RESUMEN
As of now, there exists no established therapy for ELP. Retinoids, which are standard in treating cutaneous LP, do not exhibit positive effects in ELP. While topical glucocorticosteroids often yield favorable responses in esophageal inflammation, some cases prove recalcitrant or refractory. In such instances, various immunosuppressive therapies have been attempted with variable success.This report details a severe case of ELP that showed resistance to prednisolone, acitretin, alitretinoin, adalimumab, tacrolimus, hydroxychloroquine plus mycophenolate mofetil, and cyclophosphamide. The initiation of the JAK inhibitor tofacitinib induced an impressive clinical, endoscopic, and histological remission. This positive response to a JAK inhibitor is discussed in the context of our evolving understanding of the immune-mediated pathogenesis of this disease.
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Liquen Plano , Piperidinas , Pirimidinas , Pirroles , Humanos , Piperidinas/uso terapéutico , Piperidinas/efectos adversos , Pirimidinas/uso terapéutico , Pirimidinas/efectos adversos , Liquen Plano/tratamiento farmacológico , Liquen Plano/inducido químicamente , Liquen Plano/patología , Resultado del Tratamiento , Pirroles/uso terapéutico , Pirroles/efectos adversos , Enfermedades del Esófago/tratamiento farmacológico , Enfermedades del Esófago/inducido químicamente , Enfermedades del Esófago/patología , Inducción de Remisión , Persona de Mediana Edad , Masculino , FemeninoRESUMEN
It is unclear to what extent systemic arterial blood pressure influences portal pressure. This relationship is clinically important as drugs, which are conventionally used for therapy of portal hypertension, may also influence systemic arterial blood pressure. This study investigated the potential correlation between mean arterial (MAP) and portal venous pressure (PVP) in rats with healthy livers. In a rat model with healthy livers, we investigated the effect of manipulation of MAP on PVP. Interventions consisted of 0.9% NaCl (group 1), 0.1 mg/kg body weight (bw) Sildenafil (low dose), an inhibitor of phosphodiesterase-5 (group 2), and 1.0 mg/kg bw Sildenafil (high dose, group 3) in 600 µL saline injected intravenously. Norepinephrine was used to increase MAP in animals with circulatory failure while PVP was monitored. Injection of the fluids induced a transient drop in MAP and PVP, probably due to a reversible cardiac decompensation. The drop in MAP and drop in PVP are significantly correlated. The time lag between change in MAP and change in PVP by 24 s in all groups suggests a cause-and-effect relationship. Ten minutes after the injection of the fluid, cardiac function was normalized. Thereafter, MAP gradually decreased. In the NaCl group, PVP decreases by 0.485% for a 1% drop of MAP, by 0.550% in the low-dose sildenafil group, and by 0.651% in the high-dose sildenafil group (p < 0.05 for difference group two vs. group one, group three vs. group one, and group three vs. group two). These data suggest that Sildenafil has an inherent effect on portal pressure that exceeds the effect of MAP. Injection of norepinephrine led to a sudden increase in MAP followed by an increase in PVP after a time lag. These data show a close relationship between portal venous pressure and systemic arterial pressure in this animal model with healthy livers. A change in MAP is consequently followed by a change in PVP after a distinct time lag. This study, furthermore, suggests that Sildenafil influences portal pressure. Further studies should be performed in a model with cirrhotic livers, as these may be important in the evaluation of vasoactive drugs (e.g., PDE-5-inhibitors) for therapy of portal hypertension.
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Hipertensión Portal , Presión Portal , Ratas , Animales , Citrato de Sildenafil/farmacología , Hemodinámica , Hipertensión Portal/tratamiento farmacológico , Modelos Animales , Norepinefrina/farmacologíaRESUMEN
An involvement of the esophagus in patients with lichen planus was described for the first time in 1982. Ever since, it has been seen as a rarity. However, studies over the last 10 years have shown a higher prevalence than expected. It may even be supposed that esophageal lichen planus (ELP) is more common than eosinophilic esophagitis. ELP mostly affects middleaged women. The principal symptom is dysphagia. Endoscopically, ELP is characterized by denudation and tearing of the mucosa, trachealization and hyperkeratosis and esophageal stenosis may occur in patients with long courses of the disease. Histologic findings including mucosal detachment, T-lymphocytic infiltrate, intraepithelial apoptosis (civatte bodies) and dyskeratosis are crucial. Direct immunofluorescence shows fibrinogen deposits along the basement membrane zone. So far, there is no well-established therapy but a treatment with topic steroids is effective in 2/3 of the patients. Common therapy of lichen planus of the skin seems to be ineffective for treatment of ELP. Symptomatic esophageal stenosis should be endoscopically dilated. ELP joins the group of "new" immunologic diseases of the esophagus.
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Trastornos de Deglución , Estenosis Esofágica , Liquen Plano , Humanos , Femenino , Liquen Plano/diagnóstico , Liquen Plano/patología , Piel/patologíaRESUMEN
Lichen planus (LP) is a frequent, chronic inflammatory disease involving the skin, mucous membranes and/or skin appendages. Esophageal involvement in lichen planus (ELP) is a clinically important albeit underdiagnosed inflammatory condition. This narrative review aims to give an overview of the current knowledge on ELP, its prevalence, pathogenesis, clinical manifestation, diagnostic criteria, and therapeutic options in order to provide support in clinical management. Studies on ELP were collected using PubMed/Medline. Relevant clinical and therapeutical characteristics from published patient cohorts including our own cohort were extracted and summarized. ELP mainly affects middle-aged women. The principal symptom is dysphagia. However, asymptomatic cases despite progressed macroscopic esophageal lesions may occur. The pathogenesis is unknown, however an immune-mediated mechanism is probable. Endoscopically, ELP is characterized by mucosal denudation and tearing, trachealization, and hyperkeratosis. Scarring esophageal stenosis may occur in chronic courses. Histologic findings include mucosal detachment, T-lymphocytic infiltrations, epithelial apoptosis (Civatte bodies), dyskeratosis, and hyperkeratosis. Direct immuno-fluorescence shows fibrinogen deposits along the basement membrane zone. To date, there is no established therapy. However, treatment with topical steroids induces symptomatic and histologic improvement in two thirds of ELP patients in general. More severe cases may require therapy with immunosuppressors. In symptomatic esophageal stenosis, endoscopic dilation may be necessary. ELP may be regarded as a precancerous condition as transition to squamous cell carcinoma has been documented in literature. ELP is an underdiagnosed yet clinically important differential diagnosis for patients with unclear dysphagia or esophagitis. Timely diagnosis and therapy might prevent potential sequelae such as esophageal stenosis or development of invasive squamous cell carcinoma. Further studies are needed to gain more knowledge about the pathogenesis and treatment options.
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Carcinoma de Células Escamosas , Trastornos de Deglución , Enfermedades del Esófago , Estenosis Esofágica , Liquen Plano , Humanos , Persona de Mediana Edad , Femenino , Enfermedades del Esófago/diagnóstico , Enfermedades del Esófago/terapia , Enfermedades del Esófago/patología , Trastornos de Deglución/etiología , Liquen Plano/diagnóstico , Liquen Plano/tratamiento farmacológico , Carcinoma de Células Escamosas/complicacionesRESUMEN
The NO-cGMP signal transduction pathway plays a crucial role in tone regulation in hepatic sinusoids and peripheral blood vessels. In a cirrhotic liver, the key enzymes endothelial NO synthase (eNOS), soluble guanylate cyclase (sGC), and phosphodiesterase-5 (PDE-5) are overexpressed, leading to decreased cyclic guanosine-monophosphate (cGMP). This results in constriction of hepatic sinusoids, contributing about 30% of portal pressure. In contrast, in peripheral arteries, dilation prevails with excess cGMP due to low PDE-5. Both effects eventually lead to circulatory dysfunction in progressed liver cirrhosis. The conventional view of portal hypertension (PH) pathophysiology has been described using the "NO-paradox", referring to reduced NO availability inside the liver and elevated NO production in the peripheral systemic circulation. However, recent data suggest that an altered availability of cGMP could better elucidate the contrasting findings of intrahepatic vasoconstriction and peripheral systemic vasodilation than mere focus on NO availability. Preclinical and clinical data have demonstrated that targeting the NO-cGMP pathway in liver cirrhosis using PDE-5 inhibitors or sGC stimulators/activators decreases intrahepatic resistance through dilation of sinusoids, lowering portal pressure, and increasing portal venous blood flow. These results suggest further clinical applications in liver cirrhosis. Targeting the NO-cGMP system plays a role in possible reversal of liver fibrosis or cirrhosis. PDE-5 inhibitors may have therapeutic potential for hepatic encephalopathy. Serum/plasma levels of cGMP can be used as a non-invasive marker of clinically significant portal hypertension. This manuscript reviews new data about the role of the NO-cGMP signal transduction system in pathophysiology of cirrhotic portal hypertension and provides perspective for further studies.
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GMP Cíclico/metabolismo , Hipertensión Portal/metabolismo , Hipertensión Portal/terapia , Cirrosis Hepática/metabolismo , Cirrosis Hepática/terapia , Sistemas de Mensajero Secundario , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Humanos , Hipertensión Portal/patología , Cirrosis Hepática/patología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismoRESUMEN
OBJECTIVES: Chronic diarrhea, villous atrophy and/or increased intraepithelial T-lymphocytes (IEL) occur in many inflammatory disorders including celiac disease (CD). However, a definite diagnosis is difficult to make in some patients despite an extensive diagnostic work-up. Clinical outcomes and histological phenotypes of such patients we refer to as unclassifiable enteropathy (UEP) remain unclear. MATERIAL AND METHODS: We performed a retrospective single-center analysis of patients with chronic diarrhea, weight loss and increased IEL. Patients with defined etiologies including infections, CD, drugs, immunodeficiencies or neoplasms were excluded. Clinical and histologic/immunophenotypic parameters were analyzed. RESULTS: Nine patients with UEP were identified. Small intestinal damage ranged from minor villous abnormalities to complete atrophy while all patients displayed high numbers of CD103+ CD8+ IELs. In contrast to CD, these CD8+ T cells were not confined to the surface epithelium, but also infiltrated the crypts. Additional histological features included apoptotic crypt epithelial cells and mixed inflammatory infiltrates in the tunica propria. Involvement of other segments of the gastrointestinal tract was observed in 7/9 patients. A clonal intestinal T-cell lymphoproliferative disorder developed in 2 patients, one of which had a fatal disease course. The majority of patients responded to corticosteroids, while response to immunosuppressive medications yielded heterogeneous results. CONCLUSIONS: We report a patient population with 'difficult-to-classify' enteropathies characterized by various degrees of villous atrophy and strongly increased intraepithelial CD103+ CD8+ T cells in the small intestine which harbor an increased risk for T-cell lymphoproliferative disorders. Clinical course, histology, and response to immunosuppressive therapy all suggest an autoimmune pathogenesis.
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Linfocitos T CD8-positivos , Enfermedad Celíaca , Enfermedad Celíaca/diagnóstico , Humanos , Mucosa Intestinal , Intestino Delgado , Estudios RetrospectivosRESUMEN
An involvement of the esophagus in patients with lichen planus was described for the first time in 1982. Ever since, it has been seen as a rarity. However, studies over the last 10 years have shown a higher prevalence than expected. It may even be supposed that esophageal lichen planus (ELP) is more common than eosinophilic esophagitis. ELP mostly affects middle-aged women. The principal symptom is dysphagia. Endoscopically, ELP is characterized by denudation and tearing of the mucosa, trachealization and hyperkeratosis and esophageal stenosis may occur in patients with long courses of the disease. Histologic findings including mucosal detachment, T-lymphocytic infiltrate, intraepithelial apoptosis (civatte bodies) and dyskeratosis are crucial. Direct immunofluorescence shows fibrinogen deposits along the basement membrane zone. So far, there is no well-established therapy but a treatment with topic steroids is effective in 2/3 of the patients. Common therapy of lichen planus of the skin seems to be ineffective for treatment of ELP. Symptomatic esophageal stenosis should be endoscopically dilated. ELP joins the group of "new" immunologic diseases of the esophagus.
Asunto(s)
Trastornos de Deglución , Enfermedades del Esófago , Estenosis Esofágica , Liquen Plano , Enfermedades del Esófago/diagnóstico , Enfermedades del Esófago/epidemiología , Estenosis Esofágica/diagnóstico , Estenosis Esofágica/epidemiología , Femenino , Humanos , Liquen Plano/diagnóstico , Liquen Plano/epidemiología , Persona de Mediana Edad , Membrana MucosaRESUMEN
Introduction: Despite intensive research, reliable blood-derived parameters to detect clinically significant portal hypertension (CSPH) in patients with cirrhosis are lacking. As altered homeostasis of cyclic guanosine monophosphate (cGMP), the central mediator of vasodilatation, is an essential factor in the pathogenesis of portal hypertension, the aim of our study was to evaluate plasma cGMP as potential biomarker of cirrhotic portal hypertension. Methods: Plasma cGMP was analyzed in cirrhotic patients with CSPH (ascites, n = 39; esophageal varices, n = 31), cirrhotic patients without CSPH (n = 21), patients with chronic liver disease without cirrhosis (n = 11) and healthy controls (n = 8). cGMP was evaluated as predictor of CSPH using logistic regression models. Further, the effect of transjugular intrahepatic portosystemic shunt (TIPS) placement on plasma cGMP was investigated in a subgroup of cirrhotic patients (n = 13). Results: Plasma cGMP was significantly elevated in cirrhotic patients with CSPH compared to cirrhotic patients without CSPH [78.1 (67.6-89.2) pmol/ml vs. 39.1 (35.0-45.3) pmol/l, p < 0.001]. Of note, this effect was consistent in the subgroup of patients with esophageal varices detected at screening endoscopy who had no prior manifestations of portal hypertension (p < 0.001). Cirrhotic patients without CSPH displayed no significant elevation of plasma cGMP compared to patients without cirrhosis (p = 0.347) and healthy controls (p = 0.200). Regression analyses confirmed that cGMP was an independent predictor of CSPH (OR 1.042, 95% CI 1.008-1.078, p = 0.016). Interestingly, portal decompression by TIPS implantation did not lead to normalization of plasma cGMP levels (p = 0.101). Conclusions: Plasma cGMP is a promising biomarker of CSPH in patients with cirrhosis, especially with respect to screening for esophageal varices. The lacking normalization of plasma cGMP after portal decompression suggests that elevated plasma cGMP in cirrhotic portal hypertension is mainly a correlate of systemic and splanchnic vasodilatation, as these alterations have been shown to persist after TIPS implantation.
RESUMEN
Liver cirrhosis is a frequent condition with high impact on patients' life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to morphological remodeling of the organ, a functional dysregulation of the sinusoids, the smallest functional units of liver vasculature, plays a pivotal role. Vascular tone is primarily regulated by the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, wherein soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) are key enzymes. Recent data showed characteristic alterations in the expression of these regulatory enzymes or metabolite levels in liver cirrhosis. Additionally, a disturbed zonation of the components of this pathway along the sinusoids was detected. This review describes current knowledge of the pathophysiology of PH with focus on the enzymes regulating cGMP availability, i.e., sGC and PDE-5. The results have primarily been obtained in animal models of liver cirrhosis. However, clinical and histochemical data suggest that the new biochemical model we propose can be applied to human liver cirrhosis. The role of PDE-5 as potential target for medical therapy of PH is discussed.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/genética , Guanilato Ciclasa/genética , Hipertensión Portal/enzimología , Cirrosis Hepática/enzimología , GMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Guanilato Ciclasa/metabolismo , Humanos , Hipertensión Portal/tratamiento farmacológico , Hipertensión Portal/etiología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , Terapia Molecular Dirigida , Óxido Nítrico/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND & AIMS: Phosphodiesterase-5 inhibitors (PDE-5-I) are used for treatment of erectile dysfunction (ED), which is common in patients with cirrhosis. They may improve portal hypertension (PH), but contradictory data on efficacy and side-effects have been reported. Non-selective beta blockers (NSBB) reduce portal pressure, but might aggravate ED. Thus, we evaluated the combination of PDE-5-I with NSBB and its impact on PH and ED in experimental cirrhosis. METHODS: ED was assessed in cirrhotic patients (n = 86) using standardized questionnaire. Experimental cirrhosis was induced by bile-duct-ligation or carbon-tetrachloride intoxication in rats. Corpus cavernosum pressure - a surrogate of ED -, as well as systemic and portal haemodynamics, were measured in vivo and in situ after acute administration of udenafil alone or in combination with propranolol. mRNA and protein levels of PDE-5 signalling were analysed using PCR and western Blot. RESULTS: ED in humans was related to severity of liver disease and to NSBB treatment. PDE-5 was mainly expressed in hepatic stellate cells and upregulated in human and experimental cirrhosis. Propranolol reduced corpus cavernosum pressure in cirrhotic rats and it was restored by udenafil. Even though udenafil treatment improved PH, it led to a reduction of mean arterial pressure. The combination of udenafil and propranolol reduced portal pressure and hepatic resistance without systemic side-effects. CONCLUSIONS: ED is common with advanced cirrhosis and concomitant NSBB treatment. The combination of PDE-5-I and NSBB improves ED and PH in experimental cirrhosis.
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Disfunción Eréctil , Hipertensión Portal , Cirrosis Hepática Experimental , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Disfunción Eréctil/tratamiento farmacológico , Disfunción Eréctil/etiología , Humanos , Hipertensión Portal/tratamiento farmacológico , Masculino , Inhibidores de Fosfodiesterasa 5 , Presión Portal , Ratas , Ratas Sprague-DawleyRESUMEN
Background: Although lichen planus (LP) is a common skin disorder, the prevalence of esophageal involvement (ELP) and its clinical manifestations are poorly defined. We aimed to establish diagnostic criteria and characterize disease outcomes of ELP.Methods: Clinical, endoscopic, histological, and immunofluorescence data from consecutive patients with known LP between 2013 and 2018 were analyzed. We established endoscopic (denudation and tearing of the mucosa, hyperkeratosis and trachealization) and histological criteria (mucosal detachment, T-lymphocytic infiltrate, intraepithelial apoptosis, dyskeratosis, and fibrinogen deposits along the basement membrane) to grade disease severity. Endoscopic findings were correlated with clinical symptoms. Response to medical therapy was monitored.Results: Fifty-two consecutive patients (median age 59.5 years) were analyzed. According to our grading system, 16 patients were considered as severe and 18 as mild ELP. Dysphagia was the only symptom which differentiated patients with severe (14/16) or mild ELP (8/18) from patients without ELP (1/18). Concomitant oral and genital involvement of LP was associated with the presence of ELP, while oral involvement alone was not. Follow-up of 14/16 patients with severe EPL for at least one year revealed that most of these patients responded to topical corticosteroids (budesonide: n = 9/10 or fluticasone n = 2/2). Three budesonide patients experienced a resolution of symptomatic esophageal stenosis.Conclusions: Esophageal involvement of LP is frequent, but may be asymptomatic. ELP can be diagnosed using the diagnostic criteria proposed here. Dysphagia and combined oral and genital manifestation are associated with ELP. Therapy with topical corticosteroids appears to be a prudent therapeutic approach for ELP.
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Enfermedades del Esófago/diagnóstico , Liquen Plano/diagnóstico , Corticoesteroides/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antiinflamatorios/uso terapéutico , Enfermedades del Esófago/tratamiento farmacológico , Enfermedades del Esófago/patología , Esofagoscopía , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores/uso terapéutico , Liquen Plano/tratamiento farmacológico , Liquen Plano/patología , Masculino , Persona de Mediana Edad , Diagnóstico Erróneo/prevención & control , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: Non-alcoholic steatohepatitis (NASH) has become one of the leading causes of liver disease in the western world. In obese patients weight reduction is recommended. Up to now there are no specific guidelines for weight loss in order to reduce hepatic fat content. AIM: To investigate the effects of a 24-wk guided lifestyle intervention program compared to a meal replacement regimen based on soy protein. METHODS: Twenty-six subjects with NASH participated in a randomized single-center study. They were randomly assigned to either meal replacement group (MR-G) with soy-yogurt-honey preparation or to guided lifestyle change group (LC-G) with endurance activity and nutrition counselling. Serum alanine transaminase (ALT), aspartate transaminase (AST), lipid parameters, and adipokines were measured. Liver fat content and lipid composition were determined by magnetic resonance imaging and magnetic resonance spectroscopy. Body fat mass and lean body mass were assessed using Bod Pod® device. Pre- and post-intervention monitoring of parameters was performed. Statistical analyses were conducted with SPSS software, results were expressed as median (interquartile range). RESULTS: Twenty-two subjects (MR-G, n = 11 and LC-G, n = 11) completed the study (9 women, 13 men; age 52.1 (15.0) years, body mass index (BMI) 32.3 (3.3) kg/m²). In both groups a significant weight loss was achieved (MR-G: -6.4 (3.6) kg, P < 0.01; LC-G: -9.1 (10.4) kg, P < 0.01). BMI dropped in both groups (MR-G: -2.3 (1.5) kg/m2, P = 0.003; LC-G: -3.0 (3.4) kg/m2, P = 0.006). Internal fat and hepatic lipid content were markedly reduced in both groups in comparable amount. There was a strong correlation between reduction in liver fat and decrease in ALT. Likewise, both groups showed an improvement in glycemic control and lipid profile. Changes in adipokines, particularly in adiponectin and leptin were closely related to intrahepatic lipid changes. CONCLUSION: Comprehensive lifestyle intervention and meal replacement regimen have comparable effects on body and liver fat, as well as decrease in markers of hepatic inflammation among NASH patients.
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Terapia Conductista/métodos , Dieta Reductora/métodos , Estilo de Vida Saludable , Enfermedad del Hígado Graso no Alcohólico/terapia , Obesidad/terapia , Proteínas de Vegetales Comestibles/administración & dosificación , Proteínas de Soja/administración & dosificación , Adipoquinas/sangre , Adulto , Anciano , Restricción Calórica , Femenino , Humanos , Hígado/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Comidas , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/etiología , Obesidad/sangre , Obesidad/complicaciones , Obesidad/diagnóstico por imagen , Resultado del Tratamiento , Pérdida de PesoRESUMEN
AIM: To investigate the potential effect of inhibitors of phosphodiesterase-5 (PDE-5) for therapy of portal hypertension in liver cirrhosis. METHODS: In the rat model of thioacetamide-induced liver fibrosis/cirrhosis the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway was investigated. Expression and localization of PDE-5, the enzyme that converts vasodilating cGMP into inactive 5'-GMP, was in the focus of the study. Hepatic gene expression of key components of the NO-cGMP pathway was determined by qRT-PCR: Endothelial NO synthase (eNOS), inducible NO synthase (iNOS), soluble guanylate cyclase subunits α1 and ß1 (sGCa1, sGCb1), and PDE-5. Hepatic PDE-5 protein expression and localization were detected by immunohistochemistry. Serum cGMP concentrations were measured using ELISA. Acute effects of the PDE-5 inhibitor Sildenafil (0.1 mg/kg or 1.0 mg/kg) on portal and systemic hemodynamics were investigated using pressure transducers. RESULTS: Hepatic gene expression of eNOS (2.2-fold; P = 0.003), sGCa1 (1.7-fold; P = 0.003), sGCb1 (3.0-fold; P = 0.003), and PDE-5 (11-fold; P = 0.003) was increased in cirrhotic livers compared to healthy livers. Overexpression of PDE-5 (7.7-fold; P = 0.006) was less pronounced in fibrotic livers. iNOS expression was only detected in fibrotic and cirrhotic livers. In healthy liver, PDE-5 protein was localized primarily in zone 3 hepatocytes and to a lesser extent in perisinusoidal cells. This zonation was disturbed in cirrhosis: PDE-5 protein expression in perisinusoidal cells was induced approximately 8-fold. In addition, PDE-5-expressing cells were also found in fibrous septa. Serum cGMP concentrations were reduced in rats with cirrhotic livers by approximately 40%. Inhibition of PDE-5 by Sildenafil caused a significant increase in serum cGMP concentrations [+ 64% in healthy rats (P = 0.024), + 85% in cirrhotic rats (P = 0.018)]. Concomitantly, the portal venous pressure was reduced by 19% in rats with liver cirrhosis. CONCLUSION: Overexpression and abrogated zonation of PDE-5 likely contribute to the pathogenesis of cirrhotic portal hypertension. PDE-5 inhibition may therefore be a reasonable therapeutic approach for portal hypertension.
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Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Hipertensión Portal/tratamiento farmacológico , Cirrosis Hepática Experimental/complicaciones , Inhibidores de Fosfodiesterasa 5/farmacología , Transducción de Señal/efectos de los fármacos , Animales , GMP Cíclico/sangre , GMP Cíclico/metabolismo , Guanosina Monofosfato/metabolismo , Humanos , Hipertensión Portal/sangre , Hipertensión Portal/etiología , Hipertensión Portal/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática Experimental/sangre , Cirrosis Hepática Experimental/inducido químicamente , Cirrosis Hepática Experimental/patología , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Citrato de Sildenafil/farmacología , Citrato de Sildenafil/uso terapéutico , Tioacetamida/toxicidad , Resultado del TratamientoRESUMEN
Non-selective beta-blockers are the mainstay of medical therapy for portal hypertension in liver cirrhosis. Inhibitors of phosphodiesterase-5 (PDE-5-inhibitors) reduce portal pressure in the acute setting by > 10% which may suggest a long-term beneficial effect. Currently, there is no available data on long-term treatment of portal hypertension with PDE-5-inhibitors. This case of a patient with liver cirrhosis secondary to autoimmune liver disease with episodes of bleeding from esophageal varices is the first documented case in which a treatment with a PDE-5-inhibitor for eight years was monitored. In the acute setting, the PDE-5-inhibitor Vardenafil lowered portal pressure by 13%. The portal blood flow increased by 28% based on Doppler sonography and by 16% using MRI technique. As maintenance medication the PDE-5-inhibitor Tadalafil was used for eight consecutive years with comparable effects on portal pressure and portal blood flow. There were no recurrence of bleeding and no formation of new varices. Influencing the NO-pathway by the use of PDE-5 inhibitors may have long-term beneficial effects in compensated cirrhosis.
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Colangitis Esclerosante/complicaciones , Hepatitis Autoinmune/complicaciones , Hipertensión Portal/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Administración Oral , Colangitis Esclerosante/diagnóstico por imagen , Colangitis Esclerosante/patología , Angiografía por Tomografía Computarizada , Endoscopía del Sistema Digestivo , Várices Esofágicas y Gástricas/diagnóstico por imagen , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/cirugía , Femenino , Estudios de Seguimiento , Hemorragia Gastrointestinal/diagnóstico por imagen , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/cirugía , Hemodinámica/efectos de los fármacos , Hepatitis Autoinmune/diagnóstico por imagen , Hepatitis Autoinmune/patología , Humanos , Hipertensión Portal/diagnóstico por imagen , Hipertensión Portal/etiología , Hipertensión Portal/patología , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa 5/farmacología , Síndrome , Tadalafilo/farmacología , Tadalafilo/uso terapéutico , Factores de Tiempo , Resultado del Tratamiento , Diclorhidrato de Vardenafil/farmacología , Diclorhidrato de Vardenafil/uso terapéuticoRESUMEN
Vedolizumab (VDZ) inhibits α4ß7 integrins and is used to target intestinal immune responses in patients with inflammatory bowel disease, which is considered to be relatively safe. Here we report on a fatal complication following VDZ administration. A 64-year-old female patient with ulcerative colitis (UC) refractory to tumor necrosis factor inhibitors was treated with VDZ. One week after the second VDZ infusion, she was admitted to hospital with severe diarrhea and systemic inflammatory response syndrome (SIRS). Blood stream infections were ruled out, and endoscopy revealed extensive ulcerations of the small intestine covered with pseudomembranes, reminiscent of invasive candidiasis or mesenteric ischemia. Histology confirmed subtotal destruction of small intestinal epithelia and colonization with Candida. Moreover, small mesenteric vessels were occluded by hyaline thrombi, likely as a result of SIRS, while perfusion of large mesenteric vessels was not compromised. Beta-D-glucan concentrations were highly elevated, and antimycotic therapy was initiated for suspected invasive candidiasis but did not result in any clinical benefit. Given the non-responsiveness to anti-infective therapies, an autoimmune phenomenon was suspected and immunosuppressive therapy was escalated. However, the patient eventually died from multi-organ failure. This case should raise the awareness for rare but severe complications related to immunosuppressive therapy, particularly in high risk patients.
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Anticuerpos Monoclonales Humanizados , Colitis Ulcerosa , Enteritis , Síndrome de Respuesta Inflamatoria Sistémica , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/mortalidad , Enteritis/complicaciones , Enteritis/tratamiento farmacológico , Enteritis/mortalidad , Femenino , Fármacos Gastrointestinales , Humanos , Intestino Delgado , Síndrome de Respuesta Inflamatoria Sistémica/etiologíaRESUMEN
Protein-losing enteropathy (PLE) is characterized by loss of serum proteins into the gastrointestinal tract. It may lead to hypoproteinemia and clinically present as protein deficiency edema, ascites, pleural or pericardial effusion and/or malnutrition. In most cases the site of protein loss is the small intestine. Here we present an unusual case of severe PLE in a 55-year old female with a one-year history of recurrent diarrhea, crampy abdominal pain, and peripheral edema. Endoscopy and MRI showed a diffuse inflammatory thickening of the sigmoid colon and the rectum. Surgical resection of the involved colon was performed and the symptoms were significantly resolved. The final histologic evaluation confirmed a diagnosis of a pseudomembranous colitis with cap polyposis-like features. Such a cause of PLE has never been described before.
Asunto(s)
Colon , Pólipos del Colon/complicaciones , Enterocolitis Seudomembranosa/complicaciones , Enteropatías Perdedoras de Proteínas/etiología , Biopsia , Colectomía , Colon/inmunología , Colon/patología , Colon/cirugía , Pólipos del Colon/diagnóstico , Pólipos del Colon/cirugía , Colonoscopía , Enterocolitis Seudomembranosa/diagnóstico , Enterocolitis Seudomembranosa/cirugía , Femenino , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Persona de Mediana Edad , Enteropatías Perdedoras de Proteínas/diagnóstico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
PURPOSE: To test a magnetic resonance (MR) scanning protocol as a noninvasive tool to determine hepatic hemodynamics and to assess the degree of liver fibrosis in an animal model of liver fibrosis and cirrhosis. MATERIALS AND METHODS: Fifty-four male Wistar rats were studied. Thirty-nine received thioacetamide (TAA) in their drinking water for either 12 or 16 weeks. MR measurements were performed using flow-sensitive 2D phase-contrast MRI and a 9.4T preclinical scanner. The following hemodynamic parameters were investigated: portal cross-sectional area, mean portal flow velocity, and portal and aortic flow volume rate. Therefore, rats (n = 46) were divided into three groups: CON (control, n = 13), FIB (fibrosis, n = 25), and CIR (cirrhosis, n = 8). Furthermore, the degree of liver fibrosis was assessed by a self-established MR score and verified by a standardized histological score (n = 48). RESULTS: Portal and aortic flow parameters could be reliably detected. A significant decrease in portal flow velocity was found in FIB (FIB vs. CON: -21%, P = 0.006 and CIR vs. CON: -17%, P = 0.105) and in portal flow volume rate in FIB and CIR (FIB vs. CON: -20%, P = 0.009 and CIR vs. CON: -25%, P = 0.024). If the histological score is taken as standard, the self-established MR score enabled discrimination between healthy and diseased livers (sensitivity to identify diseased livers: 89% and specificity to identify healthy livers: 100%). CONCLUSION: This MR scanning protocol presents a noninvasive tool to determine hepatic hemodynamics in healthy and diseased rats. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1526-1534.
Asunto(s)
Cirrosis Hepática/diagnóstico por imagen , Hígado/diagnóstico por imagen , Imagen por Resonancia Magnética , Animales , Hemodinámica , Humanos , Hipertensión Portal/patología , Procesamiento de Imagen Asistido por Computador , Hígado/irrigación sanguínea , Hígado/patología , Masculino , Variaciones Dependientes del Observador , Vena Porta/patología , Ratas , Ratas Wistar , Flujo Sanguíneo Regional , Tioacetamida/química , Agua/químicaRESUMEN
OBJECTIVE: Lichen planus (LP) is a classic skin disease that can involve the skin, hair, and nails, as well as the oral and genital mucosa. Histopathology is characterized by a T-lymphocytic, lichenoid, and interface dermatitis. Multiple case reports and small case series have shown that LP can involve the esophagus. However, the diagnostic criteria, incidence, and best treatment options remain uncertain. This study aimed to refine the diagnostic criteria, estimate prevalence, and present an outlook on treatment options to prevent long-term sequelae. PATIENTS AND METHODS: Thirty-two consecutive patients with LP of the skin, hair, nails, oral mucosa, and/or genital mucosa underwent a comprehensive clinicopathologic assessment. Esophagogastroduodenoscopy was performed, and biopsies were evaluated histologically, immunohistochemically, and by direct immunofluorescence. Patients diagnosed with esophageal lichen planus (ELP) were followed up prospectively where possible. RESULTS: In total, 20 of 32 patients had ELP. Ten of these 20 patients were classified as having proven ELP, with clear-cut endoscopically visible lesions; the other 10 were classified as having probable ELP. Eight of 10 patients with proven ELP were started on new or additional therapy because of esophageal findings. Treatment with a topical budesonide formulation or systemic corticosteroids was successful in most patients with proven ELP and reversed functional esophageal stenosis. CONCLUSION: ELP can be found in more than 50% of patients with proven mucocutaneous LP when clinical and pathologic findings are correlated carefully. Topical or systemic corticosteroids are the first-line therapy for ELP. Timely medical therapy seems to prevent scarring stenosis of the esophagus.
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Enfermedades del Esófago/diagnóstico , Liquen Plano/diagnóstico , Adulto , Anciano , Biopsia , Budesonida/uso terapéutico , Endoscopía del Sistema Digestivo , Enfermedades del Esófago/tratamiento farmacológico , Enfermedades del Esófago/epidemiología , Enfermedades del Esófago/patología , Femenino , Técnica del Anticuerpo Fluorescente , Glucocorticoides/uso terapéutico , Humanos , Inmunohistoquímica , Liquen Plano/tratamiento farmacológico , Liquen Plano/epidemiología , Liquen Plano/patología , Masculino , Persona de Mediana Edad , PrevalenciaRESUMEN
BACKGROUND: Phosphodiesterase-5-inhibitors may lower portal pressure. AIMS: To investigate the effect of the phosphodiesterase-5-inhibitor udenafil on hepatic and systemic haemodynamics in liver cirrhosis. METHODS: In an open-label phase-II-study, patients with liver cirrhosis Child A/B and hepatic venous pressure-gradient ≥ 12 mmHg received 12.5mg/day, 25mg/day, 50mg/day, 75 mg/day (n = 5, each), or 100mg/day (n = 10) udenafil p.o. for one week. On days 0 and 6, hepatic venous pressure-gradient was measured prior to and one hour after drug ingestion. Endpoints were reduction of hepatic venous pressure-gradient from day 0 pre to day 6 post intake and reduction in the acute setting. Pharmacokinetics were measured in the two lowest dosage groups. RESULTS: Combining the 75 and 100mg/day groups hepatic venous pressure-gradient reduction after drug intake was 19.9% (p = 0.0006) on day 0. From day 0 pre-dose to day 6 post-dose hepatic venous pressure-gradient decreased by 15.7% (p = 0.040) and in 5/15 patients by ≥ 20% or to <12 mmHg. In the 100mg/day group, mean arterial pressure decreased from 98.9 mmHg by 6.2 mmHg (p = 0.037) from day 0 pre-dose to day 6 post-dose. Heart rates or electrocardiograms were unchanged. Udenafil was eliminated with t1/2 = 25 h. CONCLUSIONS: Oral application of 75-100mg of the phosphodiesterase-5-inhibitor udenafil lowers portal pressure in the acute setting by about 20% without relevant systemic cardiovascular side effects.
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Hipertensión Portal/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/administración & dosificación , Pirimidinas/administración & dosificación , Sulfonamidas/administración & dosificación , Adulto , Anciano , Presión Sanguínea , Femenino , Humanos , Hipertensión Portal/etiología , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND: Inflammatory bowel disease constitutes a heterogeneous group of conditions, whose aetiology is only partly understood. The prevailing hypothesis on its pathogenesis is that IBD is the result of an inadequate immune response to the resident bacterial flora of the intestine. An autoimmune background, however, has been discussed since the 1950s. Lately, it has been shown that failures in interleukin-10 (IL-10) signalling due to IL-10- and IL-10 receptor (IL-10R) mutations result in IBD. Our study aimed at investigating the existence of inhibitory autoantibodies against IL-10 and IL-10R in IBD patients capable of down-modulating IL-10 signalling thereby mimicking IL-10 or IL-10R deficiency. RESULTS: Thirteen IBD patients had IgG autoantibodies against IL-10, IL-10RA and/or IL-10RB, and three patients had IgA autoantibodies against IL-10. However, the absolute OD values of the serum antibodies measured by ELISA were low, there was overall no significant difference between patients and controls, and positive sera had no neutralizing activity. CONCLUSION: No evidence for an involvement of autoantibodies against IL-10 or IL-10R in the pathogenesis of inflammatory bowel disease could be established.