17,ß-estradiol inhibits hepatitis C virus mainly by interference with the release phase of its life cycle.

BACKGROUND & AIMS: Oestrogen and oestrogen-mediated signalling protect from hepatitis C virus through incompletely understood mechanisms. We aimed to ascertain which phase(s) of hepatitis C virus life cycle is/are affected by oestrogens. METHODS: Huh7 cells infected with the JFH1 virus (genotype 2a) were exposed to dehydroepiandrosterone, testosterone, progesterone and 17ß-estradiol (tested with/without its receptor antagonist fulvestrant). Dose-response curves were established to calculate half maximal inhibitory concentration values. To dissect how 17ß-estradiol interferes with phases of hepatitis C virus life cycle, its effects were measured on the hepatitis C virus pseudo-particle system (viral entry), the subgenomic replicon N17/JFH1 and the replicon cell line Huh7-J17 (viral replication). Finally, in a dual-step infection model, infectious supernatants, collected from infected cells exposed to hormones, were used to infect naïve cells. RESULTS: Progesterone and testosterone showed no inhibitory effect on hepatitis C virus; dehydroepiandrosterone was only mildly inhibitory. In contrast, 17ß-estradiol inhibited infection by 64%-67% (IC50 values 140-160 nmol/L). Fulvestrant reverted the inhibition by 17ß-estradiol in a dose-dependent manner. 17ß-estradiol exerted only a slight inhibition (<20%) on hepatitis C virus pseudo-particles, and had no effect on cells either transiently or stably (Huh7-J17 cells) expressing the N17/JFH1 replicon. In the dual-step infection model, a significant half maximal inhibitory concentration decline occurred between primary (134 nmol/L) and secondary (100 nmol/L) infections (P=.02), with extracellular hepatitis C virus RNA and infectivity being reduced to a higher degree in comparison to its intracellular counterpart. CONCLUSIONS: 17ß-estradiol inhibits hepatitis C virus acting through its intracellular receptors, mainly interfering with late phases (assembly/release) of the hepatitis C virus life cycle.

Fibrosis progression in HCV carriers with mild hepatitis who possess the high-repetition variant of the DRD4 gene, a genetic marker for binge-drinking and risk-seeking behavior: a longitudinal study.

BACKGROUND: Alcohol is a major determinant of the outcome of chronic hepatitis C virus (HCV) infection, but self-reported drinking habits lack reliability. We hypothesized that carriage of high-repetition variants (HRV) of the variable number of tandem repeats (VNTR) in exon III of the dopamine receptor D4 gene, linked to binge-drinking and risk-seeking behavior, might be a proxy measure of alcohol consumption, and aimed to verify whether it may affect histologic outcome. METHODS: A cohort of HCV patients with normal or near-normal aminotransferases (N = 128) underwent a liver biopsy as part of diagnostic work-up. None admitted to exceed low-risk alcohol consumption; most (90/128, 70%) described themselves as teetotalers. They received advice on abstaining from alcohol, but not antiviral treatment. After a median follow-up period of 10 years, all underwent a second liver biopsy. HRV allele frequencies were compared with those of a group of healthy blood donors (N = 128) and related to liver histology. RESULTS: HRV allele frequencies were 0.19 in patients and 0.16 in controls (p = 0.182). In the subgroup of patients who admittedly had consumed alcohol, 20/38 (53%) carried HRV, in comparison with 27/90 patients (30%) who had denied to consume alcohol (p = 0.026 by Fisher's exact test). Carriage of HRV was associated with higher histologic grade (p = 0.002) and stage (p = 0.009) at the final biopsy. At multivariate analysis, among a set of variables also including viral genotype, viral load, body mass index, gender, and history of alcohol consumption, only age (OR = 1.06, 95% CI 1.02 to 1.11) and HRV (OR = 3.13, 95% CI 1.28 to 7.68) were independent predictors of significant fibrosis at the end of follow-up. CONCLUSIONS: The link between HRV carriage and histologic outcome in a subgroup of HCV patients at low risk of progression underlines the need for intense scrutiny of alcohol habits in hepatitis C.

Can apical ballooning cardiomyopathy and anterior STEMI be differentiated based on ß1 and ß2-adrenergic receptors polymorphisms?

AIM: Catecholamine excess along with an exaggerated sympathetic stimulation appears to play a major role in the pathophysiological mechanism of tako-tsubo cardiomyopathy (TTC), which mimics acute ST-elevation myocardial infarction (STEMI). The aim of the present study was to investigate differences in the distribution of allelic variants of ß1- and ß2-adrenoceptors between TTC and anterior STEMI patients compared to normal subjects. METHODS AND RESULTS: ß1- and/or ß2-adrenoceptor polymorphisms in 97 patients with TTC (92 females, 96%; mean age 66.8±11.6years; range 35 to 87years) were compared with 81 patients with anterior STEMI (77 females, 95%; mean age 72.5±12.8years; range 32 to 96years) and 101 controls (95 females, 94%; mean age 62.3±10.4years; range 44 to 92years). Differences in genotype frequencies were assessed using the Pearson χ(2) test. ß1-Adrenoceptor (Gly389Arg) and ß2-adrenoceptor (Arg16Gly and Gln27Glu) genotype frequencies were significantly different among groups (p<0.001, p=0.024, p=0.008, respectively). However, differences did not achieve statistical significance when TTC and anterior STEMI patients were compared by post-hoc analysis. The cardiovascular risk factor profile was worse in anterior STEMI patients, who more often had a history of systemic arterial hypertension, diabetes and coronary artery disease. CONCLUSIONS: In a large TTC cohort compared with anterior STEMI patients, ß-adrenoceptor polymorphisms were similar. However, the cardiovascular risk factor profile was different between the two groups. ß-Adrenoceptor polymorphisms in TTC patients differed from normal subjects.

IL28B polymorphism, blood interferon-alpha concentration, and disease stage of HCV mono-infected and HCV-HIV co-infected patients.

Interferon (IFN) preactivation, interleukin-28B (IL28B) alleles, and liver fibrosis act as predictors of response to antiviral therapy against hepatitis C. We aimed to verify if blood IFN concentration, a putative biomarker of interferon preactivation, might depend on carriage of a given IL28B genotype and/or advanced hepatic fibrosis. The study population included 187 hepatitis C patients (75 of whom were HIV coinfected), who were genotyped for the rs12979860 polymorphism and staged non-invasively by transient elastography. Blood IFN, measured by an enzyme immunoassay, was detectable in 68/187 patients (36%). Seventy-three patients (39%) were C/C homozygotes, 25 (13%) were T/T homozygotes, and 89 (48%) were heterozygotes. The fibrosis stage was F0-F1 in 70 patients (37%), F2-F3 in 54 patients (29%), and F4 in 63 patients (34%). IFN levels were higher among patients with HIV coinfection (p=0.044) and patients with better renal function (p=0.041), without association with the IL28B genotype or the hepatitis C stage. From the multivariate analysis, the only independent predictor of higher level of IFN was the age of patients (p=0.019), whereas independent predictors of a fibrosis stage ≥ F2 were age (p=0.007), belonging to the HIV/HCV group (p=0.048) and current alcohol consumption (p=0.008). In conclusion, a sizable proportion of HCV carriers have detectable IFN levels that do not indicate a greater severity of disease or display any relationships to specific rs12979860 variants.

Hepatitis B virus and lymphomagenesis: novel insights into an occult relationship.

BACKGROUND: Increasing evidence shows that Hepatitis B virus infection associates with B-cell but not T-cell malignancies. It remains unclear (a) whether this association is restricted to discrete subtypes of B-cell neoplasms and (b) if occult hepatitis B virus infection can impact on the risk of B-cell malignancy. METHODS: We analysed the prevalence of occult hepatitis B virus infection in three age and sex matched groups: patients with multiple myeloma, chronic lymphocytic leukaemia and healthy volunteers (N=80 each group). Hepatitis B virus sequences were detected by PCR in blood mononuclear cells isolated prior to treatment. RESULTS: Fifteen subjects tested positive for occult hepatitis B virus infection and its distribution significantly favoured chronic lymphocytic leukaemia (p<0.02) over the other groups. No difference in age, gender and proportion of anti-HBc seropositivity was noted according to occult hepatitis B virus infection status. Chronic lymphocytic leukaemia had an odds ratio of 4.6 (95% CI 1.5-13.9) for the presence of occult hepatitis B virus infection in comparison to multiple myeloma and controls. Most occult hepatitis B virus infection cases (10/15, 67%) were detected in completely hepatitis B virus seronegative subjects. CONCLUSIONS: Our data support a potentially causal relationship for hepatitis B virus in chronic lymphocytic leukaemia but not in multiple myeloma. HBsAg seropositivity alone may bias the study of this association, potentially leading to underestimation. Primary occult hepatitis B virus infection appears the most frequent setting in our patients, extending the clinical relevance of hepatitis B virus vaccination to a preventative measure for B-cell neoplasms.