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BACKGROUND/OBJECTIVES: We had developed the Unifying-Autoimmune-Pancreatitis-Criteria (U-AIP) to diagnose autoimmune pancreatitis (AiP) within the M-ANNHEIM classification of chronic pancreatitis. In 2011, International-Consensus-Diagnostic-Criteria (ICDC) to diagnose AiP have been published. We had applied the U-AIP long before the ICDC were available. The aims of the study were, first, to describe patients with AiP diagnosed by the U-AIP; second, to compare diagnostic accuracies of the U-AIP and other diagnostic systems; third, to evaluate the clinical applicability of the U-AIP. METHODS: From 1998 until 2008, we identified patients with AiP using U-AIP, Japanese-, Korean-, Asian-, Mayo-HISORt-, Revised-Mayo-HISORt- and Italian-criteria. We retrospectively verified the diagnosis by ICDC and Revised-Japanese-2011-criteria, compared diagnostic accuracies of all systems and evaluated all criteria in consecutive patients with pancreatitis (2009 until 2010, Pancreas-Outpatient-Clinic-Cohort, n = 84). We retrospectively validated our diagnostic approach in consecutive patients with a pancreatic lesion requiring surgery (Surgical-Cohort, n = 98). RESULTS: Overall, we identified 21 patients with AiP. Unifying-Autoimmune-Pancreatitis-Criteria and ICDC presented the highest diagnostic accuracies (each 98.8%), highest Youden indices (each 0.95238), and highest proportions of diagnosed patients (each n = 20/21, U-AIP/ICDC vs. other diagnostic systems, p < 0.05, McNemar test). In the Pancreas-Outpatient-Clinic-Cohort, seven patients were diagnosed with AiP (n = 6 by U-AIP, n = 1 by Asian-criteria). International-Consensus-Diagnostic-Criteria confirmed the diagnosis in these individuals. Based on partial fulfillment of U-AIP, AiP was initially suspected in 13% (n = 10/77) of remaining patients from the Pancreas-Outpatient-Clinic-Cohort. In the Surgical-cohort, we identified one patient with AiP by U-AIP and ICDC. CONCLUSIONS: Unifying-Autoimmune-Pancreatitis-Criteria revealed a satisfactory clinical applicability and offered an additional approach to diagnose AiP.
Assuntos
Doenças Autoimunes/diagnóstico , Pancreatite/diagnóstico , Adolescente , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Padrões de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto JovemRESUMO
BACKGROUND/AIMS: The prevalence and incidence of autoimmune pancreatitis (AiP) in those living in western countries are largely unknown. We aimed to determine the prevalence of AiP among patients with pancreatitis presenting to our tertiary referral center in Mannheim, Germany; and to estimate the incidence of AiP in the Southwest of Germany. METHODS: We performed a retrospective cross-sectional analysis and determined the prevalence of AiP in patients with acute pancreatitis (AP) or chronic pancreatitis (CP). Patients (n = 704; alcoholic pancreatitis n = 373, nonalcoholic pancreatitis n = 331) were stratified into the Retrospective-Pancreas-Cohort (RPC, period 1998-2008, n = 534) and the Pancreas-Clinic-Cohort (PCC, periods 2008-2010 and 2013-2014, n = 170, with detailed investigation for features of AiP). Diagnosis of AiP was established by International-Consensus-Diagnostic-Criteria and Unifying-Autoimmune-Pancreatitis-Criteria. RESULTS: In the RPC, the prevalence of AiP was 5.9% (n = 13/221) among individuals with nonalcoholic pancreatitis (n = 1/61 with AP, 1.6%; n = 12/160 with CP, 7.5%). In the PCC, the prevalence of AiP was 9.1% (n = 10/110) among patients with nonalcoholic pancreatitis (n = 2/24 with AP, 8.3%; n = 8/86 with CP, 9.3%), and 1.7% (n = 1/60) among subjects with alcoholic pancreatitis. We estimated the incidence of AiP with 0.29 per 100,000 population each year. CONCLUSION: The prevalence rate of AiP may account for 9% of patients with nonalcoholic pancreatitis but is almost never observed in patients with alcoholic pancreatitis. The incidence of AiP in Germany appears lower than 1 per 100,000 population.
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BACKGROUND & AIMS: Distinguishing between acute on chronic liver failure (ACLF) and decompensated liver cirrhosis is difficult due to a lack of pathological evidence. METHODS: A prospective single-center study investigated 174 patients undergoing liver transplantation due to acute decompensation of hepatitis B virus (HBV)-associated liver cirrhosis. Two groups were distinguished by the presence or absence of submassive hepatic necrosis (SMHN, defined as necrosis of 15-90% of the entire liver on explant). Core clinical features of ACLF were compared between these groups. Disease severity scoring systems were applied to describe liver function and organ failure. Serum cytokine profile assays, gene expression microarrays and immunohistochemical analyzes were used to study systemic and local inflammatory responses. RESULTS: SMHN was identified in 69 of 174 patients proven to have cirrhosis by histological means. Characteristic features of SMHN were extensive necrosis along terminal hepatic veins and spanning multiple adjacent cirrhotic nodules accompanied by various degrees of liver progenitor cell-derived regeneration, cholestasis, and ductular bilirubinostasis. Patients with SMHN presented with more severely impaired hepatic function, a higher prevalence of multiple organ failure (as indicated by higher CLIF-SOFA and SOFA scores) and a shorter interval between acute decompensation and liver transplantation than those without SMHN (p<0.01 for all parameters). Further analyzes based on serum cytokine profile assays, gene expression microarrays and immunohistochemical analyzes revealed higher levels of anti-inflammatory cytokines in patients with SMHN. CONCLUSIONS: SMHN is a critical histological feature of HBV-associated ACLF. Identification of a characteristic pathological feature strongly supports that ACLF is a separate entity in end-stage liver disease.
Assuntos
Insuficiência Hepática Crônica Agudizada/diagnóstico , Cirrose Hepática/diagnóstico , Fígado/patologia , Insuficiência Hepática Crônica Agudizada/cirurgia , Diagnóstico Diferencial , Progressão da Doença , Feminino , Seguimentos , Anticorpos Anti-Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Humanos , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Necrose/diagnóstico , Prognóstico , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
Chronic hepatitis C viral infection modulates complement. The aim of this study was to determine whether complement analysis predicts liver inflammation and fibrosis in patients with chronic hepatitis C. 50 chronic hepatitis C patients who underwent a liver biopsy were compared to 50 healthy controls and 35 patients with various liver diseases. Total plasma complement activity (CH50) in plasma was diminished in hepatitis C patients suggesting complement activation. This decrease correlated with increased necrosis (r = -0.24, p < 0.05), and patients with levels below the normal range had a higher METAVIR activity score reflecting enhanced inflammation. SC5b-9, a marker of complement activation, correlated with inflammation (r = 0.40, p < 0.05), activity (r = 0.42, p < 0.05), and fibrosis scores (r = 0.49, p < 0.05). Finally, the prevalence of C1q auto-antibodies was higher in hepatitis C patients, and their presence was associated with increased inflammation and seemed to affect fibrosis. We conclude that complement-induced liver inflammation contributes to fibrosis in patients with chronic hepatitis C.
Assuntos
Ativação do Complemento/imunologia , Hepatite C Crônica/imunologia , Hepatite C Crônica/patologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Necrose , Adulto , Autoanticorpos/imunologia , Biomarcadores/metabolismo , Complemento C1q/imunologia , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Feminino , Fibronectinas/metabolismo , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Humanos , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
The endogenous cannabinoids anandamide (N-arachidonoylethanolamide, AEA) and 2-arachidonoyl glycerol (2-AG) are upregulated during liver fibrogenesis and selectively induce cell death in hepatic stellate cells (HSCs), the major fibrogenic cells in the liver, but not in hepatocytes. In contrast to HSCs, hepatocytes highly express the AEA-degrading enzyme fatty acid amide hydrolase (FAAH) that protects them from AEA-induced injury. However, the role of the major 2-AG-degrading enzyme monoacylglycerol lipase (MGL) in 2-AG-induced hepatic cell death has not been investigated. In contrast to FAAH, MGL protein expression did not significantly differ in primary mouse hepatocytes and HSCs. Hepatocytes pretreated with selective MGL inhibitors were not sensitized towards 2-AG-mediated death, indicating a minor role for MGL in the cellular resistance against 2-AG. Moreover, while adenoviral MGL overexpression failed to render HSCs resistant towards 2-AG, FAAH overexpression prevented 2-AG-induced death in HSCs. Accordingly, 2-AG caused cell death in hepatocytes pretreated with the FAAH inhibitor URB597, FAAH(-/-) hepatocytes, or hepatocytes depleted of the antioxidant glutathione (GSH). Moreover, 2-AG increased reactive oxygen species production in hepatocytes after FAAH inhibition, indicating that hepatocytes are more resistant to 2-AG treatment due to high GSH levels and FAAH expression. However, 2-AG was not significantly elevated in FAAH(-/-) mouse livers in contrast to AEA. Thus, FAAH exerts important protective actions against 2-AG-induced cellular damage, even though it is not the major 2-AG degradation enzyme in vivo. In conclusion, FAAH-mediated resistance of hepatocytes against endocannabinoid-induced cell death may provide a new physiological concept allowing the specific targeting of HSCs in liver fibrosis.
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Amidoidrolases/metabolismo , Ácidos Araquidônicos/farmacologia , Endocanabinoides/farmacologia , Glicerídeos/farmacologia , Células Estreladas do Fígado/enzimologia , Hepatócitos/citologia , Hepatócitos/enzimologia , Monoacilglicerol Lipases/metabolismo , Amidoidrolases/genética , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Citoproteção/efeitos dos fármacos , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismoRESUMO
The endocannabinoid system is a crucial regulator of hepatic fibrogenesis. We have previously shown that the endocannabinoid anandamide (AEA) is a lipid mediator that blocks proliferation and induces death in hepatic stellate cells (HSCs), the main fibrogenic cell type in the liver, but not in hepatocytes. However, the effects of other endocannabinoids such as N-arachidonoyl dopamine (NADA) have not yet been investigated. The NADA-synthesizing enzyme tyrosine hydroxylase was mainly expressed in sympathetic neurons in portal tracts. Its expression pattern stayed unchanged in normal or fibrotic liver. NADA dose dependently induced cell death in culture-activated primary murine or human HSCs after 2-4 h, starting from 5 µM. Despite caspase 3 cleavage, NADA-mediated cell death showed typical features of necrosis, including ATP depletion. Although the cannabinoid receptors CB1, CB2, or transient receptor potential cation channel subfamily V, member 1 were expressed in HSCs, their pharmacological or genetic blockade failed to inhibit NADA-mediated death, indicating a cannabinoid-receptor-independent mechanism. Interestingly, membrane cholesterol depletion with methyl-ß-cyclodextrin inhibited AEA- but not NADA-induced death. NADA significantly induced reactive oxygen species formation in HSCs. The antioxidant glutathione (GSH) significantly decreased NADA-induced cell death. Similar to AEA, primary hepatocytes were highly resistant against NADA-induced death. Resistance to NADA in hepatocytes was due to high levels of GSH, since GSH depletion significantly increased NADA-induced death. Moreover, high expression of the AEA-degrading enzyme fatty acid amide hydrolase (FAAH) in hepatocytes also conferred resistance towards NADA-induced death, since pharmacological or genetic FAAH inhibition significantly augmented hepatocyte death. Thus the selective induction of cell death in HSCs proposes NADA as a novel antifibrogenic mediator.
Assuntos
Ácidos Araquidônicos/farmacologia , Moduladores de Receptores de Canabinoides/farmacologia , Morte Celular/efeitos dos fármacos , Dopamina/análogos & derivados , Endocanabinoides , Células Estreladas do Fígado/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Adenoviridae/genética , Fibras Adrenérgicas/efeitos dos fármacos , Fibras Adrenérgicas/enzimologia , Amidoidrolases/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Dopamina/farmacologia , Células Endoteliais/efeitos dos fármacos , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Humanos , Técnicas In Vitro , Células de Kupffer/efeitos dos fármacos , Cirrose Hepática/patologia , Cirrose Hepática/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Tirosina 3-Mono-Oxigenase/biossíntese , Cicatrização/efeitos dos fármacosRESUMO
The WHO ranks smoking and alcohol consumption as the first and third leading causes of the global burden of disease in industrialized countries, using disability-adjusted life years (DALYs) as a combined measure of premature death and disability. Smoking is responsible for 12.2% of all DALYs and alcohol consumption for 9.2%. For example in Germany, annually 110,000-140,000 humans die prematurely because of cigarette smoking and 40,000 because of alcohol drinking. In Europe and the USA, more than 20% of all hospitalized men and more than 9% of all hospitalized women suffer from alcohol-associated diseases. In Germany, about 2.0 million people in the age group 18-64 years (3.8% of all Germans) are alcohol abusers and 1.3 million people (2.4%) are alcohol-dependent. Alcohol can cause acute as well as chronic damage in nearly all body organs. Smoking damages also nearly every human body organ and is worldwide the most important single preventable health risk factor as well as the main cause for premature mortality in industrial countries. One third of the adult Germans as well as of the world population are active smokers; men smoke more frequently than women (34.0 vs. 25.1%). In this review a short overview will be given on the most important deleterious effects of alcohol and smoking. The most recent data about the pathophysiological relevance of non-alcoholic compounds of alcoholic beverages will also be discussed.
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Consumo de Bebidas Alcoólicas/efeitos adversos , Fumar/efeitos adversos , Bebidas , Humanos , Especificidade de ÓrgãosRESUMO
BACKGROUND & AIMS: Adverse alcohol effects in the liver involve oxidative metabolism, fat deposition and release of fibrogenic mediators, including TGF-beta. The work presents an assessment of liver damaging cross-talk between ethanol and TGF-beta in hepatocytes. METHODS: To investigate TGF-beta effects on hepatocytes, microarray analyses were performed and validated by qRT-PCR, Western blot analysis and immunohistochemistry. The cellular state was determined by assessing lactate dehydrogenase, cellular glutathione, reactive oxygen species, lipid peroxidation and neutral lipid deposition. RNA interference was used for gene silencing in vitro. RESULTS: TGF-beta is induced in mouse livers after chronic ethanol insult, enhances ethanol induced oxidative stress and toxicity towards cultured hepatocytes plus induces lipid-, oxidative stress metabolism- and fibrogenesis-gene expression signatures. Interestingly, TGF-beta down-regulates alcohol metabolizing enzyme Adh1 mRNA in cultured hepatocytes and liver tissue from TGF-beta transgenic mice via the ALK5/Smad2/3 signalling branch, with Smad7 as a potent negative regulator. ADH1 deficiency is a determining factor for the increased lipid accumulation and Cyp2E1 dependent toxicity in liver cells upon alcohol challenge. Further, ADH1 expression was decreased during liver damage in an intragastric ethanol infusion mouse model. CONCLUSION: In the presence of ethanol, TGF-beta displays pro-steatotic action in hepatocytes via decreasing ADH1 expression. Low ADH1 levels are correlated with enhanced hepatocyte damage upon chronic alcohol consumption by favoring secondary metabolic pathways.
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Álcool Desidrogenase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Regulação para Baixo/fisiologia , Etanol/efeitos adversos , Hepatócitos/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Hepatócitos/patologia , Metabolismo dos Lipídeos/fisiologia , Peroxidação de Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/fisiologia , Proteína Smad7/metabolismoRESUMO
UNLABELLED: It is unknown whether transforming growth factor beta1 (TGF-beta1) signaling uniformly participates in fibrogenic chronic liver diseases, irrespective of the underlying origin, or if other cytokines such as interleukin (IL)-13 share in fibrogenesis (e.g., due to regulatory effects on type I pro-collagen expression). TGF-beta1 signaling events were scored in 396 liver tissue samples from patients with diverse chronic liver diseases, including hepatitis B virus (HBV), hepatitis C virus (HCV), Schistosoma japonicum infection, and steatosis/steatohepatitis. Phospho-Smad2 staining correlated significantly with fibrotic stage in patients with HBV infection (n = 112, P < 0.001) and steatosis/steatohepatitis (n = 120, P < 0.01), but not in patients with HCV infection (n = 77, P > 0.05). In tissue with HBx protein expression, phospho-Smad2 was detectable, suggesting a functional link between viral protein expression and TGF-beta1 signaling. For IL-13, immunostaining correlated with fibrotic stage in patients with HCV infection and steatosis/steatohepatitis. IL-13 protein was more abundant in liver tissue lysates from three HCV patients compared with controls, as were IL-13 serum levels in 68 patients with chronic HCV infection compared with 20 healthy volunteers (72.87 +/- 26.38 versus 45.41 +/- 3.73, P < 0.001). Immunohistochemistry results suggest that IL-13-mediated liver fibrogenesis may take place in the absence of phospho-signal transducer and activator of transcription protein 6 signaling. In a subgroup of patients with advanced liver fibrosis (stage > or =3), neither TGF-beta nor IL-13 signaling was detectable. CONCLUSION: Depending on the cause of liver damage, a predominance of TGF-beta or IL-13 signaling is found. TGF-beta1 predominance is detected in HBV-related liver fibrogenesis and IL-13 predominance in chronic HCV infection. In some instances, the underlying fibrogenic mediator remains enigmatic.
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Interleucina-13/fisiologia , Cirrose Hepática/etiologia , Fator de Crescimento Transformador beta1/fisiologia , Humanos , Técnicas In Vitro , Hepatopatias/etiologiaRESUMO
OBJECTIVE: Hepatic stellate cells only produce fibronectin isoforms in disease states. The isoform-defining domains can be detected in the blood circulation. This study examines whether circulating levels of fibronectin isoforms show a relationship with liver fibrosis on histology in patients with chronic hepatitis C. MATERIAL AND METHODS: In a prospective study, 50 patients with chronic hepatitis C who underwent a liver biopsy were compared to 50 matched controls and 35 patients with other liver conditions. RESULTS: Circulating levels of the fibronectin isoforms were significantly higher in patients with chronic hepatitis C compared to healthy controls [oncofetal fibronectin (oFN) 2.45 +/- 0.17 versus 1.76 +/- 0.16 mg/l, P < 0.005; extra domain-A (EDA) 1.05 +/- 0.06 versus 0.86 +/- 0.06 mg/l, P < 0.05; and extra domain-B (EDB) 14.55 +/- 0.74 versus 9.31 +/- 0.58 mg/l, P < 0.001], even though total fibronectin was lower (198.9 +/- 3.5 versus 343.6 +/- 14.5 mg/l, P < 0.001). A correlation with the fibrosis score was found for both oFN (r = 0.46, P < 0.005) and EDA (r = 0.51, P < 0.001). The combination of an elevation in both markers (oFN and EDA) in the upper quartile was associated with a specificity of > 99% for predicting significant fibrosis (stages 2-4) and 95% for predicting advanced fibrosis (stages 3-4). A combination of decreased values in the lowest tertile for both markers had a specificity of 94% for excluding significant fibrosis. Based on these findings, 30% of the patients scheduled for a liver biopsy could be correctly classified as having or not having significant fibrosis. The remainder would have to proceed with a biopsy. CONCLUSION: Circulating fibronectin isoforms produced by activated stellate cells represent a viable marker for the presence of significant fibrosis or a lack thereof.
Assuntos
Fibronectinas/sangue , Hepatite C Crônica/complicações , Cirrose Hepática/sangue , Cirrose Hepática/etiologia , Isoformas de Proteínas/sangue , Adulto , Biomarcadores/sangue , Biópsia por Agulha , Estudos de Casos e Controles , Estudos Transversais , Feminino , Células Estreladas do Fígado/metabolismo , Hepatite C Crônica/patologia , Humanos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos TestesRESUMO
OBJECTIVE: New technology has considerably advanced the diagnosis of small-bowel pathology. However, its significance in clinical algorithms has not yet been fully assessed. The aim of the present analysis was to compare the diagnostic utility and yield of video-capsule enteroscopy (VCE) to that of magnetic resonance imaging (MRI) in patients with suspected or established Crohn's disease (Group I), obscure gastrointestinal blood loss (Group II), or suspected tumors (Group III). MATERIAL AND METHODS: Forty-six out of 182 patients who underwent both modalities were included: 21 in Group I, 20 in Group II, and five in Group III. Pathology was assessed in three predetermined sections of the small bowel (upper, middle, and lower). The McNemar and Wilcoxon tests were used for statistical analysis. RESULTS: In Group I, lesions were found by VCE in nine of the 21 patients and by MRI in six. In five patients, both modalities showed pathology. In Group II, pathological changes were detected in 11 of the 20 patients by VCE and in eight patients by MRI. In five cases, pathology was found with both modalities. In Group III, neither modality showed small-bowel pathology. For the patient groups combined, diagnostic yield was 43% with VCE and 30% with MRI. The diagnostic yield of VCE was superior to that of MRI in the upper small bowel in both Groups I and II. CONCLUSION: VCE is superior to MRI for the detection of lesions related to Crohn's disease or obscure gastrointestinal bleeding in the upper small bowel.
Assuntos
Endoscopia por Cápsula , Doença de Crohn/diagnóstico , Hemorragia Gastrointestinal/diagnóstico , Neoplasias Intestinais/diagnóstico , Intestino Delgado/patologia , Imageamento por Ressonância Magnética/métodos , Adolescente , Adulto , Idoso , Meios de Contraste , Doença de Crohn/patologia , Feminino , Gadolínio DTPA , Hemorragia Gastrointestinal/patologia , Humanos , Neoplasias Intestinais/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estatísticas não ParamétricasRESUMO
Alcoholic beverages contain numerous non-alcoholic compounds that could have beneficial or pathological effects. For example, up to now in beer more than 2,000 and in wine more than 1,000 organic and inorganic constituents have been identified. Whereas the role of alcohol (ethanol) in the development of pancreatic diseases - in particular acute and chronic pancreatitis - has been intensively investigated, only little is known about the effects of non-alcoholic compounds in this context. Some of the non-alcoholic constituents have been shown to be biologically active, although discussions of the results in appropriate publications were often not performed with regard to their consumption as a mixture in alcoholic beverages. In this article we provide an overview about the newest data concerning the effect of non-alcoholic constituents of alcoholic beverages, especially of beer, on pancreatic secretion and their possible role in alcoholic pancreatitis. The data indicate that non-alcoholic constituents of beer stimulate pancreatic enzyme secretion in humans and rats, at least in part, by direct action on pancreatic acinar cells. However, there is accumulating evidence that non-alcoholic compounds of alcoholic beverages exert different effects on the pancreas. The effects and mechanisms of most single compounds and their combinations are still unknown and thus caution is required in attempting to draw firm conclusions on the effect of non-alcoholic compounds of alcoholic beverages on defining alcoholic etiology of pancreatitis.
Assuntos
Bebidas Alcoólicas/efeitos adversos , Pâncreas/patologia , Animais , Cerveja/efeitos adversos , Humanos , Pâncreas/metabolismo , Pancreatite Alcoólica/patologia , Transdução de SinaisRESUMO
AIM: Application of a drug delivery device for transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). Clinical and radiological treatment assessment. PATIENTS AND METHODS: 24 patients with liver cirrhosis and uni- or multifocal HCC underwent TACE with doxorubicin beads (DC Bead). The underly-ing cause of liver cirrhosis was hepatitis (A: n = 7; B: n = 10) or alcohol consumption (n = 7). Patients presented with Child Pugh stage A (n = 15) and B (n = 9). The mean intrahepatic tumor size, considering the sum of diameters of all lesions treated, was 3.83 cm (+/-2.4). Liver function and hematological parameters were documented before and after each TACE. Magnetic resonance imaging (MRI) was performed before and 4 weeks after TACE. The T1-w 3D volume-interpolated breathhold exam (VIBE) sequence was applied for evaluation of the therapy response. RESULTS: 24 patients received a total number of 69 TACE treatments with DC beads (mean dose 160 mg). The elevation of liver function parameters after treatment did not affect the patients' clinical condition. The T1-w VIBE sequence proved very valuable for assessment of the intrahepatic tumor spread. Post-contrast images enabled delineation of the viable HCC lesions, hence facilitating the selective transcatheter approach. The tumor marker a-fetoprotein (AFP), available in 19/24 patients, dropped from 347.5 to 299.5 ng/ml, without being a reliable predictor of treatment response. A decrease of tumor size after TACE from 3.83 (+/-2.40) to 3.01 cm (+/-2.67; p < 0.0001) was evident on the T1w-VIBE sequences. The mean follow-up period was 30 months. At the time of data analysis, 10 (42%) out of 14 patients were alive. CONCLUSION: TACE with DC beads in HCC offers a safe and efficient treatment resulting in tumor response within a very short time.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/instrumentação , Doxorrubicina/administração & dosagem , Neoplasias Hepáticas/terapia , Neoplasias Primárias Múltiplas/terapia , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/efeitos adversos , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Preparações de Ação Retardada , Doxorrubicina/efeitos adversos , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Testes de Função Hepática , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Imageamento por Ressonância Magnética , Masculino , Microesferas , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Primárias Múltiplas/mortalidade , Neoplasias Primárias Múltiplas/patologia , Estudos Retrospectivos , Taxa de Sobrevida , alfa-Fetoproteínas/análiseRESUMO
Nerve growth factor (NGF), a survival factor for neurons enforces pain by sensitizing nociceptors. Also in the pancreas, NGF was associated with pain and it can stimulate the proliferation of pancreatic cancer cells. Hepatic stellate cells (HSC) respond to NGF with apoptosis. Transforming growth factor (TGF)-beta, one of the strongest pro-fibrogenic activators of pancreatic stellate cells (PSC) induced NGF and its two receptors in an immortalized human cell line (ihPSC) and primary rat PSC (prPSC) as determined by RT-PCR, western blot, and immunofluorescence. In contrast to HSC, PSC expressed both NGF receptors, although p75(NTR) expression was weak in prPSC. In contrast to ihPSC TGF-beta activated both Smad signaling cascades in prPSC. NGF secretion was diminished by the activin-like kinase (ALK)-5 inhibitor SB431542, indicating the predominant role of ALK5 in activating the NGF system in PSC. While NGF did not affect proliferation or survival of PSC it induced expression of Inhibitor of Differentiation-1. We conclude that under conditions of upregulated TGF-beta, like fibrosis, NGF levels will also increase in PSC which might contribute to pancreatic wound healing responses.
Assuntos
Fator de Crescimento Neural/metabolismo , Pâncreas/citologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Proteína 1 Inibidora de Diferenciação/genética , Proteína 1 Inibidora de Diferenciação/metabolismo , Masculino , Fator de Crescimento Neural/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Proteínas Serina-Treonina Quinases/genética , Ratos , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/genética , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
BACKGROUND: Recently, two functional IL18 promoter variants, -607C>A (rs1946518) and -137G>C (rs187238), were associated with viral clearance in patients with hepatitis C. The present study focused on their relevance for treatment response. METHODS: Seven hundred fifty-seven chronically infected European patients and 791 controls were enrolled in the study. IL18 genotyping was performed by allele-specific PCR. Liver histology was available in 67.9%. RESULTS: Genotype and allele frequencies were equally distributed in patients and controls. No significant association with various disease characteristics was observed. However, when comparing patients with sustained virological response (SR) and non-SR, statistically significant associations were found for both variants (p = 0.0416 and p = 0.0274, respectively). In viral genotype 1, the -607A allele was positively associated with treatment response (p = 0.0190; OR 1.537; 95% CI, 1.072-2.205) and the -137G allele with a higher rate of nonresponse (p = 0.0302; OR 1.524; 95% CI, 1.040-2.233). CONCLUSIONS: The association of IL18 variants with treatment response in genotype 1 hepatitis C patients implies a predictive and modifying role of these genetic variants.
Assuntos
Hepacivirus/efeitos dos fármacos , Hepacivirus/imunologia , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/genética , Interleucina-18/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Genótipo , Hepacivirus/patogenicidade , Hepatite C Crônica/imunologia , Hepatite C Crônica/fisiopatologia , Hepatite C Crônica/terapia , Humanos , Interferon-alfa/administração & dosagem , Interleucina-18/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Prognóstico , Regiões Promotoras Genéticas/imunologia , RNA Viral/análise , Ribavirina/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: Various alcoholic beverages have different effects on pancreatic enzyme secretion in vivo and in vitro. Recently we demonstrated that beer dose-dependently induces amylase release of rat pancreatic acinar cells, whereas pure ethanol and other alcoholic beverages have no effect. The aims of this study were to: (1) investigate the involved signaling pathways in the beer-induced enzyme secretion of rat pancreatic acinar cells and (2) characterize the responsible nonalcoholic compounds from beer. METHODS: Rat pancreatic AR4-2J cells were differentiated by dexamethasone treatment for 72 hours. After incubation of cells with 1 to 10% (v/v) beer (containing 4.7% v/v ethanol) in the absence or presence of the maximal effective concentration of cholecystokinin (CCK) (100 nM) for 60 minutes, protein secretion was measured using amylase activity assay. To study the involved signaling pathways, cells were pretreated with selective inhibitors or the fluorescent dye Fura2/AM for 15 and 30 minutes, respectively. To characterize the responsible compounds, beer was distilled, lyophilized, dialyzed, or treated with proteases prior stimulation of the cells. Extract of barley was prepared by boiling the crop and subsequent filtration. RESULTS: Stimulation with 5% and 10% beer (v/v) significantly (p < 0.001) increased maximally CCK-induced amylase by 55 +/- 25% and 56 +/- 37%, respectively. By using selective antagonists, we found that inhibition of phospholipase C (PLC) and inositol 1,4,5-trisphosphate-receptor binding reduced beer-induced amylase release, whereas inhibition of protein kinase C, adenylate cyclase, and protein kinase A had no significant effect. Using the fluorescent Ca(2+) indicator Fura-2/AM revealed that beer induces an increase of cytosolic free Ca(2+) concentration. Stimulation of AR4-2J cells with preproducts of beer and fermented glucose indicated that the stimulatory substances from beer derived from barley and are not produced during alcoholic fermentation. Furthermore, the stimulants from beer are thermostable, nonvolatile substances with a molecular weight higher than 15 kDa. CONCLUSIONS: Beer-induced enzyme secretion of AR4-2J cells is, at least in part, mediated by the activation of PLC and subsequent Ca(2+) release from internal stores. However, the additive effect of beer on CCK-induced amylase release suggests that additional signaling pathways are involved. The yet unknown stimulants of pancreatic enzyme secretion originate from barley and their stimulatory potential is maintained during the process of malting and brewing.
Assuntos
Cerveja/análise , Pâncreas/efeitos dos fármacos , Pâncreas/enzimologia , Transdução de Sinais/efeitos dos fármacos , Amilases/metabolismo , Animais , Cálcio/metabolismo , Linhagem Celular , Quelantes/farmacologia , Colecistocinina/farmacologia , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Fermentação , Liofilização , Glucose/farmacologia , Hordeum/química , Extratos Vegetais/farmacologia , RatosRESUMO
BACKGROUND: In contrast to pure ethanol, the effect of alcoholic beverages on the exocrine pancreas is greatly unknown. Besides ethanol, alcoholic beverages contain numerous nonalcoholic constituents which might have pathophysiological effects on the pancreas. The aim of the present study was to investigate whether some commonly used alcoholic beverages and pure ethanol influence the main function of rat pancreatic acinar cells, i.e., enzyme output in vitro. METHODS: Rat pancreatic AR4-2J cells were differentiated by dexamethasone treatment for 72 hours and freshly isolated pancreatic acini were prepared from Sprague-Dawley rats using collagenase digestion. After incubation of cells in the absence or presence of 1 to 10% (v/v) beer (containing 4.7% v/v ethanol), 10% (v/v) wine (containing 10.5 to 12.5% v/v ethanol), 10% (v/v) hard liquor (such as whisky, rum, and gin), or of the corresponding ethanol concentrations (4.03 to 80.6 mM) for 60 minutes, protein secretion was measured using amylase activity assay. RESULTS: Incubation of AR4-2J cells with beer caused a dose-dependent stimulation of basal amylase secretion that was significant at doses of beer above 0.5% (v/v). Stimulation with 10% (v/v) beer induced 92.7 +/- 25.2% of maximal amylase release in response to the most effective cholecystokinin (CCK) concentration (100 nM). In contrast, ethanol (up to 80.6 mM) did neither stimulate nor inhibit basal amylase release. Lactate dehydrogenase measurement after treatment of AR4-2J cells with beer for 24 hours indicated that the increase of amylase release was not due to cell membrane damage. Wine and hard liquor had no effect on basal amylase secretion neither diluted to the ethanol concentration of beer nor undiluted. In freshly isolated rat pancreatic acinar cells beer dose-dependently stimulated amylase secretion in a similar manner as in AR4-2J cells. CONCLUSIONS: Our data demonstrate that beer dose-dependently increases amylase output. Since neither ethanol nor the other alcoholic beverages tested caused stimulation of amylase release, our findings indicate that nonalcoholic constituents specific for beer are responsible for this increase. These as yet unknown compounds have to be identified and considered in further studies of ethanol-induced pathological and functional changes of the pancreas.
Assuntos
Bebidas Alcoólicas , Amilases/metabolismo , Cerveja , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Pâncreas/metabolismo , Vinho , Animais , Linhagem Celular , Separação Celular , Ácido Gástrico/metabolismo , Técnicas In Vitro , L-Lactato Desidrogenase/metabolismo , Masculino , Maleatos/farmacologia , Pâncreas/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ácido Succínico/farmacologiaRESUMO
Although excessive consumption of ethanol in alcoholic beverages causes multi-organ damage, moderate consumption, particularly of red wine, is protective against all-cause mortality. These protective effects could be due to one or many components of the complex mixture of bioactive compounds present in red wine including flavonols, monomeric and polymeric flavan-3-ols, highly colored anthocyanins as well as phenolic acids and the stilbene polyphenol, resveratrol. The therapeutic potential of resveratrol, firstly in cancer chemoprevention and then later for cardioprotection, has stimulated many studies on the possible mechanisms of action. Further indications for resveratrol have been developed, including the prevention of age-related disorders such as neurodegenerative diseases, inflammation, diabetes, and cardiovascular disease. These improvements are remarkably similar yet there is an important dichotomy: low doses improve cell survival as in cardio- and neuro-protection yet high doses increase cell death as in cancer treatment. Fewer studies have examined the responses to other components of red wine, but the results have, in general, been similar to resveratrol. If the nonalcoholic constitutents of red wine are to become therapeutic agents, their ability to get to the sites of action needs to be understood. This mini-review summarizes recent studies on the possible mechanisms of action, potential therapeutic uses, and bioavailability of the nonalcoholic constituents of alcoholic beverages, in particular resveratrol and other polyphenols.
Assuntos
Bebidas Alcoólicas/análise , Antioxidantes/farmacologia , Flavonoides/farmacologia , Fenóis/farmacologia , Estilbenos/farmacologia , Animais , Antioxidantes/análise , Antioxidantes/farmacocinética , Flavonoides/análise , Saúde , Humanos , Absorção Intestinal , Fenóis/análise , Polifenóis , Resveratrol , Estilbenos/análise , Estilbenos/farmacocinéticaRESUMO
Although the molecular machinery and mechanism of cell secretion in acinar cells of the exocrine pancreas is well documented and clear, only recently has the pharmacophysiology of pancreatic exocrine secretion come to light. Therefore, we focus in this article on the current understanding of the pharmacophysiology of pancreatic exocrine secretion. The pancreatic secretory response to ingestion of a meal is mediated via a complex interplay of neural, humoral and paracrine mediators. A major role in the control of the intestinal phase of pancreatic secretion is attributed to vago-vagal enteropancreatic reflexes. In the scheme of this control mechanism, afferents originating in the duodenal mucosa, and efferents mediating central input on the pancreatic ganglia, activate intrapancreatic postganglionic neurons. Experiments utilizing specific receptor antagonists demonstrate the involvement of both muscarinic M1 and M3 receptors expressed in pancreatic acinar cells. Cholecystokinin (CCK), originally implicated in the humoral secretion of pancreatic enzymes, through a direct action on acinar CCK receptors, is also essential to the enteropancreatic reflex mechanism. CCK stimulation of the exocrine pancreatic secretion through excitation of sensory afferents of the enteropancreatic reflexes, is a paracrine mode of CCK action, and is probably the only one in humans and the predominant one in rats. In dogs, however, CCK acts on the pancreas via both the humoral and a paracrine route. More recent experiments suggest further possible sites of CCK action. Additionally, at the brain stem, vago-vagal enteropancreatic reflexes may be modulated by input from higher brain centres, particularly the hypothalamic-cholinergic system in the tonic stimulation of preganglionic neurons of the dorsal motor nucleus of the vagus projecting into the pancreas.
Assuntos
Colecistocinina/metabolismo , Pâncreas Exócrino/metabolismo , Reflexo/fisiologia , Animais , Cães , Cobaias , Humanos , Camundongos , Pâncreas Exócrino/citologia , Pâncreas Exócrino/inervação , Piperidinas/metabolismo , Pirenzepina/análogos & derivados , Pirenzepina/metabolismo , Ratos , Receptor Muscarínico M1/antagonistas & inibidores , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M3/antagonistas & inibidores , Receptor Muscarínico M3/metabolismo , Receptores da Colecistocinina/efeitos dos fármacos , Receptores da Colecistocinina/metabolismo , Nervo Vago/efeitos dos fármacos , Nervo Vago/metabolismoRESUMO
Recent evidence suggests that Helicobacter pylori infections play a role in the pathogenesis of a variety of skin diseases. The best evidence for such a link is found for two diseases: chronic urticaria and immune thrombocytopenic purpura. Other diseases that have a purported, but not yet proven link to H. pylori are: cutaneous pruritus, Behçet's disease, nodular prurigo and lichen planus. Based on the current evidence for a relationship between H. pylori and chronic idiopathic thrombocytopenic purpura the European Helicobacter Study Group consensus 2007 recommended the eradication of Helicobacter pylori infection in affected patients. Lastly, single or few case reports have documented associations between Helicobacter pylori infection and rosacea, aphthous stomatitis, atopic dermatitis, alopecia areata, Schoenlein-Henoch purpura and Sjögren syndrome, but these are only descriptive in nature. Systematic studies examining the relationship between dermatologic entities and infection with H. pylori and documentation of the effect of H. pylori eradication are needed to further our understanding on this topic.