Two differentially methylated region networks in nonalcoholic fatty liver disease, viral hepatitis, and hepatocellular carcinoma.

BACKGROUND: We previously reported that two differentially methylated region (DMR) networks identified by DMR and co-methylation analyses are strongly correlated with the fibrosis stages of nonalcoholic fatty liver disease (NAFLD). In the current study, we examined these DMR networks in viral hepatitis and hepatocellular carcinoma (HCC). METHODS: We performed co-methylation analysis of DMRs using a normal dataset (GSE48325), two NAFLD datasets (JGAS000059 and GSE31803), and two HCC datasets (GSE89852 and GSE56588). The dataset GSE60753 was used for validation. RESULTS: One DMR network was clearly observed in viral hepatitis and two HCC populations. Methylation levels of genes in this network were higher in viral hepatitis and cirrhosis, and lower in HCC. Fatty acid binding protein 1 (FABP1), serum/glucocorticoid regulated kinase 2 (SGK2), and hepatocyte nuclear factor 4 α (HNF4A) were potential hub genes in this network. Increased methylation levels of the FABP1 gene may be correlated with reduced protection of hepatocytes from oxidative metabolites in NAFLD and viral hepatitis. The decreased methylation levels of SGK2 may facilitate the growth and proliferation of HCC cells. Decreased methylation levels of HNF4A in HCC may be associated with tumorigenesis. The other DMR network was observed in NAFLD, but not in viral hepatitis or HCC. This second network included genes involved in transcriptional regulation, cytoskeleton organization, and cellular proliferation, which are specifically related to fibrosis and/or tumorigenesis in NAFLD. CONCLUSIONS: Our results suggest that one DMR network was associated with fibrosis and tumorigenesis in both NAFLD and viral hepatitis, while the other network was specifically associated with NAFLD progression. Furthermore, FABP1, SGK2, and HNF4A are potential candidate targets for the prevention and treatment of HCC.

Case report: hepatitis in a child infected with SARS-CoV-2 presenting toll-like receptor 7 Gln11Leu single nucleotide polymorphism.

BACKGROUND: Covid-19 has the respiratory tract as the main target of infection, and patients present mainly dyspnea, pneumonia, dry cough, and fever. Nevertheless, organs outside the respiratory tract had been reported in recent studies, including the gastrointestinal tract and liver. The host innate immune system recognizes pathogen-associated molecular patterns (PAMPs) through their pattern recognition receptor (PRRs). Toll-like receptor 7 (TLR-7) is a pattern recognition receptor recognizing ssRNA (SARS-CoV-2 is an ssRNA). Polymorphisms are characterized by two or more alternative forms of a distinct phenotype in the same population. Polymorphisms in tlrs genes can negatively influence the immune response to infectious diseases. There are several references in the literature to non-synonymous single nucleotide (rs) polymorphisms related to several genes. Some of them are important for the innate immunity, as rs 179008 (tlr-7), rs3775291 (tlr3), rs8177374 (tir domain-containing adaptor protein, tirap), rs1024611 (monocyte chemoattractant protein-1, mcp-1) and rs61942233 (2'-5'-oligoadenylate synthase-3, oas-3). CASE PRESENTATION: We identified a 5-year-old-male child with gastrointestinal symptoms and fever presenting acholic stool and jaundice, who was positive for SARS-CoV-2 IgM, IgA, and IgG and presenting the Gln11Leu rs 179008 in tlr-7. The child presented high levels of aspartate aminotransferase, alanine aminotransferase, bilirubin, C-reactive protein, D-dimer, gamma-glutamyl transferase, alkaline phosphatase, and was negative for serological tests for hepatitis A, B, C, E, HIV 1 and 2, herpes virus, cytomegalovirus, Epstein-Barr virus, and negative for RTqPCR for Influenza A and B, RSV and SARS-CoV-2. We also investigated other SNPs in the tlr-3 (rs3775291), tirap (rs8177374), mcp-1 (rs1024611), and oas-3 (rs61942233) genes, and no mutation was detected. After an interview with the child's caregivers, any possible accidental ingestion of drugs or hepatotoxic substances was ruled out. CONCLUSION: To our knowledge, this is the first report of a SARS-CoV-2 caused hepatitis in a male child that has the tlr-7 Gln11Leu rs 179008, which could impair an efficient initial immune response. The knowledge of the patient's immune deficiency could improve the treatment to correct this deficiency with specific medications.

Human genetic basis of fulminant viral hepatitis.

In rare cases, hepatitis A virus (HAV) and hepatitis B virus (HBV) can cause fulminant viral hepatitis (FVH), characterized by massive hepatocyte necrosis and an inflammatory infiltrate. Other viral etiologies of FVH are rarer. FVH is life-threatening, but the patients are typically otherwise healthy, and normally resistant to other microbes. Only a small minority of infected individuals develop FVH, and this is the key issue to be addressed for this disease. In mice, mouse hepatitis virus 3 (MHV3) infection is the main model for dissecting FVH pathogenesis. Susceptibility to MHV3 differs between genetic backgrounds, with high and low mortality in C57BL6 and A/J mice, respectively. FVH pathogenesis in mice is related to uncontrolled inflammation and fibrinogen deposition. In humans, FVH is typically sporadic, but rare familial forms also exist, suggesting that there may be causal monogenic inborn errors. A recent study reported a single-gene inborn error of human immunity underlying FVH. A patient with autosomal recessive complete IL-18BP deficiency was shown to have FVH following HAV infection. The mechanism probably involves enhanced IL-18- and IFN-γ-dependent killing of hepatocytes by NK and CD8 T cytotoxic cells. Proof-of-principle that FVH can be genetic is important clinically, for the affected patients and their families, and immunologically, for the study of immunity to viruses in the liver. Moreover, the FVH-causing IL18BP genotype suggests that excessive IL-18 immunity may be a general mechanism underlying FVH, perhaps through the enhancement of IFN-γ immunity.

NGF (-198C > T, Ala35Val) and p75NTR (Ser205Leu) gene mutations are associated with liver function in different histopathological profiles of the patients with chronic viral hepatitis in the Brazilian Amazon.

BACKGROUNDS: Neural growth factor (NGF) is a neurotrophin that can interact with the p75NTR receptor and initiate a cascade of reactions that determines cell survival or death, and both are associated with the physiology of liver tissue. Single nucleotide polymorphisms (SNPs) in the NGF and p75NTR genes have been investigated in different pathologies; however, there are no studies that have analyzed their biological roles in the hepatic microenvironment. In the present study, we evaluated the impact of SNPs in these genes on the maintenance of liver function at different stages of inflammation and fibrosis in patients with chronic viral liver disease in the Brazilian Amazon. METHODS: The SNPs -198C > T, Arg80Gln, Val72Met, Ala35Val, Ala18Ala and Ser205Leu were genotyped by real-time PCR in samples from patients with chronic viral hepatitis stratified by stage of inflammation and liver fibrosis. Histopathological, viral load (VL), liver enzyme and comorbidities data were obtained from updated medical records. Other aspects were highlighted by applied epidemiological questionnaires. RESULTS: The -198C/T and Ala35Val polymorphisms in NGF were associated with changes in histopathological profiles, VL and liver enzymes. Ser205Leu polymorphism in p75NTR was associated only with changes in VL and liver enzymes. Polymorphic frequencies were variable among different ethnic populations, mainly for biologically relevant polymorphisms. A multifactorial network of interactions has been established based on genetic, virological, behavioral and biochemical aspects. CONCLUSION: Mutations in the NGF (-198C > T, Ala35Val) and p75NTR (Ser205Leu) genes, within the list of multifactorial aspects, are associated with liver function in different histopathological profiles of patients with chronic viral liver disease in the Brazilian Amazon.

High Viral Hepatitis Infection among Pregnant Women Attending Antenatal Clinic in Adeoyo Maternity Teaching Hospital Ibadan (AMTHI) Oyo State, Nigeria.

Hepatitis B virus (HBV), Hepatitis C virus (HCV), and Hepatitis E Virus (HEV) are highly endemic in several African countries including Nigeria with adverse effects on pregnancy outcomes resulting in fatality. This study aimed to determine the viral hepatitis in pregnant women attending antenatal clinic, AMTHI. Informed consent questionnaire was administered before blood collection via venipuncture. a total of 904 pregnant women plasma samples were tested for HBV, HCV, and HEV using ELISA kit. Data was analyzed using packages within SPSS software and P ≤ 0.05 was considered significant. Out of 904 samples analyzed, the overall prevalence of hepatitis infections among pregnant women attending antenatal clinic in AMTHI was 66(7.3%). High prevalence of the hepatitis infections was found among young women within the age group 21-30 which might be associated with active sex, intravenous drug use, sharing of sharp objects and alcoholism. Blood group O Positive had the highest prevalence of hepatitis. There was statistical significance between blood group and HBsAg infection (P < .05). Genotype AA women had highest prevalence of hepatitis. This study showed significant association between HBsAg, HCV, and HEV positive status with blood group O positive and Genotype AA pregnant women.

[Gene mutation pattern of Gilbert's syndrome combined with viral hepatitis and its relationship with the exploration of clinical data].

Objective: To study whether gene mutation pattern of Gilbert's syndrome (GS) is combined with viral hepatitis and its relationship with relevant clinical data. Methods: Clinical data of GS patients combined with viral hepatitis who was admitted to the Department of Infectious Diseases of Henan Provincial People's Hospital from August 2013 to December 2018 was retrospectively analyzed. The relationship between gene mutation pattern, general data (age, gender, etc.) and liver biochemical indexes was analyzed. The differences of the above data in patients with or without combined viral hepatitis were analyzed. The measurement data were compared by t-test. The categorical data was compared by the χ (2) test. The median and interquartile range of non-normally distributed data was used to indicate the central and discrete tendency. Results: A total of 107 GS eligible cases data were collected. The male to female ratio was 4.94:1 (89:18). The average age of onset was (36.36 ± 12.51) years. Alanine aminotransferase and total bilirubin levels were normal or slightly elevated, while aspartate aminotransferase, alkaline phosphatase, and γ-glutamyltransferase were all within the normal range. There were 49 cases in the combined viral hepatitis group (36 cases with HBV and 13 cases with HCV), and 58 cases in the GS alone group. Total bilirubin level in GS alone group was higher than the combined viral hepatitis group (z = 0.035, P < 0.05), and there were no statistically significant differences in gender, age, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma glutamyltransferase (P > 0.05). Uridine diphosphate glucuronide transferase 1A1 (UGT1A1), specifically encoded by GS was detected in all 107 cases. Mutations was mainly occurred in the upstream promoter PBREM-3263 (-3279) (86 cases) and TATA box TA insertion mutation (71 cases), and GGA-AGA Gly71Arg (57 cases) mutation in EXON1 of the coding region. All mutation forms had manifestations of homozygous and heterozygous abnormalities. The combined incidence of main mutation forms in the genetic testing data were sequenced as: A2 + B2 + C2 (17 cases, 25.23%), A1 + B1 (17 cases, 15.89%), A2 (11 cases, 10.28%), C2 (10 Cases, 9.34%), A2 + B2 (7 cases, 6.54%), A1 + B2 (7 cases, 6.54%), C1 (7 cases, 6.54%), and there was no statistically significant difference between different mutation combinations in patients with or without hepatitis (P > 0.05). The results of total data analysis showed that the total bilirubin level in the single-site mutation group was higher than the multi-site mutation group (Z=2.019, P = 0.043), and other biochemical indicators had no effect (P > 0.05) and the differences were not statistically significant. Further analysis showed that the total bilirubin level of the single-site mutation subgroup in the GS alone group was higher than the multi-site mutation subgroup (Z = 1.999, P = 0.046), and the statistical difference was similar to the combined viral hepatitis group (P > 0.05). Different mutation combinations had no effect on biochemical indexes, and had no relationship with combined viral hepatitis (P > 0.05). Conclusion: GS is common in patients with combined viral hepatitis, and there is no significant difference between the incidence of gene mutation, mutation forms, biochemical indexes, and non-hepatitis group. The increase in the number of GS mutation sites does not aggravate the deterioration of bilirubin levels due to the decrease in the content and activity of uridine diphosphate glucuronosyltransferase, and the combination of different mutation sites does not affect the changes of various biochemical indexes, and at the same time it is not related to hepatitis.

Full annotation of serum virome in Chinese blood donors with elevated alanine aminotransferase levels.

BACKGROUND: A serum alanine aminotransferase (ALT) test is currently demanded for blood donation in China. One of the major reasons to include such a test is possible etiology of known or unknown hepatotropic viruses. However, this hypothesis has never been examined convincingly. STUDY DESIGN AND METHODS: The study recruited 90 Chinese blood donors that were divided into three groups based on their ALT values. Serum virome from these donors was explored using a metagenomics approach with enhanced sensitivity resolved at single sequencing reads. RESULTS: Anellovirus and pegivirus C (GBV-C) were detected among these donors. None of them were found solely in donors with abnormal liver enzyme. Anellovirus was highly prevalent (93.3%) and the co-infection with multiple genera (alpha, beta, and gammatorquevirus) were more common in the donors with normal ALT values in comparison to those with elevated ALT (single/double/triple Anellovirus genera, 1/3/24 vs. 7/7/14 or 6/7/13, p = 0.009). For unmapped reads that accounted for 15 ± 14.9% of the data, similarity-based (BLASTN, BLASTP, and HMMER3) and similarity-independent (k-mer frequency) analysis identified several circular rep encoding ssDNA (CRESS-DNA) genomes. Direct PCR testing indicated these genomes were likely reagent contaminants. CONCLUSION: Viral etiology is not responsible for elevated ALT levels in Chinese blood donors. The ALT test, if not abandoned, should be adjusted for its cutoff in response to donor shortage in China.

Relationship of genetic polymorphisms in CTLA-4 and IL-18 with viral hepatitis: evidence from a meta-analysis.

Relationship of genetic polymorphisms in cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and interleukin-18 (IL-18) with susceptibility to viral hepatitis was already investigated by many association studies. The aim of this study was to more comprehensively analyse associations between genetic polymorphisms in CTLA-4/IL-18 and viral hepatitis by combing the results of all relevant association studies. We searched Pubmed, Embase, Web of Science and CNKI for eligible studies. We used Review Manager to combine the results of eligible studies. Thirty-seven studies were finally included in this meta-analysis. Combined results demonstrated that CTLA-4 rs231775 (recessive comparison: OR 1.31, 95% CI 1.11-1.55), IL-18 rs1946518 (dominant comparison: OR 0.82, 95% CI 0.75-0.90; recessive comparison: OR 1.29, 95% CI 1.11-1.50; allele comparison: OR 0.76, 95% CI 0.68-0.86) and IL-18 rs187238 (dominant comparison: OR 1.25, 95% CI 1.03-1.52; allele comparison: OR 1.20, 95% CI 1.05-1.37) polymorphisms were all significantly associated with viral hepatitis in the general population. Further subgroup analyses revealed that CTLA-4 rs231775, IL-18 rs1946518 and IL-18 rs187238 polymorphisms were significantly associated with susceptibility to hepatitis B virus (HBV), especially among East Asians. Moreover, CTLA-4 rs5742909, IL-18 rs1946518 and IL-18 rs187238 polymorphisms were also significantly associated with susceptibility to hepatitis C virus (HCV), especially among South Asians. So to conclude, this meta-analysis demonstrated that CTLA-4 rs231775, IL-18 rs1946518 and IL-18 rs187238 polymorphisms may confer susceptibility to HBV in East Asians, while CTLA-4 rs5742909, IL-18 rs1946518 and IL-18 rs187238 polymorphisms may confer susceptibility to HCV in South Asians.

Emerging Role of Circular RNAs as Potential Biomarkers for the Diagnosis of Human Diseases.

In the eukaryotic transcriptome, the evolutionary conserved circular RNAs naturally occur from the family of noncoding RNAs. Circular RNAs possess a unique feature to interact with nucleic acids and ribonucleoproteins and are establishing themselves as an obligatory composition for the regulatory messages which are encoded by the genome. The back-splicing mechanism leads to the formation of circularized RNA, and because of this they become resistant to exonuclease-mediated degradation. The differential and aberrant expression of circular RNAs can be detected with the help of various profiling methods by using serum, plasma, and tissue samples. In this chapter, we have highlighted the role of circular RNAs as putative biomarker for the detection of various human diseases along with its profiling methods. Here we have discussed the differentially expressed circular RNAs in neurological disorders and infectious diseases along with cancer diseases. For instance, in case of pulmonary tuberculosis, hsa_circRNA_001937 was upregulated, while hsa_circRNA_102101 got downregulated; Hsa_circ_000178 was depicted to get upregulated in breast cancer which is associated with disease progression. Furthermore, it has been observed that circRNAs are abundantly present within the mammalian brain tissues. In epileptic condition, Circ-EFCAB2 was observed to get notably upregulated within patients. Taking the above conditions into consideration, circular RNAs have proven themselves as promising noninvasive biomarker for the detection of human diseases.

Viral Surveillance in Serum Samples From Patients With Acute Liver Failure By Metagenomic Next-Generation Sequencing.

BACKGROUND: Twelve percent of all acute liver failure (ALF) cases are of unknown origin, often termed indeterminate. A previously unrecognized hepatotropic virus has been suspected as a potential etiologic agent. METHODS: We compared the performance of metagenomic next-generation sequencing (mNGS) with confirmatory nucleic acid testing (NAT) to routine clinical diagnostic testing in detection of known or novel viruses associated with ALF. Serum samples from 204 adult ALF patients collected from 1998 to 2010 as part of a nationwide registry were analyzed. One hundred eighty-seven patients (92%) were classified as indeterminate, while the remaining 17 patients (8%) served as controls, with infections by either hepatitis A virus or hepatitis B virus (HBV), or a noninfectious cause for their ALF. RESULTS: Eight cases of infection from previously unrecognized viral pathogens were detected by mNGS (4 cases of herpes simplex virus type 1, including 1 case of coinfection with HBV, and 1 case each of HBV, parvovirus B19, cytomegalovirus, and human herpesvirus 7). Several missed dual or triple infections were also identified, and assembled viral genomes provided additional information on genotyping and drug resistance mutations. Importantly, no sequences corresponding to novel viruses were detected. CONCLUSIONS: These results suggest that ALF patients should be screened for the presence of uncommon viruses and coinfections, and that most cases of indeterminate ALF in the United States do not appear to be caused by novel viral pathogens. In the future, mNGS testing may be useful for comprehensive diagnosis of viruses associated with ALF, or to exclude infectious etiologies.

Discovery of a Novel Human Pegivirus in Blood Associated with Hepatitis C Virus Co-Infection.

Hepatitis C virus (HCV) and human pegivirus (HPgV), formerly GBV-C, are the only known human viruses in the Hepacivirus and Pegivirus genera, respectively, of the family Flaviviridae. We present the discovery of a second pegivirus, provisionally designated human pegivirus 2 (HPgV-2), by next-generation sequencing of plasma from an HCV-infected patient with multiple bloodborne exposures who died from sepsis of unknown etiology. HPgV-2 is highly divergent, situated on a deep phylogenetic branch in a clade that includes rodent and bat pegiviruses, with which it shares <32% amino acid identity. Molecular and serological tools were developed and validated for high-throughput screening of plasma samples, and a panel of 3 independent serological markers strongly correlated antibody responses with viral RNA positivity (99.9% negative predictive value). Discovery of 11 additional RNA-positive samples from a total of 2440 screened (0.45%) revealed 93-94% nucleotide identity between HPgV-2 strains. All 12 HPgV-2 RNA-positive cases were identified in individuals also testing positive for HCV RNA (12 of 983; 1.22%), including 2 samples co-infected with HIV, but HPgV-2 RNA was not detected in non-HCV-infected individuals (p<0.0001), including those singly infected by HIV (p = 0.0075) or HBV (p = 0.0077), nor in volunteer blood donors (p = 0.0082). Nine of the 12 (75%) HPgV-2 RNA positive samples were reactive for antibodies to viral serologic markers, whereas only 28 of 2,429 (1.15%) HPgV-2 RNA negative samples were seropositive. Longitudinal sampling in two individuals revealed that active HPgV-2 infection can persist in blood for at least 7 weeks, despite the presence of virus-specific antibodies. One individual harboring both HPgV-2 and HCV RNA was found to be seronegative for both viruses, suggesting a high likelihood of simultaneous acquisition of HCV and HPgV-2 infection from an acute co-transmission event. Taken together, our results indicate that HPgV-2 is a novel bloodborne infectious virus of humans and likely transmitted via the parenteral route.

Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes.

UNLABELLED: A genome-wide exome association study has identified the transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 variant encoding an E167K substitution as a genetic determinant of hepatic steatosis in nonalcoholic fatty liver disease (NAFLD). The roles of this variant across a spectrum of liver diseases and pathologies and on serum lipids comparing viral hepatitis to NAFLD and viral load in chronic viral hepatitis, as well as its intrahepatic molecular signature, have not been well characterized. We undertook detailed analyses in 3260 subjects with viral and nonviral liver diseases and in healthy controls. Serum inflammatory markers and hepatic expression of TM6SF2 and genes regulating lipid metabolism were assessed in a subset with chronic hepatitis C (CHC). The rs58542926 T allele was more prevalent in 502 NAFLD patients than controls (P = 0.02) but not different in cohorts with CHC (n = 2023) and chronic hepatitis B (n = 507). The T allele was associated with alterations in serum lipids and hepatic steatosis in all diseases and with reduced hepatic TM6SF2 and microsomal triglyceride transfer protein expression. Interestingly, the substitution was associated with reduced CHC viral load but increased hepatitis B virus DNA. The rs58542926 T allele had no effect on inflammation, impacted ≥F2 fibrosis in CHC and NAFLD assessed cross-sectionally (odds ratio = 1.39, 95% confidence interval 1.04-1.87, and odds ratio = 1.62, 95% confidence interval 1.03-2.52, respectively; P < 0.03 for both), but had no effect on fibrosis progression in 1174 patients with CHC and a known duration of infection. CONCLUSION: The TM6SF2 E167K substitution promotes steatosis and lipid abnormalities in part by altering TM6SF2 and microsomal triglyceride transfer protein expression and differentially impacts CHC and chronic hepatitis B viral load, while effects on fibrosis are marginal. (Hepatology 2016;64:34-46).

Fluorescent silver nanocluster DNA probes for multiplexed detection using microfluidic capillary electrophoresis.

DNA-stabilized fluorescent silver nanoclusters (AgNC DNA) are a new class of fluorophore that are formed by sequence specific interactions between silver and single-stranded DNA. By incorporating both target-binding and fluorescent-reporting sequences into a single synthetic DNA oligomer, AgNC DNA probes eliminate the need to conjugate dye or quencher molecules. In this study, we modify a AgNC DNA probe to demonstrate single-color multiplexed detection of DNA targets. We show that appending different lengths of poly-dT to the probe sequences tunes the electrophoretic mobility of AgNC DNA probes without affecting their fluorescence spectra. We use this to introduce a set of AgNC DNA probes selective for Hepatitis A, B and C target sequences that can be processed together in a simple, single-step protocol and distinguished with a resolution of 3.47 and signal to noise ratio of 17.23 in under 10 seconds by microfluidic capillary electrophoresis.

Hepatic DNA Methylation Is Affected by Hepatocellular Carcinoma Risk in Patients with and without Hepatitis Virus.

OBJECTIVES: Several studies revealed that the proportion of hepatocellular carcinoma (HCC) without hepatitis virus infection (NBNC-HCC) is increasing. On the other hand, epigenetic alterations are reportedly responsible for HCC development. Here, we identified HCC risk factors that are associated with DNA methylation in the background liver tissue of NBNC-HCC patients. METHODS: We performed methylation analysis in 37 pairs of virus-positive and 22 pairs of NBNC-HCC and non-cancerous livers using a HumanMethylation450 BeadChip array. After the selection of differentially methylated CpGs (DM-CpGs) in cancerous and non-cancerous livers, we analyzed DNA methylation of DM-CpGs within the adjacent non-cancerous liver tissue that is affected by specific HCC risk factors. RESULTS: A total of 38,331 CpGs were selected as DM-CpGs using the following criteria: difference of ß-value between HCC and non-cancerous liver ≥0.15 and false discovery rate (FDR) q < 1.0E-12. We subsequently selected the DM-CpGs that had methylation differences with the background liver tissue (that has FDR q < 0.35). Among the virus-positive patients, the type of hepatitis virus was mostly associated with differences in methylation within the background liver tissues. However, we found that background methylation patterns were most significantly associated with aging in NBNC patients. Interestingly, age-related methylation differences in DM-CpGs were also observed in NBNC-HCC tissues. CONCLUSIONS: Hepatitis viruses affect the methylation profiles within background liver tissues. However, difference in background methylation was mostly associated with age in NCBC-HCC patients; some age-related methylation events could contribute to emergence of NBNC-HCC in elderly individuals.

Individuals having variant genotypes of cytochrome P450 2C19 are at increased risk of developing primary liver cancer in Han populations, without infection with the hepatitis virus.

Recently, many researchers have reported that the genetic polymorphisms of CYP2C19 may account for the interpatient variability of the clinical course in cancers including primary liver cancer (PLC). Besides the genetic polymorphisms of CYP2C19, hepatitis viruses (HV, including HAV, HBV, HCV, HDV, HEV, especially HBV and/or HCV) also account for the interpatient variability of the clinical course in PLC. This research covered the above two factors and divided the patients with PLC into two groups (one group with HBV infection and another without any HV infection) to find out whether the genetic polymorphisms of CYP2C19 have different effects in the progressing of PLC in different groups of patients. Eight hundred sixty-four cancer-free Han people (controls, named group 1), 207 Han PLC patients with HBV infection (group 2), and 55 Han PLC patients without any HV infection (group 3) were involved in this study. A wild-type allele (CYP2C19*1) and two mutated alleles (CYP2C19*2 and CYP2C19*3) were identified. The frequencies of the mutant alleles and genotypes were then compared with each other. The frequencies of the homozygous and heterozygous variant genotypes (*2/*2, *2/*3, *3/*3) in group 3 (25.5 %) were significantly higher than those in other groups (11.9 % in group 1 and 13.5 % in group 2, P = 0.014, 95 % confidence interval (CI)). The differences were statistically significant between group 1 and group 3 (P = 0.004, 95 % CI), but they were not statistically significant between group 1 and group 2 (P = 0.527, 95 % CI). Thus, we conclude that people which were not infected with HV but with the homozygous or heterozygous variant genotypes (*2/*2, *2/*3, *3/*3) of CYP2C19 may have higher possibilities of getting PLC than people with other allelic genotypes (*1/*1, *1/*2, *1/*3) (odds ratio (OR) = 2.523, 95 % CI = 1.329 ~ 4.788). However, in patients with HBV infection, the genetic polymorphisms of CYP2C19 did not seem to be an important factor in the risk of developing PLC (OR = 1.156, 95 % CI = 0.738 ~ 1.810).

MicroRNAs and liver disease: viral hepatitis, liver fibrosis and hepatocellular carcinoma.

MicroRNAs (miRNAs), a type of highly conserved small non-coding RNAs with an average length of 22 nucleotides, may serve as major regulators of gene expression and indispensable components of cellular gene expression networks. They have critical roles in normal biological processes and have been linked to many tumours, including hepatocellular carcinoma (HCC). HCC is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. Viral hepatitis, caused by infection with hepatitis B or C viruses (HBV or HCV), can increase the risk of HCC and contributes to a significant disease burden around the world. Because of the variety of molecular alterations that may arise during the development and progression of HCC, standard of care and treatment for patients with HCC remains unsatisfactory. MiRNAs have been shown to participate in the pathogenesis of both HBV and HCV. In addition to a role in pathogenesis, miRNAs have significant clinical value in the early diagnosis of HCC since they are present in the blood and can be used as diagnostic markers and potential targets for specific systemic treatment.

Viral hepatitis moderates the impact of TGFB1 on neurocognitive impairment.

Recent studies have identified a correlation between chronic viral hepatitis and cognitive impairment, yet the underlying mechanisms remain unclear. This study investigated the influence of TGFB1 genetic polymorphisms on cognitive function in individuals with and without hepatitis infections, hypothesizing that these polymorphisms and the viral hepatitis-induced inflammatory environment interact to affect cognitive abilities. Participants (173 with viral hepatitis and 258 healthy controls) were recruited. Genotyping of TGFB1 SNPs was performed using the C2-58 Axiom Genome-Wide TWB 2.0 Array Plate. Cognitive function was assessed using the MMSE and MoCA tests. Our results showed that healthy individuals carrying the C allele of rs2241715 displayed better performance in sentence writing (p = 0.020) and language tasks (p = 0.022). Notably, viral hepatitis was found to moderate the impact of the rs2241715 genotype on language function (p = 0.002). Similarly, those carrying the T allele of rs10417924 demonstrated superior orientation to time (p = 0.002), with viral hepatitis modifying the influence of the SNP on this particular cognitive function (p = 0.010). Our findings underscore the significant role of TGFß1 in cognitive function and the moderating impact of viral hepatitis on TGFB1 SNP effects. These findings illuminate the potential of TGFB1 as a therapeutic target for cognitive impairment induced by viral hepatitis, thus broadening our understanding of TGFß1 functionality in the pathogenesis of neurodegeneration.

MicroRNAs in liver disease.

MicroRNAs are small noncoding RNA molecules that regulate gene expression posttranscriptionally through complementary base pairing with thousands of messenger RNAs. They regulate diverse physiological, developmental, and pathophysiological processes. Recent studies have uncovered the contribution of microRNAs to the pathogenesis of many human diseases, including liver diseases. Moreover, microRNAs have been identified as biomarkers that can often be detected in the systemic circulation. We review the role of microRNAs in liver physiology and pathophysiology, focusing on viral hepatitis, liver fibrosis, and cancer. We also discuss microRNAs as diagnostic and prognostic markers and microRNA-based therapeutic approaches for liver disease.

[Viralhepatitis. Croatian Consensus Statement 2013]. / Virusni hepatitis. Hrvatska konsenzus konferencija 2013.

Croatian Consensus Conferences on Viral Hepatitis took place in 2005 and 2009. Considering the numerous novel concepts on the epidemiology, diagnosis and management of viral hepatitis (chronic hepatitis C genotype 1 in particular) that have emerged in the past four years, a new Croatian Consensus Conference on Viral Hepatitis was held in Zagreb on February 28, 2013. The abridged text of the Croatian Consensus Conference on Viral Hepatitis 2013 presents the new concepts on the epidemiology of viral hepatitis, serologic and molecular diagnosis of viral hepatitis, determination of the IL-28 gene promoter polymorphism, fibrosis grading, algorithm for patient diagnostic follow up, treatment of chronic hepatitis C (genotypes 1-6) and hepatitis B, treatment of special populations (children, dialysis patients, transplanted patients, individuals with HIV/HCV co-infection), and therapy side effects.

GB virus type C infection polarizes T-cell cytokine gene expression toward a Th1 cytokine profile via NS5A protein expression.

Human immunodeficiency virus (HIV) disease progression is associated with a helper T cell 1 (Th1) to helper T cell 2 (Th2) cytokine profile switch. Persistent GB virus type C (GBV-C) infection is associated with survival and a serum Th1 cytokine profile in HIV-infected individuals. We found that GBV-C infection increased gene expression of Th1 cytokines and decreased Th2 cytokine expression in peripheral blood mononuclear cells. Furthermore, expression of GBV-C NS5A protein in a CD4(+) cell line resulted in upregulation of Th1 cytokines (tumor necrosis factor α) and downregulation of Th2 cytokines (interleukin 4, interleukin 5, interleukin 10, interleukin 13). GBV-C-induced modulation in T-cell cytokines may contribute to the beneficial effect of GBV-C in HIV-infected individuals.