National Institute of Gastroenterology

Havana, Cuba

National Institute of Gastroenterology

Havana, Cuba
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Vilar-Gomez E.,National Institute of Gastroenterology | Vilar-Gomez E.,University of Seville | Martinez-Perez Y.,National Institute of Gastroenterology | Calzadilla-Bertot L.,National Institute of Gastroenterology | And 6 more authors.
Gastroenterology | Year: 2015

Background & Aims It is not clear how weight loss affects histologic features of liver in patients with nonalcoholic steatohepatitis (NASH). We examined the association between the magnitude of weight loss through lifestyle modifications and changes in histologic features of NASH. Methods We conducted a prospective study of 293 patients with histologically proven NASH who were encouraged to adopt recommended lifestyle changes to reduce their weight over 52 weeks, from June 2009 through May 2013, at a tertiary medical center in Havana, Cuba. Liver biopsies were collected when the study began and at week 52 of the diet and were analyzed histologically. Results Paired liver biopsies were available from 261 patients. Among 293 patients who underwent lifestyle changes for 52 weeks, 72 (25%) achieved resolution of steatohepatitis, 138 (47%) had reductions in nonalcoholic fatty liver disease activity score (NAS), and 56 (19%) had regression of fibrosis. At week fifty-two, 88 subjects (30%) had lost 5% of their weight. Degree of weight loss was independently associated with improvements in all NASH-related histologic parameters (odds ratios = 1.1-2.0; P <.01). A higher proportion of subjects with 5% weight loss had NASH resolution (51 of 88 [58%]) and a 2-point reduction in NAS (72 of 88 [82%]) than subjects who lost <5% of their weight (P <.001). All patients who lost 10% of their weight had reductions NAS, 90% had resolution of NASH, and 45% had regression of fibrosis. All patients who lost 7%-10% of their weight and had few risk factors also had reduced NAS. In patients with baseline characteristics that included female sex, body mass index 35, fasting glucose >5.5 mmol/L, and many ballooned cells, NAS scores decreased significantly with weight reductions 10%. Conclusions A greater extent of weight loss, induced by lifestyle changes, is associated with the level of improvement in histologic features of NASH. The highest rates of NAS reduction, NASH resolution, and fibrosis regression occurred in patients with weight losses 10%. © 2015 by the AGA Institute.


PubMed | University of Valencia, University of Seville, National Institute of Gastroenterology and Sir Charles Gairdner Hospital
Type: Journal Article | Journal: Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver | Year: 2016

Glucose metabolism abnormalities frequently coexist with liver cirrhosis; however, the impact of these on liver-related outcomes has not been fully investigated.We examined the influence of glucose abnormalities on overall mortality and liver-related complications in cirrhotic patients.A prospective cohort of 250 subjects with compensated hepatitis C virus-related cirrhosis and without known diabetes underwent an oral glucose tolerance test and were subsequently followed for a median 201 weeks.At baseline, 67 (27%) had type 2 diabetes. During follow-up, 28 deaths and 55 first events of decompensation occurred. After adjustment for potential confounding covariates, overall mortality/liver transplant (sHR: 2.2, 95% CI: 1.04-4.6, P=0.04) and hepatic decompensation events (sHR: 1.9, 95% CI: 1.05-3.3, P=0.03) were significantly higher in diabetic patients. Subjects with a HOMA-IR >5 showed higher rates of mortality (sHR: 2.2, 95% CI: 1.03-4.8, P=0.04). The rates of hepatic decompensation were higher in patients with HOMA-IR >3 (sHR: 1.7, 95% CI: 1.04-2.9, P=0.03). Overall, 2h-plasma glucose was the most robust predictor of overall mortality (sHR: 2.5, 95% CI: 1.03-6, P=0.04) and decompensation (sHR: 2.7, 95% CI: 1.4-5.5, P<0.01).In compensated HCV-related cirrhotic patients, diabetes and marked insulin resistance are independently associated with poorer overall survival and increased risk of hepatic decompensation.


PubMed | Indiana University, University of Valencia, University of Western Australia, National Institute of Gastroenterology and 2 more.
Type: Journal Article | Journal: Alimentary pharmacology & therapeutics | Year: 2016

Several recent studies have shown a strong association between non-alcoholic steatohepatitis (NASH) and chronic kidney disease.To examine the relationship between changes in liver histology and renal function in patients with NASH.The present analysis represents a post hoc analysis of a recently published trial that included 261 patients with NASH who were treated with lifestyle modifications during 52 weeks. Kidney function was evaluated through Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rates (eGFR, mL/min/1.73 mInterestingly, a one-stage reduction in fibrosis (r = 0.20, P < 0.01) and resolution of NASH (r = 0.17, P < 0.01) were significantly correlated with an improvement in the kidney function. The eGFR values significantly increased in patients with fibrosis improvement (+7.6 6.5 mL/min/1.73 mImprovement in liver histology due to lifestyle modification is independently associated with improved kidney function in NASH. As new drugs for NASH emerge, studies should address whether improvement in histology in response to pharmacotherapies yield the same improvement in kidney function as weight loss.


PubMed | Mount Sinai School of Medicine, University of Valencia, National Institute of Gastroenterology and University of Seville
Type: Journal Article | Journal: Gastroenterology | Year: 2015

It is not clear how weight loss affects histologic features of liver in patients with nonalcoholic steatohepatitis (NASH). We examined the association between the magnitude of weight loss through lifestyle modifications and changes in histologic features of NASH.We conducted a prospective study of 293 patients with histologically proven NASH who were encouraged to adopt recommended lifestyle changes to reduce their weight over 52 weeks, from June 2009 through May 2013, at a tertiary medical center in Havana, Cuba. Liver biopsies were collected when the study began and at week 52 of the diet and were analyzed histologically.Paired liver biopsies were available from 261 patients. Among 293 patients who underwent lifestyle changes for 52 weeks, 72 (25%) achieved resolution of steatohepatitis, 138 (47%) had reductions in nonalcoholic fatty liver disease activity score (NAS), and 56 (19%) had regression of fibrosis. At week fifty-two, 88 subjects (30%) had lost 5% of their weight. Degree of weight loss was independently associated with improvements in all NASH-related histologic parameters (odds ratios= 1.1-2.0; P< .01). A higher proportion of subjects with 5% weight loss had NASH resolution (51 of 88 [58%]) and a 2-point reduction in NAS (72 of 88 [82%]) than subjects who lost <5% of their weight (P < .001). All patients who lost 10% of their weight had reductions NAS, 90% had resolution of NASH, and45% had regression of fibrosis. All patients who lost 7%-10% of their weight and had few risk factors also had reduced NAS. In patients with baseline characteristics that included female sex, body mass index 35, fasting glucose >5.5 mmol/L, and many ballooned cells, NAS scores decreased significantly with weight reductions 10%.A greater extent of weight loss, induced by lifestyle changes, is associated with the level of improvement in histologic features of NASH. The highest rates of NAS reduction, NASH resolution, and fibrosis regression occurred in patients with weight losses 10%.


PubMed | Mount Sinai School of Medicine, University of Valencia, National Institute of Gastroenterology and University of Seville
Type: Journal Article | Journal: Hepatology (Baltimore, Md.) | Year: 2016

Liver biopsy is the gold standard method to assess nonalcoholic steatohepatitis (NASH) resolution after therapeutic interventions. We developed and validated a simple and noninvasive scoring system to predict NASH resolution without fibrosis worsening after 1 year of lifestyle intervention. This was a prospective cohort study conducted in 261 patients with histologically proven NASH who were treated with lifestyle changes for 52 weeks and underwent a second liver biopsy to confirm NASH resolution. We divided the data into development (140 subjects) and validation (121 individuals) sets. NASH resolution occurred in 28% (derivation group) and 27% (validation group). At the multivariable analysis, weight loss (odds ratio [OR] = 2.75, 95% confidence interval [CI] 1.65-4.58; P < 0.01), type 2 diabetes (OR = 0.04, 95% CI 0.005-0.49; P = 0.01), normal levels of alanine aminotransferase at the end of intervention (OR = 9.84, 95% CI 2.21-44.1; P < 0.01), age (OR = 0.89, 95% CI 0.83-0.97; P = 0.01), and a nonalcoholic fatty liver activity score 5 (OR = 0.08, 95% CI 0.01-0.43; P < 0.01) were independent predictors of NASH resolution. The area under the receiver operating characteristic curve of the selected model was 0.956 and 0.945 in the derivation and validation cohorts, respectively. Using a score threshold of 46.15, negative predictive values were 92% in the derivation and validation groups, respectively. By applying a cutoff 69.72, positive predictive values were 92% and 89% in the derivation and validation groups, respectively. Using both cutoffs, a liver biopsy would have been avoided in 229 (88%) of 261 patients, with a correct prediction in 209 (91%)A noninvasive prediction model including weight loss, type 2 diabetes, alanine aminotransferase normalization, age, and a nonalcoholic fatty liver activity score 5 may be useful to identify NASH resolution in patients under lifestyle intervention. (Hepatology 2016;63:1875-1887).


Pizarro T.T.,Case Western Reserve University | Pastorelli L.,Case Western Reserve University | Pastorelli L.,Gastroenterology and Gastrointestinal Endoscopy Unit | Pastorelli L.,University of Milan | And 9 more authors.
Inflammatory Bowel Diseases | Year: 2011

The SAMP1/YitFc mouse strain represents a model of Crohn's disease (CD)-like ileitis that is ideal for investigating the pathogenesis of chronic intestinal inflammation. Different from the vast majority of animal models of colitis, the ileal-specific phenotype characteristic of SAMP1/YitFc mice occurs spontaneously, without genetic, chemical, or immunological manipulation. In addition, SAMP1/YitFc mice possess remarkable similarities to the human condition with regard to disease location, histologic features, incidence of extraintestinal manifestations, and response to conventional therapies. SAMP1/YitFc mice also display a well-defined time course of a predisease state and phases of acute and chronic ileitis. As such, the SAMP1/YitFc model is particularly suitable for elucidating pathways that precede the clinical phenotype that may lead to preventive, and therefore more efficacious, intervention with the natural course of disease, or alternatively, for the development of therapeutic strategies directed against chronic, established ileitis. In this review we summarize important contributions made by our group and others that uncover potential mechanisms in the pathogenesis of CD using this unique murine model of chronic intestinal inflammation. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.


PubMed | University of Florence, National Institute of Gastroenterology, Italian National Cancer Institute and University of Bari
Type: Journal Article | Journal: Hepatology (Baltimore, Md.) | Year: 2016

In patients with hepatocellular carcinoma (HCC) receiving sorafenib, drug resistance is common. HCC develops in a microenvironment enriched with extracellular matrix proteins including laminin (Ln)-332, produced by hepatic stellate cells (HSCs). Ln-332 is the ligand of 31 and 64 integrins, differently expressed on the HCC cell surface, that deliver intracellular pathways. The aim of this study was to investigate the effect of Ln-332 on sorafenibs effectiveness. HCC cells were challenged with sorafenib in the presence of Ln-332 and of HSC conditioned medium (CM). Sorafenib impaired HCC cell proliferation and induced apoptosis. HSC-CM or Ln-332 inhibited sorafenibs effectiveness in HCC cells expressing both 31 and 64. Inhibiting 3 but not 6 integrin subunit using blocking antibodies or small interfering RNA abrogated the protection induced by Ln-332 and HSC-CM. Hep3B cells expressing 64 but lacking the 3 integrin were insensitive to Ln-332 and HSC-CM protective effects. Hep3B 3-positive, but not wild-type and scramble transfected, cells acquired protection by sorafenib when plated on Ln-332-CM or HSCs. Sorafenib dephosphorylated focal adhesion kinase (FAK) and extracellular signal-regulated kinases 1/2, whereas Ln-332 and HSC-CM partially restored the pathways. Silencing FAK, but not extracellular signal-regulated kinases 1/2, abrogated the protection induced by Ln-332 and HSC-CM, suggesting a specific role for FAK. Sorafenib down-regulated total FAK, inducing its proteasomal degradation, while Ln-332 and HSC-CM promoted the escape of FAK from ubiquitination, probably inducing a preferential membrane localization.This study unveils a novel mechanism of sorafenib resistance depending on the 31/Ln-332 axis and requiring FAK ubiquitination, providing new insights into personalizing therapy for patients with HCC. (Hepatology 2016;64:2103-2117).


Candore G.,University of Palermo | Caruso C.,University of Palermo | Jirillo E.,National Institute of Gastroenterology | Magrone T.,University of Bari | Vasto S.,University of Palermo
Current Pharmaceutical Design | Year: 2010

Nowadays, people are living much longer than they used to do, however they are not free from ageing. Ageing, an inexorable intrinsic process that affects all cells, tissues, organs and individuals, is a post-maturational process that, due to a diminished homeostasis and increased organism frailty, causes a reduction of the response to environmental stimuli and, in general, is associated to an increased predisposition to illness and death. However, the high incidence of death due to infectious, cardiovascular and cancer diseases underlies a common feature in these pathologies that is represented by dysregulation of both instructive and innate immunity. Several studies show that a low-grade systemic inflammation characterizes ageing and that inflammatory markers are significant predictors of mortality in old humans. This pro-inflammatory status of the elderly underlies biological mechanisms responsible for physical function decline and agerelated diseases such as Alzheimer's disease and atherosclerosis are initiated or worsened by systemic inflammation. Understanding of the ageing process should have a prominent role in new strategies for extending the health old population. Accordingly, as extensively discussed in the review and in the accompanying related papers, investigating ageing pathophysiology, particularly disentangling agerelated low grade inflammation, is likely to provide important clues about how to develop drugs that can slow or delay ageing. © 2010 Bentham Science Publishers Ltd.


Fuglem B.,Institute of Basic science and Aquatic Medicine | Jirillo E.,University of Bari | Jirillo E.,National Institute of Gastroenterology | Bjerkas I.,Institute of Basic science and Aquatic Medicine | And 6 more authors.
Developmental and Comparative Immunology | Year: 2010

Antigen uptake has been shown to occur in the teleost intestine, but so far, limited information is available on the distribution and nature of cells involved in the process, and M cells, known for their antigen-sampling abilities in mammals, have not been identified. Here, different intestinal segments from salmonid fish were exposed to gold-BSA to identify antigen-sampling cells. Sections from exposed intestine were examined by light and electron microscopy. Uptake of gold-BSA was restricted to very few dendritic-like cells and to a limited number of epithelial cells located in the mucosal folds in the second segment of the mid-intestine. Gold-positive epithelial cells displayed diverging and electron-dense microvilli with channels intruding into the cytoplasm. A lectin binding experiment demonstrated the presence of cells with mammalian M-cell characteristics in the identical regions. As the identified epithelial cells shared some morphological similarities with immature mammalian M cells, this phenotype may represent evolutionary early antigen-sampling enterocytes. © 2010 Elsevier Ltd.


Gomez E.V.,National Institute of Gastroenterology | Rodriguez Y.S.,National Institute of Gastroenterology | Bertot L.C.,National Institute of Gastroenterology | Gonzalez A.T.,National Institute of Gastroenterology | And 4 more authors.
Journal of Hepatology | Year: 2013

Background & Aims: The natural history of HCV-related compensated cirrhosis has been poorly investigated in Latin-American countries. Our study evaluated mortality and clinical outcomes in compensated cirrhotic patients followed for 6 years. Methods: Four hundred and two patients with compensated HCV-related cirrhosis were prospectively recruited in a tertiary care academic center. At the time of admission, patients were stratified as compensated (absence [stage 1] or presence [stage 2] of esophageal varices) as defined by D'Amico et al. Subjects were followed to identify overall mortality or liver transplantation and clinical complication rates. Results: Among 402 subjects, 294 were categorized as stage 1 and 108 as stage 2. Over a median of 176 weeks, 42 deaths occurred (10%), of which 30 were considered liver-related (7%) and 12 non-liver-related (3%); eight individuals (2%) underwent liver transplantation; 30 patients (7%) developed HCC, 67 individuals in stage 1 (22%) developed varices and any event of clinical decompensation occurred in 80 patients (20%). The 6-year cumulative overall mortality or liver transplantation was 15% and 45%, for stages 1 and 2, respectively (p <0.001). The cumulative 6-year HCC incidence was significantly higher among patients with varices (29%) than those without varices (9%), p <0.001. Similarly, the cumulative 6-year incidence of any clinical liver-related complication was higher in patients with stage 2 (66%) as compared to 26% in those with stage 1, respectively (p <0.001). Conclusions: Our results indicate significant morbidity and mortality and clinical outcome rates in compensated cirrhotic patients with varices (stage 2).

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