Neuroendocrine liver metastases (LM-NEN) develop in a considerable proportion of patients with ga... more Neuroendocrine liver metastases (LM-NEN) develop in a considerable proportion of patients with gastroenteropancreatic neuroendocrine neoplasms. There is a paucity of experimental models that accurately recapitulate this complex metastatic human liver microenvironment precluding scientific and clinical advancements. Here, we describe the development of a novel personalised immunocompetent precision cut tumour slice (PCTS) model for LM-NEN using resected human liver tissue. The histological assessment throughout the culture demonstrated that slices maintain viability for at least 7 days and retain the cellular heterogeneity of the original tumour. Essential clinical features, such as patient-specific histoarchitecture, tumour grade, neuroendocrine differentiation and metabolic capacity, are preserved in the slices. The PCTS also replicate the tumor-specific immunological profile as shown by the innate and adaptive immunity markers analysis. Furthermore, the study of soluble immune che...
ObjectiveAlcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the l... more ObjectiveAlcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the life-threatening decompensated phenotype, known as alcohol-related hepatitis (AH). A multidimensional study of the clinical, histological and molecular features of these subtypes is lacking.DesignTwo large cohorts of patients were recruited in an international, observational multicentre study: a retrospective cohort of patients with ndALD (n=110) and a prospective cohort of patients with AH (n=225). Clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis of both disease phenotypes were performed.ResultsAge and mean alcohol intake were similar in both groups. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma-glutamyl transferase levels than in ndALD patients. Patients with AH demonstrated profound liver failure and increased mortality. One-year mortality was 10% in ndALD and 50% in AH. Histologically, steatosis grade,...
BACKGROUND The Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score as a prognost... more BACKGROUND The Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score as a prognostic index for recurrence has been reported previously and has not been validated outside the USA. Our study has validated the score in a single center UK cohort of patients being transplanted for HCC. METHODS LT for HCC between 2008 and 2018 at our center were analyzed. Recurrence-free survival (RFS) was compared by the RETREAT score and validated using Net Reclassification Improvement (NRI) by comparing it to Milan criteria. RESULTS 346 adult HCC patients were transplanted of whom 313 were included. 28 (8.9%) had a recurrence. Summation of largest diameter and total number of viable tumors (HR = 1.19, p < 0.001), micro-/macro-vascular invasion (HR = 3.74, p = 0.002) and AFP>20 ng/ml (HR = 3.03, p = 0.005) were associated with recurrence on multivariate analysis. RFS decreased with increasing RETREAT score (log-rank p = 0.016). RETREAT performed better than Milan with significant NRI at 1- and 2-years post-transplant (0.43 (p = 0.004) and 0.38 (p = 0.03) respectively). CONCLUSION LT outcomes using the revised UK criteria are equivalent to Milan criteria. Further, RETREAT score was validated as a prognostic index for the first time in a UK cohort and may assist risk stratification, selection for adjuvant therapies and guide surveillance.
NAFLD and Alcohol-Related Liver Diseases developed a system to classify ALD under the microscope ... more NAFLD and Alcohol-Related Liver Diseases developed a system to classify ALD under the microscope by grading ALD activity and staging the extent of liver scarring. We validated the prognostic performance of this system in 445 patients from 4 European centers.
Background and AimsImmunoregulatory checkpoint receptors (CR) contribute to the profound immunopa... more Background and AimsImmunoregulatory checkpoint receptors (CR) contribute to the profound immunoparesis observed in alcohol-related liver disease (ALD) and in vitro neutralization of inhibitory-CRs TIM3/PD1 on anti-bacterial T-cells can rescue innate and adaptive anti-bacterial immunity. Recently described soluble-CR forms can modulate immunity in inflammatory conditions, but the contributions of soluble-TIM3 and soluble-PD1 and other soluble-CRs to immune derangements in ALD remain unclear.MethodsIn Alcoholic Hepatitis (AH; n = 19), alcohol-related cirrhosis (ARC; n = 53) and healthy control (HC; n = 27) subjects, we measured by Luminex technology (i) plasma levels of 16 soluble-CRs, 12 pro/anti-inflammatory cytokines and markers of gut bacterial translocation; (ii) pre-hepatic, post-hepatic and non-hepatic soluble-CR plasma levels in ARC patients undergoing TIPS; (iii) soluble-CRs production from ethanol-treated immunocompetent precision cut human liver slices (PCLS); (iv) whole-bl...
Autoimmune hepatitis is associated with varied clinical presentations and natural history, as wel... more Autoimmune hepatitis is associated with varied clinical presentations and natural history, as well as somewhat unpredictable treatment responses. Understanding how to stratify patients who require further escalation of therapy will help clinicians manage these patients. The presentation of acute severe autoimmune hepatitis (AS-AIH) is relatively uncommon, although its prevalence is potentially greater than currently perceived. Previous studies consist of small retrospective single-centre series and are not directly comparable due to the diversity of presentations, disease definitions and non-standardised treatment regimens. We define AS-AIH as those who present acutely with AIH and are icteric with an international normalised ratio > − 1.5 and no evidence of hepatic encephalopathy. Those with hepatic encephalopathy should be defined as having AS-AIH with acute liver failure. In this review, we provide a structured practical approach for diagnosing and managing this unique group of patients.
The liver parenchyma is composed of hepatocytes and bile duct epithelial cells (BECs). Controvers... more The liver parenchyma is composed of hepatocytes and bile duct epithelial cells (BECs). Controversy exists regarding the cellular origin of human liver parenchymal tissue generation during embryonic development, homeostasis or repair. Here we report the existence of a hepatobiliary hybrid progenitor (HHyP) population in human foetal liver using single-cell RNA sequencing. HHyPs are anatomically restricted to the ductal plate of foetal liver and maintain a transcriptional profile distinct from foetal hepatocytes, mature hepatocytes and mature BECs. In addition, molecular heterogeneity within the EpCAM+population of freshly isolated foetal and adult human liver identifies diverse gene expression signatures of hepatic and biliary lineage potential. Finally, we FACS isolate foetal HHyPs and confirm their hybrid progenitor phenotype in vivo. Our study suggests that hepatobiliary progenitor cells previously identified in mice also exist in humans, and can be distinguished from other parenc...
The liver is largely composed of hepatocytes and bile duct epithelial cells (BECs). Controversy e... more The liver is largely composed of hepatocytes and bile duct epithelial cells (BECs). Controversy exists as to whether a liver stem/progenitor cell capable of renewing both hepatocytes and BECs exists. Single cell RNA sequencing of freshly isolated human foetal and healthy adult liver identified hepatocyte, hepatoblast and liver progenitor cell (hLPC) populations. hLPCs, found at the interface between hepatocytes and bile ducts in both foetal and adult tissue, were distinguishable from BECs by their negative expression of TROP-2. Prospective isolation followed by in vitro culture demonstrated their potential for expansion and bi-lineage differentiation. The hLPC expression signature was also conserved within expanded cell populations specific to certain cases of liver injury and cancer. These data support the idea of a true progenitor existing within healthy adult liver that can be activated upon injury. Further work to define the mechanisms regulating hLPC behaviour could advance und...
The aim of our study was to analyze the miRNome of pancreatic ductal adenocarcinoma (PDAC) and it... more The aim of our study was to analyze the miRNome of pancreatic ductal adenocarcinoma (PDAC) and its preneoplastic lesion intraductal papillary mucinous neoplasm (IPMN), to find new microRNA (miRNA)-based biomarkers for early detection of pancreatic neoplasia. Effective early detection methods for PDAC are needed. miRNAs are good biomarker candidates. Pancreatic tissues (n = 165) were obtained from patients with PDAC, IPMN, or from control individuals (C), from Hospital Clínic of Barcelona. Biomarker discovery was done using next-generation sequencing in a discovery set of 18 surgical samples (11 PDAC, 4 IPMN, 3 C). MiRNA validation was carried out by quantitative reverse transcriptase PCR in 2 different set of samples. Set 1-52 surgical samples (24 PDAC, 7 IPMN, 6 chronic pancreatitis, 15 C), and set 2-95 endoscopic ultrasound-guided fine-needle aspirations (60 PDAC, 9 IPMN, 26 C). In all, 607 and 396 miRNAs were significantly deregulated in PDAC and IPMN versus C. Of them, 40 miRNAs...
ORIGINALES RESUMEN OBJETIVO: Describir las características de los pacientes incluidos en el regis... more ORIGINALES RESUMEN OBJETIVO: Describir las características de los pacientes incluidos en el registro de tumoraciones pancreáticas del Hospital Clínic de Barcelona. PACIENTES Y MÉTODO: Se ha incluido a todos los pacientes con tumoraciones pancreáticas atendidos desde julio de 1990 a marzo de 2003. Las variables recogidas fueron: edad, sexo, fecha de diagnóstico, diagnóstico fundamental, diagnóstico histológico, tamaño, localización y estadio del tumor, y tratamiento efectuado. Por otra parte, se ha evaluado la correlación del estadio tumoral con la edad del paciente, la fecha de diagnóstico y la localización de la tumoración. RESULTADOS: Durante el período de estudio, se ha incluido a 630 pacientes con tumoraciones pancreáticas, lo que supone una incidencia de 60 pacientes/año. La edad media fue de 66 años y la relación varón/mujer, de 1,18:1. Las lesiones malignas de páncreas fueron las más frecuentes (92%), y el adenocarcinoma ductal pancreático fue el tipo histológico más común (73%). La localización más frecuente fue la cabeza pancreática (64%). En el 28% de los pacientes el tumor se diagnosticó en estadios I y II. El 31% de los pacientes fue resecado, mientras que el 48% no recibió ningún tipo de tratamiento. La relación enfermedad localizada (estadio I)/diseminada (estadio IV) fue de 0,34. El cociente estadio I/IV aumentó con la edad, el diagnóstico anterior a 1994 y la localización en la cabeza pancreática. CONCLUSIÓN: Los registros hospitalarios de tumores permiten establecer con precisión el perfil de la población atendida, lo que puede contribuir a delinear la mejor estrategia diagnóstico-terapéutica y ser de utilidad en la investigación clínica. HOSPITAL REGISTRY OF PANCREATIC TUMORS. EXPERIENCE OF THE HOSPITAL CLÍNIC IN BARCELONA (SPAIN) OBJECTIVE: To describe the characteristics of patients included in the pancreatic tumor registry of the Hospital Clínic of Barcelona. PATIENTS AND METHOD: All patients with pancreatic tumors attended between July 1990 and March 2003 were registered. Data collection included: age, gender, date of diagnosis, diagnosis, histology, size, location and tumor stage, and treatment. The correlation between tumor stage and age, date of diagnosis, and tumor location was also evaluated. RESULTS: Six hundred thirty patients with pancreatic tumors were included, representing an incidence of 60 patients/year. The mean age was 66 years and the male-to-female ratio was 1,18:1. The most frequent lesion was malignant tumor of the pancreas (92%), and the most frequent histological type was pancreatic ductal adenocarcinoma (73%). The most frequent location was the head of the pancreas (64%). In 28% of the patients, pancreatic cancer was diagnosed in stage I and II. Resection was performed in 31% of patients, whereas 48% of the patients received no treatment. The ratio between local (stage I)/disseminated (stage IV) disease was 0,34. The ratio between stage I/IV increased with age, diagnosis prior to 1994, and tumor location in the head of the pancreas. CONCLUSION: Hospital tumor registries can be used to define the profile of the attended population, which can help to delineate the best diagnostic-therapeutic strategy and can be useful in clinical research. Este trabajo ha sido financiado por becas del Fondo de Investigaciones Sanitarias (FIS 01/0104-02) y
A case of a 62-year-old patient with hereditary hemochromatosis is reported, who developed hepato... more A case of a 62-year-old patient with hereditary hemochromatosis is reported, who developed hepatocellular carcinoma (HCC) in the absence of cirrhosis and other potential risk factors for HCC. Occurrence of HCC in patients with genetic hemochromatosis and noncirrhotic liver is a rare event which has previously been described only six times and appears to be limited to male patients.
BaCKgRoUND & aIMS: Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammatio... more BaCKgRoUND & aIMS: Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammation, monocyte dysfunction, and susceptibility to infection. Lysophosphatidylcholines (LPCs) are immune-active lipids whose metabolic regulation and effect on monocyte function in ACLF is open for study. appRoaCHeS & ReSUltS: Three hundred forty-two subjects were recruited and characterized for blood lipid, cytokines, phospholipase (PLA), and autotaxin (ATX) concentration. Peripheral blood mononuclear cells and CD14 + monocytes were cultured with LPC, or its autotaxin (ATX)derived product, lysophosphatidic acid (LPA), with or without lipopolysaccharide stimulation and assessed for surface marker phenotype, cytokines production, ATX and LPA-receptor expression, and phagocytosis. Hepatic ATX expression was determined by immunohistochemistry. Healthy volunteers and patients with sepsis or acute liver failure served as controls. ACLF serum was depleted in LPCs with up-regulated LPA levels. Patients who died had lower LPC levels than survivors (area under the receiver operating characteristic curve, 0.94; P < 0.001). Patients with high-grade ACLF had the lowest LPC concentrations and these rose over the first 3 days of admission. ATX concentrations were higher in patients with AD and ACLF and correlated with Model for End-Stage Liver Disease, Consortium on Chronic Liver Failure-Sequential Organ Failure Assessment, and LPC/LPA concentrations. Reduction in LPC correlated with higher monocyte Mer-tyrosine-kinase (MerTK) and CD163 expression. Plasma ATX concentrations rose dynamically during ACLF evolution, correlating with IL-6 and TNFα, and were associated with increased hepatocyte ATX expression. ACLF patients had lower human leukocyte antigen-DR isotype and higher CD163/MerTK monocyte expression than controls; both CD163/MerTK expression levels were reduced in ACLF ex vivo following LPA, but not LPC, treatment. LPA induced up-regulation of proinflammatory cytokines by CD14 + cells without increasing phagocytic capacity. CoNClUSIoNS: ATX up-regulation in ACLF promotes LPA production from LPC. LPA suppresses MerTK/CD163 expression and increases monocyte proinflammatory cytokine production. This metabolic pathway could be investigated to therapeutically reprogram monocytes in ACLF. (Hepatology 2021;0:1-19). A cute-on-chronic liver failure (ACLF) is a complication of cirrhosis where patients progress through acute decompensation
The liver is the most common site for colorectal cancer (CRC) metastasis and there is an urgent n... more The liver is the most common site for colorectal cancer (CRC) metastasis and there is an urgent need for new tissue culture models to study colorectal cancer liver metastasis (CRLM) as current models do not mimic the biological, biochemical, and structural characteristics of the metastatic microenvironment. Decellularization provides a novel approach for the study of the cancer extracellular matrix (ECM) as decellularized scaffolds retain tissue-specific features and biological properties. In the present study, we created a 3D model of CRC and matched CRLM using patient-derived decellularized ECM scaffolds seeded with the HT-29 CRC cell line. Here, we show an increased HT-29 cell proliferation and migration capability when cultured in cancer-derived scaffolds compared to same-patient healthy colon and liver tissues. HT-29 cells cultured in CRLM scaffolds also displayed an indication of epithelial-mesenchymal transition (EMT), with a loss of E-cadherin and increased Vimentin expressi...
Alcoholism: Clinical and Experimental Research, 2020
Background: Mitochondria play a fundamental role in the pathogenesis of alcoholic liver disease (... more Background: Mitochondria play a fundamental role in the pathogenesis of alcoholic liver disease (ALD). The preservation of functional mitochondria during toxic alcohol insults is essential for cell survival and is maintained by key processes known as mitochondrial dynamics, including fragmentation and fusion, which are regulated by mitochondria-shaping proteins (MSP). We have shown mitochondrial dynamics to be distorted by alcohol in cellular and animal models, but the effect in humans remains unknown. Methods: Hepatic gene expression of the main MSP involved in the mitochondrial fusion and fragmentation pathways was evaluated in patients with alcoholic hepatitis (AH) by DNA microarray (n = 15) and Reverse Transcription Polymerase Chain Reaction (n = 32). The activation of dynamin-1like protein (Drp1) was also investigated in mitochondria isolated from liver biopsies of ALD patients (n = 8). The effects of alcohol on mitochondrial dynamics and on MSP protein expression were studied in human precision-cut liver slices (PCLS) exposed for 24 hours to increasing doses of ethanol (EtOH; 50 to 250 mM). Results: A profound hyperactivation of the fragmentation pathway was observed in AH patients, with a significant increase in the expression of Drp1 and its adapters/receptors. The translocation of Drp1 to the mitochondria was also induced in patients with severe ALD and was affected in the PCLS with short-term exposure to EtOH but only mildly. The fusion pathway was not altered in ALD, and this was confirmed in the PCLS model. Conclusions: The present study reveals the role of mitochondrial dynamics in human ALD, confirming our previous observations in animal and cell culture models of ALD. Taken together, we show that alcohol has a significant impact on the fragmentation pathway, and we confirm Drp1 as a potential therapeutic target in severe ALD.
Introduction Ten percent of cirrhotic patients are known to have a high risk of postoperative com... more Introduction Ten percent of cirrhotic patients are known to have a high risk of postoperative complications. Ninety percent of bariatric patients suffer from non-alcoholic fatty liver disease (NAFLD), and 50% of them may develop non-alcoholic steatohepatitis (NASH) which can progress to cirrhosis. The aim of this study was to assess whether the presence of cirrhosis at the time of bariatric surgery is associated with an increased rate and severity of short- and long-term cirrhotic complications. Methods A cohort of 110 bariatric patients, between May 2003 and February 2018, who had undergone liver biopsy at the time of bariatric surgery were reassessed for histological outcome and divided into two groups based on the presence (C, n = 26) or absence (NC, n = 84) of cirrhosis. The NC group consisted of NASH (n = 49), NAFLD (n = 24) and non-NAFLD (n = 11) liver histology. Medical notes were retrospectively assessed for patient characteristics, development of 30-day postoperative compli...
The DRESS (drug rash, eosinophilia and systemic symptoms) syndrome, also known as DIHS (drug-indu... more The DRESS (drug rash, eosinophilia and systemic symptoms) syndrome, also known as DIHS (drug-induced hypersensitivity syndrome), is a severe idiosyncratic reaction to several drugs, mainly antiepileptics and antibiotics, which can occasionally produce acute liver failure. In this article we present two cases of the DRESS syndrome presenting with severe acute hepatitis, including the first case of DRESS associated with levetiracetam. Although both cases finally resolved with good outcomes, DRESS can lead to acute liver failure and has a bad prognosis when liver damage is present. Rapid diagnosis is crucial since withdrawal of the offending drug is the key of treatment, while the potential role of corticosteroids is discussed.
Alcoholic liver disease (ALD) covers a wide spectrum of pathology ranging from fatty liver diseas... more Alcoholic liver disease (ALD) covers a wide spectrum of pathology ranging from fatty liver disease to acute steatohepatitis to cirrhosis and/or hepatocellular carcinoma. Alcoholic foamy degeneration (AFD) is an uncommon, potentially life-threatening condition that is part of the spectrum of ALD. It is characterized by extensive microvesicular steatosis in the perivenular areas. Since the first description in 1983, few case reports have been described. Here, we report 2 cases of AFD in patients with a previous history of chronic alcohol abuse and histological diagnosis of AFD with typical clinical, biochemical and histological features. In both cases we provide data on the hepatic hemodynamic status, and in one of them we report liver elastography results, which are features that have not been described previously. In both cases there was rapid resolution of biochemical and clinical abnormalities after complete abstinence, which is the mainstay of treatment for AFD.
Neuroendocrine liver metastases (LM-NEN) develop in a considerable proportion of patients with ga... more Neuroendocrine liver metastases (LM-NEN) develop in a considerable proportion of patients with gastroenteropancreatic neuroendocrine neoplasms. There is a paucity of experimental models that accurately recapitulate this complex metastatic human liver microenvironment precluding scientific and clinical advancements. Here, we describe the development of a novel personalised immunocompetent precision cut tumour slice (PCTS) model for LM-NEN using resected human liver tissue. The histological assessment throughout the culture demonstrated that slices maintain viability for at least 7 days and retain the cellular heterogeneity of the original tumour. Essential clinical features, such as patient-specific histoarchitecture, tumour grade, neuroendocrine differentiation and metabolic capacity, are preserved in the slices. The PCTS also replicate the tumor-specific immunological profile as shown by the innate and adaptive immunity markers analysis. Furthermore, the study of soluble immune che...
ObjectiveAlcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the l... more ObjectiveAlcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the life-threatening decompensated phenotype, known as alcohol-related hepatitis (AH). A multidimensional study of the clinical, histological and molecular features of these subtypes is lacking.DesignTwo large cohorts of patients were recruited in an international, observational multicentre study: a retrospective cohort of patients with ndALD (n=110) and a prospective cohort of patients with AH (n=225). Clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis of both disease phenotypes were performed.ResultsAge and mean alcohol intake were similar in both groups. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma-glutamyl transferase levels than in ndALD patients. Patients with AH demonstrated profound liver failure and increased mortality. One-year mortality was 10% in ndALD and 50% in AH. Histologically, steatosis grade,...
BACKGROUND The Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score as a prognost... more BACKGROUND The Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score as a prognostic index for recurrence has been reported previously and has not been validated outside the USA. Our study has validated the score in a single center UK cohort of patients being transplanted for HCC. METHODS LT for HCC between 2008 and 2018 at our center were analyzed. Recurrence-free survival (RFS) was compared by the RETREAT score and validated using Net Reclassification Improvement (NRI) by comparing it to Milan criteria. RESULTS 346 adult HCC patients were transplanted of whom 313 were included. 28 (8.9%) had a recurrence. Summation of largest diameter and total number of viable tumors (HR = 1.19, p < 0.001), micro-/macro-vascular invasion (HR = 3.74, p = 0.002) and AFP>20 ng/ml (HR = 3.03, p = 0.005) were associated with recurrence on multivariate analysis. RFS decreased with increasing RETREAT score (log-rank p = 0.016). RETREAT performed better than Milan with significant NRI at 1- and 2-years post-transplant (0.43 (p = 0.004) and 0.38 (p = 0.03) respectively). CONCLUSION LT outcomes using the revised UK criteria are equivalent to Milan criteria. Further, RETREAT score was validated as a prognostic index for the first time in a UK cohort and may assist risk stratification, selection for adjuvant therapies and guide surveillance.
NAFLD and Alcohol-Related Liver Diseases developed a system to classify ALD under the microscope ... more NAFLD and Alcohol-Related Liver Diseases developed a system to classify ALD under the microscope by grading ALD activity and staging the extent of liver scarring. We validated the prognostic performance of this system in 445 patients from 4 European centers.
Background and AimsImmunoregulatory checkpoint receptors (CR) contribute to the profound immunopa... more Background and AimsImmunoregulatory checkpoint receptors (CR) contribute to the profound immunoparesis observed in alcohol-related liver disease (ALD) and in vitro neutralization of inhibitory-CRs TIM3/PD1 on anti-bacterial T-cells can rescue innate and adaptive anti-bacterial immunity. Recently described soluble-CR forms can modulate immunity in inflammatory conditions, but the contributions of soluble-TIM3 and soluble-PD1 and other soluble-CRs to immune derangements in ALD remain unclear.MethodsIn Alcoholic Hepatitis (AH; n = 19), alcohol-related cirrhosis (ARC; n = 53) and healthy control (HC; n = 27) subjects, we measured by Luminex technology (i) plasma levels of 16 soluble-CRs, 12 pro/anti-inflammatory cytokines and markers of gut bacterial translocation; (ii) pre-hepatic, post-hepatic and non-hepatic soluble-CR plasma levels in ARC patients undergoing TIPS; (iii) soluble-CRs production from ethanol-treated immunocompetent precision cut human liver slices (PCLS); (iv) whole-bl...
Autoimmune hepatitis is associated with varied clinical presentations and natural history, as wel... more Autoimmune hepatitis is associated with varied clinical presentations and natural history, as well as somewhat unpredictable treatment responses. Understanding how to stratify patients who require further escalation of therapy will help clinicians manage these patients. The presentation of acute severe autoimmune hepatitis (AS-AIH) is relatively uncommon, although its prevalence is potentially greater than currently perceived. Previous studies consist of small retrospective single-centre series and are not directly comparable due to the diversity of presentations, disease definitions and non-standardised treatment regimens. We define AS-AIH as those who present acutely with AIH and are icteric with an international normalised ratio > − 1.5 and no evidence of hepatic encephalopathy. Those with hepatic encephalopathy should be defined as having AS-AIH with acute liver failure. In this review, we provide a structured practical approach for diagnosing and managing this unique group of patients.
The liver parenchyma is composed of hepatocytes and bile duct epithelial cells (BECs). Controvers... more The liver parenchyma is composed of hepatocytes and bile duct epithelial cells (BECs). Controversy exists regarding the cellular origin of human liver parenchymal tissue generation during embryonic development, homeostasis or repair. Here we report the existence of a hepatobiliary hybrid progenitor (HHyP) population in human foetal liver using single-cell RNA sequencing. HHyPs are anatomically restricted to the ductal plate of foetal liver and maintain a transcriptional profile distinct from foetal hepatocytes, mature hepatocytes and mature BECs. In addition, molecular heterogeneity within the EpCAM+population of freshly isolated foetal and adult human liver identifies diverse gene expression signatures of hepatic and biliary lineage potential. Finally, we FACS isolate foetal HHyPs and confirm their hybrid progenitor phenotype in vivo. Our study suggests that hepatobiliary progenitor cells previously identified in mice also exist in humans, and can be distinguished from other parenc...
The liver is largely composed of hepatocytes and bile duct epithelial cells (BECs). Controversy e... more The liver is largely composed of hepatocytes and bile duct epithelial cells (BECs). Controversy exists as to whether a liver stem/progenitor cell capable of renewing both hepatocytes and BECs exists. Single cell RNA sequencing of freshly isolated human foetal and healthy adult liver identified hepatocyte, hepatoblast and liver progenitor cell (hLPC) populations. hLPCs, found at the interface between hepatocytes and bile ducts in both foetal and adult tissue, were distinguishable from BECs by their negative expression of TROP-2. Prospective isolation followed by in vitro culture demonstrated their potential for expansion and bi-lineage differentiation. The hLPC expression signature was also conserved within expanded cell populations specific to certain cases of liver injury and cancer. These data support the idea of a true progenitor existing within healthy adult liver that can be activated upon injury. Further work to define the mechanisms regulating hLPC behaviour could advance und...
The aim of our study was to analyze the miRNome of pancreatic ductal adenocarcinoma (PDAC) and it... more The aim of our study was to analyze the miRNome of pancreatic ductal adenocarcinoma (PDAC) and its preneoplastic lesion intraductal papillary mucinous neoplasm (IPMN), to find new microRNA (miRNA)-based biomarkers for early detection of pancreatic neoplasia. Effective early detection methods for PDAC are needed. miRNAs are good biomarker candidates. Pancreatic tissues (n = 165) were obtained from patients with PDAC, IPMN, or from control individuals (C), from Hospital Clínic of Barcelona. Biomarker discovery was done using next-generation sequencing in a discovery set of 18 surgical samples (11 PDAC, 4 IPMN, 3 C). MiRNA validation was carried out by quantitative reverse transcriptase PCR in 2 different set of samples. Set 1-52 surgical samples (24 PDAC, 7 IPMN, 6 chronic pancreatitis, 15 C), and set 2-95 endoscopic ultrasound-guided fine-needle aspirations (60 PDAC, 9 IPMN, 26 C). In all, 607 and 396 miRNAs were significantly deregulated in PDAC and IPMN versus C. Of them, 40 miRNAs...
ORIGINALES RESUMEN OBJETIVO: Describir las características de los pacientes incluidos en el regis... more ORIGINALES RESUMEN OBJETIVO: Describir las características de los pacientes incluidos en el registro de tumoraciones pancreáticas del Hospital Clínic de Barcelona. PACIENTES Y MÉTODO: Se ha incluido a todos los pacientes con tumoraciones pancreáticas atendidos desde julio de 1990 a marzo de 2003. Las variables recogidas fueron: edad, sexo, fecha de diagnóstico, diagnóstico fundamental, diagnóstico histológico, tamaño, localización y estadio del tumor, y tratamiento efectuado. Por otra parte, se ha evaluado la correlación del estadio tumoral con la edad del paciente, la fecha de diagnóstico y la localización de la tumoración. RESULTADOS: Durante el período de estudio, se ha incluido a 630 pacientes con tumoraciones pancreáticas, lo que supone una incidencia de 60 pacientes/año. La edad media fue de 66 años y la relación varón/mujer, de 1,18:1. Las lesiones malignas de páncreas fueron las más frecuentes (92%), y el adenocarcinoma ductal pancreático fue el tipo histológico más común (73%). La localización más frecuente fue la cabeza pancreática (64%). En el 28% de los pacientes el tumor se diagnosticó en estadios I y II. El 31% de los pacientes fue resecado, mientras que el 48% no recibió ningún tipo de tratamiento. La relación enfermedad localizada (estadio I)/diseminada (estadio IV) fue de 0,34. El cociente estadio I/IV aumentó con la edad, el diagnóstico anterior a 1994 y la localización en la cabeza pancreática. CONCLUSIÓN: Los registros hospitalarios de tumores permiten establecer con precisión el perfil de la población atendida, lo que puede contribuir a delinear la mejor estrategia diagnóstico-terapéutica y ser de utilidad en la investigación clínica. HOSPITAL REGISTRY OF PANCREATIC TUMORS. EXPERIENCE OF THE HOSPITAL CLÍNIC IN BARCELONA (SPAIN) OBJECTIVE: To describe the characteristics of patients included in the pancreatic tumor registry of the Hospital Clínic of Barcelona. PATIENTS AND METHOD: All patients with pancreatic tumors attended between July 1990 and March 2003 were registered. Data collection included: age, gender, date of diagnosis, diagnosis, histology, size, location and tumor stage, and treatment. The correlation between tumor stage and age, date of diagnosis, and tumor location was also evaluated. RESULTS: Six hundred thirty patients with pancreatic tumors were included, representing an incidence of 60 patients/year. The mean age was 66 years and the male-to-female ratio was 1,18:1. The most frequent lesion was malignant tumor of the pancreas (92%), and the most frequent histological type was pancreatic ductal adenocarcinoma (73%). The most frequent location was the head of the pancreas (64%). In 28% of the patients, pancreatic cancer was diagnosed in stage I and II. Resection was performed in 31% of patients, whereas 48% of the patients received no treatment. The ratio between local (stage I)/disseminated (stage IV) disease was 0,34. The ratio between stage I/IV increased with age, diagnosis prior to 1994, and tumor location in the head of the pancreas. CONCLUSION: Hospital tumor registries can be used to define the profile of the attended population, which can help to delineate the best diagnostic-therapeutic strategy and can be useful in clinical research. Este trabajo ha sido financiado por becas del Fondo de Investigaciones Sanitarias (FIS 01/0104-02) y
A case of a 62-year-old patient with hereditary hemochromatosis is reported, who developed hepato... more A case of a 62-year-old patient with hereditary hemochromatosis is reported, who developed hepatocellular carcinoma (HCC) in the absence of cirrhosis and other potential risk factors for HCC. Occurrence of HCC in patients with genetic hemochromatosis and noncirrhotic liver is a rare event which has previously been described only six times and appears to be limited to male patients.
BaCKgRoUND & aIMS: Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammatio... more BaCKgRoUND & aIMS: Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammation, monocyte dysfunction, and susceptibility to infection. Lysophosphatidylcholines (LPCs) are immune-active lipids whose metabolic regulation and effect on monocyte function in ACLF is open for study. appRoaCHeS & ReSUltS: Three hundred forty-two subjects were recruited and characterized for blood lipid, cytokines, phospholipase (PLA), and autotaxin (ATX) concentration. Peripheral blood mononuclear cells and CD14 + monocytes were cultured with LPC, or its autotaxin (ATX)derived product, lysophosphatidic acid (LPA), with or without lipopolysaccharide stimulation and assessed for surface marker phenotype, cytokines production, ATX and LPA-receptor expression, and phagocytosis. Hepatic ATX expression was determined by immunohistochemistry. Healthy volunteers and patients with sepsis or acute liver failure served as controls. ACLF serum was depleted in LPCs with up-regulated LPA levels. Patients who died had lower LPC levels than survivors (area under the receiver operating characteristic curve, 0.94; P < 0.001). Patients with high-grade ACLF had the lowest LPC concentrations and these rose over the first 3 days of admission. ATX concentrations were higher in patients with AD and ACLF and correlated with Model for End-Stage Liver Disease, Consortium on Chronic Liver Failure-Sequential Organ Failure Assessment, and LPC/LPA concentrations. Reduction in LPC correlated with higher monocyte Mer-tyrosine-kinase (MerTK) and CD163 expression. Plasma ATX concentrations rose dynamically during ACLF evolution, correlating with IL-6 and TNFα, and were associated with increased hepatocyte ATX expression. ACLF patients had lower human leukocyte antigen-DR isotype and higher CD163/MerTK monocyte expression than controls; both CD163/MerTK expression levels were reduced in ACLF ex vivo following LPA, but not LPC, treatment. LPA induced up-regulation of proinflammatory cytokines by CD14 + cells without increasing phagocytic capacity. CoNClUSIoNS: ATX up-regulation in ACLF promotes LPA production from LPC. LPA suppresses MerTK/CD163 expression and increases monocyte proinflammatory cytokine production. This metabolic pathway could be investigated to therapeutically reprogram monocytes in ACLF. (Hepatology 2021;0:1-19). A cute-on-chronic liver failure (ACLF) is a complication of cirrhosis where patients progress through acute decompensation
The liver is the most common site for colorectal cancer (CRC) metastasis and there is an urgent n... more The liver is the most common site for colorectal cancer (CRC) metastasis and there is an urgent need for new tissue culture models to study colorectal cancer liver metastasis (CRLM) as current models do not mimic the biological, biochemical, and structural characteristics of the metastatic microenvironment. Decellularization provides a novel approach for the study of the cancer extracellular matrix (ECM) as decellularized scaffolds retain tissue-specific features and biological properties. In the present study, we created a 3D model of CRC and matched CRLM using patient-derived decellularized ECM scaffolds seeded with the HT-29 CRC cell line. Here, we show an increased HT-29 cell proliferation and migration capability when cultured in cancer-derived scaffolds compared to same-patient healthy colon and liver tissues. HT-29 cells cultured in CRLM scaffolds also displayed an indication of epithelial-mesenchymal transition (EMT), with a loss of E-cadherin and increased Vimentin expressi...
Alcoholism: Clinical and Experimental Research, 2020
Background: Mitochondria play a fundamental role in the pathogenesis of alcoholic liver disease (... more Background: Mitochondria play a fundamental role in the pathogenesis of alcoholic liver disease (ALD). The preservation of functional mitochondria during toxic alcohol insults is essential for cell survival and is maintained by key processes known as mitochondrial dynamics, including fragmentation and fusion, which are regulated by mitochondria-shaping proteins (MSP). We have shown mitochondrial dynamics to be distorted by alcohol in cellular and animal models, but the effect in humans remains unknown. Methods: Hepatic gene expression of the main MSP involved in the mitochondrial fusion and fragmentation pathways was evaluated in patients with alcoholic hepatitis (AH) by DNA microarray (n = 15) and Reverse Transcription Polymerase Chain Reaction (n = 32). The activation of dynamin-1like protein (Drp1) was also investigated in mitochondria isolated from liver biopsies of ALD patients (n = 8). The effects of alcohol on mitochondrial dynamics and on MSP protein expression were studied in human precision-cut liver slices (PCLS) exposed for 24 hours to increasing doses of ethanol (EtOH; 50 to 250 mM). Results: A profound hyperactivation of the fragmentation pathway was observed in AH patients, with a significant increase in the expression of Drp1 and its adapters/receptors. The translocation of Drp1 to the mitochondria was also induced in patients with severe ALD and was affected in the PCLS with short-term exposure to EtOH but only mildly. The fusion pathway was not altered in ALD, and this was confirmed in the PCLS model. Conclusions: The present study reveals the role of mitochondrial dynamics in human ALD, confirming our previous observations in animal and cell culture models of ALD. Taken together, we show that alcohol has a significant impact on the fragmentation pathway, and we confirm Drp1 as a potential therapeutic target in severe ALD.
Introduction Ten percent of cirrhotic patients are known to have a high risk of postoperative com... more Introduction Ten percent of cirrhotic patients are known to have a high risk of postoperative complications. Ninety percent of bariatric patients suffer from non-alcoholic fatty liver disease (NAFLD), and 50% of them may develop non-alcoholic steatohepatitis (NASH) which can progress to cirrhosis. The aim of this study was to assess whether the presence of cirrhosis at the time of bariatric surgery is associated with an increased rate and severity of short- and long-term cirrhotic complications. Methods A cohort of 110 bariatric patients, between May 2003 and February 2018, who had undergone liver biopsy at the time of bariatric surgery were reassessed for histological outcome and divided into two groups based on the presence (C, n = 26) or absence (NC, n = 84) of cirrhosis. The NC group consisted of NASH (n = 49), NAFLD (n = 24) and non-NAFLD (n = 11) liver histology. Medical notes were retrospectively assessed for patient characteristics, development of 30-day postoperative compli...
The DRESS (drug rash, eosinophilia and systemic symptoms) syndrome, also known as DIHS (drug-indu... more The DRESS (drug rash, eosinophilia and systemic symptoms) syndrome, also known as DIHS (drug-induced hypersensitivity syndrome), is a severe idiosyncratic reaction to several drugs, mainly antiepileptics and antibiotics, which can occasionally produce acute liver failure. In this article we present two cases of the DRESS syndrome presenting with severe acute hepatitis, including the first case of DRESS associated with levetiracetam. Although both cases finally resolved with good outcomes, DRESS can lead to acute liver failure and has a bad prognosis when liver damage is present. Rapid diagnosis is crucial since withdrawal of the offending drug is the key of treatment, while the potential role of corticosteroids is discussed.
Alcoholic liver disease (ALD) covers a wide spectrum of pathology ranging from fatty liver diseas... more Alcoholic liver disease (ALD) covers a wide spectrum of pathology ranging from fatty liver disease to acute steatohepatitis to cirrhosis and/or hepatocellular carcinoma. Alcoholic foamy degeneration (AFD) is an uncommon, potentially life-threatening condition that is part of the spectrum of ALD. It is characterized by extensive microvesicular steatosis in the perivenular areas. Since the first description in 1983, few case reports have been described. Here, we report 2 cases of AFD in patients with a previous history of chronic alcohol abuse and histological diagnosis of AFD with typical clinical, biochemical and histological features. In both cases we provide data on the hepatic hemodynamic status, and in one of them we report liver elastography results, which are features that have not been described previously. In both cases there was rapid resolution of biochemical and clinical abnormalities after complete abstinence, which is the mainstay of treatment for AFD.
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Papers by Rosa Miquel