Persistent mucosal damage and risk of epilepsy in people with celiac disease.

BACKGROUND AND PURPOSE: Celiac disease (CD) is associated with an increased risk of developing epilepsy, a risk that persists after CD diagnosis. A significant proportion of patients with CD have persistent villous atrophy (VA) on follow-up biopsy. The objective of this study was to determine whether persistent VA on follow-up biopsy affected long-term epilepsy risk and epilepsy-related hospital emergency admissions. METHODS: This was a nationwide cohort study. We identified all people in Sweden with histological evidence of CD who underwent a follow-up small intestinal biopsy (1969-2008). We compared those with persistent VA with those who showed histological improvement, assessing the development of epilepsy and related emergency hospital admissions (defined according to relevant International Classification of Diseases codes in the Swedish Patient Register). Cox regression analysis was used to assess outcome measures. RESULTS: Villous atrophy was present in 43% of 7590 people with CD who had a follow-up biopsy. The presence of persistent VA was significantly associated with a reduced risk of developing newly-diagnosed epilepsy (hazard ratio, 0.61; 95% confidence interval, 0.38-0.98). On stratified analysis, this effect was primarily amongst males (hazard ratio, 0.35; 95% confidence interval, 0.15-0.80). Among the 58 patients with CD with a prior diagnosis of epilepsy, those with persistent VA were less likely to visit an emergency department with epilepsy (hazard ratio, 0.37; 95% confidence interval, 0.09-1.09). CONCLUSIONS: In a population-based study of individuals with CD, persisting VA on follow-up biopsy was associated with reduced future risk of developing epilepsy but did not influence emergency epilepsy-related hospital admissions. The mechanism as to why persistent VA confers this benefit requires further exploration.

[Rabeprazole induced acute interstitial nephritis]. / Néphropathie tubulo-interstitielle aiguë au cours d'un traitement par le rabéprazole (Pariet).

A 84-year-old women underwent renal biopsy because of rapidly progressive renal failure. Rabeprazole induced interstitial nephritis was diagnosed. Interstitial nephritis may complicate the course of any proton pump inhibitor treatment. It is a rare and serious complication. Clinician's awareness of this adverse event is essential for early diagnosis and prompt recovery.

Influence of HFE gene polymorphism on the progression and treatment of chronic hepatitis C.

We analysed liver histology findings in a large cohort of patients with chronic hepatitis C and in roughly half of them their response to interferon-alpha-based on iron parameters and HFE status. Histological activity and virological response to antiviral therapy (n = 146) were analysed in 273 immunocompetent and nonalcoholic patients with chronic hepatitis C, in terms of serum iron load, intrahepatic iron load (n = 110) and HFE mutations. Patients who were heterozygous for the C282Y and H63D mutations exhibited higher iron serum parameters than subjects without these mutations. The intrahepatic iron load was higher in H63D patients only. No association was observed between HFE mutations and histological activity. Increased iron parameters were associated with liver disease severity by univariate analysis only. Genotype 1 and ferritinaemia were associated with a poor response to antiviral therapy, whereas the H63D mutation emerged as a positive predictive factor for end of treatment and sustained antiviral response. Therefore, in chronic hepatitis C patients serum and intrahepatic iron levels were weakly correlated with histological activity, while HFE mutations were not. As for the response to interferon-alpha, elevated ferritinaemia constituted a negative predictive factor whereas the H63D mutation was a positive one. The H63D mutation might form part of an immunogenetic profile influencing the response to interferon therapy.

Hepatitis activity index is a key factor in determining the natural history of chronic hepatitis C.

To analyze the spontaneous pathologic progression of chronic hepatitis C, we analyzed the histopathologic semiquantitative scores (Metavir and Knodell) of sequential liver biopsies performed in untreated hepatitis C virus (HCV)-infected patients. Subjects included 35 men and 41 women, with a mean age of 41 +/- 12 years, a duration of HCV infection of 11 +/- 5 years, and an interval between liver biopsies of 3.7 +/- 2.5 years. Results obtained using the Knodell score and the Metavir score were similar. At the first biopsy, 78.9% of patients had a low activity score (A0-A1) and 82.9% had a low fibrosis score (F0-F2). At the second biopsy, the activity decreased in 9.2%, was unchanged in 72.4%, and increased in 18.5%. An increase in activity was more frequently observed in patients infected with genotype 1 (28.9%) than with others (7.7%; P =.04); the yearly progression of activity was significantly higher in patients with a low rather than high initial activity score (0.11 v -0.02; P <.01). An increase in fibrosis was noted in 13.3% of those with a low and 43.8% of those with a high initial activity score (P <.01), with a highest rate of yearly fibrosis progression (0.12 U). In multivariate analysis, only a high activity score was significantly associated with an increased risk of fibrosis progression (relative risk, 25.5; 95% confidence interval, 2.7 to 238; P =.004). Spontaneous chronic hepatitis C evolution is worsening in only 20% of patients. Fibrosis progression is significantly associated with the necroinflammatory activity suggesting that this factor should be regarded as a major clue for deciding therapy.

Safety and efficacy of interferon-ribavirin combination therapy in HCV-HIV coinfected subjects: an early report.

BACKGROUND: More severe liver disease together with a poor response rate to alpha interferon argue for the use of more potent anti-hepatitis C virus (HCV) therapies in human immunodeficiency virus (HIV)-HCV coinfected patients, but the efficacy and safety of interferon-ribavirin combination therapy in HIV infected subjects are unknown. AIM: To retrospectively evaluate the efficacy and safety of anti-HCV combination therapy in 21 HCV-HIV coinfected patients receiving antiretroviral therapy, and to access the clinical relevance of in vitro inhibition of phosphorylation by ribavirin of potent inhibitors of HIV-that is, zidovudine, stavudine, and zalcitabine. PATIENTS: Twenty one patients were treated with combined antiretroviral therapy including zidovudine (n=8) or stavudine (n=13) (in association with protease inhibitors in 12). All received ribavirin (1000 or 1200 mg/day) and alpha interferon (3 MU three times/week) for chronic hepatitis C infection. All patients had not responded (n=20) or relapsed (n=1) after a previous six month course of alpha interferon therapy. METHODS: HIV viral load (Monitor test) and CD4 cells count were measured at the beginning and every three months during and after ribavirin plus alpha interferon therapy over a mean period of 11 (1) months. Clinical and biological adverse effects were recorded. RESULTS: There was no significant variation in HIV viral load or CD4 cell counts after three or six months of ribavirin therapy compared with baseline values. Of the 21 subjects, three (14%) had an increase in HIV viral load of more than 0.5 log leading to discontinuation of ribavirin in one. Eleven of 21 (52.4%) had initial negative HCV viraemia at three (n=10) or six (n=1) months but only six were polymerase chain reaction negative at the end of therapy, leading to rates for primary response and breakthrough of 23.8% and 28.5%, respectively. Six months after completion of therapy, three patients relapsed (14. 3%) and three (14.3%) had sustained virological response. Median haemoglobin concentration decreased significantly after three and six months of ribavirin therapy (p= 0.0002 and p=0.0003, respectively) leading to withdrawal of therapy in one patient. CONCLUSIONS: These preliminary results show that: (1) despite in vitro interactions between ribavirin, zidovudine, and stavudine, significant variation in HIV replication does not usually occur in HCV-HIV coinfected patients receiving ribavirin and different antiretroviral regimens, including zidovudine and stavudine; (2) alpha interferon and ribavirin combination therapy induced primary and sustained virological responses in 28.5% and 14.3% of treated subjects (who were previous non-responders to interferon therapy), respectively; (3) anaemia is a frequent adverse event. Such results should be confirmed in larger prospective trials.

Dilated bile duct in patients receiving narcotic substitution: an early report.

Narcotic substitution is now widely used. Morphine can induce a spasm of the sphincter of Oddi but dilation of bile duct has been reported only in an anecdotal case. In June 1995, we observed a first case of dilation of the common bile duct without organic obstacle in a hepatitis C virus (HCV)-infected patient who was under narcotic substitution, suggesting a causal relationship. We conducted a prospective study to evaluate the precise prevalence of bile duct abnormalities related to narcotic substitution in active intravenous drug or ex-intravenous drug users referred to our liver unit for histologic evaluation of HCV infection. We conducted a prospective study in a 30-month period of 334 HCV-infected patients, including 36 receiving narcotic substitution with methadone or buprenorphine. Biliary tract was analyzed by ultrasonography and by endoscopy ultrasound in cases of bile duct abnormalities. Of the 36 patients under narcotic substitution, 3 (8.3%) had asymptomatic dilated bile duct without organic obstacle--defined as a common bile duct > or =9 mm--compared to 1 of 298 (0.03%; p < 0.001) of those who did not receive substitution. Narcotic substitution may lead to bile duct dilation that does not require invasive diagnosis procedures.

[Clinical forms and prognosis of hepatitis C]. / Formes cliniques et évolution de l'hépatite C.

Hepatitis C virus infects around 600,000 French people, mainly after parenteral exposure (in association with transfusion before 1990 and with intravenous drug use). Spontaneous resolution at the acute stage of the infection occurs in around 30% of cases while chronic infection is observed in around 70% of cases and its main risk is evolution to cirrhosis. Three predictive factors of cirrhosis have been identified: the duration of infection (greater than 20 years), the age at contamination (greater than 40 years) and a chronic alcohol consumption (> 80 g/day). Immunosuppressive situations (drug-related immune suppression for the prevention of graft rejection in allograft recipients or human immune deficiency virus-coinfection) as well as hepatitis B virus coinfection enhance the risk of cirrhosis and reduce the time of occurrence of cirrhosis. These predictors have to be considered in the information to the patients and in therapeutic decisions. They explain that any hepatitis C virus-infected patient has to undergo a liver biopsy to evaluate the necro-inflammatory activity and the fibrosis of the liver disease to delineate the place of a follow-up with a control of aggravation factors (alcohol discontinuation) and of an antiviral therapy.

[Prevalence of infection by hepatitis viruses in a rural area. Analysis according to risk factors and alcohol consumption]. / Prévalence des infections par les virus hépatotropes en milieu rural. Analyse en fonction des facteurs de risque viraux et de la consommation d'alcool.

OBJECTIVES: To evaluate the prevalence of serum markers of hepatitis A, B and C viruses in a rural area according to risk factors and alcohol consumption. METHODS: Transversal study of unselected subjects living and working in a rural area. Each subject included was asked to fill out an anonymous self-administered questionnaire dealing with his own risk factors, sexual behaviour and alcohol consumption. A blood sample was collected for detection of HBsAg, anti-HBc, anti-HBs, anti-HAV and anti-HCV antibodies. RESULTS: Three hundred three subjects with a mean age of 48 years were included. Main risk factors for viral infection were: blood transfusion (9.4%), intravenous drug addiction (0.73%), acupuncture (17.5%), tattoos (5. 8%), past hospitalizations (71.5%), homosexuality (1.1%), conjugal unfaithfulness (11%), sexual partners >5 (21.3%). Most subjects with at risk sexual behaviour had sexual relations without protection. Anti-HAV prevalence was 87.2% (95% confidence interval 83.4-91.0%). None of the subjects was HBsAg positive and 6.0% (confidence interval 4.7-8.7%) had anti-HBV antibodies. HBV prevalence was correlated to homosexuality only. Two subjects (0.67%, confidence interval 0-1.6%) without any identified risk factor had anti-HCV antibodies. There was no correlation between serum viral marker positivity and an excess alcohol consumption (>80 g of ethanol/d) which was present in 46 subjects. However HBV prevalence was 28.6% in the seven subjects who had been treated for alcoholism; these 7 subjects had a highly at risk sexual behaviour. CONCLUSION: In a rural area, infection by HAV is very frequent. The prevalence of HBV and HCV did not greatly differ from that observed in the general and urban population. The frequent failure to use protection in subjects with at risk sexual behaviour reinforces the need of prevention programs in rural areas.

HBV genotypic resistance to lamivudine in kidney recipients and hemodialyzed patients.

BACKGROUND: Lamivudine is a potent inhibitor of human immunodeficiency virus reverse transcriptase and hepatitis B virus (HBV) DNA polymerase. Its overall efficiency is clearly hampered by relapse at discontinuation and by risk of genotypic resistance. We describe herein the first cases of HBV resistance to lamivudine in kidney recipients and hemodialyzed patients. METHODS: We analyzed 26 HBV-infected kidney recipients and five hemodialyzed patients treated with lamivudine who became serum HBV DNA-negative (by Digene test). The biological and virological follow-up identified breakthrough as defined by the reappearance of serum HBV DNA. In two cases of breakthrough, HBV DNA was amplified and sequenced through the polymerase domain, including the YMDD motif, before the beginning of treatment and at time of breakthrough to determine genotypic mutations. RESULTS: Ten breakthroughs (reappearance of serum HBV DNA) were observed after a median follow-up of 11 months in eight kidney recipients and two hemodialyzed patients after a median duration of treatment of 16.5 (from 4 to 31) months of treatment. Previous HBe/anti-HBe seroconversion was not observed in the patients who escaped. In two kidney recipients, the comparison of HBV-DNA sequences before the treatment and after the breakthrough identified in one case a mutation of the highly conserved YMDD motif (YVDD), whereas in the second case, no genotypic mutation was observed in the sequenced region. CONCLUSION: We report the first cases of HBV genotypic resistance to lamivudine in kidney recipients and hemodialysis patients. Genotypic resistance is observed after 4-31 months of therapy. The YMDD mutation does not account for all cases of virological escape.

[Treatment of viral hepatitis in drug addicts]. / Traitements des hépatites virales des usagers de drogues.

Management of viral hepatitis in drug uses must follow a multidisciplinary approach within the framework of overall psychosocial, alcohologic, and medical care. Substitution is an important but not indispensable aspect. In patients who have achieved social, psychological and medical stability (possible initiation of antiretroviral treatment), antiviral treatments can be started and followed in the same way as for other patients. Prescriptions should aim at improving the liver disease and avoid progression to cirrhosis and complications. Ribavirin/interferon-alfa appears to be the combination of choice for first line treatment of hepatitis C (while waiting for combinations with protease inhibitors). Anti-HBV vaccination is the treatment of choice for the prevention of hepatitis B and D. Coordination and information sharing between health and social care partners is crucial for the management of these patients.

In vivo expression of a new hepatitis B virus protein encoded by a spliced RNA.

Hepatitis B virus (HBV) is a small DNA virus with a compact genomic organization. All HBV proteins identified to date have been encoded by unspliced HBV RNAs. Spliced HBV RNAs have been described, but their functions are unknown. We show here that a singly spliced HBV RNA encodes a novel HBV protein in vivo. This HBV splice-generated protein (HBSP) corresponds to the fusion of a part of the viral polymerase and a new open reading frame that is created by the splicing event. In vivo, HBSP protein was found in HBV-infected liver samples, and anti-HBSP antibodies occurred in one-third of sera samples collected from chronic HBV carriers. In vitro, the ectopic expression of HBSP had no effect on viral DNA replication or transcription but induced cell apoptosis without a cell-cycle block. Overall, our results suggest that HBV has evolved a mechanism that directly modulates virus-cell interaction through RNA splicing.

Hepatocarcinoma-intestine-pancreas/pancreatic associated protein (HIP/PAP) is expressed and secreted by proliferating ductules as well as by hepatocarcinoma and cholangiocarcinoma cells.

Hepatocarcinoma-intestine-pancreas/pancreatic associated protein (HIP/PAP) gene was identified because of its increased expression in 25% of human hepatocellular carcinoma. HIP/PAP protein, a C-type lectin, binds laminin, acts as an adhesion molecule for hepatocytes, and has also been described as an acute phase secretory protein during acute pancreatitis in humans and rats. We investigated HIP/PAP protein expression in patients with various liver diseases associated with ductular reaction. At the same time, we analyzed patients with hepatocellular carcinoma and cholangiocarcinoma, and tested HIP/PAP protein levels in sera to establish the pattern of secretion. Our data show that HIP/PAP expression was not restricted to hepatocellular carcinoma, but was also detected in cholangiocarcinoma cells as well as in reactive non-malignant bile ductules. In contrast, HIP/PAP protein expression was undetectable in normal mature hepatocytes, but some ductular cells localized at the interface of portal tracts with parenchyma were HIP/PAP immunoreactive in normal liver. Finally, we present evidence that HIP/PAP serum levels were increased in 21/28 (75%) patients with hepatocellular carcinoma, and in 25/51 (49%) patients with nonmalignant cirrhosis. Altogether, these results suggest that HIP/PAP protein may be implicated in hepatocytic and cholangiolar differentiation and proliferation.

Significance of repeatedly normal aminotransferase activities in HCV-infected patients.

The significance of repeatedly normal serum aminotransferase activities in antihepatitis C virus (anti-HCV)-positive patients is not clear. To address this issue, the authors analyzed clinical, virologic, histopathologic, and biological characteristics of such subjects. Among their active file of 1,200 anti-HCV-positive immunocompetent patients, they identified 36 subjects (3%) with repeatedly normal aminotransferase activities, as defined by at least four normal values of aminotransferase over a minimum period of 6 months without any abnormal value (mean of this period, 31 +/- 21 months). The 36 patients included 11 men and 25 women with a mean age of 45 +/- 15 years. Twenty-three of these 36 subjects (64%) had detectable HCV viremia by polymerase chain reaction. Their genotype distribution was as follows: genotype 1a or 1b, 57%; genotype 2, 26%; and genotype 3, 17%. Of the HCV ribonucleic acid (RNA)-positive and HCV RNA-negative subjects, 17 and 5 had a liver biopsy respectively. In the former, the mean Knodell score was 5.6 +/- 3.5 (range, 1 to 14), and was < 5 in 9 patients (53%) and > or = 5 in 8 (47%), including extensive fibrosis (n = 2) or cirrhosis (n = 2). In the HCV RNA-negative subjects, one patient had a Knodell score > or = 5. Comparing the 23 immunocompetent viremic subjects with repeatedly normal serum aminotransferase activities with our group (n = 564) of immunocompetent viremic patients with abnormal aminotransferase activities, there was a significant predominance of women (70% versus 44%, p < 0.05) and of genotype 2 in the former (26% versus 7%, p < 0.05), but no differences according to quantitative viremia, alcohol consumption, or distribution of risk factor were observed. Most of viremic HCV-infected patients with long-term and repeatedly normal aminotransferase values have indeed chronic active hepatitis, including extensive fibrosis or cirrhosis in as many as 20% of patients. This emphasizes the need for serum HCV RNA determination in anti-HCV-positive patients with normal aminotransferase activities. In these patients liver biopsy may be necessary and should be discussed.

Epidemiological and virological analysis of couples infected with hepatitis C virus.

BACKGROUND: If transmission of hepatitis C virus (HCV) infection through parenteral exposure is well documented, sexual transmission of HCV is still debated. AIMS: To perform extensive epidemiological and virological analysis in 24 couples in which each spouse was anti-HCV positive in order to delineate more precisely potential sexual transmission of HCV. PATIENTS: Twenty four couples in which each partner was anti-HCV positive. These 48 spouses were recruited in a liver unit by regular screening of spouses of index patients. METHODS: All 48 spouses completed an epidemiological questionnaire on risk factors for HCV. Qualitative detection of serum HCV RNA and determination of HCV type by genotyping and serotyping were performed. Sequence analysis of HCV strains by phylogenetic analysis was carried out in seven couples with concordant genotypes. RESULTS: The mean (SD) partnership duration was 12 (10) years. Serum HCV RNA was detected in both partners in 18 of the couples (75%) and in only one partner in six of the couples (25%). HCV typing showed concordant genotypes in 12 couples (50%), discordant genotypes in seven (29%), and in the other five couples (21%) only one spouse could be genotyped. Of the 48 spouses, 33 had a major risk factor for HCV transmission such as transfusion (n = 6) and intravenous drug use (n = 27). Eleven of the 12 couples infected with the same HCV genotype had at least one parenteral risk factor for viral transmission in both spouses. Whatever the genotype concordance, in most couples (75%), both spouses showed parenteral risk factors for viral transmission. Sequence analysis of HCV strains was possible in seven of 12 couples with identical genotype and showed different and identical isolates in four and three couples respectively. CONCLUSION: The study emphasises the risk of overestimating the importance of a very low sexual HCV transmission risk as against other, mainly parenteral, risk factors.

Triggering of acute alcoholic hepatitis by alpha-interferon therapy.

BACKGROUND/AIMS: Alcohol may induce autoimmunity by recognition of acetaldehyde-modified proteins which may be implicated in the pathogenicity of acute alcoholic hepatitis. We report here the potential role of alpha-interferon, a potent inducer of the autoimmunity process, in inducing alcoholic hepatitis. METHODS: We analyzed clinical, biological, virological and histological features in two cases where alpha-interferon treatment for HCV-related hepatitis led to a marked increase in aminotransferase activities. RESULTS: alpha-interferon as treatment of HCV-related hepatitis seemed to exacerbate acute alcoholic hepatitis despite moderate alcohol consumption. In Case 1, moderate daily alcohol intake of 40 g during therapy led to biopsy-proven acute alcoholic hepatitis, while the same consumption before therapy did not. In Case 2, before treatment, the liver biopsy showed mild acute alcoholic hepatitis; aminotransferases increased during alpha-interferon therapy, although no increase in alcohol intake was observed. CONCLUSION: alpha-interferon therapy by its immunomodulatory properties could be implicated in alteration of the course of acute alcoholic hepatitis. These observations emphasize that the decision to treat with alpha-interferon when there is even moderate alcohol consumption should be carefully weighted in HCV-infected patients.

Soluble tumor necrosis factor receptors in chronic hepatitis C: a correlation with histological fibrosis and activity.

BACKGROUND/AIMS: Tumor necrosis factor-alpha (TNF) is a mediator of inflammation and cellular immune response. Soluble TNF receptors (sTNFR) sTNF-R55 and sTNF-R75, which compete with cellular receptors for the binding of TNF, have been detected at high levels in infectious diseases including human immunodeficiency virus and HBV infection. In order to investigate the activation of the TNF system in HCV infection, we have analyzed the balance between TNF and sTNF-R in 60 HCV-infected subjects according to their clinical, biological, virological and histological characteristics. METHODS: Serum TNF, sTNF-R55 and sTNF-R75 levels were determined by ELISA before any therapy and were compared to a control group of 60 healthy subjects and a group of 34 HBV-infected patients. RESULTS: Mean TNF levels were 50.5+/-4.5 pg/ml in HCV patients, and undetectable (<5 pg/ml) in the control subjects. sTNF-R55 and sTNF-R75 levels were significantly higher in HCV-infected patients than in the controls: 2.88+/-0.14 ng/ml vs. 1.30+/-0.05, (p = 0.0001), and 9.54+/-0.58 ng/ml vs. 4.19+/-016, (p = 0.0001), respectively. sTNF-R55 and TNF-alpha levels in HCV patients were not significantly different from levels in HBV patients. sTNF-R75 levels were slightly lower than in HBV patients (9.54+/-0.58 vs. 11.4+/-0.79 ng/ml, p = 0.03). In contrast to other infectious diseases, there was no correlation between levels of sTNF-R and TNF. sTNF-R75 but not TNF levels were correlated with aminotransferases levels (p = 0.0001 and p = 0.0015 for aspartate and alanine aminotransferase, respectively), while sTNF-R55 levels were significantly correlated only with aspartate aminotransferase levels (p = 0.003). sTNF-R75 levels were significantly correlated with the Metavir activity index (p = 0.01), and sTNF-R55 and sTNF-R75 levels were significantly higher in patients with vs. without cirrhosis (3.22+/-0.21 vs. 2.54+/-0.17 ng/ml (p<0.02) and 11.6+/-0.86 vs. 7.5+/-0.53 ng/ml (p<0.001), respectively). sTNF-R55, sTNF-R75 and TNF levels were not correlated with viral load, genotype or response to interferon therapy. CONCLUSIONS: Levels of soluble TNF receptors, and particularly sTNF-R75, are significantly correlated with the severity of the disease but not with virological parameters such as quantitative viremia and genotype. High TNF-R production could thus suggest that HCV-related liver disease involves immunological mechanisms, including activation of the TNF system.