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BACKGROUND: Helicobacter pylori (H. pylori) has definite or possible associations with multiple local and distant manifestations. H. pylori has been isolated from multiple sites throughout the body, including the nose. Clinical non-randomized studies with H. pylori report discrepant data regarding the association between H. pylori infection and nasal polyps. The aim of this first systematic review and meta-analysis was the assessment of the strength of the association between H. pylori infection and incidence of nasal polyps. METHODS: We performed an electronic search in the three major medical databases, namely PubMed, EMBASE and Cochrane, to extract and analyze data as per PRISMA guidelines. RESULTS: Out of 57 articles, 12 studies were graded as good quality for analysis. Male-to-female ratio was 2:1, and age ranged between 17-78 years. The cumulative pooled rate of H. pylori infection in the nasal polyp group was 32.3% (controls 17.8%). The comparison between the two groups revealed a more significant incidence of H. pylori infection among the nasal polyp group (OR 4.12), though with high heterogeneity I2 = 66%. Subgroup analysis demonstrated that in European studies, the prevalence of H. pylori infection among the nasal polyp group was significantly higher than in controls, yielding null heterogeneity. Subgroup analysis based on immunohistochemistry resulted in null heterogeneity with preserving a statistically significant difference in H. pylori infection prevalence between the groups. CONCLUSION: The present study revealed a positive association between H. pylori infection and nasal polyps.
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Objective: To assess whether prophylactic irrigation and passive drainage of pancreatico-jejunal anastomosis could reduce leak and mortality rates after high-risk pancreaticoduodenectomies. Background: Postoperative pancreatic fistula (POPF) is a life-threatening complication following pancreaticoduodenectomy. Several risk factors have been proposed likewise potential mitigation strategies. Regarding the latter, surgical drain policy remains a "hot topic." We propose an innovative approach to mitigate POPF and POPF-related mortality following high-risk pancreaticoduodenectomies. Methods: One hundred fifty-seven patients undergoing pancreaticoduodenectomy between January 2012 and November 2021 were included in the study. Subjects with main pancreatic duct ≤ 3 mm and soft parenchyma were classified as high-risk for POPF development. Since August 2015, high-risk patients received prophylactic irrigation and drainage of the perianastomotic area. These patients were compared with risk-matched historical controls. Results: We identified 73 high-risk patients. Of these, the 47 subjects receiving prophylactic perianastomotic irrigation showed significantly lower POPF rates (12.7% vs 69.2%, P < 0.001). Multivariate regression analysis confirmed the significant association between irrigation drainages and POPF (odds ratio 0.014, P = 0.01). Although not significant, mortality was lower in the irrigation group (4.2% vs 13.0%, P = 0.340). However, none of the fatalities in the irrigation-drainage group were POPF-related. No significant difference in length of hospital stay was observed between the 2 groups (18.0 vs 21.0 days, P = 0.091). Conclusions: Irrigation and drainage of the perianastomotic area represents a powerful approach to reduce POPF and, potentially, mortality after high-risk pancreaticoduodenectomies.
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AIM: To evaluate the predictive value for cancer-specific survival of the models of the American Joint Committee on Cancer (AJCC) stage, NIH and Armed Forces Institute of Pathology (AFIP) among patients with gastrointestinal stromal tumors (GISTs). METHODS: Surveillance, Epidemiology and End Results database (2010-2014) was accessed. Overall survival analysis and adjusted cancer-specific Cox regression hazard was calculated. RESULTS: For gastric GISTs, concordance-index according to AJCC was 0.834; according to NIH was 0.833; according to AFIP was 0.836. Concordance-index for nongastric GISTs according to AJCC was 0.800, according to NIH was 0.801 and according to AFIP was 0.799. CONCLUSION: The performance of the three models is comparable with regards to cancer-specific survival prediction.
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Tumores del Estroma Gastrointestinal/epidemiología , Recurrencia Local de Neoplasia/epidemiología , Pronóstico , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Tumores del Estroma Gastrointestinal/patología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Programa de VERF , Análisis de SupervivenciaRESUMEN
AIM: To validate the American Joint Committee on Cancer (AJCC) clinical staging system for esophageal cancer using Surveillance, Epidemiology and End Results database. METHODS: Cancer-specific survival analyses for clinically-staged patients with esophageal cancer according to both seventh and eighth editions were conducted through Kaplan-Meier analysis. RESULTS: For cancer-specific survival according to both seventh and eighth clinical systems, p-values for pairwise comparisons were nonsignificant in many comparisons. C-index for adenocarcinoma was: 0.671 according to the seventh AJCC and 0.671 according to the clinical eighth AJCC. C-index for squamous cell carcinoma according to the seventh AJCC was: 0.634 and 0.643 according to clinical eighth AJCC. CONCLUSION: Minimal improvement was achieved by the eighth clinical AJCC staging system for esophageal cancer.
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Adenocarcinoma/patología , Carcinoma de Células Escamosas/patología , Neoplasias Esofágicas/patología , Pronóstico , Adenocarcinoma/epidemiología , Adulto , Anciano , Carcinoma de Células Escamosas/epidemiología , Supervivencia sin Enfermedad , Neoplasias Esofágicas/epidemiología , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/clasificación , Programa de VERF , Estados UnidosRESUMEN
The liver is the central regulator of iron metabolism and accordingly, chronic liver diseases often lead to systemic iron overload due to diminished expression of the iron-regulatory hormone hepcidin. To study the largely unknown regulation of iron metabolism in the context of hepatic disease, we used two established models of chronic liver injury, ie repeated carbon tetrachloride (CCl(4)) or thioacetamide (TAA) injections. To determine the impact of CCAAT/enhancer-binding protein (C/EBP)-homologous protein (CHOP) on hepcidin production, the effect of a single TAA injection was determined in wild-type and CHOP knockout mice. Furthermore, CHOP and hepcidin expression was assessed in control subjects and patients with alcoholic liver disease. Both chronic injury models developed a distinct iron overload in macrophages. TAA-, but not CCl(4) - injected mice displayed additional iron accumulation in hepatocytes, resulting in a significant hepatic and systemic iron overload which was due to suppressed hepcidin levels. C/EBPα signalling, a known hepcidin inducer, was markedly inhibited in TAA mice, due to lower C/EBPα levels and overexpression of CHOP, a C/EBPα inhibitor. A single TAA injection resulted in a long-lasting (> 6 days) suppression of hepcidin levels and CHOP knockouts (compared to wild-types) displayed significantly attenuated hepcidin down-regulation in response to acute TAA administration. CHOP mRNA levels increased 5-fold in alcoholic liver disease patients versus controls (p < 0.005) and negatively correlated with hepcidin expression. Our results establish CHOP as an important regulator of hepatic hepcidin expression in chronic liver disease. The differences in iron metabolism between the two widely used fibrosis models likely reflect the differential regulation of hepcidin expression in human liver disease.
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Hepcidinas/biosíntesis , Sobrecarga de Hierro/etiología , Cirrosis Hepática Experimental/complicaciones , Hepatopatías Alcohólicas/complicaciones , Factor de Transcripción CHOP/fisiología , Animales , Proteína alfa Potenciadora de Unión a CCAAT/biosíntesis , Proteína alfa Potenciadora de Unión a CCAAT/genética , Tetracloruro de Carbono , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Inactivación de Genes , Hepcidinas/genética , Humanos , Hierro/metabolismo , Sobrecarga de Hierro/metabolismo , Hígado/metabolismo , Cirrosis Hepática Experimental/inducido químicamente , Cirrosis Hepática Experimental/metabolismo , Hepatopatías Alcohólicas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/genética , Transducción de Señal/efectos de los fármacos , Tioacetamida , Factor de Transcripción CHOP/biosíntesis , Factor de Transcripción CHOP/deficiencia , Factor de Transcripción CHOP/genéticaRESUMEN
BACKGROUND AND STUDY AIMS: Bile stones represent a highly prevalent condition and abnormalities of the biliary tree predispose to stone recurrence due to development of biliary stasis. In our study, we assessed the importance of an altered bile duct course for stone formation. PATIENTS AND METHODS: 1,307 patients with choledocholithiasis in the absence of any associated hepatobiliary disease who underwent endoscopic retrograde cholangiopancreatography (ERCP) between 2002 and 2009 were analysed. The angle enclosed between the horizontal portion of the common bile duct (CBD) and the horizontal plane was measured (angle α). Oblique common bile duct (OCBD) was defined as a CBD with angle α < 45°. RESULTS: 103 patients (7.9%) were found to harbour OCBD and these were compared to 104 randomly selected control subjects. Compared to controls, OCBD patients were (i) significantly older (72 ± 13 vs. 67 ± 13, p<0.00001); (ii) more frequently underwent a cholecystectomy (p = 0.02) and biliary surgery (p = 0.003) prior to the diagnosis and (iii) more often developed chronic pancreatitis (p = 0.04) as well as biliary fistulae (p = 0.03). Prior to and after ERCP, OCBD subjects displayed significantly elevated cholestatic parameters and angle α negatively correlated with common bile duct diameter (r = -0.29, p = 0.003). OCBD subjects more often required multiple back-to-back ERCP sessions to remove bile stones (p = 0.005) as well as more ERCPs later on due to recurrent stone formation (p<0.05). CONCLUSION: OCBD defines a novel variant of the biliary tree, which is associated with chronic cholestasis, hampers an efficient stone removal and predisposes to recurrence of bile duct stones.
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Conductos Biliares/patología , Colangiopancreatografia Retrógrada Endoscópica , Coledocolitiasis/patología , Adulto , Anciano , Anciano de 80 o más Años , Conductos Biliares/cirugía , Fístula Biliar/diagnóstico por imagen , Fístula Biliar/etiología , Fístula Biliar/patología , Procedimientos Quirúrgicos del Sistema Biliar , Coledocolitiasis/complicaciones , Coledocolitiasis/diagnóstico por imagen , Coledocolitiasis/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Páncreas/patología , Pancreatitis Crónica/diagnóstico por imagen , Pancreatitis Crónica/etiología , Pancreatitis Crónica/patología , RecurrenciaRESUMEN
The prevalence of Parkinson's disease (PD) increases with age. Up to 50% of PD show cognitive decline in terms of a mild cognitive impairment already in early stages that predict the development of dementia, which can occur in up to 80% of PD patients over the long term, called Parkinson's disease dementia (PDD). So far, diagnosis of PD/PDD is made according to clinical and neuropsychological examinations while laboratory data is only used for exclusion of other diseases. The aim of this study was the identification of possible biomarkers in cerebrospinal fluid (CSF) of PD, PDD and controls (CON) which predict the development of dementia in PD. For this, a proteomic approach optimized for CSF was performed using 18 clinically well characterized patients in a first step with subsequent validation using 84 patients. Here, we detected differentially sialylated isoforms of Serpin A1 as marker for differentiation of PD versus PDD in CSF. Performing 2D-immunoblots, all PDD patients could be identified correctly (sensitivity 100%). Ten out of 24 PD patients showed Serpin A1 isoforms in a similar pattern like PDD, indicating a specificity of 58% for the test-procedure. In control samples, no additional isoform was detected. On the basis of these results, we conclude that differentially sialylated products of Serpin A1 are an interesting biomarker to indicate the development of a dementia during the course of PD.
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Demencia/metabolismo , Enfermedad de Parkinson/metabolismo , alfa 1-Antitripsina/metabolismo , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/metabolismo , Encéfalo/metabolismo , Demencia/diagnóstico , Demencia/etiología , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Isoformas de Proteínas/líquido cefalorraquídeo , Isoformas de Proteínas/metabolismo , Procesamiento Proteico-Postraduccional , Proteómica , Sensibilidad y Especificidad , alfa 1-Antitripsina/líquido cefalorraquídeoRESUMEN
BACKGROUND: Homozygous C282Y mutation in HFE gene is responsible for the majority of hereditary hemochromatosis cases. Since 1996 this mutation can be identified by a simple genetic test. AIMS: To determine the clinical presentations in patients with homozygous HFE C282Y mutation and the impact of genetic testing on the time needed for diagnosis. METHODS: A total of 414 patients diagnosed with C282Y homozygous hereditary hemochromatosis before and after the introduction of genetic testing were evaluated regarding symptoms and clinical findings at diagnosis as well as first hemochromatosis-related clinical features in their past medical history. RESULTS: At the time of diagnosis, the predominant symptom was joint pain, in particular of the hands/wrists. Those patients presenting with hand/wrist arthralgia had significantly higher ferritin levels than patients without this joint involvement (p = 0.0005 for males and p < 0.0001 for females). After the introduction of the HFE genetic test an earlier diagnosis after first onset of hemochromatosis-associated clinical features was observed between 2006 and 2009 vs. 2000-2005 p = 0.01). CONCLUSIONS: Arthralgia, in particular of the hands/wrists, is a hallmark of hereditary hemochromatosis and its presence is associated with higher ferritin levels. Despite the availability of a genetic test, it often takes more than 6 years from the first onset of clinical features to diagnose hereditary hemochromatosis. This underlines the importance of raising the awareness of hemochromatosis and its typical clinical presentations.
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Pruebas Genéticas/métodos , Hemocromatosis/diagnóstico , Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Adulto , Comorbilidad , Femenino , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación , Estudios Retrospectivos , Estadísticas no Paramétricas , Factores de TiempoRESUMEN
BACKGROUNDS AND AIMS: Hepcidin is an antimicrobial peptide and the central regulator of iron metabolism. Given that hepcidin was shown to be expressed in a variety of extrahepatic tissues and that stomach plays a role in iron absorption and in defence against infections, this study analysed the importance of hepcidin in the stomach. METHODS: Expression and localisation of gastric hepcidin was studied by quantitative RT-PCR, western blot, immunofluorescence and in situ hybridisation. Regulation of gastric hepcidin expression was analysed both in vitro and in vivo. Hepcidin wild-type (WT) and knockout (KO) animals were used to determine the impact of hepcidin on gastric bacterial overgrowth as well as gastric acid secretion. RESULTS: Hepcidin was abundantly expressed in the gastric fundus and corpus of all tested species. Treatment of AGS cells with ferric nitrilotriacetate solution downregulated hepcidin expression levels, while desferroxamine, interleukin 6 and Helicobacter pylori infection upregulated it. In humans, gastric hepcidin expression was elevated during H pylori infection and normalised after successful eradication. Gastric hepcidin is localised in parietal cells that are indispensable for gastric acid secretion. Comparisons of WT and hepcidin KO mice revealed that acid secretion in hepcidin-deficient mice is markedly reduced and is associated with gastric bacterial overgrowth, expression changes in multiple factors involved in acid secretion (Atp4a, Cck2r,Gas, Sst and Sst2r) and with reduced circulating gastrin levels. In WT mice, pantoprazole activated and histamine downregulated hepcidin expression levels. CONCLUSIONS: Hepcidin is a product of parietal cells regulating gastric acid production and may contribute to development of gastric ulcers under stress conditions.
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Péptidos Catiónicos Antimicrobianos/metabolismo , Mucosa Gástrica/metabolismo , Infecciones por Helicobacter/metabolismo , Helicobacter pylori , Animales , Western Blotting , Línea Celular , Femenino , Técnica del Anticuerpo Fluorescente , Ácido Gástrico/metabolismo , Mucosa Gástrica/microbiología , Hepcidinas , Humanos , Hibridación in Situ , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Parietales Gástricas/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Increased levels of hepcidin, the master regulator of iron homeostasis, contribute to the diversion of iron underlying the anemia of chronic disease. Yet hepcidin levels are low in anemia of chronic disease with concomitant true iron deficiency. Here we clarify the different underlying pathways regulating hepcidin expression under these conditions in vivo. DESIGN AND METHODS: We used rat models of iron deficiency anemia, anemia of chronic disease and anemia of chronic disease with concomitant true iron deficiency and investigated upstream signaling pathways controlling hepcidin transcription in the liver. Protein and mRNA levels of iron metabolism genes and genes involved in SMAD1/5/8 and STAT3 signaling were determined by RT-PCR, Western blotting and immunohistochemistry. RESULTS: SMAD1/5/8 phosphorylation and in parallel hepcidin mRNA expression were increased in anemia of chronic disease but significantly down-regulated in anemia of chronic disease with concomitant iron deficiency, either on the basis of phlebotomy or dietary iron restriction. Iron deficiency resulted in reduced bone morphogenetic protein-6 expression and impaired SMAD1/5/8 phosphorylation and trafficking, two key events for hepcidin transcription. Reduced SMAD1/5/8 activity in association with phlebotomy was paralleled by increased expression of the inhibitory factor, SMAD7, dietary iron restriction appeared to impair hepcidin transactivating SMAD pathways via reduction of membrane bound hemojuvelin expression. CONCLUSIONS: This study evaluated hepcidin signaling pathways in anemia of chronic disease with/without concomitant iron deficiency in vivo. While iron deficiency in general decreased bone morphogenetic protein-6 expression, phlebotomy or dietary iron restriction inhibited inflammation driven SMAD1/5/8 mediated hepcidin formation by different pathways, indicating alternate hierarchic signaling networks as a function of the mode and kinetics of iron deficiency. Nonetheless, iron deficiency inducible regulatory pathways can reverse inflammation mediated stimulation of hepcidin expression.
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Anemia Ferropénica/metabolismo , Péptidos Catiónicos Antimicrobianos/biosíntesis , Regulación de la Expresión Génica , Hígado/metabolismo , Transducción de Señal , Anemia Ferropénica/patología , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Femenino , Hepcidinas , Hierro/metabolismo , Hígado/patología , Fosforilación , ARN Mensajero/biosíntesis , Ratas , Ratas Endogámicas Lew , Factor de Transcripción STAT3/metabolismo , Proteínas Smad/metabolismoRESUMEN
BACKGROUND/AIMS: Hepcidin (gene name HAMP), an IL-6-inducible acute phase peptide with antimicrobial properties, is the key negative regulator of iron metabolism. Liver is the primary source of HAMP synthesis, but it is also produced by other tissues such as kidney or heart and is found in body fluids such as urine or cerebrospinal fluid. While the role of hepcidin in biliary system is unknown, a recent study demonstrated that conditional gp130-knockout mice display diminished hepcidin levels and increased rate of biliary infections. METHODS: Expression and localization of HAMP in biliary system was analyzed by real time RT-PCR, in-situ hybridization, immunostaining and -blotting, while prohepcidin levels in human bile were determined by ELISA. RESULTS: Hepcidin was detected in mouse/human gallbladder and bile duct epithelia. Biliary HAMP is stress-inducible, in that it is increased in biliary cell lines upon IL-6 stimulation and in gallbladder mucosa of patients with acute cholecystitis. Hepcidin is also present in the bile and elevated prohepcidin levels were observed in bile of primary sclerosing cholangitis (PSC) patients with concurrent bacterial cholangitis compared to PSC subjects without bacterial infection (median values 22.3 vs. 8.9; p = 0.03). In PSC-cholangitis subjects, bile prohepcidin levels positively correlated with C-reactive protein and bilirubin levels (r = 0.48 and r = 0.71, respectively). In vitro, hepcidin enhanced the antimicrobial capacity of human bile (p<0.05). CONCLUSION: Hepcidin is a stress-inducible peptide of the biliary epithelia and a potential marker of biliary stress. In the bile, hepcidin may serve local functions such as protection from bacterial infections.
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Péptidos Catiónicos Antimicrobianos/genética , Sistema Biliar/química , Estrés Fisiológico/genética , Activación Transcripcional , Animales , Antibacterianos , Péptidos Catiónicos Antimicrobianos/análisis , Péptidos Catiónicos Antimicrobianos/fisiología , Conductos Biliares/química , Sistema Biliar/metabolismo , Sistema Biliar/patología , Colangitis Esclerosante/metabolismo , Colangitis Esclerosante/microbiología , Colangitis Esclerosante/patología , Células Epiteliales/química , Vesícula Biliar/química , Hepcidinas , Humanos , Interleucina-6/farmacología , RatonesRESUMEN
BACKGROUND AND AIMS: Tissue specimen collection represents a cornerstone in diagnosis of proximal biliary tract malignancies offering great specificity, but only limited sensitivity. To improve the tumor detection rate, we developed a new method of forceps biopsy and compared it prospectively with endoscopic transpapillary brush cytology. PATIENTS AND METHODS: 43 patients with proximal biliary stenoses, which were suspect for malignancy, undergoing endoscopic retrograde cholangiography were prospectively recruited and subjected to both biopsy [using a double-balloon enteroscopy (DBE) forceps under a guidance of a pusher and guiding catheter with guidewire] and transpapillary brush cytology. The cytological/histological findings were compared with the final clinical diagnosis. RESULTS: 35 out of 43 patients had a malignant disease (33 cholangiocarcinomas, 1 hepatocellular carcinoma, 1 gallbladder carcinoma). The sensitivity of cytology and biopsy in these patients was 49 and 69%, respectively. The method with DBE forceps allowed a pinpoint biopsy of the biliary stenoses. Both methods had 100% specificity, and, when combined, 80% of malignant processes were detected. All patients with non-malignant conditions were correctly assigned by both methods. No clinically relevant complications were observed. CONCLUSIONS: The combination of forceps biopsy and transpapillary brush cytology is safe and offers superior detection rates compared to both methods alone, and therefore represents a promising approach in evaluation of proximal biliary tract processes.
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Neoplasias de los Conductos Biliares/diagnóstico , Biopsia/métodos , Carcinoma Hepatocelular/diagnóstico , Colangiocarcinoma/diagnóstico , Neoplasias Hepáticas/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Colangiopancreatografia Retrógrada Endoscópica , Vesícula Biliar/patología , Humanos , Hígado/patología , Persona de Mediana Edad , Instrumentos Quirúrgicos , Adulto JovenRESUMEN
BACKGROUND: Hepcidin is a liver-derived peptide hormone regulating iron metabolism. Changes in the expression of hepcidin are known to be the key pathogenic factors in hereditary hemochromatosis and are associated with infection and inflammation. To better understand the hormone's function in human disease, we aimed to establish an immunoassay to determine hepcidin concentrations in serum. METHODS: Monoclonal antibodies mHK(8) and mHK(9) were generated and characterized by dot blot, Western blot, and immunofluorescence. A competitive enzyme-linked immunosorbent assay (ELISA) was established with mHK(9). RESULTS: Both antibodies recognized hepcidin, by dot blot and Western blot, respectively. In human liver, mHK(8)/(9) showed an immunofluorescence staining pattern in hepatocytes identical to that of established prohepcidin antibodies. The developed immunoassay with mHK(9), reliably detecting mature hepcidin in serum over a large concentration range (0.9-140 ng ml⻹), showed high sensitivity and precision (intra-/interassay coefficients of variation: 4-5 and 7-11%; mean linearity: 85-112%; mean recovery: 87-114%). To test the clinical functionality of the developed assay we measured hepcidin serum concentrations in healthy volunteers, hepatitis C virus (HCV) patients, and two groups of hemochromatotic patients undergoing phlebotomy. The assay distinguished low hepcidin level in HCV and homozygous hemochromatosis patients from normal-range controls and compound heterozygous hemochromatosis patients. In healthy subjects and HCV patients, hepcidin levels were correlated with iron and transferrin saturation; no correlation was observed in the hemochromatotic patients. CONCLUSION: We developed a monoclonal antibody ELISA that quantifies serum hepcidin levels with high sensitivity, robustness, and reliability of detection. The hepcidin ELISA should help to enhance our understanding of hepcidin-related human disorders.
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Anticuerpos Monoclonales/inmunología , Péptidos Catiónicos Antimicrobianos/sangre , Ensayo de Inmunoadsorción Enzimática/métodos , Hemocromatosis/sangre , Adulto , Anciano , Animales , Péptidos Catiónicos Antimicrobianos/inmunología , Western Blotting , Estudios de Casos y Controles , Femenino , Técnica del Anticuerpo Fluorescente/métodos , Hepatitis C/sangre , Hepcidinas , Humanos , Immunoblotting , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Adulto JovenRESUMEN
Recent evidence suggests that iron metabolism contributes to the ischemic damage after myocardial infarction. Hepcidin, a recently discovered peptide hormone, regulates iron uptake and metabolism, protecting the body from iron overload. In this study we analyzed the regulation of hepcidin in the heart and blood of rats after myocardial infarction. To induce a myocardial infarction in the rats, left anterior descending coronary artery ligation was performed. After 1-24h, biopsies from the ischemic and the non-ischemic myocardium were taken. In these biopsies, the mRNA levels and the protein expression of hepcidin were analyzed by quantitative RT-PCR and immunoblot analysis, respectively. In parallel, the serum levels of prohepcidin were measured by ELISA. Six hours after myocardial infarction, the hepcidin mRNA expression was temporally upregulated in the ischemic and in the non-ischemic myocardium. The upregulation was specific for hepcidin, since other iron-related genes (hemojuvelin, IREG-1) remained unchanged. Furthermore, the alteration of the hepcidin protein expression in the ischemic area was connected to the level of hepcidin in the serum of the infarcted rats, where hepcidin also raised up. Angiotensin receptor blockade with candesartan did not influence the mRNA regulation of hepcidin. Together, these data show a particular upregulation of the iron-regulatory peptide hepcidin in the ischemic and the non-ischemic myocardium after myocardial infarction. It is speculated that upregulation of hepcidin may reduce iron toxicity and thus infarct size expansion in an infarcted heart.
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Péptidos Catiónicos Antimicrobianos/metabolismo , Proteínas Reguladoras del Hierro/metabolismo , Infarto del Miocardio/metabolismo , Isquemia Miocárdica/metabolismo , Miocardio/metabolismo , Regulación hacia Arriba , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Péptidos Catiónicos Antimicrobianos/sangre , Péptidos Catiónicos Antimicrobianos/genética , Biopsia , Proteínas Ligadas a GPI , Corazón/efectos de los fármacos , Proteína de la Hemocromatosis , Hepcidinas , Homeostasis , Proteína 1 Reguladora de Hierro/genética , Proteína 1 Reguladora de Hierro/metabolismo , Proteínas Reguladoras del Hierro/sangre , Proteínas Reguladoras del Hierro/genética , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Infarto del Miocardio/sangre , Precursores de Proteínas/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND & AIMS: In patients with primary sclerosing cholangitis (PSC) treated with ursodeoxycholic acid (UDCA), dominant stenoses are associated with reduced survival free of liver transplantation and the role of inflammatory bowel disease (IBD) in such patients is unclear. In the present study the influence of IBD on the outcome in patients with and without dominant stenosis has been evaluated. METHODS: In a prospective study, 171 patients were followed for up to 20 years. All patients were treated with ursodeoxycholic acid; patients with dominant stenosis in addition were treated endoscopically. RESULTS: A total of 97 out of 171 patients had or developed dominant bile duct stenoses and 96 out of 97 were treated endoscopically. In patients with dominant stenosis without IBD, no carcinoma was found whereas all six bile duct and two gallbladder carcinomas and 6/7 colo-rectal carcinomas were found in patients with dominant stenosis with IBD (p=0.012). In patients without dominant stenosis but with IBD, 1 out of 7 had colo-rectal carcinoma. In patients with dominant stenosis without IBD (n=30), actuarial survival free of liver transplantation at 18 years was 77.8% and in those with dominant stenosis and inflammatory bowel disease (n=67) it was 23.0% (p=0.045). In PSC patients without dominant stenosis and without IBD (n=21), actuarial survival free of liver transplantation at 18 years was 68.2% and in those with inflammatory bowel disease (n=53) it was 78.4% (n.s.). CONCLUSIONS: In patients without dominant stenosis, IBD had no effect on the incidence of carcinomas and survival. Only patients with dominant stenosis with additional IBD had an increased carcinoma rate. This may contribute to the reduced survival free of liver transplantation in such patients.
Asunto(s)
Neoplasias de los Conductos Biliares/epidemiología , Colangitis Esclerosante/complicaciones , Colangitis Esclerosante/mortalidad , Colestasis/complicaciones , Neoplasias Colorrectales/epidemiología , Neoplasias de la Vesícula Biliar/epidemiología , Enfermedades Inflamatorias del Intestino/complicaciones , Adolescente , Adulto , Anciano , Colangitis Esclerosante/terapia , Colestasis/epidemiología , Comorbilidad , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Enfermedades Inflamatorias del Intestino/epidemiología , Estimación de Kaplan-Meier , Trasplante de Hígado , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tasa de Supervivencia , Ácido Ursodesoxicólico/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: Primary sclerosing cholangitis is characterized by progressive fibrotic inflammation and obliteration of intra- and/or extrahepatic bile ducts. Total or subtotal stenoses of major bile ducts are associated with reduced survival. OBJECTIVE: To evaluate the outcome after long-term endoscopic treatment. DESIGN: Prospective, single-center study. SETTING: Tertiary care academic medical center. PATIENTS: A total of 171 patients treated with ursodeoxycholic acid were followed for as long as 20 years. At entry, 20 patients had dominant stenoses, and during a median follow-up period of 7.1 years, dominant stenosis developed in another 77. INTERVENTIONS: Ninety-six patients with dominant stenoses were treated by repeated balloon dilation; 5 patients with complete obstruction with bacterial cholangitis were stented. MAIN OUTCOME MEASUREMENTS: Survival free of liver transplantation, number of procedures, complications. RESULTS: In total, 500 balloon dilations were performed and 5 stents were placed. Complications were pancreatitis (2.2%), bacterial cholangitis (1.4%), and bile duct perforation (0.2%); there were no deaths. Repeated endoscopic interventions allowed the preservation of a functioning common bile duct and of at least 1 hepatic duct up to 2 cm above the bifurcation in all patients. Progression of intrahepatic bile duct and liver disease led to the need for liver transplantation in 22 of 96 patients. Five years after the first dilation of a dominant stenosis, the survival free of liver transplantation rate was 81%, and after 10 years, it was 52%. LIMITATIONS: Single-center study, no control group, primary end-stage liver disease excluded. CONCLUSION: Repeated endoscopic balloon dilations of dominant stenoses allow the preservation of a functioning common bile duct for many years.
Asunto(s)
Cateterismo/métodos , Colangitis Esclerosante/patología , Colangitis Esclerosante/terapia , Colangitis Esclerosante/cirugía , Endoscopía del Sistema Digestivo , Femenino , Humanos , Trasplante de Hígado/estadística & datos numéricos , Masculino , Estudios Prospectivos , Retratamiento , Stents , Resultado del TratamientoRESUMEN
Hepcidin, a cysteine-rich peptide hormone with antimicrobial and iron-regulatory activity, plays a central role in regulating iron metabolism during inflammation, hypoxia, iron deficiency, and iron overload. The aim of this study was to isolate and sequence the guinea pig hepcidin gene and show peptide's tissue distribution to identify the guinea pig as good animal model to study the regulation and function of hepcidin. The guinea pig hepcidin cDNA contains a 252 bp open reading frame encoding for an 83 amino acid protein with eight highly conserved cysteine residues. Phylogenetic analyses showed that guinea pig hepcidin was more related to human and chimpanzee than to rodents like mouse or rat. RT-PCR studies revealed that hepcidin mRNA was most abundant in liver, less ample in pancreas, heart, and kidney and not detectable in lung and biliary system. Western blot analyses showed a distinct immunoreactive band of approximately 8 kDa, consistent with the predicted size of prohepcidin, and revealed that guinea pig hepcidin protein is synthesized predominantly in the liver, and with lower expression in kidney, heart, and pancreas. Immunohistochemical studies showed hepcidin predominantly at the basolateral membrane domain of hepatocytes in periportal regions. In pancreas, hepcidin immunoreactivity was confined to endocrine islets of Langerhans, while hepcidin was seen in tubules, but not in the glomeruli in the kidney. Our data identify guinea pig as a convenient model organism to study the role of hepcidin, given the remarkable sequence similarity and tissue distribution pattern largely identical to human.
Asunto(s)
Péptidos Catiónicos Antimicrobianos/genética , Péptidos Catiónicos Antimicrobianos/metabolismo , Cobayas/genética , Hierro/metabolismo , Secuencia de Aminoácidos , Animales , Anticuerpos/farmacología , Péptidos Catiónicos Antimicrobianos/inmunología , Secuencia de Bases , Clonación Molecular , ADN Complementario , Corazón/fisiología , Hepcidinas , Riñón/fisiología , Hígado/fisiología , Masculino , Datos de Secuencia Molecular , Páncreas/fisiología , Filogenia , Homología de Secuencia de AminoácidoRESUMEN
BACKGROUND/AIMS: In primary sclerosing cholangitis (PSC) dominant stenoses are frequently associated with bacterial, and in part, also fungal infections of the bile ducts. In the present study, the influence of dominant stenoses and of biliary infections on the long-term outcome was studied. METHODS: In a prospective study, 171 patients were followed up for 20 years. All patients were treated with ursodeoxycholic acid. Dominant stenoses were treated endoscopically and during endoscopic procedures, bile was obtained for microbiologic analysis. RESULTS: Of the 171 patients, 97 had or developed major bile duct stenoses and 96/97 were treated endoscopically. In the 55/97 patients with dominant stenosis, bile samples were obtained and of these, 41/55 had bacteria, five had also Candida and 2/55 had only Candida in their bile. Survival free of liver transplantation in patients without dominant stenosis at 18 years was 73.1% and of patients with dominant stenosis was 25.0% (p=0.011). Bacteria in bile had no effect on survival whereas Candida in bile was associated with reduced survival (p=0.025). CONCLUSIONS: In patients with dominant stenosis, survival free of liver transplantation is reduced. Bacteria in bile do not worsen the outcome if dominant stenoses are opened endoscopically and infection is adequately treated with antibiotics. Candida in bile is associated with a poor prognosis and these patients need liver transplantation relatively soon.