DNA methylation markers in the detection of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and has a poor prognosis. Epigenetic modification has been shown to be deregulated during HCC development by dramatically impacting the differentiation, proliferation, and function of cells. One important epigenetic modification is DNA methylation during which methyl groups are added to cytosines without changing the DNA sequence itself. Studies found that methylated DNA markers can be specific for detection of HCC. On the basis of these findings, the utility of methylated DNA markers as novel biomarkers for early-stage HCC has been measured in blood, and indeed superior sensitivity and specificity have been found in several studies when compared to current surveillance methods. However, a variety of factors currently limit the immediate application of these exciting biomarkers. In this review, we provide a detailed rationalisation of the approach and basis for the use of methylation biomarkers for HCC detection and summarise recent studies on methylated DNA markers in HCC focusing on the importance of the aetiological cause of liver disease in the mechanisms leading to cancer.</p

Hepatitis E virus infection in the United States: Seroprevalence, risk factors and the influence of immunological assays

In the United States (U.S.), a hepatitis E virus (HEV) seroprevalence between 6 and 21% has been described, with a decreasing trend. We aimed to investigate HEV infection in the U.S. population from 2009 to 2016, and examine the differences in seroprevalence using different assays. We used data from the National Health and Nutrition Examination Survey (NHANES-CDC) to estimate HEV seroprevalence and analyze demographic variables related to the infection. Additionally, we compared 4 serological tests used. The estimated HEV seroprevalence between 2009?2016 was 6.1% (95% CI: 5.6%-7.0%) for IgG and 1.02% (0.8%-1.2%) for IgM. Higher HEV IgG prevalences were found in older people, females, non-Hispanic Asians and those born outside of the U.S. The in-house immunoassay and the Wantai HEV-IgG ELISA presented the highest sensitivity values in the tested population. The highest specificity values corresponded to the DSI-EIA-ANTI-HEV-IgG assay. The kappa statistical values showed concordances no greater than 0.64 between the assays. HEV prevalence in our study was similar to previously reported, and a decline in the prevalence was observed through the NHANES assessments (from 1988 to 2016). The sensitivity and specificity of the assays varied widely, making comparisons difficult and highlighting the need to develop a gold standard assay.Fil: Pisano, María Belén. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología Dr. J. M. Vanella; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Campbell, Christopher. University of Minnesota; Estados UnidosFil: Anugwom, Chimaobi. University of Minnesota; Estados UnidosFil: Ré, Viviana Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología Dr. J. M. Vanella; ArgentinaFil: Debes, José D.. University of Minnesota; Estados Unido

Serum biomarkers for the prediction of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of global cancer death. Major etiologies of HCC relate to chronic viral infections as well as metabolic conditions. The survival rate of people with HCC is very low and has been attributed to late diagnosis with limited treatment options. Combining ultrasound and the biomarker alpha-fetoprotein (AFP) is currently one of the most widely used screening combinations for HCC. However, the clinical utility of AFP is controversial, and the frequency and operator-dependence of ultrasound lead to a variable degree of sensitivity and specificity across the globe. In this review, we summarize recent developments in the search for non-invasive serum biomarkers for early detection of HCC to improve prognosis and outcome for patients. We focus on tumor-associated protein markers, immune mediators (cytokines and chemokines), and micro-RNAs in serum or circulating extracellular vesicles and examine their potential for clinical application.Fil: Debes, José D.. Erasmus MC Rotterdam; Países Bajos. University of Minnesota; Estados UnidosFil: Romagnoli, Pablo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Grupo Vinculado Centro de Investigación en Medicina Traslacional Severo R. Amuchástegui - Cimetsa | Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Grupo Vinculado Centro de Investigación en Medicina Traslacional Severo R. Amuchástegui - Cimetsa | Instituto de Investigación Médica Mercedes y Martín Ferreyra. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Grupo Vinculado Centro de Investigación en Medicina Traslacional Severo R. Amuchástegui - Cimetsa; Argentina. Instituto Universitario de Ciencias Biomédicas de Córdoba; ArgentinaFil: Prieto, Jhon. Centro de Enfermedades Hepáticas y Digestivas; ColombiaFil: Arrese, Marco. Pontificia Universidad Católica de Chile; ChileFil: Mattos, Angelo Z.. Universidade Federal de Ciencias Da Saúde de Porto Alegre; BrasilFil: Boonstra, André. Erasmus MC Rotterdam; Países Bajo

Hypermethylation of DNA Methylation Markers in Non-Cirrhotic Hepatocellular Carcinoma

Aberrant DNA methylation changes have been reported to be associated with carcinogenesis in cirrhotic HCC, but DNA methylation patterns for these non-cirrhotic HCC cases were not examined. Therefore, we sought to investigate DNA methylation changes on non-cirrhotic HCC using reported promising DNA methylation markers (DMMs), including HOXA1, CLEC11A, AK055957, and TSPYL5, on 146 liver tissues using quantitative methylation-specific PCR and methylated DNA sequencing. We observed a high frequency of aberrant methylation changes in the four DMMs through both techniques in non-cirrhotic HCC compared to cirrhosis, hepatitis, and benign lesions (p &lt; 0.05), suggesting that hypermethylation of these DMMs is specific to non-cirrhotic HCC development. Also, the combination of the four DMMs exhibited 78% sensitivity at 80% specificity with an AUC of 0.85 in discriminating non-cirrhotic HCC from hepatitis and benign lesions. In addition, HOXA1 showed a higher aberrant methylation percentage in non-cirrhotic HCC compared to cirrhotic HCC (43.3% versus 13.3%, p = 0.039), which was confirmed using multivariate linear regression (p &lt; 0.05). In summary, we identified aberrant hypermethylation changes in HOXA1, CLEC11A, AK055957, and TSPYL5 in non-cirrhotic HCC tissues compared to cirrhosis, hepatitis, and benign lesions, providing information that could be used as potentially detectable biomarkers for these unusual HCC cases in clinical practice.</p

Acute and chronic HBV infection in central Argentina: High frequency of sub-genotype F1b, low detection of clinically relevant mutations and first evidence of HDV

Introduction: Genomic analysis of hepatitis B virus (HBV) identifies phylogenetic variants, which may lead to distinct biological and clinical behaviors. The satellite hepatitis D virus (HDV) may also influence clinical outcomes in patients with hepatitis B. The aim of this study was to investigate HBV genetic variants, including clinically relevant mutations, and HDV infection in acute and chronic hepatitis B patients in central Argentina. Methods: A total of 217 adult HBV infected patients [acute (AHB): n = 79; chronic (CHB): n = 138] were studied; 67 were HBV/human immunodeficiency virus (HIV) coinfected. Clinical and demographic data were obtained from medical records. Serological markers were determined. Molecular detection of HBV and HDV was carried out by RT-Nested PCR, followed by sequencing and phylogenetic analysis. Results: Overall, genotype (gt) F [sub-genotype (sgt) F1b] was the most frequently found. In AHB patients, the gts/sgts found were: F1b (74.7%) > A2 (13.9%) > F4 (7.6%) > C (2.5%) > A1 (1.3%). Among CHB patients: F1b (39.1%) > A2 (23.9%) > F4 (18.2%) > D (9.4%) > C and F6 (3.6% each) > A1, A3 and B2 (0.7% each). The distribution of sgt A2 and gt D was significantly different between HBV mono and HBV/HIV coinfected patients [A2: 15.9% vs. 35.7% (p < 0.05), respectively and D: 14.6% vs. 1.8% (p < 0.05), respectively]. Mutation frequency in basal core promoter/pre-Core (BCP/pC) region was 35.5% (77/217) [AHB: 20.3% (16/79), CHB: 44.2% (61/138)]. In the open reading frame (ORF) S, mutations associated with vaccine escape and diagnostic failure were detected in 7.8% of the sequences (17/217) [AHB: 3.8% (3/79), CHB: 10.1% (14/138)]. ORF-P amino acid substitutions associated with antiviral resistance were detected in 3.2% of the samples (7/217) [AHB: 1.3% (1/79), CHB 4.3%, (6/138)]. The anti-HDV seropositivity was 5.2% (4/77); one sample could be sequenced, belonging to gt HDV-1 associated with sgt HBV-D3. Discussion: We detected an increase in the circulation of genotype F in Central Argentina, particularly among AHB patients, suggesting transmission advantages over the other genotypes. A low rate of mutations was detected, especially those with antiviral resistance implications, which is an encouraging result. The evidence of HDV circulation in our region, reported for the first time, alerts the health system for its search and diagnosis.Fil: Castro, Gonzalo Manuel. Ministerio de Salud de la Provincia de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sosa, María J.. Ministerio de Salud de la Provincia de Córdoba; ArgentinaFil: Sicilia Don, Paola Ermelinda. Ministerio de Salud de la Provincia de Córdoba; ArgentinaFil: Riberi, María I.. Universidad Católica de Córdoba; ArgentinaFil: Moreno, Claudia. Ministerio de Salud de la Provincia de Córdoba; ArgentinaFil: Cattaneo, Rodolfo. Ministerio de Salud de la Provincia de Córdoba; ArgentinaFil: Debes, José D.. University of Minnesota; Estados UnidosFil: Barbás, María G.. Ministerio de Salud de la Provincia de Córdoba; ArgentinaFil: Cudolá, Analía E.. Ministerio de Salud de la Provincia de Córdoba; ArgentinaFil: Pisano, María Belén. Universidad Nacional de Córdoba. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Ré, Viviana Elizabeth. Universidad Nacional de Córdoba. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentin

Unexpected high seroprevalence of hepatitis e virus in patients with alcohol-related cirrhosis

Introduction: Little is known about hepatitis E virus (HEV) infection in patients with cirrhosis. The aim of the present study was to describe the frequency of HEV infection and associated risk factors in patients with cirrhosis from Argentina. Materials and methods: We evaluated HEV seroprevalence (IgG anti-HEV) and acute infections (IgM and RNA) in patients with cirrhosis (n = 140) vs. healthy controls (n = 300). Additionally, we compared the same outcomes in individuals with alcohol-related cirrhosis (n = 43) vs. patients with alcohol use disorder (without cirrhosis, n = 72). Results: The overall HEV seroprevalence in the cohort of subjects with cirrhosis was 25% (35/140), compared to 4% in the healthy control group [12/300; OR = 8; (95% CI = 4-15.99); p<0.05]. HEV seropositivity was significantly higher in alcohol-related cirrhosis compared to other causes of cirrhosis [39.5% vs. 12.4%; OR = 4.71; (95% CI = 1.9-11.6); p<0.05] and to healthy controls [OR = 15.7; (95% CI = 6.8-36.4); p = 0.0001]. The HEV seroprevalence in alcoholic-related cirrhosis vs. with alcohol use disorder was 39.5% vs. 12.5% [OR = 4.58; (95% CI = 1.81-11.58); p<0.001]. Conclusion: We found a high seroprevalence of HEV in patients with cirrhosis and in individuals with alcohol use disorder. The simultaneous presence of both factors (cirrhosis + alcohol) showed more association to HEV infection. Larger studies with prospective follow up are needed to further clarify this interaction.Fil: Fantilli, Anabella Clara. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología Dr. J. M. Vanella; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Trinks, Julieta. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Hospital Italiano. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional E Ingenieria Biomedica.; ArgentinaFil: Marciano, Sebastian. Hospital Italiano; ArgentinaFil: Zárate, Raúl Fabián. Hospital Córdoba; ArgentinaFil: Balderramo, Domingo. Instituto Universitario del Hospital Italiano de Buenos Aires; ArgentinaFil: Martínez Wassaf, Maribel G.. LACE Laboratorios; ArgentinaFil: Haddad, Leila. Hospital Italiano; ArgentinaFil: Gadano, Adrián. Hospital Italiano; ArgentinaFil: Debes, José D.. University of Minnesota; Estados UnidosFil: Pisano, María Belén. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología Dr. J. M. Vanella; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Ré, Viviana Elizabeth. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología Dr. J. M. Vanella; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentin

Hepatitis E virus infection in patients on dialysis and in solid organ transplant recipients in Argentina: exploring associated risk factors

Infection with hepatitis E virus (HEV) leads to acute hepatitis infection in immunocompetent hosts. HEV genotype 3 can present with high frequency and lead to chronic infection in individuals with a compromised immune system. The risk factors related to increased seroprevalence or chronicity in this population are not entirely understood. Moreover, most studies addressing risk factors for HEV in non-endemic areas come from developed areas such as North America and Europe. In this study we evaluated seroprevalence, chronicity and risk factors for HEV in 120 transplant recipients and 88 patients on dialysis in Argentina. We found a significantly higher seroprevalence of HEV IgG in those undergoing dialysis compared with healthy controls (10.2% and 4.3% respectively, p = 0.03). No difference in HEV seroprevalence was observed between healthy controls and transplant recipients (5.8%). We found no association between previously identified risk factors for HEV, such as pork consumption or use of tacrolimus, and HEV seroprevalence. In univariate and multivariate analyses, consumption of fish was associated with higher seroprevalence of HEV (OR = 9.33; 95% CI: 2.07–42.2; p = 0.04). None of the samples showed HEV RNA amplification, indicating that chronicity does not seem to be an issue in these cohorts. Our results show increased seroprevalence of HEV in individuals undergoing dialysis but not in transplant recipients. We also found that fish consumption can be a potential risk factor for acquiring HEV.Fil: Pisano, María Belén. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología Dr. J. M. Vanella; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Balderramo, Domingo. Hospital Privado Centro Médico de Córdoba; ArgentinaFil: Martinez Wassaf, Maribel Graciela. LACE Laboratories; Argentina. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología Dr. J. M. Vanella; ArgentinaFil: Lotto, Martín Miguel. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología Dr. J. M. Vanella; ArgentinaFil: Carlino, Yanina. Hospital Privado Centro Médico de Córdoba; ArgentinaFil: Ré, Viviana Elizabeth. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología Dr. J. M. Vanella; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Debes, José D.. University of Minnesota; Estados Unido

Hepatitis E virus infection in hemodialysis patients: A prospective analysis

This study highlights variations in HEV serological status inpatients with ESRD undergoing HD.To assess the dynamics of HEV infection in thispopulation, we prospectively evaluated individuals with end-stagerenal disease (ESRD) undergoing HD at a private hospital in Cordoba, Argentina, between November 2014 and November 2017.Fil: Pisano, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Cordoba. Facultad de Medicina. Instituto de Virología; ArgentinaFil: Leathers, James. Vanderbilt University School Of Medicine; Estados UnidosFil: Balderramo, Domingo. Hospital Privado Centro Médico de Córdoba; ArgentinaFil: Diehl, Fernando. Hospital Privado Centro Médico de Córdoba; ArgentinaFil: Bolomo, Andrea. Hospital Privado Centro Médico de Córdoba; ArgentinaFil: Fernández, Pehuen. Hospital Privado Centro Médico de Córdoba; ArgentinaFil: Martínez Wassaf, Maribel. Laboratorios Clínicos Especializados- Lace; ArgentinaFil: Cristani, Carla. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Di Cola Bucciarelli, Guadalupe. Universidad Nacional de Cordoba. Facultad de Medicina. Instituto de Virología; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: De la Fuente, Jorge. Hospital Privado Centro Médico de Córdoba; ArgentinaFil: Debes, José D.. Universidad de Minnesota; Estados UnidosFil: Ré, Viviana Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Cordoba. Facultad de Medicina. Instituto de Virología; Argentin

Increased Hepatitis E Virus Seroprevalence Correlates with Lower CD4+ Cell Counts in HIV-Infected Persons in Argentina

<div><p>Hepatitis E virus (HEV) is a single-stranded RNA virus that can cause hepatitis in an epidemic fashion. HEV usually causes asymptomatic or limited acute infections in immunocompetent individuals, whereas in immunosuppressed individuals such as transplant recipients, HEV can cause chronic infections. The risks and outcomes of HEV co-infection in patients infected with human immunodeficiency virus (HIV) are poorly characterized. We used a third generation immunoassay to measure serum IgG antibodies specific for HEV in 204 HIV-infected individuals from Argentina and a control group of 433 HIV-negative individuals. We found 15 of 204 (7.3%, 95%CI 3.74–10.96%) individuals in the HIV-positive group to have positive HEV IgG levels suggestive of previous infection, compared to 19 of 433 (4.4%, 95% CI 2.5–6.3%) individuals in the HIV-negative control group (p = 0.12). Among HIV-positive individuals, those with HEV seropositivity had lower CD4 counts compared to those that were HEV seronegative (average CD4 count of 234 vs 422 mm³, p = 0.01), indicating that patients with lower CD4 counts were more likely to be HEV IgG positive. Moreover, HEV seropositivity in patients with CD4 counts <200 mm³ was 16%, compared to 4.5% in those with CD4 counts >200 mm³ (p = 0.012). We found a positive PCR result for HEV in one individual. Our study found that increased seroprevalence of HEV IgG correlated with lower CD4 counts in HIV-infected patients in Argentina.</p></div

HEV seroprevalence according to CD4 count cut off.

<p>HEV seroprevalence according to CD4 count cut off.</p