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Andreu M.,University Pompeu Fabra | Marquez L.,University Pompeu Fabra | Domenech E.,Hospital Germans Trias | Domenech E.,Research Center Biomedica en Red en Enfermedades Hepaticas y Digestivas | And 25 more authors.
Journal of Crohn's and Colitis | Year: 2014

Background: Phenotypic traits of familial IBD relative to sporadic cases are controversial, probably related to limited statistical power of published evidence. Aim: To know if there are phenotype differences between familial and sporadic IBD, evaluating the prospective Spanish registry (ENEIDA) with 11,983 cases. Methods: 5783 patients (48.3%) had ulcerative colitis (UC) and 6200 (51.7%) Crohn's disease (CD). Cases with one or more 1st, 2nd or 3rd degree relatives affected by UC/CD were defined as familial case. Results: In UC and CD, familial cases compared with sporadic cases had an earlier disease onset (UC: 33. years [IQR 25-44] vs 37. years [IQR 27-49]; p. <. 0.0001); (CD: 27. years [IQR 21-35] vs 29. years [IQR 22-40]; p. <. 0.0001), higher prevalence of extraintestinal immune-related manifestations (EIMs) (UC: 17.2% vs 14%; p. = 0.04); (CD: 30.1% vs 23.6%; p. <. 0.0001). Familial CD had higher percentage of ileocolic location (42.7% vs 51.8%; p. = 0.0001), penetrating behavior (21% vs 17.6%; p. = 0.01) and perianal disease (32% vs 27.1%; p. = 0.003). Differences are not influenced by degree of consanguinity. Conclusion: When a sufficiently powered cohort is evaluated, familial aggregation in IBD is associated to an earlier disease onset, more EIMs and more severe phenotype in CD. This feature should be taken into account at establishing predictors of disease course. © 2013 European Crohn's and Colitis Organisation.


Ruiz-Gaspa S.,Research Center Biomedica en Red en Enfermedades Hepaticas y Digestivas | Ruiz-Gaspa S.,Metabolic Bone Diseases Unit | Guanabens N.,Research Center Biomedica en Red en Enfermedades Hepaticas y Digestivas | Guanabens N.,Metabolic Bone Diseases Unit | And 17 more authors.
European Journal of Clinical Investigation | Year: 2010

Background Osteoporosis is a common complication in chronic cholestasis. It has been proposed that retained substances such as bile acids may produce a damaging effect on bone cells. This study analyses the effects of lithocholic acid (LCA) on cell survival and vitamin D metabolism in human osteoblasts (hOB). Materials and methods Human osteoblasts cultures were performed with or without foetal bovine serum (FBS) or human albumin (HA) at different LCA concentrations and times with or without vitamin D. Results Lithocholic acid at concentrations higher than 10 -5M decreased cell survival. This effect was partially prevented by the presence of FBS or HA. Vitamin D stimulated CYP24A, BGLAP and TNFSF11 expression in hOB and these effects were modified by nontoxic LCA concentrations. LCA significantly decreased vitamin D stimulation of CYP24A, BGLAP and TNFSF11 gene expression at 72%, 79% and 56% (respectively). LCA alone has an agonistic effect, as has vitamin D, thus partially increasing CYP24A and BGLAP expression, but with no changes on TNFRSF11B expression. Equivalent effects of the LCA were observed by performing gene reporter assays using MG-63 cells transfected with constructs containing CYP24A1 promoter regions. Conclusions Lithocholic acid decreases the stimulatory effect of vitamin D on CYP24A, BGLAP and TNFSF11 expression in hOB. This effect is produced through vitamin D response elements (VDREs), located in the promoter regions of these genes, suggesting that LCA acts as a mild analogous of vitamin D, interacting with the vitamin D receptor. These results may explain the potential deleterious effects of retained bile acids on hOB. © 2009 Stichting European Society for Clinical Investigation Journal Foundation.


Serra-Prat M.,Unitat de Recerca | Serra-Prat M.,Research Center Biomedica en Red en Enfermedades Hepaticas y Digestivas | Palomera E.,Unitat de Recerca | Roca M.,Servei de Farmacia
Clinical Endocrinology | Year: 2010

Background Ghrelin stimulates GH release and hunger at a central level. Ghrelin declines with age, which may be partially responsible for functional impairment and frailty. Objective To describe the evolution of nutritional status and functional capacity of noninstitutionalized old people over a 2-year period, as well as to evaluate the relationship between ghrelin and long-term changes in nutritional and functional status in this population. Design A population-based cohort study was designed in which 313 randomly selected persons, 70 years old or older, were followed for a 2-year period. Functional (Barthel and Guralnik scores and hand grip) and nutritional (MNA-SF, weight and BMI) assessments were performed during basal and 2-year follow-up visits. Ghrelin and hormonal components of the gonadotrophe and somatotrophe axis were determined. Results During follow-up, 13% of men and 20% of women showed a >5% weight loss, and the nutritional status of 18% of men and 39% of women deteriorated. Men lost 12·1% and women lost 9·7% of their initial hand grip strength. In men, low basal ghrelin levels were associated with higher weight loss and poorer hand grip but not with the MNA-SF measure, whereas in women, low basal ghrelin levels were associated with a decline in nutritional status (MNA-SF) but not with weight loss and hand grip decline. Conclusion Low ghrelin levels have been related to worsening nutritional status in a 2-year follow-up period in people 70 years old or older, which suggests this hormone could become a useful therapeutic target in the elderly. © 2010 Blackwell Publishing Ltd.


De La Garza R.G.,University of Navarra | Sarobe P.,Research Center Medica Aplicada | Merino J.,University of Navarra | Lasarte J.J.,Research Center Medica Aplicada | And 15 more authors.
Liver Transplantation | Year: 2013

Recipients of liver transplantation (LT) may develop immunological tolerance. Factors predictive of tolerance are not clearly understood. Transplant recipients with normal liver function tests and without active viral hepatitis or autoimmune disease who presented with side effects of immunosuppression or a high risk of de novo malignancies were selected to participate in this prospective study. Twenty-four patients fulfilled the inclusion criteria and, therefore, underwent a gradual reduction of immunosuppression. Tolerance was defined as normal liver function tests after immunosuppression withdrawal. Basal clinical and immunological characteristics, including lymphocyte counts and subpopulations (T, B, natural killer, CD4 +, CD8+, and regulatory T cells) and the phytohemagglutinin stimulation index (SI), were compared for tolerant and nontolerant patients. Fifteen of the 24 patients (62.5%) were tolerant at a median of 14 months (interquartile range = 8.5-22.5 months) after complete immunosuppression withdrawal. Tolerant patients had a longer median interval between transplantation and inclusion in the study (156 for tolerant patients versus 71 months for nontolerant patients, P = 0.003) and a lower median SI (7.49 for tolerant patients versus 41.73 for nontolerant patients, P = 0.01). We identified 3 groups of patients with different probabilities of tolerance: in the first group (n = 7 for an interval > 10 years and an SI < 20), 100% reached tolerance; in the second group (n = 10 for an interval > 10 years and an SI > 20 or an interval < 10 years and an SI < 20), 60% reached tolerance; and in the third group (n = 7 for an interval < 10 years and an SI > 20), 29% reached tolerance. In conclusion, a high proportion of select LT recipients can reach tolerance over the long term. Two simple basal variables - the time from transplantation and the SI - may help to identify these patients. Liver Transpl 19:937-944, 2013. © 2013 AASLD. © 2013 American Association for the Study of Liver Diseases.


Bernardi M.,University of Bologna | Moreau R.,French Institute of Health and Medical Research | Moreau R.,University Paris Diderot | Moreau R.,Unity University | And 6 more authors.
Journal of Hepatology | Year: 2015

The peripheral arterial vasodilation hypothesis has been most influential in the field of cirrhosis and its complications. It has given rise to hundreds of pathophysiological studies in experimental and human cirrhosis and is the theoretical basis of life-saving treatments. It is undisputed that splanchnic arterial vasodilation contributes to portal hypertension and is the basis for manifestations such as ascites and hepatorenal syndrome, but the body of research generated by the hypothesis has revealed gaps in the original pathophysiological interpretation of these complications. The expansion of our knowledge on the mechanisms regulating vascular tone, inflammation and the host-microbiota interaction require a broader approach to advanced cirrhosis encompassing the whole spectrum of its manifestations. Indeed, multiorgan dysfunction and failure likely result from a complex interplay where the systemic spread of bacterial products represents the primary event. The consequent activation of the host innate immune response triggers endothelial molecular mechanisms responsible for arterial vasodilation, and also jeopardizes organ integrity with a storm of pro-inflammatory cytokines and reactive oxygen and nitrogen species. Thus, the picture of advanced cirrhosis could be seen as the result of an inflammatory syndrome in contradiction with a simple hemodynamic disturbance. © 2015 European Association for the Study of the Liver.

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