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Fecha de publicación: 25 Octubre 2011
Garcia-valdecasas Merino, M.; del Campo, J.; Romero-gómez, M.
VALME HOSPITAL. SEVILLE.
Chronic hepatitis C is linked to the development of insulin resistance. This relation is not known at a molecular level, and it is necessary to study the proteins in the insulin signaling pathway (ISP) with HCV present to identify new therapeutic targets. We analyzed changes in gene expression of the ISP in the Huh 7.5 cell line infected with JFH1 virus treated with different treatments.
Cells from the Huh 7.5.1 cell line were cultured with: insulin (10 nM), interferon alfa-2a (500U/ml), rapamycin (10 nM), metformin (2 mM) and with their combinations. The cells were infected with the JFH1 virus (1 particle/cell), changing the medium 24 or 48 hours after infection and re-adding the treatments. RNA extraction was performed 48 hours after the change of medium. Gene expression was quantified by qRT-PCR. Results The IRS1, PTP1, MAP3K, mTOR, PI3K, AKT expression with different treatments had the same pattern. Metformin increases the expression, but it increases even more with Rapamycin and a synergistic effect can be noticed when combined. AKT, mTOR and MAP3K genes increased their expression even more in the rapamycin-virus combination (24 h). However, when virus incubation (48 h) was increased, the levels of expression of the genes decreased to rapamycin control levels. With interferon alfa all genes expression increased with the rapamycin-interferon-JFH1 interaction. Metformin and rapamycin inhibit viral replication by 77% and 68% compared with the interferon inhibitory efficiency (100%).
Hepatitis c virus modulates the gene expression of the protein kinases of the insulin signaling pathway, and thus it could become a therapeutic option for HCV.
Gutiérrez, I.1; Pascasio, J.1; Alcalde, A.1; Ferrer, M.1; Sousa, J.2; Sayago, M.2; Giráldez, A.2; Márquez, J.1
1VIRGEN DEL ROCIO UNIVERSITY HOSPITAL, CLINICAL MANAGEMENT UNIT, GASTROENTEROLOGY SERVICE. SEVILLE 2VIRGEN DEL ROCIO UNIVERSITY HOSPITAL, CLINICAL MANAGEMENT UNIT, GASTROENTEROLOGY SERVICE. SEVILLE
Estimating the need for vaccination against HBV and HAV in cirrhotic patients evaluated for liver transplantation (LT). Approach Retrospective study of 568 cirrhotic patients (75% men, 54 ± 9 years old, 20% of them diabetic) evaluated for LT. We investigated the indication for vaccination against HBV and HAV and its relation with age, sex and etiology.
Etiology: alcohol (68%), HCV (35%), other (10.4%). Child-Pugh: A (26%), B (44%) and C (30%). 36.8% of patients showed markers of HBV (+) infection: 7.6%, HBsAg (+); 10%, isolated anti-HBc (+); 3.3%, isolated anti-HBs (+); 15.8%, anti-HBc (+ )/anti-HBs (+). 73.2% of patients had indication of vaccination against HBV (negative HBV markers and positive isolated anti-HBc). The indication of vaccination against HBV was more common in women (82.3% vs 70.3%, p = 0.005), and no differences related to age or etiology were observed. 8.2% of patients (44/538) had anti-HAV IgG negative and therefore indication for vaccination against HAV, which was more frequent in younger patients [younger than 45 (27.6%), between 46-55 (7.2%) and older than 55 (2.6%) p <0.0001)], in non-diabetic patients (9.5% vs 2.8%, p = 0.023), in non-alcoholic patients (11.4% vs 6.6%, p = 0.056) and in patients without HBV markers (10.2% vs. 4.6%, p = 0.023).There were 3 patients older than 60 with anti-HAV IgG (-).
Over 70% of cirrhotic patients candidates for LT indicated vaccination against HBV. The indication for vaccination against HAV is low in general (8.2%), but it reaches a significant frequency in younger patients, being less frequent in diabetic, alcoholic patients and patients with HBV markers (+).As it was possible to find patients with anti-HAV IgG (-) who were older than 60, it is desirable to investigate the immune status against HAV in all groups.
González Ojeda, R.1; Aguilar Melero, P.1; Linares Luna, C.1; Ferrín Sánchez, G.1; Muntané Relat, J.2
1REINA SOFIA HOSPITAL, IMIBIC. CORDOVA. 2VIRGEN DEL ROCIO UNIVERSITY HOSPITAL, LIVER RESEARCH UNIT/IBIS. SEVILLE.
The regulation of nitric oxide (NO) production has been shown to exert a significant antitumor activity in various experimental models. The aim of this study was the identification of the alteration of CD95, TNF-R1 and TRAIL-R1 dependent cell death intracellular signals by NO in HeG2 cells.
The intracellular concentration of NO was increased either by treatment with NO donor (NONOate), or by stable transfection with a pcDNA4/TO overexpression plasmid of nitric oxide synthase type 3 (NOS-3) generating the hepatoma cell line 4TO-NOS derived from HepG2. The proliferation ability of liver tumor control cells with NOS-3 overexpression was assessed in cultured cells and in an ectopic cell graft model in immunocompromised mice. The NOS-3 activity and the NO, caspase -3, -8 and -9 production were assessed by various methods. The p53, CD95, TNF-R1, TRAIL-R1, cFLIPS, cFLIPL expression and the nitration degree were determined by Western blot analysis. The CD95, TNF-R1 and TRAIL-R1 immunoprecipitation allowed to determine the alteration of the inhibitory subunit expression of the cell death signal (cFLIPL / S) either bounded or unbounded to the cell death receptor.
The administration of a NO donor or the NOS-3 overexpression increased the p53, CD95, TNF-R1 and TRAIL-R1 expression, the oxidative stress and reduced the proliferation of hepatoma cells. These effects were related to an increase of nitrated cellular proteins, to the activation of caspase-3 and -8, and to the release of cellular lactate dehydrogenase (LDH). The administration of Trail induced cell death in a more powerful way (caspase-3: 605%, and LDH release: 183%, compared to control cells) than the administration of anti-CD95 agonist (187% and 156%, respectively) and TNF-α (163% and 157%, respectively) after 12 hours of stimulation in HepG2 control cells. The administration of a NO donor and NOS-3 overexpression altered the cell death signal by Trail, TNF-α and anti-CD95 in HepG2 cells. In this sense, the NOS-3 overexpression increased caspase-3 activity induced by TNF-α (215%) and CD95 (175%), but reduced that induced by Trail (80%). Interestingly, administration of cell death agonists and/or NOS-3 overexpression reduced the cFLIPL / cFLIPS ratio linked to cell death receptor. Ectopic implantation of tumor cells, injected subcutaneously into immunosuppressed mice, induced liver tumor growth in all mice (4/4). However, NOS-3 overexpression reduced the number of animals with tumor growth (quarter).
Overexpression of NOS-3 increased oxidative and nitrosative stress that was related to decreased cell proliferation and increased cell death in hepatoma cells. The increase of NO induced an increase in cell death dependent on TNF-α and CD95, but reduced Trail-dependent cell death pathway in HepG2 cells. The imbalance of cFLIPS vs cFLIPL was related to induction of cell death in hepatoma cells. The results show in vitro and in vivo that NO increased intracellular production reduces the proliferation of liver tumor cells.
Navarro Jarabo, J.1; Mendez Sanchez, I.2; Rosales Zabal, J.3; Fernandez Cano, F.2; Moreno Mejías, P.2; Pérez Francisco, F.4; Vera Rivero, F.2; Benitez Parejo, N.5
1COSTA DEL SOL HEALTH AGENCY. GASTROENTEROLOGY SERVICE AND CIBERESP. MARBELLA. 2COSTA DEL SOL HEALTH AGENCY. GASTROENTEROLOGY SERVICE. MARBELLA. 3COSTA DEL SOL HEALTH AGENCY. GASTROENTEROLOGY SERVICE. MARBELLA. 4COSTA DEL SOL HEALTH AGENCY. GASTROENTEROLOGY SERVICE. MARBELLA. 5COSTA DEL SOL HEALTH AGENCY. RESEARCH SUPPORT UNIT. MARBELLA.
Chronic infection with HCV genotype 3 has a high probability of cure (70-80%) when a daily dose of 800 mg of peginterferon is administered in combination with ribavirin for 6 months, as deduced from registration studies. There is no therapeutic alternative today for non-respondent patients. In the treatment regimen of our clinic, a weight-adjusted dosing of ribavirin was established for patients (<75 kg: 1000 mg/day; >75 kg: 1200 mg), and therapy was prolonged to 48 weeks for a subgroup of patients (most patients with HCVRNA at week 4 and/or cirrhotic patients). Aims of this study We propose to analyze baseline factors associated with SVR.
We studied the mono-infected naïve patients under treatment and included in our database. The independent variables analyzed were sex, age, viral load, cirrhosis, adherence to treatment, rapid viral response (RVR) defined as RNA negative at week 4, treatment duration, ribavirin dose (mg/kg), development of anemia (defined as Hb <10 g/dl), and certain laboratory parameters determined basally and during treatment.
Out of the 49 patients with an average age of 41.00 (43 men and 6 women), 35 (71.4%) were cured (SVR), 12 (24.5%) were cirrhotic, 41 (83.6 %) showed an excellent adherence to treatment, 13 (26.5%) required treatment to be extended to 48 weeks and 10 (20%) developed anemia. The answer to the first month treatment was assessed in 30 patients and RVR was achieved in 24 (80%). Of all the variables, only intra-treatment AST (SVR 26 IU/dL (CI95: 20.5 to 34.5), nonSVR 38.5 IU/dL (CI95: 25.5 to 77.8), p 0.027), baseline Hb (SVR 15.5 g/dl (CI95 14.7 to 16), nonSVR 14.3 g/dL (CI95 14-15), p 0.014) and the dose of ribavirin (SVR 15.7 mg/kg (CI95: 14.2 to 17), nonSVR 13.3 mg/kg (CI95: 11.9 to 15), p 0.024), were associated with achieving SVR. Although more non-cirrhotic patients than cirrhotic ones were cured (80% vs. 50%), the difference did not reach statistical significance (p 0.09). Only 2 out of the 6 patients (33.3%) without RVR achieved SVR, compared to 70.8% who achieved RVR, although the difference was not significant (p 0.156) probably due to the sample size. Treatment extension to 48 weeks did not mean an increase on effectiveness over 24 weeks treatments (69.2% vs. 72.2%, ns).
In our series, the treatment efficacy for genotype 3 HCV infection was similar to that described in registration studies, and while it was high, it was not effective in 30% of patients. The adjustment of the dose of ribavirin, administered depending on weight, seems to have a beneficial effect, since patients who received more doses of ribavirin responded better, and therefore we believe that the recommended fixed dosing for genotype 3 HCV infection should be reconsidered.
Baeyens Cabrera, E.1; Padilla Ávila, F.2; Rodriguez Ramos, L.3; Carrillo Ortega, G.3; Morales Alcazar, F.3; Tercero Lozano, M.3
1JAEN HOSPITAL, GASTROENTEROLOGY SERVICE. JAEN. 2TORRECARDENAS HOSPITAL, GASTROENTEROLOGY SERVICE. ALMERÍA. 3JAEN HOSPITAL, GASTROENTEROLOGY SERVICE. JAEN.
Nonalcoholic fatty liver disease (NAFLD) is one of the growing health problems in recent years, closely related to the metabolic syndrome.
Assessing the prevalence of NAFLD in a given population in patients with abnormal liver function tests. Correlating ultrasonographic findings with visceral fat accumulation, rate of insulin resistance and liver function tests.
From September 2010 to May 2011, 186 patients from the San Felipe CS Health Center were chosen for the study, excluding 42 of them for taking more than 20 g alcohol/day or for having a viral or autoimmune liver disease. Patients' body mass index (BMI) and waist circumference (WC) were measured as well as they underwent an abdominal ultrasound to measure the fatty liver following Hamaguchi criteria.
80 (55.5%) out of 144 patients who did not drink alcohol showed some degree of steatosis on ultrasound. When comparing both groups, patients with NAFLD had a higher BMI (30.5/25.8), WC (106.3/91.6) and HOMA (3.2/2.0). Comparing patient groups with different degrees of steatosis, they differed in GOT (31.86/40.8) and GPT (55.9/41.8), and a progressive increasing BMI (31.3/29.8), WC (106.3/100.3) and HOMA (3.46/3.05) related to how high was the degree of steatosis in ultrasound. Cutoff point taken: HOMA 2.64, associated with a higher WC (100.7/89.7) and increased GGT (155.8/89.7) in patients without steatosis, and with higher BMI and WC in a group of patients with steatosis.
- 55.5% of patients with abnormal liver function tests suffered from NAFLD.
- HOMA is the best index for NAFLD with an excellent correlation with WC.
Robles Díaz, M.1; García Cortés, M.2; Fernández Castañer, A.3; Borraz, Y.4; Ulzurrum, E.4; Stephens, C.4; Lucena, M.5; Andrade Bellido, R.2
1VIRGEN DE LA VICTORIA UNIVERSITY HOSPITAL, MALAGA UNIVERSITY SCHOOL OF MEDICINE, RESEARCH CENTER, GASTROENTEROLOGY SERVICE; DEPARTMENT OF MEDICINE. MALAGA. 2VIRGEN DE LA VICTORIA UNIVERSITY HOSPITAL, MALAGA UNIVERSITY SCHOOL OF MEDICINE, RESEARCH CENTER, GASTROENTEROLOGY SERVICE; DEPARTMENT OF MEDICINE. MALAGA. 3VIRGEN DE LA VICTORIA UNIVERSITY HOSPITAL, GASTROENTEROLOGY SERVICE. MALAGA. 4MALAGA UNIVERSITY SCHOOL OF MEDICINE, NETWORKING BIOMEDICAL RESEARCH CENTRE IN LIVER DISEASES, PHARMACOLOGY SERVICE. MALAGA. 5VIRGEN DE LA VICTORIA UNIVERSITY HOSPITAL, MALAGA UNIVERSITY SCHOOL OF MEDICINE, RESEARCH CENTER, PHARMACOLOGY SERVICE; DEPARTMENT OF PHARMACOLOGY. MALAGA.
The alanine amino transferase (ALT) and alkaline phosphatase (ALP) values at the start of the disease are used to calculate the pattern of DILI by determining the ratio [R = (ALT/ULN) / (ALP/ULN)]. A recent consensus (Aithal et al Clin Pharmacol There 2011) recommends the use of aspartate amino transferase (AST) when there ALT levels are not available. Our goal is to study the validity of using AST values instead of ALT ones in the calculation of R (ratio) in DILI.
The study population consisted of 588 patients with idiosyncratic DILI included in the Spanish Registry of Drug-Induced Liver Diseases that met international consensus. Age, sex, BMI, diabetes mellitus, hyperlipidemia, alcohol consumption and administered drug were identified as cofactors.
There was a high linear correlation between (ALT/ULN) / (ALP/ULN) and (AST/ULN) / (ALP/ULN) with 76% overlap between ratios. The degree of agreement for the hepatocellular pattern was 96%, 61.4% for thr cholestatic pattern and 41% for the mixed pattern (p = 0.0001). There were no significant differences between the agreement of the ratios in terms of the demographic characteristics or the underlying pathology. The overlap between ratios ranged from 87% to 95% with antiulcer drugs, antituberculosis drugs, antiepileptic drugs, herbs, flutamide, "other antibacterial" drugs, antineoplastic drugs and immunomodulating drugs, while it was much worse (48% -58%) with amoxicillin-clavulanate, ibuprofen and Angiotensin II receptor blockers (ARBs) (p = 0.0001).
AST values can be used to determine the pattern of DILI especially when the resulting pattern is an hepatocellular one.
Ruiz Cuesta, P.1; Montero Álvarez, J.2; Jurado García, J.3; Nuñez, F.3; Barrera Baena, P.2; Poyato González, A.2; Costán Rodero, G.2; Fraga Rivas, E.2; Ciria, R.4; López Cillero, P.4; de La Mata García, M.3
1REINA SOFIA UNIVERSITY HOSPITAL, GASTROENTEROLOGY SERVICE. CORDOVA. 2REINA SOFIA UNIVERSITY HOSPITAL, GASTROENTEROLOGY SERVICE. HEPATOLOGY UNIT. CORDOVA. 3REINA SOFIA UNIVERSITY HOSPITAL, GASTROENTEROLOGY SERVICE. CORDOVA. 4REINA SOFIA UNIVERSITY HOSPITAL, GENERAL AND DIGESTIVE SURGERY. CORDOVA.
The progressive generalization of prioritization in the liver transplantation waiting list is controversial as it could lead to an increase in morbidity and mortality after transplantation.
Compare the early morbidity and mortality after liver transplantation in patients prioritized according to Meld and/or special indications.
The population chosen were adult patients who had undergone a liver transplantation (excluding those who had suffered from an acute liver failure and/or those who had undergone a retransplantation) who had been part of a prioritized waiting list chosen for transplantation according to Meld scores and other special indications (refractory ascites and hepatocellular carcinoma). Clinical and laboratory variables as well as the outcome of patient and donor were studied.
The study included 116 patients (93 men, 80.2%) whose average age was 54.09 ± 0.74 (23-73) and with an overall early survival of 86.2% (100/116). The indications were: 50 (43.1%) hepatocellular failure (HF), 20 (17.2%), refractory ascites (RA), 38 (32.7%) hepatocellular carcinoma (HCC) and 8 (6.9%) other. There were significant differences among the first 3 groups (HF, RA and HCC) in relation to pretransplantation MELD scores (HF 20.52 ± 4.79, RA Meld and Meld-Na 12.70 ± 3.8 and 20.10 ± 4.91, HCC 11.45 ± 4.6, p < 0.05) as well as in relation to the time on the waiting list measured in days (108.59 ± 90.59, 216.95 ± 130.31 and 177, 81 ± 93.76), but it was not possible to demonstrate significant differences in mortality (4/50, 3/20 and 4/38, p 0.75). There were also no significant differences in the characteristics of the donor (preservation injury, steatosis, age), or posttransplantation complications (renal failure, vascular and biliary complications, infection, transplant rejection), length of stay in hospital, use of blood products, or duration of mechanical ventilation.
Prioritization in the liver transplantation waiting list according to MELD and/or special indications does not affect mortality or the occurrence of complications after transplantation. In our prioritization system the group with hepatocellular failure was favored although this did not mean differences in morbidity and mortality between groups.
Ampuero, J.; Millán-lorenzo, M.; Cano-medel, C.; Aparcero, R.; Maraver, M.; Hoyas, E.; Suarez, E.; Figueruela, B.; Romerogómez, M.
VALME HOSPITAL, DIGESTIVE DISEASES SERVICE. SEVILLE.
Assessing in a single-center retrospective study whether insulin sensitizers (IS) modify the natural history of cirrhosis and its complications.
The study included 66 diabetic patients with alcoholic cirrhosis (62%), cirrhosis due to HCV (23%) and cirrhosis due to other causes (15%). There were 51 men and 15 women, whose average age was 61 ± 9 and whose initial Child-Pugh score was 6 ± 1.4 and their MELD score was 9.5 ± 3.6. They were classified into 2 groups: those treated with metformin, with or without glitazones (n = 31), and those treated with insulin or on a diet (n = 35). There were no differences in the baseline characteristics. In addition, we analyzed insulin, glucose, glucagon, leptin, adiponectin and HOMA-IR. The objectives were: progression of cirrhosis, defined by an increase of at least 2 points in the Child-Pugh score or 5 points in the Meld score; and its complications, including hepatic encephalopathy (HE), variceal hemorrhage (EVH), ascites, spontaneous bacterial peritonitis (SBP) and hepatocellular carcinoma (HCC). Follow-up lasted 43 +25 months. We used the Kaplan-Meier and chi-square distribution methods for the univariate analysis and Cox regression method for the multivariate analysis.
IS were associated with reduction of HE (log-rank = 9.91; p = 0.002), ascites (log-rank: 4.37; p = 0.037) and SBP (log-rank = 4.16; p = 0.041), as well as with a reduction in the progression of cirrhosis (p = 0.01) but not with HCC. We found a trend with EVH (log-rank: 2.67, p = 0.1). In the multivariate analysis, IS [HR 9.54 (95% CI :1.09-83.21), p = 0.041] along with MELD [HR 1.30 (95% CI :1.13-1.50), p = 0.0001] were independently associated with HE, whereas IS [HR 5.15 (95% CI :1.01-26.26), p = 0.048] and Child-Pugh [HR 1.68 (95% CI :1.15-2 .45), p = 0.007] were associated with ascites and TNFR2 with SBP [HR 1.13 (95% CI: 1.04-1.22), p = 0.004].
Insulin sensitizers appear to protect against some complications of cirrhosis such as hepatic encephalopathy, ascites and spontaneous bacterial peritonitis and slow its progression. Prospective studies are needed to improve the management of diabetes in cirrhotic patients.
Gutiérrez, I.1; Pascasio, J.1; Alcalde, A.1; Morillo, A.2; Ferrer, M.1; Sousa, J.1; Sayago, M.1; Giráldez, Á.1; Márquez, J.1
1VIRGEN DEL ROCIO UNIVERSITY HOSPITAL, CLINICAL MANAGEMENT UNIT, GASTROENTEROLOGY SERVICE. SEVILLE 2VIRGEN DEL ROCIO UNIVERSITY HOSPITAL, PREVENTIVE MEDICINE. SEVILLE.
Evaluating the response to a vaccination pattern against HBV with four 40μg doses and the factors associated with it in cirrhotic patients who are candidates for liver transplantation (LT).
Retrospective study of 278 cirrhotic patients (70% men, 54 ± 9 years old) evaluated for LT, in which the response to HBV vaccination with four doses of 40μg (at 0, 1st, 2nd, 6th month) and associated factors was investigated. 57 patients who showed no response underwent revaccination with the same pattern.
Etiology: alcohol (66%), HCV (32%), other (13%). Child-Pugh: A (33%), B (41%), C (26%). MELD: 12.7 ± 5, 3 (5-29). There were 10 patients with isolated anti-HBc (+) and 19% of the patients were diabetic. 50 (18%) patients were administered three doses of vaccine and 209 (75.2%) patients, four.The overall response rate was 39.2%; 36% with three doses, and 40.7% with four.51% of patients responded to revaccination. The variables associated with a higher response were: better liver function [Child-Pugh (A 53.8% B 33.3% C 30.1%; p = 0.002), MELD (11.4 vs. 13.6, p = 0.001)], absence of diabetes (43.6% vs 20.8%; p = 0.002), anti-HBc (+) (80% vs 37.7%; p = 0.007) and being young (<45 years , 52.2%; 45-50 years, 40.4%; > 45 years, 34.1%; p = 0.031). In 79 patients the response was known after the third and fourth dose, being the seroconversion rate 36.7% and 53% respectively.
The response rate to HBV vaccination in cirrhotic patients evaluated for LT reached 36% of those who received at least 3 doses, being higher in patients with anti-HBc (+), better liver functions, those who were younger and nondiabetic. Given the minor increase in the response to the fourth dose, it seems advisable to indicate revaccination in case of absence of response to 3 doses. HBV vaccination shall be initiated in early stages of the disease.
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