives include simultaneous or sequential use of antiviral agents.
The need for fast bioanalytical methods within the pharmaceutical sector is rapidly growing. Sample preparation is often the bottleneck step. A new approach to increasing sample throughput involves precipitated protein removal by filtration in the 96-well format, thereby eliminating the need for centrifugation and manual handling of individual tubes. The potential for such a new technique has been investigated for the determination of an iron chelator, a highly protein-bound compound (> or =99.5%) in plasma. An analog was used as internal standard. Acetonitrile and plasma were sequentially aspirated, separated by an air gap, using a manual electronic pipettor. They were then dispensed into the channel of an Empore filter PPT plate above the filter, and a slight vacuum was applied. The eluate was collected and diluted prior to injection. The compounds were then separated by reversed-phase chromatography and detected by UV at 295 nm. The chromatographic run time was 6 min. The mean recovery following protein precipitation was 78%, which shows that the technique can apply to a highly protein-bound compound. Replicate quality control samples were prepared in drug-free normal human plasma at four different concentrations. The mean accuracy ranged from 87 to 108% with the CV ranging from 3 to 8%. The described procedure is simple, fast and reproducible. It requires minimal equipment. The time required to prepare a plate manually is only about 20 min. The use of 12-channel repeater pipettors reduces the risk of error and improves productivity. Automation should be an aid to further increasing sample throughput when more than one plate a day is to be prepared.
Nonalcoholic steatohepatitis (NASH) may progress to liver fibrosis and cirrhosis. Mechanisms directly involved in the development of fibrosis have been poorly investigated. Because connective tissue growth factor (CTGF) is an intermediate key molecule involved in the pathogenesis of fibrosing chronic liver diseases and is potentially induced by hyperglycemia, the aims of this study were to (1) study the expression of CTGF in vivo both in human liver biopsy specimens of patients with NASH and in an experimental model of obesity and type II diabetes (Zucker rats); and (2) analyze the effects of hyperglycemia and insulin in vitro on hepatic stellate cells. In vivo, CTGF overexpression was observed in the liver tissue of all of the 16 patients with NASH. CTGF immunostaining was mild in 7 cases (44%) and moderate or strong in 9 cases (56%). Staining was mainly detected in the liver extracellular matrix in parallel with the amount of liver fibrosis. Liver from fa/fa rats also showed CTGF overexpression by comparison with Fa/fa rats both at the messenger RNA (mRNA) level (3-fold increase) and protein level. In vitro, both CTGF mRNA and protein were significantly increased when hepatic stellate cells were incubated with either glucose or insulin. A slight increase in type I procollagen mRNA level was also observed in hepatic stellate cells incubated with glucose. In conclusion, this study suggests that hyperglycemia and insulin are key-factors in the progression of fibrosis in patients with NASH through the up-regulation of CTGF.
BACKGROUND: A prospective multicentre study was initiated in HCV-infected haemodialysis patients to assess the tolerance and efficacy of alpha-2b interferon. METHODS: We had planned to include 120 patients with HCV RNA detectable by polymerase chain reaction (PCR) (Amplicor Roche) and histologically documented chronic hepatitis. The dose of alpha-interferon was 3 million units (MU) three times weekly (TTW), to be reduced to 1.5 MU TTW in case of side-effects. Tolerance was evaluated monthly; virological efficacy was evaluated by PCR. A liver biopsy was performed at month 18 (M18). RESULTS: (a) TOLERANCE: After 37 patients had been included, the study was discontinued by the promoting institution because of severe side-effects requiring that treatment be stopped in 19 patients. The side-effects were: cardiac (4) neuropsychiatric (2), digestive (3), acute necrosis of the graft (1), severe asthenia (9), minor side-effects were observed in 22 patients. A complete 12-month course was completed in 12 patients for the 3 MU TTW dose and in six patients for the 1.5 MU TTW reduced dose. Normal ALT level (OR, 0.16; CI 95%, 0.03-0.89) at inclusion was associated with interruption of treatment (univariate analysis). (b) EFFICACY: Sustained virological response was observed in only seven (18.9%), of the 18 patients who completed the treatment (38%). Increased ALT at inclusion (OR, 1.04; CI 95%, 1.01-1.09) and cumulated doses of interferon (OR, 1.01; CI 95%, 1.004-1.026) were jointly associated with a sustained response, while positive PCR at M2 was strongly predictive of treatment failure. CONCLUSION: Tolerance of interferon is poor in haemodialysis patients. Sustained response is fairly high in patients who have 12 months of treatment and seems to be based on the immune status of the patients (ALT) and the cumulative doses of interferon.
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OBJECTIVE: Although percutaneous liver biopsy (PLB) can be a painful procedure, common practice has not included intravenous sedation or analgesia. Patient-administered nitrous oxide/oxygen (N2O/O2) inhalation has demonstrated analgesic efficacy in various procedures associated with mild to moderate pain. The aim of this study was to investigate the safety and efficacy of analgesia with N2O/O2 inhalation for PLB. METHODS: One hundred consecutive patients undergoing a first PLB (for chronic hepatitis C: 56, for alcoholic liver disease: 23, for miscellaneous reasons: 21). Patients were randomly assigned to self-administrate from a facial mask with a demand valve, for 5 min before and during biopsy, either a breathing mixture of 50% N2O/O2 (N2O group, n = 51), or a breathing oxygen placebo (P group, n = 49). Liver biopsy was performed at bedside after adequate local anesthesia with xylocaine. At the end of the procedure, patients were asked to self-evaluate pain experienced using a visual analogue scale (VAS) with scoring from 0 to 100 mm. RESULTS: N2O/O2 administration resulted in the absence of pain in a significantly higher number of patients treated than in patients of the P group: 19 versus 2, respectively (p = 0.0001). Patients receiving N2O/O2 had significantly lower pain scores than those of the P group: 12+/-12 versus 28+/-19 mm (p < 0.0001). No serious complication was observed. Side effects of N2O/O2 were minor and reversible. The average cost per biopsy was 4 US dollars. CONCLUSIONS: Patient-administered N2O/O2 inhalation provides safe and effective analgesia, at a reasonable cost, for PLB. Its routine use could be useful for the management of patients with chronic liver disease undergoing PLB as it may enhance patients compliance with future biopsies.
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AIM: To evaluate the natural course of focal nodular hyperplasia according to hormonal status. METHODS: Forty-four patients were included in this retrospective study. Tumor size was assessed with ultrasound examination. We studied the influence of hormone status on the course of the disease. RESULTS: All patients were women, the median age at diagnosis was 35 years and the median follow-up was 45 months. Ten patients were symptomatic at diagnosis, while none were symptomatic at the end of follow-up. The median size of the lesions was 56 mm. No complications occurred. The size of the tumor remained stable in 19 patients, increased in 12 and decreased in 13. Twenty-one of 37 patients stopped taking oral contraceptives at diagnosis: the lesion remained stable in 11 patients, increased in 3 and decreased in 7. Two patients didn't stop taking oral contraceptives: the lesion increased in one, decreased in the other. Six patients became pregnant and 6 patients went into menopause during follow-up: the lesion remained stable in 3 and 4 patients respectively. CONCLUSION: Focal nodular hyperplasia is a benign lesion. Tumor size remained stable in most cases. It seems that the hormonal status has little or no influence on the course of the disease.