RESUMO
INTRODUCCIÓN: Este documento técnico se realizó en el marco de la Guía de Práctica Clínica para pacientes pediátricos con falla intestinal; la pregunta PICO fue la siguiente: P: pacientes de 0-18 años con resección ileal por cualquier causa; I: colestiramina; C: placebo, colestipol, colesevelam, dietas modificadas o suplementos dietéticos; O: frecuencia de deposiciones, cambio en el peso o masa de las heces y eventos adversos. a. Cuadro clínico: Los ácidos biliares son moléculas cuya función principal es ayudar en la digestión y absorción de lípidos. En personas sanas, más del 95% de ácidos biliares se reabsorben en el íleon terminal. La reabsorción insuficiente de ácidos biliares en el íleon terminal incrementa la concentración en el colon, produciendo diarrea secretora. Se estima que la malabsorción de ácidos biliares (MAB) afecta al 1% de la población de países occidentales y cerca del 90% de pacientes con resección ileal. El tratamiento de la diarrea por MAB consiste en un manejo dietético y farmacológico. Los pacientes con diarrea y esteatorrea moderada deben someterse a una dieta baja en grasas (30 g/día) con o sin adición de triglicéridos de cadena media. El tratamiento farmacológico se basa en secuestrantes de ácidos biliares como colestiramina, colestipol o colesevelam. b. Tecnología sanitaria: Colestiramina es un secuestrante de ácidos biliares que se une con alta afinidad a los ácidos biliares en el intestino para formar un complejo estable e insoluble que se excreta en las heces. Pese a no ser una indicación aprobada, se emplea hace varias décadas para el tratamiento de MAB. Su forma de presentación consiste en sachets conteniendo 4 gr de polvo. Las dosis empleadas para la diarrea por MAB deben adaptarse a la respuesta del paciente, con una dosis máxima de 36 gr al día. Los eventos adversos suelen ser dependientes de la dosis, siendo los más frecuentes: malestar gastrointestinal, dispepsia, flatulencia, estreñimiento, náuseas y vómitos. Colestiramina cuenta en Perú con un registro sanitario vigente. Según el observatorio de precios de medicamentos de DIGEMID, el costo más bajo en el sector privado de 100 sobres de colestiramina asciende a S/. 13.00 (S/. 0.13 por cada sobre) mientras que no se hallaron precios disponibles en el sector público. OBJETIVO: Describir la evidencia científica sobre la eficacia y seguridad de colestiramina para el tratamiento de diarrea por malabsorción de ácidos biliares secundaria a resección ileal en población pediátrica. METODOLOGÍA: La búsqueda de evidencia se desarrolló en Medline, Web of Science, The Cochrane Library y LILACS hasta el 04 de octubre de 2021, limitado a estudios en español o inglés. La búsqueda de guías de práctica clínica (GPC) y evaluaciones de tecnología sanitaria (ETS) se desarrolló en repositorios digitales de agencias elaboradoras de estos documentos. Adicionalmente, se realizó una búsqueda de GPC en PubMed. Se valoró el riesgo de sesgo empleado la herramienta de la Colaboración Cochrane. RESULTADOS: No se identificó ningún estudio en población pediátrica. Se consideró como evidencia indirecta cuatro estudios primarios desarrollados en adultos. Frecuencia de deposiciones: El estudio de Hofmann (1969) reportó una reducción en la frecuencia diaria de deposiciones (p<0.05) durante el tratamiento con colestiramina en pacientes con <100 cm de resección ileal, comparado con placebo. En pacientes con >100 cm de íleon resecado (n=8) no se observaron diferencias. Un segundo estudio de Hofmann (1972) reportó una disminución en la frecuencia de deposiciones diarias de pacientes con resección ileal <100 cm tratados con colestiramina y triglicéridos de cadena larga (TCL) o media (TCM), en comparación con solo TCL o TCM. En pacientes con resección ileal >100 cm, colestiramina redujo la frecuencia de deposiciones, aunque la mayor reducción se observó cuando se reemplazó TCL por TCM, ambos sin colestiramina (p<0.025). El estudio de Jacobsen reportó una reducción del número de evacuaciones fecales durante el tratamiento con colestiramina comparado con placebo (15 vs 23, p<0.05). El estudio de Williams reportó una disminución del número de deposiciones al día en pacientes tratados colestiramina comparado con una dieta control (2.3 vs 4.6; p=0.027). Volumen de masa fecal El estudio de Hofmann (1969) reportó que 4 de 6 pacientes con <100 cm de resección ileal alcanzaron una reducción significativa de la masa fecal comparado con placebo (p<0.05). En pacientes con >100 cm de íleon resecado (n=3), colestiramina no produjo reducción significativa de la masa fecal en ningún participante. El estudio de Jacobsen reportó una reducción del volumen de masa fecal durante el tratamiento con colestiramina comparado con placebo (p<0.05). El estudio de Williams reportó una disminución significativa de la masa fecal en pacientes tratados colestiramina comparado con una dieta control de 2000 Kcal con TCL (media: 394 gr/día vs 568 gr/día; p=0.027). Eventos adversos: Ningún estudio informó sobre la presencia de eventos adversos. Recomendaciones en GPC: Las GPC de la Asociación Argentina de Nutrición Enteral y Parenteral (AANEP) y de la Canadian Association of Gastroenterology (CAG) recomiendan colestiramina para el manejo de la MAB. Las GPC de la European Society for Clinical Nutrition and Metabolism (ESPEN), Cleveland Clinic, British Society of Gastroenterology (BSG), y American Gastroenterological Association (AGA) no recomiendan su uso en pacientes con resección ileal extensa. Evaluaciones de Tecnología Sanitaria: Una ETS desarrollada por IETSI concluyó con evidencia limitada aprobar el uso de colestiramina para el tratamiento de pacientes con diarrea crónica por MAB. Sin embargo, su aprobación fue revocada un año después por tratarse de una indicación terapéutica "fuera de etiqueta". Evaluación de la calidad metodológica: Tres estudios tuvieron alto riesgo de sesgo de selección. Dos estudios tuvieron alto riesgo de sesgo de realización y detección. El riesgo de sesgo de reporte fue considerado poco claro en todos los estudios. Todos los estudios fueron considerados como alto riesgo de otro tipo de sesgos por un reporte insuficiente o nulo de las fuentes de financiamiento y el conflicto de interés de los autores. CONCLUSIONES: Los hallazgos sobre la eficacia de colestiramina no fueron concluyentes. Dos estudios reportaron una reducción en la frecuencia de deposiciones y volumen fecal en pacientes tratados con colestiramina, mientras que otros dos estudios mostraron una reducción significativa solo en pacientes con resección ileal <100 cm, y un efecto limitado o nulo en pacientes con resección ileal extensa (>100 cm). No se informaron resultados sobre la seguridad de colestiramina. Los estudios incluidos enrolaron un número pequeño de participantes, con periodos cortos de seguimiento, presentaron alta heterogeneidad en el diseño, características de los participantes e intervenciones, y tuvieron un alto riesgo de sesgo en la mayoría de dimensiones evaluadas. Dos GPC consideran el uso de colestiramina como terapia para pacientes con diarrea por MAB, mientras que cuatro GPC recomiendan limitar su uso en pacientes con resección ileal extensa. Una ETS realizada por IETSI (Perú) concluyó aprobar el uso de colestiramina para el tratamiento de pacientes con diarrea crónica por MAB. Sin embargo, su aprobación fue revocada un año después por tratarse de una indicación terapéutica "fuera de etiqueta".
Assuntos
Humanos , Criança , Ácidos e Sais Biliares/deficiência , Resina de Colestiramina/uso terapêutico , Diarreia Infantil/tratamento farmacológico , Absorção Intestinal , Eficácia , Análise Custo-BenefícioRESUMO
PURPOSE OF REVIEW: To evaluate recently published information about the frequency of maldigestion and malabsorption in older individuals, likely diagnoses causing these problems, and the diagnostic scheme when these diagnoses are being considered. RECENT FINDINGS: Although the prevalence of malnourishment and frank malnutrition may be increasing among older adults admitted to the hospital, this appears to be due to reduced food intake rather than maldigestion or malabsorption. The mechanisms of food digestion and absorption seem to be resilient, even in old age, but concurrent illness may produce malabsorption in older individuals. Illnesses that may be more common among the elderly include small intestinal bacterial overgrowth, exocrine pancreatic insufficiency, enteropathies, vascular disease, diabetes, and certain infections, such as Whipple's disease. In addition, older adults may have had previous surgeries or exposure to medicines which may induce malabsorption. The presentation of maldigestion and malabsorption in the elderly may be different than in younger individuals, and this may contribute to delayed recognition, diagnosis, and treatment. Diagnostic testing for maldigestion and malabsorption generally is similar to that used in younger patients. Maldigestion and malabsorption occur in older individuals and require a high level of suspicion, especially when weight loss, sarcopenia, or nutrient deficiencies are present.
Assuntos
Síndromes de Malabsorção , Desnutrição , Idoso , Ácidos e Sais Biliares/deficiência , Ácidos e Sais Biliares/metabolismo , Síndrome da Alça Cega/diagnóstico , Síndrome da Alça Cega/etiologia , Complicações do Diabetes/diagnóstico , Complicações do Diabetes/etiologia , Diarreia/diagnóstico , Diarreia/etiologia , Dissacarídeos/deficiência , Insuficiência Pancreática Exócrina/diagnóstico , Insuficiência Pancreática Exócrina/etiologia , Gastroenteropatias/diagnóstico , Gastroenteropatias/etiologia , Humanos , Enteropatias/diagnóstico , Enteropatias/etiologia , Intestino Delgado/fisiopatologia , Síndromes de Malabsorção/diagnóstico , Síndromes de Malabsorção/etiologia , Desnutrição/diagnóstico , Desnutrição/etiologia , Esteatorreia/diagnóstico , Esteatorreia/etiologiaRESUMO
Prostaglandin E receptor subtype 4 (EP4) knockout mice develops spontaneous hypercholesterolemia but the detailed mechanisms by which EP4 affects cholesterol homeostasis remains unexplored. We sought to determine the cause of hypercholesterolemia in EP4 knockout mice, focusing on the role of EP4 in regulating the synthesis and elimination of cholesterol. Deficiency of EP4 significantly decreased total bile acid levels in the liver by 26.2% and the fecal bile acid content by 27.6% as compared to wild type littermates, indicating that the absence of EP4 decreased hepatic bile acid synthesis and their subsequent excretion in stools. EP4 deficiency negatively regulate bile acid synthesis through repression of phosphorylated extracellular signal-regulated kinase 1/2 (ERK)-mediated cholesterol 7α-hydroxylase (CYP7A1) expression and that the hypercholesterolemia in EP4 knockout mice is due to a defect in cholesterol conversion into bile acids. Deficiency of EP4 also increased de novo cholesterol synthesis and altered cholesterol fluxes in and out of the liver. Treating high fat diet-challenged mice with the pharmacological EP4 agonist, CAY10580 (200⯵g/kg body weight/day i.p) for three weeks effectively prevented diet-induced hypercholesterolemia, enhanced endogenous bile acid synthesis and their fecal excretion. In summary, EP4 plays a critical role in maintaining cholesterol homeostasis by regulating the synthesis and elimination of bile acids. Activation of EP4 serves as an effective novel strategy to promote cholesterol disposal in the forms of bile acids in order to lower plasma cholesterol levels.
Assuntos
Anticolesterolemiantes/farmacologia , Ácidos e Sais Biliares/deficiência , Colesterol/metabolismo , Dinoprostona/análogos & derivados , Hipercolesterolemia/genética , Pirrolidinonas/farmacologia , Receptores de Prostaglandina E Subtipo EP4/genética , Animais , Ácidos e Sais Biliares/biossíntese , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Dieta Hiperlipídica/efeitos adversos , Dinoprostona/farmacologia , Fezes/química , Regulação da Expressão Gênica , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Receptores de Prostaglandina E Subtipo EP4/deficiência , Transdução de SinaisRESUMO
BACKGROUND & AIMS: Short-term administration of delayed-release chenodeoxycholic acid to patients with irritable bowel syndrome with constipation (IBS-C) accelerates colonic transit and reduces symptoms. A preliminary study has shown that patients with IBS-C have reduced levels of bile acids (BAs) in feces and reduced synthesis of BA. We compared the levels of primary and secondary BAs in fecal samples collected over a 48-hour period from patients with IBS-C on a diet that contained 100 g fat per day, and compared them with levels in samples from healthy volunteers (controls). We also examined the relationship between overall colonic transit and biomarkers of BAs in patients with IBS-C. METHODS: We performed a retrospective study of 45 patients with IBS-C and 184 controls. For controls, we estimated the 10th percentile of fasting serum levels of 7α-hydroxy-4-cholesten-3-one (C4, n = 184) and 48-hour fecal BAs (n = 46), and the 90th percentile of the fasting serum level of fibroblast growth factor 19 (FGF19, n = 50). Colonic transit was measured in patients using a validated scintigraphic method. Data from patients with IBS-C were analyzed using Spearman correlations to determine the relationships among levels of C4, FGF19, fecal BAs, and colonic transit. RESULTS: Among the patients with IBS-C, 2 of 45 had low serum levels of C4, 4 of 43 had increased serum levels of FGF19, and 6 of 39 had low levels of BAs in feces collected over 48 hours. Patients with IBS-C had a significant increase in the proportions of fecal lithocholic acid compared with controls (P = .04), and a decrease in deoxycholic acid compared with controls (P = .03). In patients with IBS-C, there were inverse relationships between serum levels of C4 and FGF19 and correlations among levels of 48-hour fecal BAs, colonic transit, and serum C4 and FGF19. CONCLUSIONS: Approximately 15% of patients with IBS-C have reduced total BAs and level of deoxycholic acid in fecal samples collected over 48 hours on a 100 g fat diet. In these patients, lower levels of excretion of BAs into feces correlated with slower colonic transit.
Assuntos
Ácidos e Sais Biliares/deficiência , Biomarcadores/análise , Constipação Intestinal/epidemiologia , Fezes/química , Síndrome do Intestino Irritável/complicações , Soro/química , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Human steroid-5ß-reductase (aldo-keto reductase 1D1, AKR1D1) stereospecifically reduces Δ(4)-3-ketosteroids to 5ß-dihydrosteroids and is essential for steroid hormone metabolism and bile acid biosynthesis. Genetic defects in AKR1D1 cause bile acid deficiency that leads to life threatening neonatal hepatitis and cholestasis. The disease-associated P133R mutation caused significant decreases in catalytic efficiency with both the representative steroid (cortisone) and the bile acid precursor (7α-hydroxycholest-4-en-3-one) substrates. Pro133 is a second shell residue to the steroid binding channel and is distal to both the cofactor binding site and the catalytic center. Strikingly, the P133R mutation caused over a 40-fold increase in Kd values for the NADP(H) cofactors and increased the rate of release of NADP(+) from the enzyme by 2 orders of magnitude when compared to the wild type enzyme. By contrast the effect of the mutation on Kd values for steroids were 10-fold or less. The reduced affinity for the cofactor suggests that the mutant exists largely in the less stable cofactor-free form in the cell. Using stopped-flow spectroscopy, a significant reduction in the rate of the chemical step was observed in multiple turnover reactions catalyzed by the P133R mutant, possibly due to the altered position of NADPH. Thus, impaired NADPH binding and hydride transfer is the molecular basis for bile acid deficiency in patients with the P133R mutation. Results revealed that optimal cofactor binding is vulnerable to distant structural perturbation, which may apply to other disease-associated mutations in AKR1D1, all of which occur at conserved residues and are unstable.
Assuntos
Ácidos e Sais Biliares/deficiência , NADP/metabolismo , Oxirredutases/genética , Oxirredutases/metabolismo , Ácidos e Sais Biliares/metabolismo , Sítios de Ligação , Humanos , Modelos Moleculares , Oxirredutases/química , Mutação Puntual , Ligação Proteica , Esteroides/metabolismo , Especificidade por SubstratoRESUMO
AIM: Liver radiofrequency ablation (RFA) has been shown to disrupt the mechanical component of the gut barrier. The aim of the present study was to investigate the consequences of liver RFA on the biological gut barrier in terms of the effects of bile production rate and bowel inflammatory state on intestinal microflora balance. METHOD: A total of 25 New Zealand rabbits were assigned to five groups (n = 5 per group): group CBD: subjected to common bile duct (CBD) extracorporeal bypass; group CBD-RFA: subjected to CBD bypass plus one session of open liver RFA; group RFA: subjected to liver RFA; group sham: subjected to sham operation; and group TBD: subjected to total bile deviation (TBD). In groups CBD and CBD-RFA, bile production rate was assessed for 48 h. In groups sham and RFA, measurement of biliary glycine conjugates of cholic and deoxycholic acid levels, histopathologic examination of the non-ablated liver tissue, morphometric analysis, and histopathologic examination of the terminal ileum and microbiological analysis of fecal and tissue samples collected from the jejunum and the cecum (and in group TBD) were performed at 48 h post-operation. RESULTS: One session of liver RFA resulted in ablation of 18.7 ± 2.7% of liver weight. Following liver RFA, bile production rate was reduced, while the levels of biliary bile salts were not affected. There was mild injury of the non-ablated liver parenchyma, mild intestinal wall inflammation, intestinal mucosa atrophy, and intestinal microbial population overgrowth. CONCLUSION: Reduced in bile production and mild bowel inflammation secondary to liver RFA impaired the biological gut barrier as manifested by intestinal microflora imbalance.
Assuntos
Ácidos e Sais Biliares/deficiência , Colestase Intra-Hepática/fisiopatologia , Modelos Animais de Doenças , Imunidade nas Mucosas , Hospedeiro Imunocomprometido , Mucosa Intestinal/microbiologia , Fígado/fisiopatologia , Técnicas de Ablação , Animais , Atrofia , Ácidos e Sais Biliares/metabolismo , Ductos Biliares/cirurgia , Colestase Extra-Hepática/imunologia , Colestase Extra-Hepática/microbiologia , Colestase Extra-Hepática/patologia , Colestase Extra-Hepática/fisiopatologia , Colestase Intra-Hepática/imunologia , Colestase Intra-Hepática/microbiologia , Colestase Intra-Hepática/patologia , Fezes/microbiologia , Fungos/crescimento & desenvolvimento , Fungos/imunologia , Fungos/isolamento & purificação , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Negativas/imunologia , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Positivas/crescimento & desenvolvimento , Bactérias Gram-Positivas/imunologia , Bactérias Gram-Positivas/isolamento & purificação , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Mucosa Intestinal/fisiopatologia , Intestinos/imunologia , Intestinos/microbiologia , Intestinos/patologia , Intestinos/fisiopatologia , Fígado/metabolismo , Fígado/cirurgia , Coelhos , Distribuição Aleatória , Índice de Gravidade de DoençaRESUMO
Human aldo-keto reductases AKR1C1-AKR1C4 and AKR1D1 play essential roles in the metabolism of all steroid hormones, the biosynthesis of neurosteroids and bile acids, the metabolism of conjugated steroids, and synthetic therapeutic steroids. These enzymes catalyze NADPH dependent reductions at the C3, C5, C17 and C20 positions on the steroid nucleus and side-chain. AKR1C1-AKR1C4 act as 3-keto, 17-keto and 20-ketosteroid reductases to varying extents, while AKR1D1 acts as the sole Δ(4)-3-ketosteroid-5ß-reductase (steroid 5ß-reductase) in humans. AKR1 enzymes control the concentrations of active ligands for nuclear receptors and control their ligand occupancy and trans-activation, they also regulate the amount of neurosteroids that can modulate the activity of GABAA and NMDA receptors. As such they are involved in the pre-receptor regulation of nuclear and membrane bound receptors. Altered expression of individual AKR1C genes is related to development of prostate, breast, and endometrial cancer. Mutations in AKR1C1 and AKR1C4 are responsible for sexual development dysgenesis and mutations in AKR1D1 are causative in bile-acid deficiency.
Assuntos
20-Hidroxiesteroide Desidrogenases/metabolismo , Oxirredutases/metabolismo , Esteroides/metabolismo , 20-Hidroxiesteroide Desidrogenases/genética , Ácidos e Sais Biliares/deficiência , Transtornos do Desenvolvimento Sexual/enzimologia , Transtornos do Desenvolvimento Sexual/genética , Humanos , Mutação , Oxirredutases/genética , Receptores Citoplasmáticos e Nucleares/metabolismoRESUMO
Farnesoid X receptor (FXR, Nr1h4) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is essential in maintaining bile acid (BA) homeostasis, and FXR(-/-) mice develop cholestasis, inflammation, and spontaneous liver tumors. The signal transducer and activator of transcription 3 (STAT3) is well known to regulate liver growth, and STAT3 is feedback inhibited by its target gene, the suppressor of cytokine signaling 3 (SOCS3). Strong activation of STAT3 was detected in FXR(-/-) mouse livers. However, the mechanism of STAT3 activation with FXR deficiency remains elusive. Wild-type (WT) and FXR(-/-) mice were used to detect STAT3 pathway activation in the liver. In vivo BA feeding or deprivation was used to determine the role of BAs in STAT3 activation, and in vitro molecular approaches were used to determine the direct transcriptional regulation of SOCS3 by FXR. STAT3 was activated in FXR(-/-) but not WT mice. BA feeding increased, but deprivation by cholestyramine reduced, serum inflammatory markers and STAT3 activation. Furthermore, the Socs3 gene was determined as a direct FXR target gene. The elevated BAs and inflammation, along with reduced SOCS3, collectively contribute to the activation of the STAT3 signaling pathway in the liver of FXR(-/-) mice. This study suggests that the constitutive activation of STAT3 may be a mechanism of liver carcinogenesis in FXR(-/-) mice.
Assuntos
Fígado/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Ácidos e Sais Biliares/deficiência , Ácidos e Sais Biliares/metabolismo , Ácidos e Sais Biliares/farmacologia , Resina de Colestiramina/farmacologia , Citocinas/sangue , Citocinas/metabolismo , Fígado/efeitos dos fármacos , Camundongos , Camundongos Knockout , Receptores Citoplasmáticos e Nucleares/genética , Fator de Transcrição STAT3/genética , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Transcrição GênicaRESUMO
Interruption of the enterohepatic circulation of bile acids increases cholesterol catabolism, thereby stimulating hepatic cholesterol synthesis from acetate. We hypothesized that such treatment should lower the hepatic acetate pool which may alter triglyceride and glucose metabolism. We explored this using mice deficient of the ileal sodium-dependent BA transporter (Slc10a2) and ob/ob mice treated with a specific inhibitor of Slc10a2. Plasma TG levels were reduced in Slc10a2-deficient mice, and when challenged with a sucrose-rich diet, they displayed a reduced response in hepatic TG production as observed from the mRNA levels of several key enzymes in fatty acid synthesis. This effect was paralleled by a diminished induction of mature sterol regulatory element-binding protein 1c (Srebp1c). Unexpectedly, the SR-diet induced intestinal fibroblast growth factor (FGF) 15 mRNA and normalized bile acid synthesis in Slc10a2-/- mice. Pharmacologic inhibition of Slc10a2 in diabetic ob/ob mice reduced serum glucose, insulin and TGs, as well as hepatic mRNA levels of Srebp1c and its target genes. These responses are contrary to those reported following treatment of mice with a bile acid binding resin. Moreover, when key metabolic signal transduction pathways in the liver were investigated, those of Mek1/2-Erk1/2 and Akt were blunted after treatment of ob/ob mice with the Slc10a2 inhibitor. It is concluded that abrogation of Slc10a2 reduces hepatic Srebp1c activity and serum TGs, and in the diabetic ob/ob model it also reduces glucose and insulin levels. Hence, targeting of Slc10a2 may be a promising strategy to treat hypertriglyceridemia and diabetes.
Assuntos
Glicemia , Mucosa Intestinal/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidores , Triglicerídeos/metabolismo , Adaptação Fisiológica , Animais , Ácidos e Sais Biliares/deficiência , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Colesterol 7-alfa-Hidroxilase/metabolismo , Dieta , Ácidos Graxos/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fígado/metabolismo , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/metabolismo , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Simportadores/genética , Simportadores/metabolismo , Triglicerídeos/sangueRESUMO
Segments from almost all parts of the bowel have been used for urinary diversion. As a result, the available absorptive surface area of the bowel is reduced, and the incorporation of bowel segments into the urinary tract may have metabolic consequences. This is an area somewhat neglected in the literature. Metabolic complications are rare, but sub-clinical metabolic disturbances are quite common. Several studies have demonstrated that some of the absorbent and secreting properties of the bowel tissue are preserved after incorporation into the urinary tract. Hyperchloraemic metabolic acidosis can occur if ileal and/or colon segments are used, as well as malabsorption of vitamin B(12) and bile acid after the use of ileal segments. These metabolic effects are not as severe as may be suspected and can be prevented by prophylactic substitution. Secondary malignancies can develop as a long-term consequence of bladder augmentation. Using colonic segments, tumours are most likely to occur at the ureteral implantation site. To prevent metabolic complications, careful patient selection and meticulous and lifelong follow up, as well as prophylactic treatment, are mandatory. Endoscopy for early detection has been recommended, starting 10 years postoperatively for patients who underwent surgery for a benign condition.
Assuntos
Acidose , Ureter/cirurgia , Bexiga Urinaria Neurogênica/cirurgia , Derivação Urinária/efeitos adversos , Derivação Urinária/métodos , Acidose/sangue , Acidose/etiologia , Acidose/prevenção & controle , Ácidos e Sais Biliares/sangue , Ácidos e Sais Biliares/deficiência , Colo/metabolismo , Colo/transplante , Humanos , Íleo/metabolismo , Íleo/transplante , Seleção de Pacientes , Complicações Pós-Operatórias , Prognóstico , Deficiência de Vitamina B 12/sangue , Deficiência de Vitamina B 12/etiologia , Deficiência de Vitamina B 12/prevenção & controleRESUMO
The stereospecific 5ß-reduction of Δ(4)-3-ketosterols is very difficult to achieve chemically and introduces a 90° bend between ring A and B of the planar steroid. In mammals, the reaction is catalyzed by steroid 5ß-reductase, a member of the aldo-keto reductase (AKR) family. The human enzyme, AKR1D1, plays an essential role in bile-acid biosynthesis since the 5ß-configuration is required for the emulsifying properties of bile. Deficient 5ß-reductase activity can lead to cholestasis and neo-natal liver failure and is often lethal if it remains untreated. In five patients with 5ß-reductase deficiency, sequencing revealed individual, non-synonymous point mutations in the AKR1D1 gene: L106F, P133R, G223E, P198L and R261C. However, mapping these mutations to the AKR1D1 crystal structure failed to reveal any obvious involvement in substrate or cofactor binding or catalytic mechanism, and it remained unclear whether these mutations could be causal for the observed disease. We analyzed the positions of the reported mutations and found that they reside in highly conserved portions of AKR1D1 and hypothesized that they would likely lead to changes in protein folding, and hence enzyme activity. Attempts to purify the mutant enzymes for further characterization by over-expression in Escherichia coli yielded sufficient amounts of only one mutant (P133R). This enzyme exhibited reduced K(m) and k(cat) values with the bile acid intermediate Δ(4)-cholesten-7α-ol-3-one as substrate reminiscent of uncompetitive inhibition. In addition, P133R displayed no change in cofactor affinity but was more thermolabile as judged by CD-spectroscopy. When all AKR1D1 mutants were expressed in HEK 293 cells, protein expression levels and enzyme activity were dramatically reduced. Furthermore, cycloheximide treatment revealed decreased stability of several of the mutants compared to wild type. Our data show, that all five mutations identified in patients with functional bile acid deficiency strongly affected AKR1D1 enzyme functionality and therefore may be causal for this disease.
Assuntos
Doença/genética , Oxirredutases/genética , Mutação Puntual , Animais , Ácidos e Sais Biliares/biossíntese , Ácidos e Sais Biliares/deficiência , Sequência Conservada , Células HEK293 , Humanos , Oxirredutases/química , Oxirredutases/metabolismoAssuntos
Síndromes de Malabsorção/diagnóstico , Síndromes de Malabsorção/etiologia , Ácidos e Sais Biliares/deficiência , Metabolismo dos Carboidratos , Criança , Proteínas Alimentares/metabolismo , Insuficiência Pancreática Exócrina/complicações , Humanos , Metabolismo dos Lipídeos , Linfangiectasia Intestinal/complicações , Síndromes de Malabsorção/fisiopatologia , Microvilosidades/metabolismo , Vitaminas/metabolismoRESUMO
Bile acid deficiency is a serious syndrome in newborns that can result in death if untreated. 5beta-Reductase deficiency is one form of bile acid deficiency and is characterized by dramatically decreased levels of physiologically active 5beta-reduced bile acids. AKR1D1 (aldo-keto reductase 1D1) is the only known human enzyme that stereo-specifically reduces the Delta(4) double bond in 3-keto steroids and sterols to yield the 5beta-hydrogenated product. Analysis of the AKR1D1 gene in five patients with 5beta-reductase deficiency revealed five different mutations resulting in an amino acid substitution in the protein. To investigate a causal role for these observed point mutations in AKR1D1 in 5beta-reductase deficiency, we characterized their effect on enzymatic properties. Attempts to purify mutant enzymes by overexpression in Escherichia coli only yielded sufficient amounts of the P133R mutant for further characterization. This enzyme displayed a highly reduced K(m) and V(max) reminiscent of uncompetitive kinetics with 4-cholesten-7alpha-ol-3-one as substrate. In addition, this mutant displayed no change in cofactor affinity but was more thermolabile in the absence of NADPH as judged by CD spectroscopy. All mutants were compared following expression in HEK 293 cells. Although these enzymes were equally expressed based on mRNA levels, protein expression and functional activity were dramatically reduced. Cycloheximide treatment also revealed that several of the expressed mutants were less stable. Our findings show that the reported mutations in AKR1D1 in patients with 5beta-reductase lead to significantly decreased levels of active enzyme and could be causal in the development of bile acid deficiency syndrome.
Assuntos
Ácidos e Sais Biliares/deficiência , Oxirredutases/genética , Linhagem Celular , Dicroísmo Circular , Cicloeximida/farmacologia , Vetores Genéticos , Humanos , Cinética , Modelos Moleculares , Conformação Molecular , Mutação , NADP/química , Oxirredutases/fisiologia , Mutação Puntual , Inibidores da Síntese de Proteínas/farmacologia , Espectrometria de Fluorescência/métodosRESUMO
Los avances en genética molecular han cambiado nuestro abordaje de los pacientes con colestasis intrahepática. La identificación de mutaciones enciertos genes nos permite hoy arribar al diagnóstico genético de varias formas de colestasis, agrupadas previamente como colestasis intrahepáticafamiliar progresiva. Las tres formas descriptas:tipos 1, 2 y 3, son el resultado de mutaciones en los genes ATP8B1, ABCB11 y ABCB4. Hallazgosclínicos, bioquímicos e histológicos nos orientan en el diagnóstico. El tratamiento tiene como objetivosaliviar los síntomas y mejorar la calidadde vida. Los errores congénitos en la síntesis de ácidos biliares representan un subgupo de las colestasis familiares. El tratamiento de reemplazo con ácido ursodesoxicólico y ácido cólico evitanla progresión de la lesión hepática.
Assuntos
Lactente , Pré-Escolar , Colestase Intra-Hepática/classificação , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/etiologia , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/terapia , Ácidos e Sais Biliares/deficiência , Diagnóstico DiferencialRESUMO
As the number of persons living long lives following ostomy and bowel resection surgery increases, so do their questions about the effect of surgery on chronic conditions commonly associated with aging. The literature was reviewed to evaluate current evidence about the effect of bowel resection on the absorption of vitamins and minerals and related health concerns such as osteoporosis, gallstones, and renal calculi. Present knowledge about the process of vitamin and mineral absorption in the intestine and clinical study results suggest that chronic inflammation and corticosteroid use may adversely affect absorption. In general, a history of bowel resection does not appear to increase the risk of developing osteoporosis, gallstones, or renal calculi and the body can adjust to losing significant sections of intestine. Strategies to help prevent the majority of long-term complications should be encouraged, including monitoring hydration and transit time, consuming low-digestible carbohydrates, and avoiding processed foods as well as agents with chelating properties.
Assuntos
Enterostomia/efeitos adversos , Intestinos/cirurgia , Síndromes de Malabsorção/etiologia , Deficiência de Vitaminas/etiologia , Deficiência de Vitaminas/prevenção & controle , Ácidos e Sais Biliares/deficiência , Cálculos Biliares/etiologia , Cálculos Biliares/prevenção & controle , Humanos , Cálculos Renais/etiologia , Cálculos Renais/prevenção & controle , Síndromes de Malabsorção/prevenção & controle , Minerais/metabolismo , Osteoporose/etiologia , Osteoporose/prevenção & controleRESUMO
The hypothesis that higher molecular weight (MW) quaternary ammoniums (QAs) form lipophilic ion-pair complexes with bile salts in the liver, and are subsequently excreted into bile via a canalicular transporter, P-gp, was re-examined in the present study for its validity. The biliary excretion of tributylmethyl ammonium (TBuMA), a QA with a MW of 200, in bile salt-depleted rats was determined. Depletion was induced by a daily oral administration of a resin, cholestyramine, at a dose of 0.5 g/kg for 2 consecutive weeks, which decreased the concentration of total bile salts in the liver by 38%. When TBuMA was administered intravenously (12 micromol/kg) to these rats, the plasma level, area under the plasma concentration-time curve (AUC), systemic clearance (CL) and volume of distribution (V(ss)) of the compound remained unchanged, whereas bile flow (23.03 vs 16.94 microl/min, p<0.05) and biliary clearance (CL(bile), 12.75 vs 5.34 ml/min/kg, p<0.01) were decreased significantly. These results implied the biliary clearance of TBuMA in rats with bile salt depletion was significantly decreased as a result of decreased ion-pair complexation of TBuMA. The above results are consistent with our hypothesis and the existence of a MW threshold (i.e. 200+/-50 for rats) for the biliary excretion of QAs.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Ácidos e Sais Biliares/metabolismo , Bile/metabolismo , Compostos de Amônio Quaternário/farmacocinética , Animais , Resinas de Troca Aniônica/farmacologia , Área Sob a Curva , Ácidos e Sais Biliares/deficiência , Transporte Biológico Ativo , Resina de Colestiramina/farmacologia , Injeções Intravenosas , Fígado/metabolismo , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
Cholestasis is associated with systemic accumulation of bile salts and with deficiency of bile in the intestinal lumen. During the past years bile salts have been identified as signaling molecules that regulate lipid, glucose, and energy metabolism. Bile salts have also been shown to activate signaling routes leading to proliferation, apoptosis, or differentiation. It is unclear, however, whether cholestasis affects the constitution and absorptive capacity of the intestinal epithelium in vivo. We studied small intestinal morphology, proliferation, apoptosis, expression of intestine-specific genes, and carbohydrate absorption in cholestatic (1 wk bile duct ligation), bile-deficient (1 wk bile diversion), and control (sham) rats. Absorptive capacity was assessed by determination of plasma [(2)H]- and [(13)C]glucose concentrations after intraduodenal administration of [(2)H]glucose and naturally enriched [(13)C]sucrose, respectively. Small intestinal morphology, proliferation, apoptosis, and gene expression of intestinal transcription factors (mRNA levels of Cdx-2, Gata-4, and Hnf-1alpha, and Cdx-2 protein levels) were similar in cholestatic, bile-deficient, and control rats. The (unlabeled) blood glucose response after intraduodenal administration was delayed in cholestatic animals, but the absorption over 180 min was quantitatively similar between the groups. Plasma concentrations of [(2)H]glucose and [(13)C]glucose peaked to similar extents in all groups within 7.5 and 30 min, respectively. Absorption of [(2)H]glucose and [(13)C]glucose in plasma was similar in all groups. The present data indicate that neither accumulation of bile salts in the body, nor their intestinal deficiency, two characteristic features of cholestasis, affect rat small intestinal proliferation, differentiation, apoptosis, or its capacity to digest and absorb carbohydrates.
Assuntos
Ácidos e Sais Biliares/metabolismo , Colestase Extra-Hepática/metabolismo , Carboidratos da Dieta/metabolismo , Digestão , Absorção Intestinal , Jejuno/metabolismo , Animais , Apoptose , Ácidos e Sais Biliares/sangue , Ácidos e Sais Biliares/deficiência , Ductos Biliares/cirurgia , Glicemia/metabolismo , Fator de Transcrição CDX2 , Isótopos de Carbono , Diferenciação Celular , Proliferação de Células , Colestase Extra-Hepática/patologia , Colestase Extra-Hepática/fisiopatologia , Carboidratos da Dieta/administração & dosagem , Sacarose Alimentar/metabolismo , Modelos Animais de Doenças , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/metabolismo , Glucose/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Intubação Gastrointestinal , Jejuno/patologia , Jejuno/fisiopatologia , Ligadura , Metabolismo dos Lipídeos , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Fatores de Tempo , Transativadores/genética , Transativadores/metabolismoAssuntos
Ácidos e Sais Biliares/deficiência , Colestase Intra-Hepática/fisiopatologia , Hepatoblastoma/patologia , Hepatócitos/patologia , Neoplasias Hepáticas/patologia , Transplante de Fígado , Pré-Escolar , Colestase Intra-Hepática/patologia , Consanguinidade , Feminino , Hepatoblastoma/cirurgia , Humanos , Cirrose Hepática/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Resultado do TratamentoRESUMO
The metabolism of intravenously infused bile salts, tauroursodeoxycholate, tauro-beta-muricholate and their corresponding unconjugated forms in the liver was investigated in bile salt-depleted bile fistula rats. The biliary bile salt composition was determined by gas chromatography-mass spectrometry using chemical positive ionization and electron-impact methods. For an infusion rate of 2 micromol/min/kg, all bile salts were efficiently secreted in bile, inducing similar choleresis. Only tauroconjugated bile salts were recovered; no glucuronide or glyco derivatives were detected. The infusion of free ursodeoxycholate led to the appearance of a metabolite identified as a Delta22 derivative (12%). A similar biotransformation rate (11%) was observed following free beta-muricholate infusion. In contrast, no metabolite was observed after infusion of the tauroconjugated form of ursodeoxycholate and beta-muricholate. The unsaturation process probably depends on the availability of the carboxyl group for the starting step of the beta-oxidation mechanism. In conclusion, the current in vivo study demonstrates a hepatic origin for Delta22 bile salts. It also shows that free bile salts were sensitive to Delta22 formation while conjugation with taurine totally prevented the side-chain oxidation of the two 7beta-hydroxylated bile salts.
Assuntos
Ácidos e Sais Biliares/metabolismo , Fístula Biliar/metabolismo , Fígado/efeitos dos fármacos , Taurina/farmacologia , Animais , Ácidos e Sais Biliares/deficiência , Biotransformação , Cromatografia Gasosa-Espectrometria de Massas , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
The regulation of the classic and alternative bile acid synthetic pathways by key hepatic enzyme activities (microsomal cholesterol 7alpha-hydroxylase and mitochondrial sterol 27-hydroxylase, respectively) was examined in bile acid depletion and replacement and cholesterol-feeding experiments with rats, guinea pigs, and rabbits. The bile acid pool was depleted by creating a bile fistula (BF) and collecting bile for 2 to 5 days, and it was replaced by intraduodenal infusion of the major biliary bile acids (taurocholic acid [TCA], glycochenodeoxycholic acid [GCDCA], and glycocholic acid [GCA] in the rat, guinea pig, and rabbit, respectively) at rates equivalent to the measured hepatic flux of the bile acids. To study the effects of cholesterol, the animals were fed for 7 days on a basal diet with and without 2% cholesterol. Cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase activities, measured by isotope incorporation assays, were related to bile acid output and composition and hepatic cholesterol concentrations. Intraduodenal infusion of bile acids increased the output of the tested bile acids, but did not significantly change hepatic cholesterol concentrations and had no effect on sterol 27-hydroxylase activity. Neither bile acid depletion nor replacement affected sterol 27-hydroxylase activity when three different substrates (cholesterol, 5beta-cholestane-3alpha,7alpha-diol, and 5beta-cholestane-3alpha,7alpha,12alpha-triol) were tested. In contrast, feeding 2% cholesterol increased hepatic cholesterol concentrations in rats, guinea pigs, and rabbits threefold, twofold, and eightfold, respectively, and increased hepatic mitochondrial sterol 27-hydroxylase activity (conversion of cholesterol to 27-hydroxycholesterol) in all three animal models. The stimulation and feedback inhibition of cholesterol 7alpha-hydroxylase activity by bile acid depletion and replacement were observed in all three animal models, whereas the effect of cholesterol feeding was species-dependent (cholesterol 7alpha-hydroxylase activity increased in the rat, did not change in the guinea pig, and was inhibited in the rabbit). Thus, in contrast to sterol 27-hydroxylase, which was upregulated by cholesterol but not affected by bile acid depletion and replacement in all three animal models, cholesterol 7alpha-hydroxylase activity was controlled consistently and inversely by the hepatic flux of bile acids, but was species-dependent in its response to a 1-week feeding with 2% cholesterol.