:::: CASA DA HEPATITE - Universidade Metropolitana de Santos ::::

Hepatite B / Hepatite C

Retreatment with pegylated interferon plus ribavirin of chronic hepatitis C non-responders to interferon plus ribavirin: A meta-analysis.
Efficacy of retreatment with pegylated interferon (PEG-IFN) plus ribavirin of non-responders to standard or pegylated IFN plus ribavirin has been assessed in various studies, but sustained virologic response (SVR) rates are variable and factors influencing efficacy and tolerability still remain incompletely defined. We aimed to focus on SVR rates and to identify factors influencing them in this meta-analysis. MEDLINE as well as a manual search were used. Studies were included if they were controlled or uncontrolled trials, if they had been published as full-length papers and if they included non-responders to standard or pegylated IFN and ribavirin therapy. Fourteen trials were included in the meta-analysis. Data on study populations, interventions, and outcomes were extracted from trials using a random-effects model. Primary outcome was the SVR rate. The pooled estimate of SVR rate was 16.3% (95% Confidence Interval – 95% CI, 8.3–29.6%). There was a significant heterogeneity among studies (p < 0.0001). Heterogeneity was less apparent in studies that included fewer patients with cirrhosis or overweight. By meta-regression, higher SVR rate was observed in trials with a lower prevalence of subjects with genotype 1 infection and with fewer overweight patients. The use of a 24-week retreatment stopping rule did not affect SVR rate. The overall modest efficacy argues against an indiscriminate retreatment with PEG-IFN and ribavirin of all non-responders. Restricting retreatment to non-overweight patients or to those with genotype 2 or 3 infection, using a 24-week retreatment stopping rule, would optimize the potential benefit with a scarce likelihood of missing a curative response. (JOURNAL OF HEPATOLOGY 2009; 51:675-681).

Frequent HCV reinfection and superinfection in a cohort of injecting drug users in Amsterdam.
This study investigates the occurrence of HCV reinfection and superinfection among HCV seroconverters participating in the Amsterdam Cohort Studies among drug users from 1985 through 2005. HCV seroconverters (n = 59) were tested for HCV RNA at five different time points: the last visit before seroconversion (t = -1), the first visit after seroconversion (t = 1), six months after (t = 2) and one year after (t = 3) seroconversion, and the last visit prior to November 2005 (t = 4). If HCV RNA was present, part of the NS5B region was amplified and sequenced. Additional phylogenetic analysis and cloning was performed to establish HCV reinfection and superinfection. Multiple HCV infections were detected in 23/59 (39%) seroconverters; 7 had HCV reinfections, 14 were superinfected, and 2 had reinfection followed by superinfection. At the moment of HCV reinfection, 7/9 seroconverters were HIV-negative: persistent HCV reinfection developed in both HIV-positive cases but also in 4/7 HIV-negative cases. In total, we identified 93 different HCV infections, varying from 1 to 4 infections per seroconverter. Multiple HCV infections were observed in 10/24 seroconverters with spontaneous HCV clearance (11 reinfections, 3 superinfections) and in 13/35 seroconverters without viral clearance (20 superinfections). HCV reinfection and superinfection are common among actively injecting drug users. This might further complicate the development of an effective HCV vaccine. (JOURNAL OF HEPATOLOGY 2009; 51:667-674).

Cirrose Hepática

Increased Mortality Risk in Patients With Phenotypic Hereditary Hemochromatosis But Not in Their First-Degree Relatives.
Hereditary hemochromatosis (HH) is an autosomal-recessive disorder characterized by iron overload. Relatives of HH patients were screened and those with HH-associated mutations and an increased iron load were identified. However, little is known about their mortality or strategies for their management. We assessed mortality among Swedish patients with HH and their first-degree relatives using health and census registers. We performed a matched population-based cohort study of 3832 patients with HH and their 14,496 first-degree relatives using data collected from 1990 through 2007. Mortality data from these groups were compared with that of 38,969 population controls and their 143,349 first-degree relatives using Cox regression analyses. Patients identified on the basis of hospitalization with HH had an increased risk (relative risk [RR]) for death (RR, 2.45; 95% confidence interval [CI], 2.27–2.64; 857 deaths). Patients identified through other means had a mortality risk that was lower than those identified in the hospital but higher than controls (RR, 1.15; 95% CI, 1.00–1.33; 216 deaths). Their first-degree relatives had only a marginally increased mortality risk (RR, 1.05; 95% CI, 1.01–1.10); this RR was similar to that of patients' spouses (RR, 1.09; 95% CI, 0.86–1.38; 82 deaths). Patients with HH who also had a family history of HH did not have an increased mortality risk compared with other groups (RR, 1.05; 95% CI, 0.67–1.62; 21 deaths).Patients with HH have a modestly increased mortality risk compared with controls. The mortality of relatives is increased marginally compared with controls, and is similar among biological and nonbiological relatives (GASTROENTEROLOGY 2009; 137:1301-1309).

Thrombotic risk factors in patients with liver cirrhosis: Correlation with MELD scoring system and portal vein thrombosis development.
Prognostic scores currently used in cirrhotic patients do not include thrombotic risk factors (TRFs). Predicting factors of portal vein thrombosis (PVT) development are still unknown. We wanted to describe TRFs as a function of liver disease severity using the MELD score and assess the role of local and systemic TRFs as predictors of PVT development in cirrhotic patients. One hundred consecutive patients with liver cirrhosis were included in the study. TRFs, D-dimers, MELD score, portal vein patency and flow velocity were evaluated in all subjects at baseline and every 6 months thereafter. Variables able to predict PVT development within 1 year were identified by means of multiple logistic regression. The plasma levels of protein C and antithrombin were lower and the concentration of D-dimers was higher in patients with advanced disease. Plasma levels of antithrombin, protein C and protein S resulted significantly lower in PVT group at univariate analysis, but reduced portal vein flow velocity was the only variable independently associated with PVT development. Lower concentrations of natural coagulation inhibitors are frequently detected in patients with liver cirrhosis. A reduced portal flow velocity seems to be the most important predictive variable for PVT development in patients with cirrhosis. (JOURNAL OF HEPATOLOGY 2009; 51:682-689).

Esteatose Hepática

Non-alcoholic fatty liver disease in patients with chronic plaque psoriasis.
Non-alcoholic fatty liver disease (NAFLD) and chronic plaque psoriasis are both associated with metabolic syndrome and increased risk of incident cardiovascular disease. We assessed the frequency and characteristics of NAFLD in patients with chronic plaque psoriasis. One hundred and thirty consecutive patients with chronic plaque psoriasis and 260 apparently healthy controls matched for age, sex and body mass index were enrolled. NAFLD was diagnosed by abdominal ultrasound after excluding other secondary causes of chronic liver disease. The frequency of NAFLD was remarkably greater in psoriasis patients than in controls (47% vs. 28%; p < 0.0001). Patients with psoriasis and NAFLD (n = 61) were more likely to have metabolic syndrome and had higher serum C-reactive protein concentrations and greater severity of psoriasis according to the Psoriasis Area and Severity Index (PASI) score (14.2 ± 12.6 vs. 9.6 ± 7.4; p < 0.01) than those with psoriasis alone (n = 69). In a subgroup of psoriasis patients (n = 43), those with NAFLD (n = 21) also had significantly higher serum interleukin-6 and lower serum adiponectin levels. Notably, in multivariate regression analysis, NAFLD was associated with higher PASI score independently of age, gender, body mass index, psoriasis duration, and alcohol consumption.NAFLD is frequent in patients with chronic plaque psoriasis – affecting up to nearly half of these patients – and is strongly associated with psoriasis severity. Early recognition of NAFLD by radiological imaging tests in this group of patients is warranted.

Carcinoma Hepatocelular

Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo.
The success of sorafenib in the treatment of advanced hepatocellular carcinoma (HCC) has focused interest on the role of Ras signaling in this malignancy. We investigated the molecular alterations of the Ras pathway in HCC and the antineoplastic effects of sorafenib in combination with rapamycin, an inhibitor of mTOR pathway, in experimental models. Gene expression (qRT-PCR, oligonucleotide microarray), DNA copy number changes (SNP-array), methylation of tumor suppressor genes (methylation-specific PCR) and protein activation (immunohistochemistry) were analysed in 351 samples. Anti-tumoral effects of combined therapy targeting the Ras and mTOR pathways were evaluated in cell lines and HCC xenografts. Different mechanisms accounted for Ras pathway activation in HCC. H-ras was up-regulated during different steps of hepatocarcinogenesis. B-raf was overexpressed in advanced tumors and its expression was associated with genomic amplification. Partial methylation of RASSF1A and NORE1A was detected in 89% and 44% of tumors respectively, and complete methylation was found in 11 and 4% of HCCs. Activation of the pathway (pERK immunostaining) was identified in 10.3% of HCC. Blockade of Ras and mTOR pathways with sorafenib and rapamycin reduced cell proliferation and induced apoptosis in cell lines. In vivo, the combination of both compounds enhanced tumor necrosis and ulceration when compared with sorafenib alone. Ras activation results from several molecular alterations, such as methylation of tumor suppressors and amplification of oncogenes (B-raf). Sorafenib blocks signaling and synergizes with rapamycin in vivo, preventing tumor progression. These data provide the rationale for testing this combination in clinical studies. (JOURNAL OF HEPATOLOGY 2009; 51:725-733).