RNA editing blood biomarkers for predicting mood alterations in HCV patients.

Treatment-emergent depression is a common complication in patients with chronic hepatitis C virus (HCV) infection undergoing antiviral combination therapy with IFN-α and ribavirin. It has recently been shown that changes in A-to-I RNA editing rates are associated with various pathologies such as inflammatory disorders, depression and suicide. Interestingly, IFN-α induces gene expression of the RNA editing enzyme ADAR1-1 (ADAR1a-p150) and alters overall RNA editing activity. In this study, we took advantage of the high prevalence of pharmacologically induced depression in patients treated with IFN-α and ribavirin to test the interest of RNA editing-related biomarkers in white blood cells of patients. In this 16-week longitudinal study, a small cohort of patients was clinically evaluated using standard assessment methods prior to and during antiviral therapy and blood samples were collected to analyse RNA editing modifications. A-I RNA editing activity on the phosphodiesterase 8A (PDE8A) gene, a previously identified RNA editing hotspot in the context of lupus erythematosus, was quantified by using an ultra-deep next-generation sequencing approach. We also monitored gene expression levels of the ADAR enzymes and the PDE8A gene during treatment by qPCR. As expected, psychiatric evaluation could track treatment-emergent depression, which occurred in 30% of HCV patients. We show that PDE8A RNA editing is increased in all patients following interferon treatment, but differently in 30% of patients. This effect was mimicked in a cellular model using SHSY-5Y neuroblastoma cells. By combining the data of A-I RNA editing and gene expression, we generated an algorithm that allowed discrimination between the group of patients who developed a treatment-emergent depression and those who did not. The current model of drug-induced depression identified A-I RNA editing biomarkers as useful tools for the identification of individuals at risk of developing depression in an objective, quantifiable biological blood test.

[Tropism of hepatitis C virus for leukocytes-- importance of the analysis of viral E1 and E2 envelope glycoprotein genes by sequencing]. / Tropisme leucocytaire du virus de l'hépatite C - intérêt de l'analyse des séquences des gènes des glycoprotéines d'enveloppe virales E1 et E2.

The ability of hepatitis C virus (HCV) to infect leukocytes could favour HCV pathogenesis. Although viral infection of these immunocompetent cells is poorly (or not) productive, the impact on their immunomodulatory functions could be important. Viral envelope glycoproteins E1 and E2, because of their crucial role in the recognition of viral receptors on permissive cells, could contribute to viral leukocytic tropism and, as a consequence, to the pathophysiology of HCV chronic infection.

[Study of hepatitis C virus leukotropism by characterization of viral quasispecies in the liver transplantation setting]. / Etude du leucotropisme du virus de l'hépatite C par analyse des quasi-espèces virales dans le contexte de la transplantation hépatique.

Besides hepatocytes, representing the main replication site of hepatitis C virus, peripheral blood mononuclear cells also represent a crucial target for viral infection. Hepatitis C virus compartmentalization (i.e., non-random distribution) of viral variants between plasma and peripheral blood mononuclear cells, more frequently observed in liver transplant patients compared to non-transplanted patients, makes liver transplantation an interesting model for the analysis of hepatitis C leukotropism. This article aims to present, firstly, in clinical and biological features arguing favour of hepatitis C virus infection leukotropism and, secondly, to review current knowledge about compartmentalization between plasma and peripheral blood mononuclear cells, especially in the liver transplantation setting.

[Hepatitis C, cirrhosis and hepatocellular carcinoma]. / Hépatite C, cirrhose et carcinome hépatocellulaire.

The screening for the detection of hepatocellular carcinoma is based on ultrasound sonography which should be realised in patients with post-hepatitis C cirrhosis with a delay between 3 and 6 months according to the most identified risk factors, in particular age and sex male. In the case of discovery of hypoechogen nodule < or = 1cm, a follow-up is mandatory because it is usually untypical by ultrasound sonography and to propose a liver biopsy in the case of an increasing in size is shown. The ultrasound guided cutting biopsy can precise the histological characteristics of the nodule, the grade, and indicate prognostic factors. The liver biopsy is also mandatory in the case of a nodule > 2 cm and when the ultrasound sonography is not contributive, especially when the nodule is between 1 and 2 cm in size.

Multicentre randomised phase III trial comparing Tamoxifen alone or with Transarterial Lipiodol Chemoembolisation for unresectable hepatocellular carcinoma in cirrhotic patients (Fédération Francophone de Cancérologie Digestive 9402).

The FFCD 9402 multicentre phase III trial was designed to compare the effects of the combination of Transarterial Lipiodol Chemoembolisation (TACE) and tamoxifen with tamoxifen alone on overall survival and quality of life in the palliative treatment of hepatocellular carcinoma with cirrhosis. From 1995 to 2002, 138 patients were randomised between the two groups. One hundred and twenty three patients were eligible including 61 in the Tamoxifen group and 62 in the TACE group. Baseline characteristics were similar: Child-Pugh class A: 70%, alcoholic cirrhosis: 76%, Okuda stage I: 71%, multinodular tumour: 70% and segmental portal vein thrombosis: 10%. At 2years, the overall survival was 22% and 25% in the Tamoxifen and TACE groups (P=.68), respectively. Multivariate analysis identified four independent prognostic factors for survival: alpha-fetoprotein (AFP)>400ng/mL (P=.008), abdominal pain (P=.011), hepatomegaly (P=.023) and Child-Pugh score (P=.032). The Spitzer Index level assessing the quality of life during follow-up did not differ between the two groups (P=.70). Amongst patients with stage Okuda I, the 2-year overall survival was 28% in the Tamoxifen group and 32% in the TACE group (P=.58). In this subgroup, two prognostic factors were statistically significant for survival: AFP>400ng/mL (P=.004) and Spitzer Index (P=.013) as shown by multivariable analysis. In conclusion, this study suggests that TACE improves neither the survival nor the quality of life in patients with HCC and cirrhosis.

Prognosis of advanced hepatocellular carcinoma: comparison of three staging systems in two French clinical trials.

OBJECTIVE: The objective of this study was to assess the performance of three staging systems [Okuda, Cancer of the Liver Italian Program (CLIP) and Barcelona Clinic Liver Cancer group (BCLC)], for predicting survival in patients with hepatocellular carcinoma (HCC) and to explore how to improve prognostic classification among French patients with HCC whose main etiology is alcoholic cirrhosis. METHODS: We have pooled two randomized clinical trials in palliative condition from the Fédération Francophone de Cancerologie Digestive. They had included 416 and 122 patients. Performances of Okuda, CLIP and BCLC scores have been compared using Akaike information criterion, discriminatory ability (Harrell's C and the Royston's D statistics), monotonicity of gradients and predictive accuracy (Schemper statistics Vs). To explore how to improve classifications, univariate and multivariate Cox model analyses were carried out. RESULTS: The pooled database included 538 patients. The median survival was 5.3 months (95% confidence interval 4.6-6.2). For all statistics CLIP staging system had a better prognostic ability. Performances of all staging systems were rather disappointing. World Health Organization performance status (WHO PS) for CLIP or alpha-fetoprotein for BCLC allowed a significant improvement of prognostic information. CONCLUSION: Our results indicate that CLIP staging seems to be most adapted to palliative setting and that it could be better by associating WHO PS.

[Benefits of a preventive psychiatric accompaniment in patients Hepatitis C Virus seropositive (HCV): prospective study concerning 39 patients]. / Bénéfice d'une prise en charge préventive psychiatrique chez les patients séropositifs à l'hépatite C (VHC): étude prospective concernant 39 patients.

UNLABELLED: Hepatitis C represents a major public health challenge due to its chronic evolution and major complications (eg liver tumor and cirrhosis). New treatment strategies (interferon pégylé +/- ribavirine) have recently improved the prognosis except in case of poor compliance. Psychiatric comorbidity, especially affective disorders, is commonly associated with hepatitis C and constitutes the main cause of poor compliance, therapeutic discontinuations and treatment contra-indication. At this moment of new therapeutic protocols and the possibility of curing HCV infections, it is of utmost importance to widen antiviral treatment in many indications, to upgrade compliance, and to limit therapeutic discontinuations. In this context, where anxious and depressive disorders are the main reasons for failure in curing, it is necessary to anticipate the appearance of these troubles within an earlier multidisciplinary taking in charge. The primary aim of our study is to emphasize the utility of a multi-disciplinary approach including psychiatric evaluation, preventive follow-up and preventive treatment. The secondary objective is to show that a previous story of depression or use of drugs should not be considered as an insuperable contra-indication provoding the implementation of a specific follow-up. Thirty nine interferon treated patients were included in a prospective study. Our data confirm the high rate (28%) of Major Depressive Disorders among the population of hepatitis C treated patients in a preventive follow-up. A previous story of alcoholism, of suicide attempt or break off treatment with Major Depressive disorders might be predictive of such a complication. According to the subjective feeling of these patients with previous break'off treatment associated, specific psychiatric follow-up may improve tolerance for the treatment. METHODS AND OBJECTIVES: 39 patients (17 men and 22 women) accepted, on (or after) the non-systematic proposal of their hepatologist, to consult the psychiatrist of the network, prior to any therapeutic decision. The first objectives of the consultations were to inform the patient (and, with his agreement, his -relatives), about the risk of depressive disorders while under treatment by interferon, as well as their potential consequences. Moreover, the psychiatrist answers their questions concerning this issue, and proposes him a long-term psychotherapeutic follow up (up to several months after the antiviral treatment end) including availability in emergency if necessary and preventive antidepressive treatment. In this framework, we assessed in a prospective way the frequency, the intensity and the time (or moments) when major depressive episode (MDE) (according to the DSM IV) appeared under interferon alpha, the predictive factors for these MDE, the interest and the quality of a preventive antidepressive treatment prescription and the psycho-social benefits of this taking in charge for the patient. RESULTS: Among these 39 patients -regularly followed during and after the antiviral therapy, 11 (28%) had a MDE while under treatment. These MDE, except for 2 (5%) of them which led to an hospitalization, were mild to moderate. They mainly appeared within the 2 first quarters of treatment without significant difference. Patients with antecedents of suicide attempt (80%), drug addiction (50%) or alcohol addiction (50%) are more likely to have a MDE under interferon alpha than other patients, but these risk factors are not a contra-indication for treatment because 95% of the patients ended their treatment and the 2 antiviral treatment discontinuations observed were secon-dary to (or following) an acute psychotic episode (hospitalization) and a maniac episode in a schizophrenic patient (outpatient care). The existence of antecedents of antiviral treatment discontinuations due to MDE (33%) does not seem to be a risk factor anymore when preventive care is provided. It is interesting to point out the existence of a certain male fragility, men are more psychologically sensitive to interferon alpha than women. About 90% of patients chose to take an antidepressant. The latter was mainly a treatment with sertraline (45% out of cases), with citalopram (40% out of cases), and for 15% of them antidepressive treatment previously prescribed and non modified because they were well-tolerated and efficient. 86% of the first prescriptions were not changed during the follow up. 75% of patients already treated by a previous antiviral treatment with interferon alpha estimated that an earlier psychiatric accompaniment was very beneficial for them, in terms of compliance and socio-professional insertion. CONCLUSION: A specialized psychiatric accompaniment within a coherent multidisciplinary network provides a major benefit to the patients in terms of compliance and safe care (even for population considered as having higher risks) although it is not possible to define accurately the influence of the preventive prescription of a antidepressant (which is not prejudicial anyway). a previous story of depressive disorder should not be considered as a contra-indication, but should imply a specific psychiatric follow-up especially when alcoholism, previous story of suicidal attempt and previous break'off treatment are reported.

[Do general practitioners want to manage chronic hepatitis C and take part in hepatitis C health networks? A national survey]. / Les médecins généralistes souhaitent-ils prendre en charge l'hépatite chronique virale C et participer aux réseaux ville-hôpital?

OBJECTIVES: To assess information that general practitioners had on hepatitis C and on the hepatitis C network in hospitals and private practice. METHODOLOGY: A national telephone survey of 604 general practitioners was conducted between March 18 and 23, 1998. RESULTS: Screening and management of hepatitis C was important for 89% and 97% of general practitioners. Screening was performed in relation to the relative risk (IV drug users 89%, blood transfusion before 1991 88%). General practitioners wanted more information on treatment (54%), patient counselling (42%) and the potential risks of the disease (42%). Of 604 general practitioners, 6% were involved in a hepatitis C network, while 21% were involved in another network (drug users 9%, AIDS 8%). Of the 94% general practitioners who were not part of the network, 33% were willing to join a hepatitis C network. Only 56% were aware of a hepatitis C network (press article 30%, mailing 17% or local meeting 12%). The difficulties for the involvement of general practitioners were: lack of time, topics not adapted to daily practice and geographic constraints (74%), too few patients in their practice (52%), no need (38%), the idea itself of a network and lack of information (28%). CONCLUSION: General practitioners screen patients at risk of hepatitis C. They want to be better informed about treatment, patient counselling, and the potential risks of hepatitis C. They are less involved in hepatitis C networks than in other networks (drug, AIDS). However, one third of general practitioners would like to be involved in a hepatitis C network. These results could be useful for implementing post-graduate courses and general practitioner training.

[Chemoembolization techniques for hepatocellular carcinoma in cirrhosis]. / Les techniques de chimio-embolisations des carcinomes hépatocellulaires sur cirrhose.

Transcatherter oily chemoembolisation, that should not be confused with other different and less effective techniques also called "chemoembolisation" is the most widely used therapy for loco-regional palliative treatment of hepatocellular carcinoma, which will become increasingly frequent, due to HCV infection; the cancer itself is often discovered at an advanced stage, when neoplastic extension precludes radical treatment that is liver transplantation. Performed with the best techniques, it offers a 1- and 5-yr survival of 60 and 30%, that is under confirmation by a randomized trial.

[Etiological treatment of cirrhosis in adults]. / Traitement étiologique des cirrhoses de l'adulte.

Etiological treatment is based upon: abstinence in case of alcoholic cirrhosis; alpha-interferon in case of B or C viral cirrhosis; corticosteroids in case of autoimmune cirrhosis; ursodeoxycholic acid in case of primary biliary cirrhosis; stopping the drug in case of drug-induced cirrhosis; surgery in case of secondary biliary cirrhosis; venesections in case of genetic haemochromatosis; liver transplantation in cases of Wilson's disease and alpha 1-anti-trypsin deficiency. Overall, these treatment are more effective when undertaken early in the course of the liver disease.

Comparison of resection, liver transplantation and transcatheter oily chemoembolization in the treatment of hepatocellular carcinoma.

BACKGROUND/AIMS: Resection and liver transplantation are currently considered as the most useful treatments for hepatocellular carcinoma. However, transcatheter oily chemoembolization may be favourably compared with these two surgical treatments in patients with anatomically operable tumors. METHODS: Between 1985 and 1991, 122 patients with an Okuda stage I tumor were hospitalized in two French hospitals. Among these patients, 33 remained untreated, 42 were treated by transcatheter oily chemoembolization, 30 by resection and 17 by liver transplantation. The four groups were closely comparable except for age, the patients in the two surgical groups being significantly younger. Moreover, the frequency of pTNM II tumor was significantly higher in the resection group. RESULTS: The 5-year probability of survival was close to 45% in each of the three treated groups and was significantly higher than in the untreated group (0% at 4 years, p < 0.0001). The probability of cancer recurrence and/or metastatic dissemination was lower after transcatheter oily chemoembolization than after surgery. CONCLUSION: Thus, transcatheter oily chemoembolization seems comparable at 5 years with resection or transplantation for the treatment of resectable hepatocellular carcinoma.

[Serum cardiolipin antibodies in patients with alcoholic cirrhosis]. / Anticorps sériques anticardiolipides chez les malades atteints de cirrhose alcoolique.

OBJECTIVE: Although portal obstruction is a complication in cirrhosis which is usually associated with hepatocellular carcinoma, its precise neoplastic or thrombotic nature is not easy to determine. Serum antiphospholipid antibodies could be involved in thrombosis-related portal obstruction. PATIENTS AND METHODS: The presence of serum anticardiolipid antibodies was investigated by an immunoenzymatic technique in 129 patients with alcoholic cirrhosis, 47 patients with hepatocellular carcinoma with (n = 18) or without (n = 29) portal obstruction, and 82 patients without hepatocellular carcinoma or portal obstruction. Five control groups were included: patients with non alcoholic cirrhosis (n = 21), non cirrhotic alcoholic liver disease (n = 21), chronic viral hepatitis (n = 14), extra-hepatic cholestasis (n = 9), and hypergammaglobulinemia associated with human immunodeficiency virus infection without liver disease (n = 28). RESULTS: The prevalence of serum anticardiolipid antibodies was 57% in patients with alcoholic cirrhosis, which was significantly different from the prevalence in the control groups which ranged from 0 to 32%. Anticardiolipid antibodies were of IgA isotypes in 90.5% of the cases, mainly related to the degree of liver failure but not to hepatocellular carcinoma or portal obstruction. CONCLUSION: In alcoholic cirrhosis, serum anticardiolipid antibodies do not seem to be related to the pathogenesis of portal obstruction in patients with hepatocellular carcinoma. They could rather reflect liver lesions and immunological dysfunctions.

[Hepatosplenic silicosis]. / Silicose hépatosplénique.

A case of hepatosplenic silicosis complicating a pulmonary silicosis is reported. Numerous calcified splenic nodules seen with conventional radiology, ultrasound or computed tomography, hepatic microcalcifications and "egg shell" abdominal lymph nodes best seen with computed tomography represent the radiologic signs. However, hepatosplenic silicosis can only be confirmed by pathological examination of liver biopsies showing birefringent particles within hyalinized nodules.

Transcatheter oily chemoembolization for hepatocellular carcinoma. A 4-year study of 127 French patients.

BACKGROUND: In Western countries, only a small proportion of patients with hepatocellular carcinoma (HCC) can be treated with surgical resection. For other patients, locoregional management by transcatheter oily chemoembolization seems to be useful and warrants evaluation. METHODS: One hundred and twenty-seven French patients with an inoperable HCC were treated by transcatheter oily chemoembolization. The efficiency of the treatment was assessed by a comparison of this group with a group of 127 untreated patients. Each patient of the treated group was matched closely with an untreated patient for all the main clinical, anatomic, and biologic features that characterize the spontaneous evolution of HCC. RESULTS: The overall probabilities of survival in the treated group were 64%, 38%, 27%, and 27% at 1, 2, 3, and 4 years, respectively; those for the untreated group were 18%, 6%, and 5% at 1, 2 and 3 years, respectively (P < 0.0001). The survival was significantly increased in patients with Okuda Stage I and II disease (P < 0.0001), but not in those with Stage III. Karnofsky and Child-Pugh scores remained stable during the follow-up period and dropped only shortly before patients died. CONCLUSION: Transcatheter oily chemoembolization is an efficient treatment for unresectable HCC for the palliation of symptoms as well as for the prolongation of survival with a good quality of life.

Comparison of different lipid substrates on intestinal adaptation in the rat.

The relative effects of medium chain (MCT) and long chain triglycerides (LCT) on intestinal morphology and functions were compared. Adult rats received intragastrically for 10 days an isoenergetic mixture containing either 50% MCT/50% LCT or 100% LCT. The other constituents of the diets were identical, and animals fed a standard diet orally were used as a reference group. Animals who were given the MCT/LCT diet showed a higher mucosal mass and protein content and increased villus length and crypt depth in the proximal part of the small intestine compared with the LCT and control diet groups. Administration of [3H] thymidine 12 hours before death resulted in a significant increase in the incorporation of the precursor into cellular DNA in the jejunum of rats given MCT. In rats given LCT as the only fat, the free fatty acid content of the microvillus membrane showed a 20 fold increase and at the same time there was a significant drop in the cholesterol content and in the cholesterol/protein ratio. Differences in the lipid composition of enterol diet or in the microvillus membrane did not effect adversely membrane bound hydrolase activities. These findings suggest that MCT in the diet confers advantages in addition to the provision of rapidly available energy.