ABSTRACT
Resumen: Introducción: Los errores innatos en la síntesis de ácidos biliares son un grupo de defectos genéticos que representan del 1 al 2% de las enfermedades colestásicas crónicas en lactantes, niños y adolescentes. La deficiencia de 3β-Δ5-C27-hidroxiesteroide oxidoreductasa (3β-HSDH) es el defecto más comúnmente reportado. El cuadro clínico característico consiste en hepatitis neonatal, hepatomegalia, esplenomegalia, malabsorción, desnutrición y enfermedad hepática de aparición tardía. Caso clínico: Lactante masculino con antecedente de ictericia en escleras a los 4 meses que se resolvió espontáneamente; posteriormente, a los 18 meses, presentó enfermedad colestásica. Durante su abordaje se documentó gamma-glutamil transpeptidasa normal, hallazgo que es altamente sugestivo de alteración en la síntesis de ácidos biliares. El diagnóstico se realizó con espectrometría de masas en orina. Se inició tratamiento con ácido cólico oral, y presentó mejoría inmediata. Conclusiones: El resultado en los ácidos biliares urinarios es definitivo para el defecto genético y consistente con mutaciones homocigotas en el gen HSD3B7. Este padecimiento constituye un diagnóstico de exclusión en las enfermedades colestásicas de la infancia, particularmente el hallazgo de gamma-glutamil transpeptidasa normal o levemente aumentada, y responde adecuadamente al tratamiento oral, por lo que debe identificarse de forma temprana.
Abstract: Background: Inborn errors in bile acid synthesis are a group of genetic defects accounting for 1 to 2% of chronic cholestatic diseases in infants, children and adolescents. Deficiency of 3β-Δ5-C27-hydroxysteroid dehydrogenase (3β-HSDH) is the most common defect in this disease. Clinical features consist of neonatal hepatitis, hepatomegaly, splenomegaly, malabsorption, malnutrition, and late-onset liver disease. Case report: A male infant who presented jaundice in sclera at 4 months that resolved spontaneously, later presented cholestatic disease at 18 months. During his approach, normal gamma-glutamyl transpeptidase was documented, a finding that is highly suggestive of alteration in the synthesis of bile acids. The diagnosis was made using urine mass spectrometry. Oral colic acid treatment was started, presenting immediate improvement. Conclusions: The result in urinary bile acids is definitive for the genetic defect and consistent with homozygous mutations in the HSD3B7 gene. This condition is a diagnosis of exclusion in childhood cholestatic diseases, particularly in the presence of normal or mildly enlarged gamma-glutamyl transpeptidase, and responds adequately to oral treatment; it should be identified early.
Subject(s)
Humans , Infant , Male , Bile Acids and Salts/metabolism , Cholestasis/diagnosis , 3-Hydroxysteroid Dehydrogenases/genetics , Metabolism, Inborn Errors/diagnosis , Cholestasis/genetics , Cholic Acid/administration & dosage , Jaundice/etiology , Metabolism, Inborn Errors/geneticsABSTRACT
Introducción: Los errores innatos en la síntesis de ácidos biliares son un grupo de defectos genéticos que representan del 1 al 2% de las enfermedades colestásicas crónicas en lactantes, niños y adolescentes. La deficiencia de 3b-Δ5-C27-hidroxiesteroide oxidoreductasa (3b-HSDH) es el defecto más comúnmente reportado. El cuadro clínico característico consiste en hepatitis neonatal, hepatomegalia, esplenomegalia, malabsorción, desnutrición y enfermedad hepática de aparición tardía. Caso clínico: Lactante masculino con antecedente de ictericia en escleras a los 4 meses que se resolvió espontáneamente; posteriormente, a los 18 meses, presentó enfermedad colestásica. Durante su abordaje se documentó gamma-glutamil transpeptidasa normal, hallazgo que es altamente sugestivo de alteración en la síntesis de ácidos biliares. El diagnóstico se realizó con espectrometría de masas en orina. Se inició tratamiento con ácido cólico oral, y presentó mejoría inmediata. Conclusiones: El resultado en los ácidos biliares urinarios es definitivo para el defecto genético y consistente con mutaciones homocigotas en el gen HSD3B7. Este padecimiento constituye un diagnóstico de exclusión en las enfermedades colestásicas de la infancia, particularmente el hallazgo de gamma-glutamil transpeptidasa normal o levemente aumentada, y responde adecuadamente al tratamiento oral, por lo que debe identificarse de forma temprana. Background: Inborn errors in bile acid synthesis are a group of genetic defects accounting for 1 to 2% of chronic cholestatic diseases in infants, children and adolescents. Deficiency of 3b-Δ5-C27-hydroxysteroid dehydrogenase (3ß-HSDH) is the most common defect in this disease. Clinical features consist of neonatal hepatitis, hepatomegaly, splenomegaly, malabsorption, malnutrition, and late-onset liver disease. Case report: A male infant who presented jaundice in sclera at 4 months that resolved spontaneously, later presented cholestatic disease at 18 months. During his approach, normal gamma-glutamyl transpeptidase was documented, a finding that is highly suggestive of alteration in the synthesis of bile acids. The diagnosis was made using urine mass spectrometry. Oral colic acid treatment was started, presenting immediate improvement. Conclusions: The result in urinary bile acids is definitive for the genetic defect and consistent with homozygous mutations in the HSD3B7 gene. This condition is a diagnosis of exclusion in childhood cholestatic diseases, particularly in the presence of normal or mildly enlarged gamma-glutamyl transpeptidase, and responds adequately to oral treatment; it should be identified early.
Subject(s)
3-Hydroxysteroid Dehydrogenases/genetics , Bile Acids and Salts/metabolism , Cholestasis/diagnosis , Metabolism, Inborn Errors/diagnosis , Cholestasis/genetics , Cholic Acid/administration & dosage , Humans , Infant , Jaundice/etiology , Male , Metabolism, Inborn Errors/geneticsABSTRACT
Bile acids or its derivatives may influence non-alcoholic fatty liver disease development through multiple mechanisms. Intestinal L-cells secrete glucagon-like peptide-1 (GLP-1) and can be activated by bile acids (BA) influencing insulin resistance and hepatic steatosis development and progression. The aim of the present study was to assess the effects of cholic acid (CA) or ursodeoxycholic acid (UDCA) administration on portal and systemic levels of GLP-1 in genetically obese mice with established hepatic steatosis. Eight-week-old ob/ob mice were fed CA or UDCA during 4 weeks. Systemic and portal GLP-1 levels were measured as well as glucose tolerance test, serum and biliary parameters, hepatic triglyceride content, liver histology, and hepatic gene expression of relevant genes related to bile secretion. Eight-week-old ob/ob mice exhibited marked obesity, hyperinsulinemia, and fasting hyperglycemia. Administration of both CA and UDCA was associated to decreased hepatic triglyceride content and complete reversion of histological steatosis. BA-fed animals did not exhibit significant differences in glucose tolerance. In addition, neither CA nor UDCA administration significantly influenced portal or systemic GLP-1 levels. CA and UDCA strongly ameliorated established fatty liver in ob/ob mice independently of the GLP-1 incretin pathway. Thus, the anti-steatotic action of these bile acids is likely related to direct hepatic effects.
Subject(s)
Bile Acids and Salts/administration & dosage , Glucagon-Like Peptide 1/blood , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 11 , ATP-Binding Cassette Transporters/genetics , Animals , Cholesterol 7-alpha-Hydroxylase/genetics , Cholic Acid/administration & dosage , Gene Expression/drug effects , Glucose Tolerance Test , Incretins/metabolism , Liver/drug effects , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Obese , Non-alcoholic Fatty Liver Disease/pathology , Organic Anion Transporters, Sodium-Dependent/genetics , Receptors, Cytoplasmic and Nuclear/genetics , Symporters/genetics , Triglycerides/metabolism , Ursodeoxycholic Acid/administration & dosageABSTRACT
Etiopathogenesis of biliary atresia remains unknown. Among several theories, one proposes that the disorder may be caused by the toxic effect of monohydroxy bile acids on fetal and neonatal hepatobiliary system. In this paper we evaluated toxic effects produced by ingestion of cholic acid, a trihydroxy bile acid, and lithocholic acid, a monohydroxy bile acid in the hepatobiliary system of a hamster during gestational and perinatal periods. A diet composed by 0.5% cholic acid and 0.25% lithocholic acid was administrated to pregnant hamsters. Liver and bile ducts of the adult and newborn animals were analyzed to point out the changes induced by these acids after birth. Because hamsters and humans have a similar bile metabolism, these animals were eligible for the study. The ingestion of 0.5% lithocholic acid, during hamster's gestation, caused maternal intense ductal/ductular proliferation, inflammatory signs, hepatic cells degeneration and regeneration, hyperplasia of extra hepatic ducts epithelium, and abortion. Both 0.5% cholic acid and 0.25% lithocholic acid ingested by pregnant hamsters, caused ductal/ductular proliferation and hepatobiliary inflammatory damage in a different degree of intensity in adult animals and mild intensity in the young; and also the number of the young was reduced in the litter. We found that the ingestion of these bile acids by hamsters, during gestational period caused different degrees of toxicity on maternal and neonatal hepatobiliary systems. The histopathologic findings observed in biliary atresia patients could not be found in newborn hamsters. New experimental models are needed in the attempt to establish a correlation of these acids with neonatal cholestatic diseases.
Subject(s)
Biliary Tract/drug effects , Cholic Acid/toxicity , Lithocholic Acid/toxicity , Liver/drug effects , Administration, Oral , Animals , Animals, Newborn , Biliary Atresia/etiology , Cholic Acid/administration & dosage , Cricetinae , Female , Lithocholic Acid/administration & dosage , Male , Maternal-Fetal Exchange , PregnancyABSTRACT
A atresia de vias biliares é a causa mais comum de icterícia obstrutiva, cirrose e transplante hepático da infância. Sua etiopatogenia permanente desconhecida. Dentre várias teorias, uma propõe que a enfermidade pode ser causada pelo efeito tóxico de ácidos biliares monohidroxilados no sistema hepatobiliar fetal e neonatal. As características do metabolismo biliar nesta fase da vida e possíveis alterações bioquímicas desses ácidos poderiam causar reaçäo inflamatória e obstruçäo ductal. Ainda näo foi feito qualquer estudo experimental da açäo desses ácidos sobre o sistema hepatobiliar durante a gravidez. Neste trabalho, avaliaram-se os efeitos tóxicos provocados pela ingestäo de um ácido biliar trihidroxilado, o cólico, e um monohidroxilado, o litocólico, sobre o sistema hepatobiliar de hamsters durante os períodos gestacional e perinatal. A escolha deste animal deve-se à semelhança de seu metabolismo biliar com o humano. A ingestäo de ácido litocólico a 0,5 por cento durante a gestaçäo de hamsters, provocou proliferaçäo ductal/ductular acentuada, sinais inflamatórios, degeneraçäo e regeneraçäo celular hepática, hiperplasia do epitélio dos ductos extra-hepáticos maternos e aborto. Tanto o ácido cólico a 0,5 por cento como o ácido litocólico a 0,25 por cento, quando ingeridos por hamsters grávidas, provocaram proliferaçäo ductal/ductular e lesäo inflamatória hepatobiliar em graus variáveis no animal adulto e de leve intensidade nos filhotes. Induziu, ainda, a reduçäo da ninhada. Portanto, verificou-se que a ingestäo destes ácidos biliares por hamsters durante o período gestacional provocou toxicidade variável sobre o sistema hepatobibliar materno e de recém-nascidos