Long-Term Safety of In Utero Exposure to Anti-TNFα Drugs for the Treatment of Inflammatory Bowel Disease: Results from the Multicenter European TEDDY Study.

OBJECTIVES: The long-term safety of exposure to anti-tumor necrosis factor (anti-TNFα) drugs during pregnancy has received little attention. We aimed to compare the relative risk of severe infections in children of mothers with inflammatory bowel disease (IBD) who were exposed to anti-TNFα drugs in utero with that of children who were not exposed to the drugs. METHODS: Retrospective multicenter cohort study. Exposed cohort: children from mothers with IBD receiving anti-TNFα medication (with or without thiopurines) at any time during pregnancy or during the 3 months before conception. Non-exposed cohort: children from mothers with IBD not treated with anti-TNFα agents or thiopurines at any time during pregnancy or the 3 months before conception. The cumulative incidence of severe infections after birth was estimated using Kaplan-Meier curves, which were compared using the log-rank test. Cox-regression analysis was performed to identify potential predictive factors for severe infections in the offspring. RESULTS: The study population comprised 841 children, of whom 388 (46%) had been exposed to anti-TNFα agents. Median follow-up after delivery was 47 months in the exposed group and 68 months in the non-exposed group. Both univariate and multivariate analysis showed the incidence rate of severe infections to be similar in non-exposed and exposed children (1.6% vs. 2.8% per person-year, hazard ratio 1.2 (95% confidence interval 0.8-1.8)). In the multivariate analysis, preterm delivery was the only variable associated with a higher risk of severe infection (2.5% (1.5-4.3)). CONCLUSIONS: In utero exposure to anti-TNFα drugs does not seem to be associated with increased short-term or long-term risk of severe infections in children.

Epidemiologic study on the current incidence of inflammatory bowel disease in Madrid.

INTRODUCTION: The incidence of inflammatory bowel disease (IBD) varies widely according to geographical area and has been reported to have increased in the last few years. No data are available on the current incidence of this disease in Madrid (Spain). AIM: to determine the incidence of inflammatory bowel disease in the area of influence of University Hospital Fundación Alcorcón (Madrid), and to compare our results with those from other Spanish and European series. PATIENTS AND METHODS: A prospective, population-based study was performed to determine the incidence of IBD in the area of University Hospital Fundación Alcorcón in Madrid between 2003 and 2005. Total population: 213,587 inhabitants (177,490 older than 14 years). Crude rates and age- and sex-specific rates adjusted to the European standard population were calculated. A retrospective study (1998-2003) was also performed. RESULTS: A total of 69 cases were diagnosed -Crohn s disease (CD): 35, ulcerative colitis (UC): 33, indeterminate colitis: 1- in the prospective period. Crude rates of CD and UC were 7.92 and 7.47 cases/100,000 inhabitants/year, respectively (the population aged 0-14 years). Specific rates were 8.0 (95% CI, 7.03-8.97) and 7.47 (95% CI, 6.5-8.4), respectively. Mean age at diagnosis was 31.02+/- 10.76 and 39.91+/-16.19 years for CD and UC, respectively. Incidence in the retrospective study was 7.13 and 6.22 cases/100,000 inhabitants/year, respectively for CD and UC. CONCLUSIONS: The incidence of CD and UC in Madrid has increased in the last decades, with rates close to those in northern European countries for CD, higher than those recently published in Spanish prospective studies and similar to those previously described in Spain and southern countries for UC. Rates were higher in the prospective period than in the retrospective one.

Epidemiologic study on the current incidence of inflammatory bowel disease in Madrid

Introduction: the incidence of inflammatory bowel disease(IBD) varies widely according to geographical area and has beenreported to have increased in the last few years. No data are availableon the current incidence of this disease in Madrid (Spain).Aim: to determine the incidence of inflammatory bowel diseasein the area of influence of University Hospital Fundación Alcorcón(Madrid), and to compare our results with those from otherSpanish and European series.Patients and methods: a prospective, population-basedstudy was performed to determine the incidence of IBD in thearea of University Hospital Fundación Alcorcón in Madrid between2003 and 2005. Total population: 213,587 inhabitants(177,490 older than 14 years). Crude rates and age- and sex-specificrates adjusted to the European standard population were calculated.A retrospective study (1998-2003) was also performed.Results: a total of 69 cases were diagnosed –Crohn´s disease(CD): 35, ulcerative colitis (UC): 33, indeterminate colitis: 1– inthe prospective period. Crude rates of CD and UC were 7.92 and7.47 cases/100,000 inhabitants/year, respectively (the populationaged 0-14 years). Specific rates were 8.0 (95% CI, 7.03-8.97) and 7.47 (95% CI, 6.5-8.4), respectively. Mean age at diagnosiswas 31.02± 10.76 and 39.91±16.19 years for CD andUC, respectively. Incidence in the retrospective study was 7.13and 6.22 cases/100,000 inhabitants/year, respectively for CDand UC.Conclusions: the incidence of CD and UC in Madrid has increasedin the last decades, with rates close to those in northernEuropean countries for CD, higher than those recently publishedin Spanish prospective studies and similar to those previously describedin Spain and southern countries for UC. Rates were higherin the prospective period than in the retrospective one(AU)

[Effect of pentoxifylline on survival, cardiac function and both portal and systemic hemodynamics in advanced alcoholic cirrhosis--a randomized double-blind placebo-controlled trial]. / Effecto de la pentoxifilina en la supervivencia, la función cardiaca y en la hemodinámica portal y sistémica de la cirrosis alcohólica avanzada.

OBJECTIVE: To assess the effect of pentoxiphylline (a potent inhibitor of tumor necrosis factor alpha) on survival, on systemic and portal hemodynamics, and on cardiac function in patients with alcoholic cirrhosis. DESIGN: A randomized double-blind placebo-controlled trial. SETTING: A single center using parallel groups of patients to compare pentoxiphylline with placebo. PATIENTS: We recruited 24 patients with alcoholic cirrhosis (8 Child-Pugh B and 16 Child-Pugh C). INTERVENTIONS: Patients were randomly assigned to receive pentoxiphylline (400 mg tid; n = 12) or placebo (n = 12) over a 4-week period. OUTCOME MEASURES: The primary outcome was to extend short-term and long-term survival. Secondary outcomes included hemodynamic benefits (improvement in cardiac function and/or systemic vascular resistance index, or decrease in portal pressure). RESULTS: Portal pressure and cardiac function remained unchanged and there were no significant differences in short-term or long-term survival between treatment and placebo groups. The group on pentoxiphylline increased systemic vascular resistance and decreased cardiac indices (from 1,721 +/- 567 to 2,082 +/- 622 dyn.sec(-1) cm(-5) m(-2) and from 4.17 +/- 1.4 to 3.4 +/- 0.9 l.m(-2), p = 0.05). CONCLUSIONS: Although pentoxiphylline seems to provide some short-term hemodynamic benefits in patients with advanced alcoholic cirrhosis, this drug has no effect on survival or portal pressure in these patients.

Efecto de la pentoxifilina en la supervivencia, la función cardiaca y en la hemodinámica portal y sistémica de la cirrosis alcohólica avanzada / No disponible

Objetivo: valorar el efecto de la pentoxifilina (un potente inhibidordel factor de necrosis tumoral alfa) en la supervivencia, en lahemodinámica sistémica y portal y en la función cardiaca en la cirrosisalcohólica avanzada.Diseño: estudio aleatorizado, doble-ciego, controlado con placebo.Contexto: estudio unicéntrico utilizando grupos de pacientesen paralelo para comparar pentoxifilina y placebo.Pacientes: se incluyeron 24 pacientes con cirrosis alcohólica(8 en estadio B de Child-Pugh y 16 en estadio C de Child-Pugh).Intervención: los pacientes fueron aleatorizados a recibirpentoxifilina (400 mg, 3 veces al día, n = 12) o placebo (n = 12)durante 4 semanas.Determinaciones: el objetivo principal fue la supervivencia acorto/largo plazo. Los objetivos secundarios fueron observar beneficioshemodinámicos (mejoría en la función cardiaca y/o en elíndice de resistencias vasculares sistémicas o disminución de lapresión portal).Resultados: la presión portal y la función cardiaca no se modificarony no hubo diferencias en la supervivencia a corto y largoplazo entre los grupos tratados y placebo. Los índices de resistenciavascular sistémica y cardiaco cambiaron en el grupo de pentoxifilina(de 1.721 ± 567 a 2.082 ± 622 Din.seg1 cm-5 m-2 y de4,17 ± 1,4 a 3,4 ± 0,9 lm-2, p = 0,05).Conclusiones: aunque la pentoxifilina parece producir algúnbeneficio hemodinámico a corto plazo en pacientes con cirrosis alcohólicaavanzada, no tiene efecto sobre la tasa de supervivencia, lafunción cardiaca ni sobre la presión portal en estos pacientes

Objective: to assess the effect of pentoxiphylline (a potent inhibitorof tumor necrosis factor alpha) on survival, on systemicand portal hemodynamics, and on cardiac function in patientswith alcoholic cirrhosis.Design: a randomized double-blind placebo-controlled trial.Setting: a single center using parallel groups of patients tocompare pentoxiphylline with placebo.Patients: we recruited 24 patients with alcoholic cirrhosis (8Child-Pugh B and 16 Child-Pugh C).Interventions: patients were randomly assigned to receivepentoxiphylline (400 mg tid; n = 12) or placebo (n = 12) over a 4-week period.Outcome measures: the primary outcome was to extendshort-term and long-term survival. Secondary outcomes includedhemodynamic benefits (improvement in cardiac function and/orsystemic vascular resistance index, or decrease in portal pressure).Results: portal pressure and cardiac function remained unchangedand there were no significant differences in short-term orlong-term survival between treatment and placebo groups. Thegroup on pentoxiphylline increased systemic vascular resistanceand decreased cardiac indices (from 1,721 ± 567 to 2,082 ± 622dyn.sec-1 cm-5 m-2 and from 4.17 ± 1.4 to 3.4 ± 0.9 l.m-2, p =0.05).Conclusions: although pentoxiphylline seems to providesome short-term aemodynamic benefits in patients with advancedalcoholic cirrhosis, this drug has no effect on survival or portalpressure in these patients

Prevalence of macrocreatinkinase type 1 in patients with inflammatory bowel disease.

Macro-creatine-kinases are isoenzymes of creatinine-kinases (CK). They have been classified in two types: type 1 (CK bound to an immunoglobulin) and type 2 (an oligomeric mitochondrial CK). CK type 1 has been found in patients with ulcerative colitis (UC) but not in Crohn's disease (CD). However, there are no studies evaluating macro-creatinkinase prevalence in inflammatory bowel disease (IBD). We included 159 consecutive patients (72 UC, 85 CD; 2 indeterminate colitis). Creatin-kinase total activity and isoenzymes activities were determined. Twelve (16.7%) patients with UC and one of the two patients with indeterminate colitis had serum macro-creatinkinase type 1 while no CD patients displayed this macromolecule (P < 0,001). Sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratio were calculated for ulcerative colitis versus Crohn's disease diagnosis, being 16.7, 98.9, 92.3, 59, 14.5, and 0.84% respectively. There was no correlation with age, gender, time from diagnosis, associated diseases, concomitant medication or disease activity. In conclusion our data suggests that the presence of macro-CK in IBD favors the diagnosis of ulcerative colitis. Further studies are necessary to understand the significance of this finding in a subset of patients with IBD.

Long-term reversal of hypocholesterolaemia in patients with chronic hepatitis C is related to sustained viral response and viral genotype.

BACKGROUND: Genotype-3 of hepatitis C virus (HCV) has been associated with serum lipid changes (reversible with sustained viral response) and liver steatosis. AIM: To characterize the relationships among hepatic steatosis, cholesterol and sustained viral response in these patients. METHODS: Patients (n = 215) with chronic hepatitis C (157 with genotype-1 of HCV) had age, body mass index, gender, alcohol intake, glycaemia, serum lipids, transaminases, grade and stage (METAVIR and Scheuer), degree of liver steatosis, sustained viral response, insulinaemia, leptinaemia, beta-hydroxybutyrate and glycerol measured, and were compared with 32 hepatitis B virus (HBV)-infected subjects. RESULTS: Genotype-3 of HCV patients had age-adjusted hypocholesterolaemia and more frequent hepatic steatosis (P < 0.001). Steatosis was inversely correlated with serum cholesterol (P < 0.01) and directly with viral load (P < 0.03). In patients with genotype-3 of HCV and sustained viral response, serum cholesterol increased from 138 (95% CI: 120-151) to 180 mg/dL (95% CI: 171-199) 12 months after treatment conclusion (P < 0.0001). By contrast, cholesterol values were unchanged in genotype-3 of HCV non-responders and in patients with genotype-1 of HCV regardless of response. Rising cholesterol in sustained viral response did not parallel the changes in beta-hydroxybutyrate. CONCLUSIONS: Besides causing hepatic steatosis, genotype-3 specifically decreases serum cholesterol. This interference with the metabolic lipid pathway is related to viral load, is reversed with sustained viral response, and seems unrelated to mitochondrial dysfunction.

Síndrome metabólico y progresión de la lesión hepática en la infección por el virus de la hepatitis C y el hígado graso no alcohólico / No disponible

No disponible

Toxicidad hepática por flutamida / Liver toxicity associated with flutamide

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Diagnostic and therapeutic approach to cholestatic liver disease.

When cholestatic liver disease is present, liver ultrasound should be performed to ascertain if cholestasis is extrahepatic or intrahepatic. If bile ducts appear dilated and the probability of interventional treatment is high, endoscopic retrograde cholagio-pancreatography (ERCP) or trans-hepatic cholangiography (THC) should be the next step. If the probability of interventional therapeutics is low, cholangio-MRI should be performed. Once bile duct dilation and space occupying lesions are excluded, a work up for intrahepatic cholestasis should be started. Some specific clinical situations may be helpful in the diagnostic strategy. If cholestasis occurs in the elderly, drug-induced cholestatic disease should be suspected, whereas if it occurs in young people with risk factors, cholestatic viral hepatitis is the most likely diagnosis. During the first trimester of pregnancy cholestasis may occur in hyperemesis gravidorum, and in the third trimester of gestation cholestasis of pregnancy should be suspected. A familial history of recurrent cholestasis points to benign recurrent intrahepatic cholestasis. The occurrence of intrahepatic cholestasis in a middle-aged woman is a frequent presentation of primary biliary cirrhosis, whereas primary sclerosing cholangitis should be suspected in young males with inflammatory bowel disease. The presence of vascular spider nevi, ascites, and a history of alcohol abuse should point to alcoholic hepatitis. Neonatal cholestasis syndromes include CMV, toxoplasma and rubinfections or metabolic defects such as cystic fibrosis, alpha1-antitrypsin deficiency, bile acid synthesis defects, or biliary atresia. The treatment of cholestasis should include a management of complications such as pruritus, osteopenia and correction of fat soluble vitamin deficiencies. When hepatocellular failure or portal hypertension-related complications occur, liver transplantation should be considered.

Abordaje diagnóstico y terapéutico del síndrome colestásico / Diagnostic and therapeutic approach to cholestatic liver disease

Ante la presencia de colestasis, se debe determinar si su naturaleza es extra o intrahepática. Si la ecografía hepática no muestra dilatación de la vía biliar ni lesiones' ocupantes de espacio, se debe iniciar el estudio de una colestasis intrahepática. Si la obstrucción de la vía biliar extrahepática es cuestionable o la probabilidad de intervencionismo terapéutico es baja, se debe completar el estudio mediante colangio-pancreatografia-RM (CPRM). Si la probabilidad de intervencionismo es alta, se debe realizar colangiopancreatografía retrógrada endoscópica (CPRE) o colangiografía transparieto-hepática (CTPH). En caso de colestasis intrahepática, determinadas situaciones específicas ayudan a orientar el diagnóstico. Si la colestasis intrahepática ocurre en ancianos, se debe sospechar colestasis por fármacos, mientras que en pacientes jóvenes con antecedentes de riesgo, la hepatitis viral es la causa más frecuente. En el primer trimestre del embarazo la hiperemesis gravídica es la causa más probable y en el segundo o tercero la colestasis gravídica. La historia familiar y el curso recurrente deben orientar hacia una colestasis intrahepática recurrente benigna. La presencia de colestasis intrahepática en una mujer de edad media debe hacer sospechar CBP, mientras que en un varón joven con EIIC, una colangitis esclerosante primaria. La presencia de arañas vasculares, ascitis e historia de abuso de alcohol, apuntan hacia una hepatitis alcohólica como causa más probable. En el periodo neonatal, los síndromes colestásicos incluyen infecciones por CMV, toxoplasma, rubeola o defectos metabólicos como la fibrosis quística, el déficit de alfa1-antitripsina, defectos en la síntesis de ácidos biliares o atresia biliar. El tratamiento de la colestasis debe incluir el manejo de complicaciones como el prurito, la osteopenia y el déficit de vitaminas liposolubles. En caso de insuficiencia hepatocelular o complicaciones de la hipertensión portal, el manejo es similar al de otras etiologías y se debe valorar el trasplante hepático (AU)

When cholestatic liver disease is present, liver ultrasound should be performed to ascertain if cholestasis is extrahepatic or intrahepatic. If bile ducts appear dilated and the probability of interventional treatment is high, endoscopic retrograde cholagio-pancreatography (ERCP) or trans-hepatic cholangiography (THC) should be the next step. If the probability of interventional therapeutics is low, cholangio-MRI should be performed. Once bile duct dilation and space occupying lesions are excluded, a work up for intrahepatic cholestasis should be started. Some specific clinical situations may be helpful in the diagnostic strategy. If cholestasis occurs in the elderly, drug-induced cholestatic disease should be suspected, whereas if it occurs in young people with risk factors, cholestatic viral hepatitis is the most likely diagnosis. During the first trimester of pregnancy cholestasis may occur in hyperemesis gravidorum, and in the third trimester of gestation cholestasis of pregnancy should be suspected. A familial history of recurrent cholestasis points to benign recurrent intrahepatic cholestasis. The occurrence of intrahepatic cholestasis in a middle-aged woman is a frequent presentation of primary biliary cirrhosis, whereas primary sclerosing cholangitis should be suspected in young males with inflammatory bowel disease. The presence of vascular spider nevi, ascites, and a history of alcohol abuse should point to alcoholic hepatitis. Neonatal cholestasis syndromes include CMV, toxoplasma and rubinfections or metabolic defects such as cystic fibrosis, alpha1-antitrypsin deficiency, bile acid synthesis defects, or biliary atresia. The treatment of cholestasis should include a management of complications such as pruritus, osteopenia and correction of fat soluble vitamin deficiencies. When hepatocellular failure or portal hypertension-related complications occur, liver transplantation should be considered (AU)

Use of adefovir in the treatment of the chronic hepatitis B virus infection with resistance to lamivudine.

Current therapies for the treatment of chronic hepatitis B virus (HBV) infection do not eliminate viral replication once therapy is stopped, resulting in a rapid rebound of viremia in a majority of patients. Prolonged therapy results in emergence of resistant virus, which is a major clinical concern. The appearance of resistant HBV is associated with decreased seroconversion rates as well as worse liver histology. Adefovir dipivoxil, a nucleotide analogue with potent antiviral activity against HBV and human immunodeficiency virus (HIV), has shown in vivo and in vitro to have activity against lamivudine-resistant HBV. We present a series of 6 patients with chronic HBV infection and lamivudine-resistant HBV treated with adefovir dipivoxil. The viremia decreased in all patients; in 4 of them, serum HBV DNA was negative by chain reaction (PCR) in a mean period of 10 months from beginning of treatment. Resistance to adefovir after 12 months of treatment has not been detected. Alanine aminotransferase (ALT) levels decreased in all patients and, at this moment, 5 of 6 patients present normal levels. There were no toxic side effects due to adefovir treatment. The data confirm that adefovir treatment has efficacy against HBV lamivudine-resistant forms.

Hipertensión portal extrahepática: trombosis espleno-portal secundaria a déficit de proteína C / Extrahepatic portal hypertension: portal and splenic vein thrombosis secondary to protein C deficiency

La trombosis portal es la causa más común de hipertensión portal prehepática. Representa un trastorno poco frecuente, que aparece normalmente relacionado con la existencia de cirrosis, enfermedades malignas hepatobiliares o alteraciones de la coagulación, siendo estas últimas uno de los factores de riesgo más importantes. El tratamiento anticoagulante debe emplearse en todos los casos de trombosis portal aguda y en la trombosis portal crónica cuando se identifique un factor protrombótico causal. Presentamos el caso de un varón de 29 años, diagnosticado de hipertensión portal prehepática, secundaria a trombosis portal y esplénica, que debutó con la aparición clínica de esplenomegalia y de alteraciones de la coagulación. Tras detectar un déficit de proteína C se instauró tratamiento anticoagulante. Un año después el paciente no ha presentado complicaciones en relación con su patología ni con el tratamiento pautado (AU)

Portal vein thrombosis (PVT) is the most frequent cause of hypertension portal extrahepatic. It is a rare disorder an the main risk factors are cirrhosis, hepatobiliary malignancies and prothrombotic disorders, which have been identified as major risk . Therapy with anticoagulants must to be considered in acute portal trombosis or chronic one and proven hypercoagulability. We present the case of a twenty-nine years old patient, with extrahepatic portal hypertension secondary to portal and splenic vein thrombosis, who was diagnosed because of splenomegaly and a coagulation disorder. A protein C deficiency were discovered and anticoagulation and beta-blocker therapy were iniciated. One year later the patient had not presented complications concerning to the disease or to the treatment (AU)

[Extrahepatic portal hypertension: spleno-portal thrombosis secondary to protein C deficiency]. / Hipertensión portal extrahepática: trombosis espleno-portal secundaria a déficit de proteína C.

Portal vein thrombosis (PVT) is the most frequent cause of hypertension portal extrahepatic. It is a rare disorder an the main risk factors are cirrhosis, hepatobiliary malignancies and prothrombotic disorders, which have been identified as major risk. Therapy with anticoagulants must to be considered in acute portal thrombosis or chronic one and proven hypercoagulability. We present the case of a twenty-nine years old patient, with extrahepatic portal hypertension secondary to portal and splenic vein thrombosis, who was diagnosed because of splenomegaly and a coagulation disorder. A protein C deficiency were discovered and anticoagulation and beta-blocker therapy were initiated. One year later the patient had not presented complications concerning to the disease or to the treatment.

Compresión gástrica extrínseca simulando un tumor submucoso: diagnóstico por ecoendoscopia / Submucosal impression of the stomach like a submucosal tumour: diagnosis by endoscopic ultrasound

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[Presentation of Crohn's disease with esophageal involvement]. / Inicio de la enfermedad de Crohn con afección esofágica.

Inflammatory bowel disease basically consists of two entities: ulcerative colitis (UC) and Crohn's disease (CD). Both processes are characterized by chronic inflammation of the intestine, which in the case of CD may affect the entire digestive tract. We present the case of a young man who was diagnosed with esophageal CD after presenting dysphagia and odynophagia. Intestinal involvement was subsequently found. Esophageal involvement is infrequent and as the first manifestation of CD it is extremely rare. It should, however, be borne in mind in patients with esophageal ulcerations without symptoms or endoscopic signs compatible with peptic etiology, even though other indications of inflammatory disease are absent.

Lipase-catalysed synthesis of new acetylcholinesterase inhibitors: N-benzylpiperidine aminoacid derivatives.

New acetylcholinesterase inhibitors were synthetized via a lipase-mediated regioselective amidation using Candida antarctica lipase B as a biocatalyst in the key step. The new compounds have two different structural fragments: a N-benzylpiperidine moiety to anchor the enzyme active site and a dicarboxylic aminoacid to act as a biological carrier. Some analogues of N-benzylpiperazine were also synthesised and studied but they did not display AChE inhibitor activity. A preliminary structure activity relationship study was performed employing some computational techniques as similarity indices and electrostatic potential maps.