A. Picciotto

Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis

A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 × 10−11, odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 × 10−10, OR = 1.63) and 17q12-21 (P = 1.7 × 10−10, OR = 1.38).

Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patients.

Hepatitis C virus (HCV) readily establishes high‐level lifelong persistent infection in the majority of immunocompetent adults with failure of HCV‐specific CD8+ CTL to clear viral replication. Virus‐induced conditioning of innate immune responses is a possible mechanism that may contribute to the impairment of virus‐specific CD8+ CTL responses. Here, we analyzed whether triggering of NK cell receptor expression and function is affected during chronic viremic HCV infection. Flow cytometric analysis of purified resting peripheral NK cells showed no evidence of NK cell activation, while analysis of natural cytotoxicity receptors (NCR) showed that NK cells from HCV‐infected patients had selective increased expression of NKp30 and NKp46. NK cells had corresponding conserved cytotoxic activity against all targets with the exception of HepG2 hepatoma cells. Freshly separated NK cells from HCV patients showed significant production of IL‐10 and normal concentrations of IFN‐γ upon cell‐mediated triggering. Thus, increased expression of NKp30 during HCV infection with increased IL‐10 production could contribute, once NK cells localize in the liver, to a NK‐DC crosstalk leading to skewing of subsequent adaptive immune responses and lack of virus control.

Practice guidelines for the treatment of hepatitis C: Recommendations from an AISF/SIMIT/SIMAST expert opinion meeting

It is increasingly clear that a tailored therapeutic approach to patients with hepatitis C virus infection is needed. Success rates in difficult to treat and low-responsive hepatitis C virus patients are not completely satisfactory, and there is the need to optimise treatment duration and intensity in patients with the highest likelihood of response. In addition, the management of special patient categories originally excluded from phase III registration trials needs to be critically re-evaluated. This article reports the recommendations for the treatment of hepatitis C virus infection on an individual basis, drafted by experts of three scientific societies.

Virological profiles in patients with chronic hepatitis C and overt or occult HBV infection

OBJECTIVES:The virological profiles of hepatitis B and C viruses (HBV and HCV) and their interplay in cases of coinfection are undefined. A suppressed and occult HBV infection may occur in hepatitis B surface antigen (HBsAg) negative patients with chronic hepatitis C. The HCV core protein is able to inhibit HBV “in vitro,” and serines at positions 99 and 116 are essential for such inhibition. We aimed to assess the HBV and HCV virological profiles in cases of coinfection and to evaluate the relationship between HCV core gene variability and HBV activity.METHODS:Eighty-two anti-HCV positive patients were examined: 35 cases were HBsAg positive, 24 were HBsAg negative with “occult” HBV infection, and 23 were HBV negative. HBV and HCV viremia levels were evaluated in all cases. HCV genomic region coding for the aminoacid sequence 99–116 of core protein was amplified and sequenced in all HCV RNA positive cases. The entire core gene was amplified and sequenced in three randomly selected cases.RESULTS:Serum HCV RNA was detected in all cases but 13, all HBsAg positive individuals; HCV viremia levels of the other 22 HBsAg positive subjects were similar to those detected in HBsAg negative patients with or without occult HBV infection. Among the 35 HBsAg positive patients both HBV DNA and HCV RNA were detected in five cases, HCV RNA alone in 17, and HBV DNA alone in six, whereas seven cases had undetectable levels of both viruses. Sequencing analyses showed that the HCV core gene was highly preserved in all patients.CONCLUSION:A wide spectrum of HCV and HBV virological patterns may occur in a case of coinfection. HCV core variability is not related to HBV activity “in vivo.”

Effects of acute administration of recombinant interferon alpha 2b on pituitary hormone secretion in patients with chronic active hepatitis

Abstract The effect of a single intramuscular (IM) dose of 10 × 10 6 IU of recombinant interferon alpha-2b (alpha IFN) on adrenocorticotropin (ACTH), beta-endorphin (β-EP), thyrotropin (TSH), growth hormone (GH), luteotropin (LH), and prolactin (PRL) was evaluated in seven patients suffering from chronic viral hepatitis (CVH). Alpha IFN increased ACTH (from 11.2 ± 1.1 ng/L to 16.3 ± 2.6 ng/L) and β-EP (from 25.0 ± 1.9 ng/L to 37.6 ± 1.7 ng/L) plasma concentrations and lowered plasma TSH concentrations (from 2.4 ± 0.4 mIU/L to 1.0 ± 0.2 mIU/L). These effects were recorded between the fourth and the 12th hour after alpha IFN administration and occurred without significant variations in the remaining plasma hormonal levels. In seven additional patients who received a 3 × 10 6 -IU IM dose of the same IFN, no significant variations in ACTH, β-EP, or TSH plasma levels were found. Data indicate that alpha IFN may influence the neural mechanisms controlling anterior pituitary secretion. However, high alpha IFN doses are required for this effect to occur.

Peripheral blood serum markers for apoptosis and liver fibrosis: are they trustworthy indicators of liver realness?

BACKGROUND/AIMS No reliable serum markers for liver inflammation, apoptosis and fibrosis have been established yet, although a large number have been evaluated. Moreover, it is not clear if a molecule detected and quantified in peripheral vein blood is a really trustworthy marker of the liver condition. To answer to this question, we had the opportunity to study paired serum samples drawn simultaneously during haemodynamic study from the right hepatic vein and from a peripheral vein from patients with hepatitis C virus related cirrhosis. METHODS The serum levels of transforming growth factor beta-1, tumour necrosis factor-alpha, hyaluronic acid, soluble (s)human leukocyte class I antigens, soluble FAS ligand, and stumour necrosis factor related ligand were assessed in a consecutive series of 15 patients with hepatitis C virus related cirrhosis. RESULTS No statistically significant differences were found between hepatic vein and peripheral vein levels for the cytokines, substance or soluble molecules evaluated, excepted for shuman leukocyte class I antigens. Instead a strong correlation between hepatic vein and peripheral vein levels was present for: hepatic vein, shuman leukocyte class I antigens, tumour necrosis factor-alpha, soluble FAS ligand and stumour necrosis factor related ligand, but not for transforming growth factor beta-1. CONCLUSIONS Our results show that peripheral vein measurements seem to reflect the liver compartment in a large majority of cases, but not for all molecules and probably for any liver diseases. Further studies on this line are warranted in particular for new molecules.

Effect of interferon therapy on serum alpha-fetoprotein levels in patients with chronic hepatitis C virus infection

Serum alpha-fetoprotein (AFP) levels were determined monthly for 1 year in 30 patients with biopsy-proven chronic hepatitis C virus (HCV) infection before, during, and after recombinant interferon alfa-2b (IFN) therapy. On the basis of their response to therapy, as evaluated by serum alanine aminotransferase levels, patients were classified as responders (10 patients), partial responders (10), and nonresponders (10). Ten healthy subjects comprised the control group. In patients with chronic HCV infection, baseline serum AFP levels (7.2 ± 1.0 ng/mL, 5.2 ± 0.4 ng/mL, and 6.2 ± 0.7 ng/mL in responders, partial responders, and nonresponders, respectively) were slightly but significantly higher than those recorded in healthy subjects (2.2 ± 0.3 ng/mL). Furthermore, IFN therapy caused a decrease in serum AFP levels that was more evident and prolonged in responders but that also occurred in partial responders and nonresponders. However, in the latter groups, this reduction in serum AFP levels was evident only during IFN therapy. These data suggest that IFN therapy may affect AFP secretion, possibly throughout the improvement of hepatic necrosis and, consequently, of hepatic regeneration.

Porphyrin Elevation in a Patient on Treatment With Simeprevir: Could It Be a Possible Explanation for Simeprevir-Associated Photosensitivity?

To the Editor: The recent development of novel direct-acting antivirals has been of paramount importance in the treatment of hepatitis C. However, all direct-acting antivirals are known to present with additional dermatological events compared to pegylated-interferon/ribavirin (RBV) (1). In particular, photosensitivity seems to be specifically associated with simeprevir (SMV), a second-generation hepatitis C virus (HCV) protease inhibitor, and has been reported in 3–4% of cases (2, 3). We observed a cutaneous reaction on photo-exposed areas in an HCV patient treated with SMV and sofosbuvir (SOF).

Genomic scale analysis of NK cells impact on response to IFN-α

Recently, several works have shown that both the innate and adaptive immunity contribute to different responsiveness to cancer therapy. Similar portraits have been described in autoimmunity diseases and viral infections. Based on these observations we here explored in hepatitis C (HCV) infected patients the role of NK cells in therapy response. For the last decade, the standard treatment for HCV infection has been limited to IFN-a + ribavirin (IR) combination therapy. Recently immunogenetic aspects regarding inhibitory receptors of NK cells (KIRs): HLA and IL-28B have been partly associated to IR response. However, the ability to couple the screening of these markers with other easily measured biomarkers may make the prediction more sensitive and specific resulting very useful in the clinical setting. In the current study we conducted high throughput screening of NK cells derived from healthy individuals and chronically infected HCV-1 patients prospectively collected before undergoing IR treatment and we identified that the treatment outcome of HCV patients is associated with the expression pattern of molecules involved in post-transcriptional modifications of RNA/protein trafficking. With the devel opment of ah ighly stringent prediction model we identified gene signatures whose expression was able to predict with 100% accuracy the outcome of treatment. Among the predictive genes, snoRNAs genes were playing a major role suggesting an unexpected relevance of the non-coding RNAs (ncRNAs) in clinical outcome of HCV patients. These data indicate that the relevance of the non-coding genome is not limited to microRNA expression and function; instead also other not coding RNAs (i.e.:snoRNAs) represent key elements of cellular homeostasis and immune responses. Moreover, our results support in humans the existence of RNA-based gene- expression regulatory system carried by introns and other noncoding genomic regions which, in HCV infection, is associated with diverging treatment response. Altogether our results showed that NK cells evaluation to HCV patients provide comprehensive explanation of useful determinants of clinical response. Thus, the usage of the NK molecular signatures could identify the proportion of chronically infected patients who would most benefit from IR treatment and it could also be further applied for the screening of predictive parameters of HCVassociated conditions (i.e. hepatocarcinoma).