Inflammatory Gene Expression Associates with Hepatitis B Virus cccDNA- but Not Integrant-Derived Transcripts in HBeAg Negative Disease.

Chronic hepatitis B virus (HBV) infection is a global health problem that presents as a spectrum of liver disease, reflecting an interplay between the virus and the host immune system. HBV genomes exist as episomal covalently closed circular DNA (cccDNA) or chromosomal integrants. The relative contribution of these genomes to the viral transcriptome in chronic hepatitis B (CHB) is not well-understood. We developed a qPCR method to estimate the abundance of HBV cccDNA- and integrant-derived viral transcripts and applied this to a cohort of patients diagnosed with CHB in the HBe antigen negative phase of disease. We noted a variable pattern of HBV transcripts from both DNA templates, with preS1/S2 mRNAs predominating and a significant association between increasing age and the expression of integrant-derived mRNAs, but not with inflammatory status. In contrast, cccDNA-derived transcripts were associated with markers of liver inflammation. Analysis of the inflammatory hepatic transcriptome identified 24 genes significantly associated with cccDNA transcriptional activity. Our study uncovers an immune gene signature that associates with HBV cccDNA transcription and increases our understanding of viral persistence.

Eosinophilic gastroenteritis in pregnancy: A review of the literature.

Eosinophilic gastroenteritis (EGE) is an uncommon and heterogeneous disease characterized by eosinophilic infiltration of the gastrointestinal tract. There are very few reports in literature describing pregnancies in EGE patients, and no review has ever been published. We found a total of 12 cases including one that occurred in our clinic. In 5 out of 12 cases, EGE was diagnosed after delivery and pregnancies are described as uneventful. Of the 5 patients who already had a diagnosis of EGE before pregnancy, only one registered an improvement of symptoms during gestation, while the rest had no significant changes, and their pregnancies needed to be monitored as high risk. Regarding pregnancy complications, only two patients had a pre-term delivery. Both patients had not only EGE, but a remarkable obstetrical history, that could slightly complicate the interpretation of the events that occurred in their pregnancies. More studies are necessary to demonstrate if EGE is connected with pre-term onset of labor. It's not easy to define the reasons of some patient's pre term labor, and we could suppose that a combination of different mechanisms leads to this condition of breakdown of maternal-fetal tolerance. Nevertheless, we know that spontaneous preterm labor is a syndrome attributable to multiple pathologic processes and most of them are yet to be understood. However, we cannot exclude that EGE is related to late preterm delivery. We hope that this review will provide some measures of guidance to those clinicians who must satisfy the questions of young female patients diagnosed with EGE and wishing for a pregnancy.

Prevalence and risk factors for delayed adrenal insufficiency after liver transplantation.

Liver transplantation (LT) recipients are at risk for early and delayed adrenal insufficiency for multiple reasons. Although early adrenal insufficiency is known to occur in a high proportion of recipients maintained on steroid-free immunosuppressive regimens, the prevalence and risk factors associated with delayed functional adrenal gland atrophy (FAGA) are unknown because routine evaluation for this condition is not standard practice among LT centers. We investigated a group of 87 patients (64 males) transplanted for end-stage liver disease related to different etiologies. All underwent a standard corticotropin stimulation test (CST) when, after gradual steroid tapering, they had been maintained for at least 1 week on oral prednisone at a daily dose of 5 mg. FAGA, defined by a serum cortisol concentration that, 60 minutes after corticotropin administration, did not double the baseline level and remained <20 mug/dL, was diagnosed in 23/87 patients (26.4%). Stepwise logistic regression analysis selected as significant predictors of FAGA the cumulative dosage of corticosteroids administered (P < 0.01), the increase in the body mass index after LT (P < 0.01), a low serum cholesterol concentration (P = 0.005), and a high adrenocorticotropin hormone (ACTH) serum level (P < 0.05) at the time CST was performed. In conclusion, FAGA is a common condition among LT recipients who are maintained on prolonged corticosteroid immunosuppressive treatment. Factors associated with FAGA include the cumulative steroid dose, weight changes after LT, and ACTH and cholesterol levels at the time of steroid withdrawal.

Valopicitabine dihydrochloride:a specific polymerase inhibitor of hepatitis C virus.

Idenix Pharmaceuticals Inc and Novartis AG are codeveloping valopicitabine dihydrochloride, a once-daily oral nucleoside for the potential treatment of HCV infection. In January 2005, a phase IIa clinical trial comparing valopicitabine dihydrochloride with pegylated IFN in treatment-naive HCV patients was ongoing, in addition to a phase IIb trial in patients that had previously failed pegylated IFN and ribavirin combination therapy. In January 2006, an international phase III trial in treatment-refractory patients was planned for the first half of the year, with a phase III trial in treatment-naive individuals planned for the second half of the year.

Assessment of liver fibrosis progression in patients with chronic hepatitis C and normal alanine aminotransferase values: the role of AST to the platelet ratio index.

OBJECTIVES: To verify the value of indirect serum markers in the non-invasive assessment of liver fibrosis in patients with persistently normal or near normal alanine aminotransferases levels (NALT). DESIGN AND METHODS: Forty HCV RNA positive, untreated patients with NALT (30 non-drinkers) underwent two liver biopsies, with a median interval of 78.5 months. The AST/ALT ratio, age-platelet index, AST to platelet ratio index (APRI), Forns fibrosis index and Bonacini's discriminant score were simultaneously determined. RESULTS: In 19 patients, worsening of fibrosis was observed at the second biopsy in comparison to the index biopsy. Among non-drinkers, an APRI >0.4 had a 100% sensitivity in identifying subjects with significant liver fibrosis (Ishak staging score >2) and an APRI < or =0.4 had a 100% negative predictive value in excluding significant liver fibrosis. CONCLUSIONS: APRI performs better, in comparison to all other markers, in correctly classifying patients with NALT with no progression to significant liver fibrosis.

Antiviral treatment in patients with hepatitis C virus-related cirrhosis awaiting liver transplantation.

End stage liver disease due to hepatitis C virus (HCV) infection is the most common indication for liver transplantation (LT) worldwide. Regretfully, infection of the graft by HCV occurs almost universally after LT, causing chronic hepatitis and early progression to cirrhosis in a significant proportion of recipients. Moreover, graft and patient survival are significantly worse in patients undergoing LT for HCV-related cirrhosis than in those transplanted for other indications. Therefore, many LT centers consider antiviral treatment with interferon and ribavirin the mainstay of managing recurrent HCV disease in LT recipients. The optimal time to start treatment is unclear. In most instances, treatment is initiated when histological evidence of disease recurrence, either at protocol or on-demand liver biopsies, is observed after LT. However, antiviral treatment initiated before LT is a potential option for some patients for two reasons: first, clearing or suppressing HCV before LT may reduce or eliminate the risk of recurrent hepatitis C in the transplanted liver and thereby improve survival; second, clearing HCV in cirrhotic patient may halt disease progression and avoid the need for transplantation. In this article, the results obtained by pre-transplant antiviral regimens administered to HCV-positive cirrhotic patients awaiting LT are discussed.

Pancreatobiliary reflux resulting in pancreatic ascites and choleperitoneum after gallbladder perforation.

A 65-year-old man with chronic hepatitis C and no history of alcohol abuse was admitted to our liver unit for the recent development of massive ascites and presumed hepatorenal syndrome. In the preceding two weeks, he had received medical treatment for acute pancreatitis and cholecystitis. Abdominal paracentesis demonstrated a cloudy, orange peritoneal fluid, with total protein concentration 3.6 g/dl, serum-ascites albumin gradient 1.0 g/dl, and ratios of ascites-serum bilirubin and amylase approximately 8:1. Diagnostic imaging demonstrated no pancreatic pseudocysts. Ten days later, at laparotomy, acalculous perforation of the gallbladder was identified. After cholecystectomy, amylase concentration in the ascitic fluid dropped within a few days to 40% of serum values; ascites disappeared within a few weeks. We conclude that in the presence of a perforated gallbladder, pancreatobiliary reflux was responsible for this unusual combination of choleperitoneum and pancreatic ascites, which we propose to call pancreatobiliary ascites.

Usefulness of six non-proprietary indirect markers of liver fibrosis in patients with chronic hepatitis C.

BACKGROUND: The aim of the study was to perform a comprehensive diagnostic evaluation of six popular, non-proprietary, indirect markers of liver fibrosis in a cohort of patients with chronic hepatitis C representing the full spectrum of disease severity. METHODS: A total of 167 consecutive, hepatitis C virus RNA positive, untreated patients with chronic hepatitis C were studied. Liver biopsy with histological evaluation and age/platelet index, aspartate aminotransferase/alanine aminotransferase ratio, aspartate aminotransferase to platelet ratio index, Bonacini's discriminant score, Forn's fibrosis index and FibroIndex were assessed in all patients. RESULTS: The area under the receiver operating characteristic curves of the six tests was always greater when performed to discriminate patients with METAVIR score F4 than when assessed to discriminate patients with METAVIR score > or =F2. At step-wise discriminant analysis the only indirect marker of fibrosis entered was FibroIndex, with the following correct classification of the patients: total=52.1, patients with scores F0-F1=62.2, patients with scores F2-F3=26.0 and patients with score F4=68.4. CONCLUSIONS: The ability to correctly classify patients using a panel of non-proprietary indirect markers of liver fibrosis is far from being ideal. Among them, FibroIndex appears to possess the best discriminating capacity. The simultaneous use of several indirect markers of liver fibrosis does not improve their diagnostic accuracy.

Updates on antiviral therapy for chronic hepatitis C.

Hepatitis C virus (HCV) infection is a major public health problem around the world and it is estimated that there are about 200 million infections globally. The majority of HCV infected patients develop chronic infection, which can progress to liver cirrhosis, hepatocellular carcinoma, and liver failure. Since the discovery of the virus in 1989, impressive progress has been made in the treatment of HCV hepatitis. However, the actual standard of care in treating HCV infection, represented by the combination therapy of pegylated interferon alpha 2a or 2b with ribavirin, fails to cure near half of treated patients. This paper aimed to trace a brief overview of the progress made by interferon-based treatments for HCV hepatitis since their introduction in the early 1990s, and to highlight the results of recent clinical studies concerning new and emerging drugs.

Comparison between HOMA-IR and ISI-gly in detecting subjects with the metabolic syndrome.

BACKGROUND: To verify whether, as index of insulin resistance, ISI-gly (insulin sensitivity index) is more efficient than HOMA-IR (homeostatic model assessment) or QUICKI (quantitative insulin sensitivity check index) in detecting patients with the metabolic syndrome. METHODS: Excluding patients with known diabetes, endocrine, liver and kidney diseases, we enrolled 553 subjects who were screened for metabolic abnormalities. After 5 days of a balanced weight maintenance diet, we performed an OGTT (oral glucose tolerance test) and measured fasting and 2-h postload blood sugar and insulin, from which we calculated ISI-gly, HOMA-IR and QUICKI, stratifying patients in tertiles. Statistical comparisons were performed for a number of metabolic variables between tertiles of the same index, as well as between tertiles of different indexes presumably expressing identical insulin resistance. RESULTS: All variables reflecting the metabolic syndrome were significantly more altered in the top as compared to the intermediate and the lowest tertile for HOMA-IR, the opposite for ISI-gly. Comparing homologous measurements of the top tertile of HOMA-IR with the lowest tertile of ISI-gly (presumably expressing identical insulin resistance), fasting glucose and insulin were significantly higher, while 2-h OGTT values were significantly lower. The opposite occurred comparing the lowest HOMA-IR to the highest ISI-gly tertile, the diagnostic predictive values of the latter in detecting metabolic derangements being also higher. Data from QUICKI 1st to 3rd tertiles exactly matched those obtained from HOMA-IR 3rd to 1st tertile. CONCLUSIONS: ISI-gly, which includes postload glucose and insulin concentrations, provides a more accurate estimate of whole-body insulin sensitivity than HOMA-IR or QUICKI, derived from fasting measurements only, thus constituting a more sensitive tool for screening and preventing metabolic abnormalities.

Value of two noninvasive methods to detect progression of fibrosis among HCV carriers with normal aminotransferases.

The course of hepatitis C virus (HCV) infection carriers with normal/near-normal aminotransferases (NALT) is usually mild; however, in a few, fibrosis progression occurs. We aimed to verify whether monitoring by liver biopsy might be replaced by noninvasive methods and to identify factors associated with fibrosis progression in patients with persistently normal alanine aminotransferases. We studied 40 untreated HCV-RNA-positive subjects (22 male; median age, 44 years), who underwent two liver biopsies, with a median interval of 78.5 months, during which alanine aminotransferase concentrations (median number of determinations: 12) never exceeded 1.2 times the upper normal limit. Within 9 months from the second biopsy, they were tested by the shear elasticity probe (Fibroscan) and the artificial intelligence algorithm FibroTest. METAVIR fibrosis scores were analyzed in relationship to demographic, clinical, and viral parameters. Weighted kappa analysis was used to verify whether the results of noninvasive methods agreed with histology. Significant fibrosis (> or = F2), present at the first biopsy in only one patient (2.5%), was observed at the second biopsy in 14 patients (35%). At multivariate analysis, excess alcohol consumption in the past (>20 g/d; P = .017) and viral load (>8.0 x 10(6) copies/mL; P = .021) were independent predictors of progression. In identifying patients with significant fibrosis, inter-rater agreement was excellent for Fibroscan (weighted kappa = 1.0), and poor for FibroTest (weighted kappa = -0.041). In conclusion, among HCV carriers with NALT, Fibroscan is superior to the FibroTest in the noninvasive identification of fibrosis, for which excess alcohol consumption in the past and high viral load represent risk factors.