Rosa Miquel

IDIBAPS August Pi i Sunyer Biomedical Research Institute, Barcino, Catalonia, Spain

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Publications (122)728.54 Total impact

  • Journal of Hepatology 11/2014; · 10.40 Impact Factor
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    ABSTRACT: To evaluate the long-term results of conventional chemoradiotherapy and laparoscopic mesorectal excision in rectal adenocarcinoma patients without adjuvant therapy.
    World journal of gastroenterology : WJG. 11/2014; 20(42):15820-9.
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    ABSTRACT: Liver biopsy is still the gold standard for evaluation of acute and chronic liver diseases, despite achievements regarding noninvasive diagnosis and staging in liver diseases. Transjugular liver biopsy (TJLB) has proved a good option when ascites and/or significant coagulopathy precludes a percutaneous approach. Because diagnostic hemodynamic procedures can be performed during the same session, it is useful in many clinical settings, regardless of the absence of percuteaneous contraindications. TJLB is a safe technique able to provide good-quality specimens with a low rate of complications. This article presents an overview of TJLB that discusses the technique, applicability, indications, contraindications, complications, and diagnostic accuracy. Copyright © 2014 Elsevier Inc. All rights reserved.
    Clinics in Liver Disease 08/2014; · 2.70 Impact Factor
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    ABSTRACT: Pathogen-induced immune responses prevent the establishment of transplantation tolerance in experimental animal models. Whether this occurs in humans as well remains unclear. The development of operational tolerance in liver transplant recipients with chronic hepatitis C virus (HCV) infection allows us to address this question. We conducted a clinical trial of immunosuppression withdrawal in HCV-infected adult liver recipients to elucidate (i) the mechanisms through which allograft tolerance can be established in the presence of an ongoing inflammatory response and (ii) whether anti-HCV heterologous immune responses influence this phenomenon. Of 34 enrolled liver recipients, drug withdrawal was successful in 17 patients (50%). Tolerance was associated with intrahepatic overexpression of type I interferon and immunoregulatory genes and with an expansion of exhausted PD1/CTLA4/2B4-positive HCV-specific circulating CD8(+) T cells. These findings were already present before immunosuppression was discontinued and were specific for HCV infection. In contrast, the magnitude of HCV-induced proinflammatory gene expression and the breadth of anti-HCV effector T cell responses did not influence drug withdrawal outcome. Our data suggest that in humans, persistent viral infections exert immunoregulatory effects that could contribute to the restraining of alloimmune responses, and do not necessarily preclude the development of allograft tolerance.
    Science translational medicine 06/2014; 6(242):242ra81. · 14.41 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S315. · 10.40 Impact Factor
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    ABSTRACT: Significant liver fibrosis (F⩾2) and portal hypertension (hepatic venous pressure gradient [HVPG] ⩾6mmHg) 1 year after liver transplantation (LT) are predictors of severe hepatitis C recurrence. Periportal sinusoidal fibrosis (SF) is an early expression of the fibrogenic process in response to liver injury. We aimed to evaluate whether SF in early liver biopsies represents an early and accurate marker for identifying patients with severe HCV recurrence after LT. A total of 101 HCV LT patients with early biopsy (<6 months), and HVPG measurement and/or liver biopsy one year after LT were included. Early biopsies were stained with Sirius Red and SF was graded semi-quantitatively. Results were compared between groups (significant SF vs. non-significant SF) and correlated with the development of severe HCV recurrence one year after LT. Patients with early significant SF had older donor age and higher necroinflammatory activity (NIA). The presence of early significant SF enabled identification of 78.9% and 90.6% of patients with F⩾2 and HVPG⩾6 mmHg, respectively, one year after LT. Donor age and NIA were independent predictors of significant fibrosis (F⩾2) one year after LT, whereas donor age, ALT (3 months), NIA, and SF grade were independent predictors of portal hypertension (HVPG⩾6). Significant SF in early biopsies is a good predictor of severe hepatitis C recurrence. This histological finding, when combined with simple variables, may be useful to select the best candidates for early antiviral therapy after LT.
    Journal of Hepatology 04/2014; · 9.86 Impact Factor
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    ABSTRACT: There is no histologic classification system to determine prognoses of patients with alcoholic hepatitis (AH). We identified histologic features associated with disease severity and created a histologic scoring system to predict short-term (90 day) mortality. We analyzed data from 121 patients admitted to the Liver Unit (Hospital Clinic, Barcelona, Spain) from January 2000 through January 2008 with features of AH, and developed a histologic scoring system to determine risk of death using logistic regression. The system was tested and updated in a test set of 96 patients from 5 academic centers in the US and Europe, and a semi-quantitative scoring system was developed, called the alcoholic hepatitis histologic score (AHHS). The system was validated in an independent set of 109 patients. Inter-observer agreement was evaluated by weighted κ statistic analysis. Degree of fibrosis, neutrophil infiltration, type of bilirubinostasis, and presence mega-mitochondria were independently associated with 90 day mortality. We used these 4 parameters to develop the AHHS to identify patients with low (0-3 points), moderate (4-5 points), and high (6-9 points) risks of death within 90 days (3%, 19%, and 51%, respectively; P<.0001). The AHHS estimated 90 day mortality in the training and test sets with an area under the receiver operating characteristic value of 0.77 (95% confidence interval, 0.71-0.83). Inter-rate agreement values were 0.65 for fibrosis, 0.86 for bilirubinostasis, 0.60 for neutrophil infiltration, and 0.46 for megamitochondria. Interestingly, the type of bilirubinostasis predicted the development of bacterial infections. We identified histologic features associated with severity of AH and developed a patient classification system that might be used in clinical decision making.
    Gastroenterology 01/2014; · 12.82 Impact Factor
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    ABSTRACT: The value of transient elastography (TE) to assess clinical outcomes in hepatitis C recurrence after liver transplantation (LT) has not been explored so far. We studied 144 hepatitis C-infected and 48 non-hepatitis C virus (HCV)-infected LT recipients and evaluated the prognostic value of TE 1 year after transplantation to predict clinical decompensations and graft and patient survival. In HCV patients, cumulative probabilities of liver decompensation 5 years after LT were 8% for patients with liver stiffness measurement (LSM) <8.7 kilopascals (kPa) versus 47% for patients with LSM ≥ 8.7 kPa (p < 0.001). Five-year graft and patient cumulative survival were 90% and 92% in patients with LSM < 8.7 kPa (p < 0.001) and 63% and 64% in patients with LSM ≥ 8.7 kPa, respectively (p < 0.001). Patients with low LSM 1 year after LT had excellent outcomes independently from receiving antiviral treatment or achieving sustained virological response (SVR). In contrast, graft survival significantly improved in patients with LSM ≥ 8.7 kPa who achieved SVR. No association between outcomes and LSM at 12 months was observed in non-HCV patients. In conclusion, LSM 1 year after LT is a valuable tool to predict hepatitis C-related outcomes in recurrent hepatitis C and can be used in clinical practice to identify the best candidates for antiviral therapy.
    American Journal of Transplantation 01/2014; · 6.19 Impact Factor
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    ABSTRACT: Idiopathic portal hypertension (IPH) is a rare cause of intrahepatic portal hypertension. Data on natural history and prognosis of IPH is limited. We sought to describe the complications and long-tem outcome of IPH by retrospective studying 69 biopsy-proven IPH. Mean duration of follow-up was 6.7 ± 4.6 years. All patients had evidence of portal hypertension at diagnosis, 42% were symptomatic. Variceal bleeding was the most common manifestation. In those without bleeding at diagnosis, 74% had varices at first endoscopy. In those with large varices, the 1-year probability of first bleeding despite primary prophylaxis was 9%. The 1-year probability of re-bleeding was 22%. Ascites and hepatic encephalopathy was documented in 26% and 7% of patients, respectively at least once during the clinical course. The 1-year probability of developing portal vein thrombosis (PVT) was 9% and 53% of patients receiving anticoagulation achieved recanalization. HIV infection and variceal bleeding at diagnosis were the independent predictors of PVT. Seven patients died (6 due to IPH-related cause) and 2 were transplanted. Probability of liver transplantation (LT)-free survival was 82% at 10 years. Presence of a severe associated disorder and ascites as a presenting symptom were associated with poor survival. Conclusion: Variceal bleeding is a major complication of IPH. Using in IPH patients the same management approach for portal hypertension as in cirrhosis is safe and maintains a low incidence of first bleeding and re-bleeding in IPH patients. PVT is a frequent complication, particularly in those with HIV infection. Despite several complications, overall survival of patients with IPH is considerably good. (Hepatology 2013;).
    Hepatology 10/2013; · 11.19 Impact Factor
  • Gastroenterología y Hepatología 10/2013; · 0.83 Impact Factor
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    ABSTRACT: PPARγ plays an essential role in the transcriptional regulation of genes involved in lipid and glucose metabolism, insulin sensitivity and inflammation. We recently demonstrated that PPARγ plays a causative role in hepatocyte lipid deposition, contributing to the pathogenesis of hepatic steatosis. In this study, we investigated the role of PPARγ in the inflammatory and fibrogenic response of the liver. Heterozygous floxed/null Cre/LoxP mice with targeted deletion for PPARγ in either hepatocytes (Alb-Cre), macrophages (LysM-Cre) or hepatic stellate cells (HSCs) (aP2-Cre), were submitted to carbon tetrachloride (CCl4) liver injury. Further analysis were performed in precision-cut liver slices (PCLS) and primary cultures of hepatocytes, macrophages and HSCs. LysM-Cre mice displayed an exacerbated response to chronic CCl4 injury and showed higher necroinflammatory injury, lipid peroxidation, inflammatory infiltrate, cleaved-caspase-3 and caspase 3/7 activity, and COX-2, TNF-α, CXCL2 and IL-1β expression than Alb-Cre and control mice. The deleterious effects of PPARγ disruption in liver macrophages were confirmed in an acute model of CCl4 injury as well as in PCLS incubated with LPS. Moreover, LysM-Cre mice showed an aggravated fibrogenic response to CCl4, as revealed by more prominent Sirius Red and Masson's trichrome staining, elevated hydroxyproline content and induced α-SMA and TIMP-1 expression. Importantly, aP2-Cre mice with specific disruption of PPARγ in HSCs, as confirmed by immunocytochemical analysis of individual liver cells, also showed exacerbated liver damage and fibrogenic response to CCl4. These data unveil antiinflammatory and antifibrogenic roles for PPARγ in non-parenchymal liver cells.
    Journal of Hepatology 07/2013; · 9.86 Impact Factor
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    ABSTRACT: BACKGROUND & AIMS: The detection of native hepatitis C virus (HCV) antigens in liver tissue may be relevant for diagnostic purposes and to better understand the pathogenesis of HCV infection. The aim of our study was to characterize HCV antigens in liver grafts. METHODS: We selected 32 liver transplant (LT) recipients with recurrent hepatitis C. HCV core and NS5A antigens were detected in formalin-fixed, paraffin-embedded (FFPE) liver biopsies obtained immediately after graft reperfusion (negative controls), during the acute phase of HCV infection (1-6 months) and during follow-up (7-74 months) after LT. Viral antigens were assessed by immunohistochemistry and confocal microscopy. RESULTS: All reperfusion biopsies were negative for both antigens. Core protein was detected in 75% and 33% of acute phase and follow-up biopsies, respectively. HCV antigens were not detected in any of the 10 samples from patients who cleared HCV after antiviral treatment. Immunostaining was hepatocellular, with a granular cytoplasmic pattern and a wide spectrum of intensity. We found a significant association between viral load and the presence of HCV core-positive hepatocytes (p=0.004). NS5A colocalized strongly with core (66%) and adipophilin (36%), supporting the localization of core and NS5A around lipid droplets. A detailed three-dimensional analysis showed that NS5A surrounded the core and adipophilin-positive areas. CONCLUSIONS: HCV antigens can be detected in FFPE liver biopsies by immunohistochemistry. The in vivo colocalization of core and NS5A proteins around the lipid droplets supports that the latter may play a role in virus particle production, similar to that reported in vitro.
    Journal of Hepatology 03/2013; · 9.86 Impact Factor
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    ABSTRACT: Lifelong immunosuppression increases morbidity and mortality in liver transplantation. Discontinuation of immunosuppressive drugs could lessen this burden, but the safety, applicability and clinical outcomes of this strategy need to be carefully defined. We enrolled 102 stable liver recipients at least 3 years after transplantation in a single-arm multi-center immunosuppression withdrawal trial. Drugs were gradually discontinued over a 6-9 month period. The primary end-point was the development of operational tolerance, defined as successful immunosuppressive drug cessation maintained for at least 12 months with stable graft function and no histopathologic evidences of rejection. Out of the 98 recipients evaluated, 57 rejected and 41 successfully discontinued all immunosuppressive drugs. In non-tolerant recipients rejection episodes were mild and resolved over 5.6 months (2 non-tolerant patients still exhibited mild gradually improving cholestasis at the end of follow-up). In tolerant recipients no progressive clinically-significant histological damage was apparent in follow-up protocol biopsies performed up to 3 years following drug withdrawal. Tolerance was independently associated with time since transplantation (OR 1.353; p = 0.0001), recipient age (OR 1.073; p = 0.009), and male gender (OR 4.657; p = 0.016). A predictive model incorporating the two first clinical variables identified subgroups of recipients with very high (79%), intermediate (30-38%), and very low (0%) likelihood of successful withdrawal. Conclusion: When conducted at late time points after transplantation, immunosuppression withdrawal is successful in a high proportion of carefully selected liver recipients. A combination of clinical parameters could be useful to predict the success of this strategy. Additional prospective studies are now needed to confirm these results and to validate clinically-applicable diagnostic biomarkers. (HEPATOLOGY 2013.).
    Hepatology 03/2013; · 11.19 Impact Factor
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    ABSTRACT: Endothelial dysfunction drives vascular derangement and organ failure associated with sepsis. However, the consequences of sepsis on liver sinusoidal endothelial function are largely unknown. Statins might improve microvascular dysfunction in sepsis. The present study explores liver vascular abnormalities and the effects of statins in a rat model of endotoxemia. For this purpose, lipopolysaccharide (LPS) or saline was given to: (1) rats treated with placebo; (2) rats treated with simvastatin (25 mg/kg, orally), given at 3 and 23 hours after LPS/saline challenge; (3) rats treated with simvastatin (25 mg/kg/24 h, orally) from 3 days before LPS/saline injection. Livers were isolated and perfused and sinusoidal endothelial function was explored by testing the vasodilation of the liver circulation to increasing concentrations of acetylcholine. The phosphorylated endothelial nitric oxide synthase (PeNOS) / endothelial nitric oxide synthase (eNOS) ratio was measured as a marker of eNOS activation. LPS administration induced an increase in baseline portal perfusion pressure and a decrease in vasodilation to acetylcholine (sinusoidal endothelial dysfunction). This was associated with reduced eNOS phosphorylation and liver inflammation. Simvastatin after LPS challenge did not prevent the increase in baseline portal perfusion pressure, but attenuated the development of sinusoidal endothelial dysfunction. Treatment with simvastatin from 3 days before LPS prevented the increase in baseline perfusion pressure and totally normalized the vasodilating response of the liver vasculature to acetylcholine and reduced liver inflammation. Both protocols of treatment restored a physiologic PeNOS/eNOS ratio. Conclusion: LPS administration induces intrahepatic endothelial dysfunction that might be prevented by simvastatin, suggesting that statins might have potential for liver protection during endotoxemia. (HEPATOLOGY 2013)
    Hepatology 03/2013; 57(3). · 11.19 Impact Factor
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    ABSTRACT: OBJECTIVES:Idiopathic portal hypertension (IPH) is a rare cause of portal hypertension that lacks a specific diagnostic test. Requiring ruling-out other causes of portal hypertension it is frequently misdiagnosed. This study evaluates whether using high-throughput techniques there is a metabolomic profile allowing a noninvasive diagnosis of IPH.METHODS:Thirty-three IPH patients were included. Matched patients with cirrhosis (CH) and healthy volunteers (HV) were included as controls. Metabolomic analysis of plasma samples was performed using UPLC-time-of-flight-mass spectrometry. We computed Student's P-values, corrected by multiple comparison and VIP score (Variable Importance in the Projection). The metabolites were selected with an adjusted Benjamini Hochberg P value <0.05. We use markers with a greater VIP score, to build partial least squares projection to latent structures regression with discriminant analysis (PLS-DA) representative models to discriminate IPH from CH and from HV. The performance of the PLS-DA model was evaluated using R(2) and Q(2) parameter. An additional internal cross-validation was done.RESULTS:PLS-DA analysis showed a clear separation of IPH from CH with a model involving 28 metabolites (Q(2)=0.67, area under the curve (AUC)=0.99) and a clear separation of IPH from healthy subjects with a model including 31 metabolites (Q(2)=0.75, AUC=0.98). After cross-validation, both models showed high rates of sensitivity (94.8 and 97.5), specificity (89.1 and 89.7), and AUC (0.98 and 0.98), reinforcing the strength of our findings.CONCLUSIONS:A metabolomic profile clearly differentiating patients with IPH from CH and healthy subjects has been identified using subsets of 28 and 31 metabolites, respectively. Therefore, metabolomic analysis appears to be a valuable tool for the noninvasive diagnosis of IPH.Am J Gastroenterol advance online publication, 19 February 2013; doi:10.1038/ajg.2013.11.
    The American Journal of Gastroenterology 02/2013; · 9.21 Impact Factor
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    ABSTRACT: In this descriptive study, we examined the role of single-operator cholangioscopy (SOC) in the evaluation of biliary complications after liver transplantation (LT). We prospectively included adult recipients of deceased donor LT who were referred for endoscopic retrograde cholangiopancreatography between June 2009 and July 2011. All patients underwent SOC with biopsy of the biliary anastomosis. Sixteen patients were included: 12 with biliary anastomotic strictures (ASs), 2 with common bile duct stones, 1 with a bile leak, and 1 with sphincter of Oddi dysfunction. Patients with ASs displayed 1 of 2 patterns: (A) mild erythema (n = 9) or (B) edema, ulceration, and sloughing (n = 3). Those without ASs displayed a pale mucosa with mild edema at the anastomosis. Patients with ASs and pattern B required a longer period of stenting than patients with pattern A (457 versus 167 days, P = 0.02). In addition, patients with pattern A had a better response and better resolution of their strictures with endoscopic therapy than those with pattern B (66% versus 33%, P = 0.13). Histological examinations of ASs showed nonspecific intraepithelial inflammation in patients with patterns A and B. Biopsy samples from patients without ASs showed normal columnar epithelial bile duct cells. The total cholangioscopy time for all procedures was 26.8 ± 10.1 minutes. In conclusion, SOC in LT recipients is feasible and allows adequate visualization and tissue sampling of ASs and bile ducts. Two distinct visual patterns that are easily identified with SOC may help to predict the outcomes of endoscopic therapy in patients with biliary complications after LT. Liver Transpl 19:199-206, 2013. © 2012 AASLD.
    Liver Transplantation 02/2013; 19(2):199-206. · 3.79 Impact Factor
  • Gastroenterología y Hepatología. 01/2013;
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    ABSTRACT: BACKGROUND: The efficacy of antiviral therapy in patients with hepatitis C recurrence after liver transplantation (LT) is far from optimal and a careful selection of candidates with the best chances to achieve sustained virological response (SVR) is relevant. Moreover, investigating the effects of sustained viral clearance on clinical outcomes is particularly significant. We aimed to identify and combine the best baseline predictors of SVR and to assess the clinical outcomes of antiviral therapy after LT. METHODS: We studied 144 hepatitis C virus (HCV)-infected LT recipients who underwent antiviral therapy following transplantation. Baseline predictors of SVR including donor and recipient interleukin IL28B (IL28B) rs12979860 genotype were evaluated, and the long-term effects of antiviral therapy on clinical outcomes were assessed. RESULTS: The presence of an IL28B CC genotype with either low viral load (VL), young donor age, or cyclosporine A (CsA)-based immunosuppression identified individuals with 69-80 % probabilities of SVR. In contrast, only 20 % of recipients with a CT/TT IL28B genotype and either high VL, old donor age, or non-CsA immunosuppression achieved an SVR (p = 0.004). Regarding clinical outcomes, the 5-year cumulative probability of graft loss was 2 % for the SVR patients and 48 % for non-responders (p < 0.001). CONCLUSIONS: The use of simple combinations of baseline variables including IL28B polymorphisms identifies HCV-infected LT recipients with different probabilities of response to antiviral treatment. SVR is associated with improved clinical outcomes.
    Journal of Gastroenterology 09/2012; · 4.02 Impact Factor
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    ABSTRACT: Idiopathic portal hypertension is a rare cause of portal hypertension, frequently misdiagnosed as cryptogenic cirrhosis. This study evaluates specific findings at hepatic vein catheterisation or liver stiffness in idiopathic portal hypertension. 39 cases of idiopathic portal hypertension patients were retrospectively reviewed. Hepatic vein catheterisation and liver stiffness measurements were compared to matched patients with cirrhosis and portal hypertension, and non-cirrhotic portal vein thrombosis, included as controls. Hepatic vein-to-vein communications were found in 49% idiopathic portal hypertension patients precluding adequate hepatic venous pressure gradient measurements in 12. In the remaining 27 patients, mean hepatic venous pressure gradient (HVPG) was 7.1±3.1mmHg. Only 5 patients had HVPG≥10mmHg. HVPG was markedly lower than in cirrhosis (17±3mmHg, p<0.001). Mean liver stiffness in idiopathic portal hypertension was 8.4±3.3kPa; significantly higher than in non-cirrhotic portal vein thrombosis (6.4±2.2kPa, p=0.009), but lower than in cirrhosis (40.9±20.5kPa, p=0.005). Only 2 idiopathic portal hypertension patients had liver stiffness >13.6kPa. Patients with idiopathic portal hypertension frequently have hepatic vein-to-vein communications and, despite unequivocal signs of portal hypertension, HVPG and liver stiffness values much lower than the cut-off for clinical significant portal hypertension in cirrhosis. These findings oblige to formally rule-out idiopathic portal hypertension in the presence of signs of portal hypertension.
    Digestive and Liver Disease 06/2012; 44(10):855-60. · 2.89 Impact Factor
  • ASCO 2012., Chicago; 05/2012

Publication Stats

2k Citations
728.54 Total Impact Points


  • 2003–2014
    • IDIBAPS August Pi i Sunyer Biomedical Research Institute
      Barcino, Catalonia, Spain
  • 2000–2014
    • University of Barcelona
      • • Department of Medicine
      • • Biomedical Research Centre Esther Koplowitz
      Barcino, Catalonia, Spain
  • 1996–2014
    • Hospital Clínic de Barcelona
      Barcino, Catalonia, Spain
  • 2008–2010
    • Centro de Investigación Biomédica Esther Koplowitz
      Barcino, Catalonia, Spain
  • 2002
    • Institut Marqués, Spain, Barcelona
      Barcino, Catalonia, Spain
  • 2001
    • Southern Medical Clinic
      San Fernando, City of San Fernando, Trinidad and Tobago