Distinctive HLA-II association with primary biliary cholangitis on the Island of Sardinia

Background: The HLA DRB1*08 allele associated with primary biliary cholangitis (PBC) among Caucasians is of low frequency in the Sardinian population. Objective: The aim of our study was to type a cohort of PBC patients from the island of Sardinia for HLA class II antigens. Methods: Twenty Sardinian patients affected by PBC, 14 with autoimmune hepatitis (AIH) and 89 healthy controls (HCs) were typed for HLA class II alleles by dot-blot analysis. Results: The PBC-associated HLA DRB1*08 allele was detected in none of the studied individuals. The DRB1*0301–DQB1*0201 was the prevalent HLA haplotype, detected in 19 (47.5%) out of 40 PBC haplotypes (OR = 3.0; 95% CI 1.5–6.2) and in 11 (39.3%) out of 28 AIH haplotypes (OR = 2.2; 95% CI 0.94–5.0), but in only 41 (23%) out of 178 HC haplotypes. Moreover, PBC patients showed an increased frequency of homozygosity for the DQB1*0201 allele (35% compared with 6.7% of the HCs; OR = 7.5; 95% CI 2.2–25.7). The frequency of the DRB1*11 allele in the PBC group was about half of that seen in the Sardinian HCs (7.5% vs 15.7%) (p = ns). Conclusions: Our study confirmed the low frequency of the HLA DRB1*08 allele among Sardinians, either in the general population or PBC patients. The high prevalence of the HLA DRB1*0301–DQB1*0201 haplotype is a distinctive genetic feature of PBC among Sardinians. Our study strengthens the hypothesis that still unknown genetic, epigenetic, and environmental factors must be involved in the pathogenesis of different HLA-associated liver diseases, and it represents a pathfinder that warrants exploration in a future extensive study

Association of chronic hepatitis C with major depressive disorders: irrespective of interferon-alpha therapy

Abstract Background Mood and anxiety symptoms in chronic hepatitis C (CHC) may be related to the patient awareness of the diagnosis and prognosis, to side effects induced by interferon (IFN)-alpha treatment, as well as to substance abuse. However, the observation of metabolic alterations in patients with CHC has led to hypothesize a direct effect of hepatitis C virus (HCV) on brain function. This study was aimed at elucidating whether CHC is associated with specific anxiety or mood disorders independently of confounding factors. Methods Patient cohort: consecutive patients, 135 with CHC and 76 with chronic hepatitis B (CHB). Exclusion criteria: previous treatment with IFN-alpha, co-infection with HCV and hepatitis B virus, infection with human immunodeficiency virus, drug or alcohol abuse, or malignancies. Controls: subjects without evidence of hepatitis randomly extracted from the database of a previous epidemiological study; they were divided into two groups of 540 (332 males) and 304 (220 males) as controls for patients with CHC and CHB, respectively. The psychiatric diagnosis was formulated by means of the Composite International Diagnostic Interview Simplified carried out by a physician according to DSM-IV criteria. Results A higher lifetime prevalence of major depressive disorder (MDD) was observed among CHC compared to CHB or controls. The risk of MDD was not statistically different between CHB and controls. Both the CHC and CHB groups showed a significantly higher frequency of panic disorder when compared to controls. No statistical differences were observed in the prevalence of general anxiety disorder and social phobia when CHC or CHB were compared to controls. Conclusion The present study provides the first evidence of an association between CHC and MDD, diagnosed on the basis of well-defined international criteria. This association is independent of treatment with IFN-alpha and is not influenced by substance or alcohol abuse. By contrast, anxiety disorders do not appear to be specifically associated with CHC

Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus - associated hepatocellular carcinoma

Abstract Background The molecular mechanisms whereby hepatitis B virus (HBV) induces hepatocellular carcinoma (HCC) remain elusive. We used genomic and molecular techniques to investigate host-virus interactions by studying multiple areas of the same liver from patients with HCC. Methods We compared the gene signature of whole liver tissue (WLT) versus laser capture-microdissected (LCM) hepatocytes along with the intrahepatic expression of HBV. Gene expression profiling was performed on up to 17 WLT specimens obtained at various distances from the tumor center from individual livers of 11 patients with HCC and on selected LCM samples. HBV markers in liver and serum were determined by real-time polymerase chain reaction (PCR) and confocal immunofluorescence. Results Analysis of 5 areas of the liver showed a sharp change in gene expression between the immediate perilesional area and tumor periphery that correlated with a significant decrease in the intrahepatic expression of HB surface antigen (HBsAg). The tumor was characterized by a large preponderance of down-regulated genes, mostly involved in the metabolism of lipids and fatty acids, glucose, amino acids and drugs, with down-regulation of pathways involved in the activation of PXR/RXR and PPARα/RXRα nuclear receptors, comprising PGC-1α and FOXO1, two key regulators critically involved not only in the metabolic functions of the liver but also in the life cycle of HBV, acting as essential transcription factors for viral gene expression. These findings were confirmed by gene expression of microdissected hepatocytes. Moreover, LCM of malignant hepatocytes also revealed up-regulation of unique genes associated with cancer and signaling pathways, including two novel HCC-associated cancer testis antigen genes, NUF2 and TTK. Conclusions Integrated gene expression profiling of whole liver tissue with that of microdissected hepatocytes demonstrated that HBV-associated HCC is characterized by a metabolism switch-off and by a significant reduction in HBsAg. LCM proved to be a critical tool to validate gene signatures associated with HCC and to identify genes that may play a role in hepatocarcinogenesis, opening new perspectives for the discovery of novel diagnostic markers and therapeutic targets

Delta hepatitis: an update

Hepatitis delta virus (HDV) is a unique defective RNA virus that requires the helper function of hepatitis B virus (HBV), which provides the essential coat protein for virion assembly and propagation. It is the smallest animal virus and the only one to possess a circular RNA genome, as seen in plant viruses. HDV has evolved into three major genotypes that differ in their geographic distribution. Infection with HDV has a worldwide distribution, although a dramatic decline in the incidence has been observed in the last decade in the Mediterranean area, likely as a result of HBV vaccination programs and improved socioeconomic conditions. HDV can be acquired either by coinfection with HBV or by superinfection of chronic HBsAg carriers. Whereas coinfection commonly resolves, superinfection progresses to chronicity in over 90 % of the cases. Chronic hepatitis D is a severe and progressive disease leading to cirrhosis in about 70 % of the cases. The pathogenesis of HDV-induced liver injury is still unknown. Regardless, dramatic advances have been made in the biology of HDV, as well as in the understanding of the complex interactions between HDV, HBV and the host. Currently, interferon-alfa at high doses is the only drug that can induce amelioration of the disease in about half the patients, but it has little effect on HDV viremia. Liver transplantation is the only valid therapeutic option for the treatment of end-stage HDV liver disease. Although the recent progress in molecular biology has dramatically advanced ou