Congreso Americano 2013-3

Study of the influence of HLA genetic factors on the vertical transmission and chronification of hepatitis C virus

Angeles Ruiz-Extremera 1,2,3, Esther-J. Pavón-Castillero4, Mónica Florido4, Paloma Muñoz-de-Rueda2,4, JoseAntonio Muñoz-Gámez4, Jorge Casado4, Angel Carazo4, Rosa Quiles2,4, Laura Sanjuan5, Sergio Jiménez-Ruiz5, Pepi León2,4, Javier Salmerón2,4,5

1 Pediatric Unit, Hospital Universitario San Cecilio, Granada, Spain  2 CIBER Enfermedades Hepáticas y Digestivas, CIBERehd, Instituto de Salud Carlos III, Spain  3 Pediatric Department, Granada University, Granada, Spain  4 Clinical Management Unit of Digestive Diseases, UNAI, Hospital Universitario San Cecilio, Granada, Spain  5 Medicine Department, Granada University, Granada, Spain

BACKGROUND:

Vertical transmission (VT) is considered the main route of hepatitis C virus (HCV) infection in children but the risk factors in this respect have yet to be fully identified, except maternal HIV co-infection. The aim of this study is to analyze the role of human leukocyte antigen (HLA) genetic factors in HCV-VT.

PATIENTS AND METHODS:

Between September 1991 and December 2009, 123 HCV-RNA positive (HIV negative) mothers were recruited, with their 130 children. The following risk factors for HCV were analyzed: HCV viral load, viral genotype, IL28B polymorphism (single nucleotide polymorphism rs12979860), delivery mode, ALT levels and breast-feeding. The infants were tested for HCV-RNA at birth, at 2, 4, 6, 8, 10, 12, 18 and 24 months, and then annually at 3, 4, 5 and 6 years. VT was defined as children who presented HCV-RNA positive for at least two subsequent blood samples. Chronic or persistent infection was defined as children with HCV-RNA positive at the end of the study. The frequencies of HLA class I alleles (A, B and Cw) and of HLA class II alleles (DRB1, DQA1, DQB1, DPA1 and DPB1) were analyzed.

RESULTS:

Of the 123 mothers (and 130 children) included in the study, VT occurred in 24 cases. Of these, 8 children suffered chronic infection and in 16 the virus was eliminated. VT study: Among the 123 mothers, the alleles related to VT were the presence of B*0702 (P=0.024), Cw*0702 (P=0.050) DQA1*0301 (P=0.011, Pc=0.04) and DPB1*0201 (P=0.046) and the absence of B*3501 (P=0.030) and Cw*0602 (P=0.006, Pc=0.05). Among the 130 children, however, the only allele related to VT was the presence of DPB1*0201 (P=0.038). Chronification of the virus: In this case, the associated alleles of the mothers (n=24) were DQA1*0101 (P=0.028) and

DQB1*0604 (P=0.028), and among the children (n=24) they were B*0801 (P=0.037), DRB1*0301 (P=0.037), DQA1*0501 (P=0.037) and DQB1*0603 (P=0.034). Mother/child allelic concordance was higher among the children with chronic infection than in those with no chronification (67% ± 4.06 vs. 57% ± 1.34, P=0.045).

CONCLUSIONS:

The HLA alleles of the mother are of greater importance than those of the child with respect to HCV-VT. Thus, the presence of the HLA allele, class I Cw*0602 and of the HLA allele, class II DQA1*0301 in the mother is directly related to VT. Moreover, the greater allelic concordance among the children, with respect to their mothers, is associated with the chronification of the virus in these children.

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Congreso Americano 2013-2

Study of hepatic leptin and insulin signaling during non-alcoholic fatty liver disease (NAFLD) progression in morbid obesity

 

Introduction

NAFLD is considered the hepatic exponent of metabolic syndrome, in which insulin resistance is the most important factor. Accordingly, hepatic and systemic insulin resistance have been reported in patients with NAFLD. Moreover, many arguments suggest that obese patients with NAFLD also develop hepatic leptin resistance. However, the molecular mechanisms that lead to liver leptin resistance have yet to be described. The main objective of this study is to analyze the relation between NAFLD progression during morbid obesity and the expression level of genes related to hepatic leptin and insulin signaling.

Method

The patient cohort included 87 morbidly obese subjects who underwent bariatric surgery. Liver biopsies were obtained at the moment of surgery. NAFLD was diagnosed by anatomopathological evaluation of liver biopsies using the Kleiner score. Hepatic gene expression level was estimated by measuring mRNA concentration using a methodology based on Real Time PCR (including normalization of mRNA concentration by three housekeeping genes). Seven expression levels were analyzed: long and short leptin receptor isoforms (OB-Rb and OB-Ra), insulin receptor (INS-R), ISR-1, IRS-2 (Insulin Receptor Substrate 1 and 2), SOCS-1 and SOCS-3 (Suppressor of Cytokine Signaling 1 and 3).

Results

The patients were classified into three groups: 10 without NAFLD (group 1); 33 with liver steatosis but without steatohepatitis (group 2, Kleiner score<3) and 44 with probable or confirmed steatohepatitis (group 3, Kleiner score≥3). Comparison of the average gene expression levels in obese patients without NAFLD (group 1) and in those with NAFLD (groups 2 and 3) revealed a non-significant tendency toward a decrease in leptin and insulin receptors, IRS-1 and SOCS-3 (P<0.1), and a non-significant tendency toward an increase in SOCS-1 (P<0.1). Moreover, the patients without NAFLD presented a marked degree of correlation between the expression of leptin and insulin signaling-related genes (above 0.8 in all combinations and a maximum of 0.986 for both leptin receptor isoforms). Interestingly, all these genetic correlation levels decreased or disappeared as NAFLD progressed.

Conclusions

In morbidly obese patients without NAFLD, high levels of correlation between leptin and insulin signaling-related genes suggest that hepatic leptin and insulin signaling pathways share key expression factors. Moreover, the reduction in these correlations as NAFLD progresses suggests that liver endocrine homeostasis is affected by NAFLD development. This study presents new perspectives on the mechanism that gives rise to leptin and insulin hepatic resistance during NAFLD origin and progression.

 

Congreso Americano 2013-1

Ribavirin priming pegylated-Interferon combination therapy in chronic hepatitis C patients: study of plasma Ribavirin trough concentrations, anaemia, viral kinetic and genetic variability

Paloma Muñoz-de-Rueda, PhD, Alicia Martín-Lagos1, MD,  Rosa Quiles, PhD, Ana Gila, MDPhD, Ana Martín, BS, Esther Pavón, PhD, Elena Ruiz-Escolano, MD, Angeles Ruiz-Extremera, MDPhD, Javier Salmerón, MDPhD.

 1Unidad de Ap. Digestivo y 2Servicio de Pediatría H. U. San Cecilio de Granada and3CIBEREHD, Spain.

 Aim: Ribavirin (RBV) remains essential to chronic hepatitis C (CHC) treatment. We aimed to investigate the influence of RBV priming to steady state before combined pegylated-Interferon/RBV (pegIFN/RBV) treatment on viral kinetics, alanine aminotransferase (ALT) levels, anaemia, RBV trough concentrations (RBV Ctrough), genetic variability within HCV–core, -NS5B and –NS5A (ISDR, PKRbd), and response to antiviral therapy.

Methods: Prospective cohort study. 27 chronic hepatitis C genotype 1 naïve patients received 4 weeks of RBV monotherapy followed by pegIFN-α-2a and RBV for 48 weeks (group A). The results were compared with a control/historical group (group B) of 27 patients undergoing treatment with pegIFN α-2a and RBV for 48 weeks. The study of mutations being done in the majority sequence of core, NS5B and NS5A (ISDR and PKRbd).

Results: No differences in main baseline characteristics were found between the treatment arms. Rapid, early and sustained virological response values were 44%, 89% and 52%, respectively, in group A, and 41%, 89% and 48% in group B, with no statistically significant differences. However, in the 4-week combined treatment, group A patients showed a greater decrease in HCV-RNA (2.3 log10 IU/mL vs 1.2 log10IU/mL; P=0.04), lower levels of Hb (12.48±1.7 g/dL vs 13.6±1.9 g/dL; P=0.039), lower levels of ALT (23.5±1.3 U/L vs 60.11±18 U/L; P<0.001) and higher mean RBV Ctrough (3.28±1.26 mg/L vs 1.76±0.69 mg/L; P=0.001). Did not observe variation, with respect to the baseline, in the number of mutations after RBV monotherapy, nor in the NS5B, ISDR, or PKRbd, however we observe a decrease of silent mutations in core (P=0.04) (Table 1).

Conclusions: A 4-week course of induction therapy, priming with RBV, does not improve SVR rates in HCV genotype 1 naïve infected patients. However, the greater reductions in viral load, Hb and ALT, and higher RBV Ctrough values at week 4 of combined treatment could reflect the greater effectiveness of the treatment. RBV monotherapy does not cause an increase in the number of mutations in the majority sequence of the regions core, NS5B and NS5A (ISDR and PKRbd).

Variation of Transaminases, HCV-RNA Levels and Th1 Th2 Cytokine Production durin the PosPartum Period in Pregmant Women with Chronic Hepatitis C

Ribavirin priming pegylated-Interferon combination therapy in chronic hepatitis C patients: study of plasma Ribavirin trough concentrations, anaemia, viral kinetic and genetic variability

Paloma Muñoz-de-Rueda, PhD, Alicia Martín-Lagos1, MD, Rosa Quiles, PhD, Ana Gila, MDPhD, Ana Martín, BS, Esther Pavón, PhD, Elena Ruiz-Escolano, MD, Angeles Ruiz-Extremera, MDPhD, Javier Salmerón, MDPhD. Hospital Universitario San Cecilio de Granada and Ciberehd

The 64th Annual Meeting of the American Association for the Study the Liver Diseases. November 1-5 2013, Washington, DC.  Ribavirin priming pegylated-Interferon combination therapy in chronic hepatitis C patients: study of plasma Ribavirin trough concentrations, anaemia, viral kinetic and genetic variability   Paloma Muñoz-de-Rueda, PhD, Alicia Martín-Lagos1, MD,  Rosa Quiles, PhD, Ana Gila, MDPhD, Ana Martín, BS, Esther Pavón, PhD, Elena Ruiz-Escolano, MD, Angeles Ruiz-Extremera, MDPhD, Javier Salmerón, MDPhD. Hospital Universitario San Cecilio de Granada and Ciberehd

The 64th Annual Meeting of the American Association for the Study the Liver Diseases. November 1-5 2013, Washington, DC.
Ribavirin priming pegylated-Interferon combination therapy in chronic hepatitis C patients: study of plasma Ribavirin trough concentrations, anaemia, viral kinetic and genetic variability
Paloma Muñoz-de-Rueda, PhD, Alicia Martín-Lagos1, MD, Rosa Quiles, PhD, Ana Gila, MDPhD, Ana Martín, BS, Esther Pavón, PhD, Elena Ruiz-Escolano, MD, Angeles Ruiz-Extremera, MDPhD, Javier Salmerón, MDPhD.
Hospital Universitario San Cecilio de Granada and Ciberehd

The 64th Annual Meeting of the American Association for the Study the Liver Diseases. November 1-5 2013, Washington, DC.

 Los próximos días 27 y 28 de noviembre se van a realizar las Segundas Jornadas de Granada sobre Enfermedades Digestivas en el hotel Puerta de los Aljibes destinadas a especialistas de aparato digestivo, medicina y interna, atención primaria y residentes cuyo objetivo es fomentar y mejorar la atención de los pacientes con patología digestiva, compartir  las pautas de actuación y  los criterios de derivación, así como la implantación de los distintos procesos asistenciales de estas enfermedades, con el fin último de mejorar la calidad asistencial. Esperamos vuestra asistencia.


Los próximos días 27 y 28 de noviembre se van a realizar las Segundas Jornadas de Granada sobre Enfermedades Digestivas en el hotel Puerta de los Aljibes destinadas a especialistas de aparato digestivo, medicina y interna, atención primaria y residentes cuyo objetivo es fomentar y mejorar la atención de los pacientes con patología digestiva, compartir las pautas de actuación y los criterios de derivación, así como la implantación de los distintos procesos asistenciales de estas enfermedades, con el fin último de mejorar la calidad asistencial. Esperamos vuestra asistencia.

Defensa del trabajo fín de máster titulado: ESTUDIO DE LA VARIABILIDAD GENÉTICA DEL VIRUS DE LA HEPATITIS C Y LA RESPUESTA INMUNE DEL HOSPEDADOR EN LOS PACIENTES CON HEPATITIS CRÓNICA C TRATADOS CON INTERFERÓN PEGILADO Y RIBAVIRINA. La defensa será el próximo jueves a las 10:00 a.m en el Centro de Investigación Biosanitaria del Campus Tecnológico de la Salud de Granada.