Relations of neuropeptide Y and heme oxygenase-1 expressions with fetal brain injury in rats with intrahepatic cholestasis of pregnancy

Abstract Purpose: To investigate the relations of neuropeptide Y (NPY) and heme oxygenase-1 (HO-1) expressions with fetal brain injury in rats with intrahepatic cholestasis of pregnancy (ICP). Methods: Sixty rats pregnant for 15 days were randomly divided into experimental and control groups. The ICP model was established in experimental group. On the 21st day, the blood biochemical test, histopathological examination of pregnant rat liver and fetal brain tissues and immunohistochemical analysis of fetal rat brain tissues were performed. Results: On the 21st day, the alanineaminotransferase, aspartate aminotransferase and total bile acid levels in experimental group were significantly higher than control group (P<0.01). Compared with control group, there was obvious vacuolar degeneration in pregnant rat liver tissue and fetal brain tissue in experimental group. NPY expression in fetal brain tissue was negative in control group and positive in experimental group. HO-1 expression in fetal brain tissue was strongly positive in control group and positive in experimental group. There was significant difference of immunohistochemical staining optical density between two groups (P<0.01). Conclusion: In fetal brain of ICP rats, the NPY expression is increased, and the HO-1 expression is decreased, which may be related to the fetal brain injury.

Alterações hepáticas da gravidez / Liver disorders in pregnancy

A gestação é um período de significativas modificações no organismo materno, que objetivam promover a homeostase do binômio materno-fetal. Sob o ponto de vista hepático, demais das alterações conspícuas à gravidez, deve o obstetra detectar precocemente anomalias envolvendo o fígado, que complicam até 3% das gestações e são responsáveis por elevada mortalidade materna e perinatal. Por outro lado, certas doenças hepáticas têm sua história natural modificada quando ocorrem durante a gestação, demandando cuidados especiais de uma equipe multidisciplinar que envolva o obstetra e o hepatologista. Este artigo revisa as modificações fisiológicas do sistema hepático na gravidez, assim como suas alterações hepáticas mais prevalentes no Brasil. O objetivo é auxiliar e fornecer orientações ao obstetra e guiar o melhor cuidado das pacientes a fim de prevenir e reduzir as complicações hepáticas na gravidez.(AU)

Pregnancy is a period of significant changes in the mother's organism aimed at promoting the mother-fetus homeostasis. From the hepatic standpoint, the obstetrician should detect early the abnormalities attacking the liver, which complicates up to 3% of pregnancies and are responsible for high rates of maternal and perinatal mortality. On the other hand, some liver diseases have their natural evolution changed when they occur during the pregnancy, requiring special care of a multidisciplinary team involving obstetrician and hepatologist specialists. This study presents the physiological changes of the hepatic system during pregnancy, as well as the most prevalent pregnancy hepatic disorders occurring in Brazil. It aims to help the obstetrician and guide the best patient care to prevent and reduce hepatic complications in pregnancy.(AU)

Pamidronate for the treatment of osteoporosis secondary to chronic cholestatic liver disease in Wistar rats

Osteoporosis is a major complication of chronic cholestatic liver disease (CCLD). We evaluated the efficacy of using disodium pamidronate (1.0 mg/kg body weight) for the prevention (Pr) or treatment (Tr) of cholestasis-induced osteoporosis in male Wistar rats: sham-operated (Sham = 12); bile duct-ligated (Bi = 15); bile duct-ligated animals previously treated with pamidronate before and 1 month after surgery (Pr = 9); bile duct-ligated animals treated with pamidronate 1 month after surgery (Tr = 9). Rats were sacrificed 8 weeks after surgery. Immunohistochemical expression of IGF-I and GH receptor was determined in the proximal growth plate cartilage of the left tibia. Histomorphometric analysis was performed in the right tibia and the right femur was used for biomechanical analysis. Bone material volume over tissue volume (BV/TV) was significantly affected by CCLD (Sham = 18.1 ± 3.2 vs Bi = 10.6 ± 2.2%) and pamidronate successfully increased bone volume. However, pamidronate administered in a preventive regimen presented no additional benefit on bone volume compared to secondary treatment (BV/TV: Pr = 39.4 ± 12.0; Tr = 41.2 ± 12.7%). Moreover, the force on the momentum of fracture was significantly reduced in Pr rats (Sham = 116.6 ± 23.0; Bi = 94.6 ± 33.8; Pr = 82.9 ± 22.8; Tr = 92.5 ± 29.5 N; P < 0.05, Sham vs Pr). Thus, CCLD had a significant impact on bone histomorphometric parameters and pamidronate was highly effective in increasing bone mass in CCLD; however, preventive therapy with pamidronate has no advantage regarding bone fragility.

Longitudinal evaluation of hepatic osteodystrophy in children and adolescents with chronic cholestatic liver disease

Bone mass loss is a major complication of chronic cholestatic liver disease (CCD). However, the long-term impact of CCD on bone mass acquisition is unknown. We longitudinally assessed bone mineral density (BMD) and factors involved in bone remodeling in 9 children and adolescents with CCD Child-Pugh A (5 boys/4 girls) and in 13 controls (6 boys/7 girls). The groups were evaluated twice, at baseline (T0) and after 3 years (T1), when osteocalcin, deoxypyridinoline, 25-hydroxyvitamin-D, parathyroid hormone, insulin-like growth factor-I (IGF-I), and BMD (L1-L4, proximal femur and total body) were determined. Serum levels of receptor activator for nuclear factor kB ligand (RANKL) and osteoprotegerin were measured only at T1. Lumbar spine BMD was reanalyzed twice: after adjustment for bone age and to compensate for the height factor. Volumetric density was also estimated mathematically in L2-L4. The BMD of L1-L4 was lower in the CCD group (Z-score at T0: control = -1.2 ± 0.8 vs CCD = -2.2 ± 1.4, P < 0.05; T1: control = -0.7 ± 0.8 vs CCD = -2.1 ± 1.1, P < 0.05). Osteocalcin and deoxypyridinoline were similar for the two groups. The CCD group presented lower IGF-I (Z-score at T1: control = 1.4 ± 2.8 vs CCD = -1.5 ± 1.0, P < 0.05) and RANKL (control = 0.465 ± 0.275 vs CCD = 0.195 ± 0.250 pM, P < 0.05) than control. Children with compensated CCD Child-Pugh A showed early impairment of bone acquisition, with the impact being more severe in an initial phase and then tapering in a slowly progressive way. Reduction in endocrine IGF-I has a crucial role in this process.

Nutrición enteral en hepatopatías crónicas en niños y adolescentes / Enteral nutrition in chronic liver disease in children and adolescents

La desnutrición que se observa en enfermedades hepáticas crónicas en niños se asocia a un aumento de requerimientos por gasto calórico elevado. La historia clínica incluye un recordatorio de alimentación, evaluación clínica, antropometría. Los niños con colestasis deben recibir una dieta hipercalórica. Es fundamental garantizar el aporte calórico calculado completo y la alimentación enteral. Se debe garantizar un crecimiento adecuado en un niño en lista de espera para trasplante. Los niños con enfermedades metabólicas requieren el uso de fórmulas comerciales especiales.

Malnutrition seen in chronic liver disease in children is associated with increased requirements for high caloric expenditure. The medical history includes a reminder of food, clinical evaluation, anthropometry. Children with cholestasis should receive a high calorie diet. It is essential to ensure complete and estimated calorie enteral feeding. It must ensure adequate growth in a child on the waiting list for transplantation. Children with metabolic diseases require the use of special comercial formulations.

Clinical and laboratory evaluation of 101 patients with intrahepatic neonatal cholestasis / Avaliação clínica e laboratorial de 101 pacientes com colestase neonatal intra-hepática

BACKGROUND: Intrahepatic neonatal cholestasis can be the initial manifestation of a very heterogeneous group of illnesses of different etiologies. AIM: To evaluate and compare clinical and laboratory data among intrahepatic neonatal cholestasis groups of infectious, genetic-endocrine-metabolic and idiopathic etiologies. METHODS: The study evaluated retrospectively clinical and laboratory data of 101 infants, from March 1982 to December 2005, 84 from the State University of Campinas Teaching Hospital, Campinas, SP, Brazil, and 17 from the Child’s Institute of the University of São Paulo, SP, Brazil. The inclusion criteria consisted of: jaundice beginning at up to 3 months of age and hepatic biopsy during the 1st year of life. It had been evaluated: clinical findings (gender, age, birth weight, weight during the first medical visit, stature at birth, jaundice, acholia/hipocholia, choluria, hepatomegaly and splenomegaly) and laboratorial (ALT, AST, FA, GGT, INR). RESULTS: According to diagnosis, patients were classified into three groups: group 1 (infectious) n = 24, group 2 (genetic-endocrine-metabolic) n = 21 and group 3 (idiopathic) n = 56. There were no significant differences in relation to the variables: age, gender, stature at birth, jaundice, acholia/hipocholia, choluria, hepatomegaly, splenomegaly, AST, ALT, ALP, GGT, DB and albumin. Significant differences were observed in relation to the following variables: birth weight and weight during the first medical visit. Birth weight of group 1 was lower in relation group 2 and 3. Weight during the first medical visit followed the same pattern. There was a statistically significant difference in relation to the INR, as the patients of the group 2 presented higher values in relation to groups 2 and 3, despite the median was still pointing out normal values. CONCLUSIONS: There were no significant differences in relation to age, gender, stature at birth, jaundice, acholia/hipocholia, choluria, ...

RACIONAL: A colestase neonatal intra-hepática pode ser a manifestação inicial de um grupo muito heterogêneo de doenças de diferentes causas. OBJETIVO: Avaliar e comparar características clínicas e laboratoriais entre os grupos de colestase neonatal intra-hepática de causa infecciosa, genético-endócrino-metabólica e idiopática. MÉTODOS: Foram revistos os prontuários de 101 pacientes com diagnóstico de colestase neonatal intra-hepática no período de março de 1982 a dezembro de 2005, 84 avaliados no Hospital das Clínicas da Universidade Estadual de Campinas, SP, e 17 no Instituto da Criança da Universidade de São Paulo. Os critérios de inclusão foram: história de surgimento de icterícia até 3 meses de idade e realização da biopsia hepática durante o primeiro ano de vida. Foram avaliados: quadro clínico (gênero, idade, peso ao nascimento, peso à primeira consulta, estatura ao nascimento, icterícia, acolia ou hipocolia, colúria, hepatomegalia e esplenomegalia) e laboratorial (ALT, AST, FA, GGT, INR, BD). RESULTADOS: Os pacientes foram divididos em grupos, de acordo com o diagnóstico etiológico: grupo 1 (infeccioso) n = 24; grupo 2 (genético-endócrino-metabólico) n = 21 e grupo 3 (idiopático) n = 56. Não houve diferença estatisticamente significante em relação às variáveis: gênero, idade, estatura ao nascimento, icterícia, acolia/hipocolia, colúria, hepatomegalia, esplenomegalia, AST, ALT, FA, GGT, BD e albumina. O peso ao nascimento e o peso na primeira consulta dos pacientes com colestase neonatal intra-hepática de etiologia infecciosa foi menor. Houve diferença estatisticamente significante em relação ao INR: os pacientes com causas genético-endócrino-metabólicas apresentaram valor mais prolongado, porém com a mediana se situando dentro dos valores de normalidade. CONCLUSÃO: Não houve diferença estatisticamente significativa entre os grupos em relação às variáveis: gênero, idade, estatura ao nascimento, icterícia, acolia/hipocolia, colúria, ...

Colestasis intrahepática por dietiletilbestrol / Intrahepatic cholestasis due to diethylstilbestrol

El síndrome ictérico es causa frecuente de ingreso en nuestros hospitales, en particular la colestasis, término preferido al de íctero obstructivo, ya que no es imprescindible que exista una obstrucción mecánica. Puede ser provocado por causas intrahepáticas o extrahepáticas, entre las primeras, la toxicidad medicamentosa constituye la segunda causa más frecuente. Se presentó un paciente que se atendió con colestasis intrahepática como efecto adverso del dietiletilbestrol, medicamento que se utiliza frecuentemente para el tratamiento de la neoplasia de próstata.

The icteric syndrome is a frequent cause of admission in our hospitals, particularly, cholestasis, a term preferred for obstructive icterus, since the existance of a mechanical obstruction is not indispensable. It may be produced by intrahepatic or extrahepatic causes. Among the first, drug toxicity is the second most common cause. A patient with intrahepatic cholestasis as an adverse effect of diethylstilbestrol, a drug that is usually used for the treatment of prostatic neoplasia, was presented.

Síndrome de dificultad respiratoria aguda por ácidos biliares en un recién nacido de término / Acute respiratory distress syndrome by biliary acids in a term newborns

Describimos las características clínicas de un recién nacido a término que presentó un síndrome de dificultad respiratoria aguda. Su madre cursó una colestasis intrahepática del embarazo. Por la severidad del cuadro se indicó asistencia respiratoria mecánica y se administró surfactante. Se descartaron procesos infecciosos. Por antecedentes maternos de colestasis intrahepática del embarazo se sugiere el diagnóstico de dificultad respiratoria aguda por ácidos biliares. Conclusión: Sugerimos tener en cuenta el diagnóstico de dificultad respiratoria aguda por ácidos biliares, en todo neonato a término, nacido de una madre con colestasis intrahepática del embarazo.

Byler disease progressive familial intrahepatic cholestasis [PFIC]

A 20-month old boy delivered to a consanguineous parents presented early in the infantile period with deep jaundice, his investigations showed progressive cholestatic jaundice, high liver enzymes and high GGT. Hepatitis and metabolic errors were excluded. The liver biopsy showed a prominent parenchymal bile stasis without features of bile obstruction or an evidence of paucity of bile ducts. These findings are going with the diagnosis of Byler Disease or progressive familial intrahepatic cholestasis [PFIC3] which is a chronic cholestasis syndrome that begins in infancy and usually progresses to cirrhosis and hepatic failure in the first few years of life. Few patients have survived into the third decade of life without treatment. Liver transplantation is the only effective treatment for this type of the disease

Benign recurrent intrahepatic cholestasis.

Benign recurrent intrahepatic cholestasis (BRIC) is a rare cause of cholestasis in children. The disease may start in infancy or early childhood. Jaundice persists or recurs throughout life but does not lead to chronic liver disease or cirrhosis. Treatment is mostly symptomatic. The condition has not been reported in Indian children. We report an interesting case of BRIC in a 9-year-old boy who had recurrent episodes of jaundice since when he was 1 yr old.

Liver disease in cystic fibrosis

En las últimas dos décadas, la sobrevida de los pacientes con fibrosis quística ha mejorado notablemente, permitiendo la aparición de complicaciones entre las cuales destaca el compromiso hepático. Hasta ahora ha sido difícil detectar la hepatopatía de la fibrosis quística y reconocer sus características. En años recientes se han conseguido progresos en la comprensión de su patogenia, así como una mayor experiencia con ciertas modalidades terapéuticas, lo que se discute en esta revisión

Acidos biliares en orina y riesgo perinatal en pacientes con colestasia intrahepática del embarazo / Urinary bile acids and perinatal risk in patients with intrahepatic cholestasis of pregnancy

La colestasia gravídica es una enfermedad de causa desconocida, caracterizada por prurito y anormalidades funcionales hepáticas. Aparece durante la segunda mitad del embarazo y desaparece después del parto. La incidencia en Chile alcanza rangos de 12 a 22 por ciento. La muerte fetal es un evento obstétrico repentino que no se puede predecir por el test convencionales y ultrasonografía (26). De los métodos recientes el nivel de ácidos biliares urinarios parece correlacionarse con el cuadro clínico. Se realizó un estudio prospectivo, caso control, doble ciego en pacientes atendidas en nuestra unidad perinatal durante el transcurso del año 2000 que ingresaron con este diagnóstico. Los datos serán analizados mediante X² cuadrado y se considerará significativo un p > = 0,05. Un total de 5067 partos en el año 2000, 168 cursaron con una colestasia intrahepática del embarazo. El grupo de estudio correspondió a 74 pacientes. Se observa una alta tasa de inducción del parto (41,89 por ciento) una no despreciable tasa de cesárea (33,78 por ciento). Existe un aumento significativo del parto pretérmino y del Apgar menor a 7 al minuto, ambas significativas. No se observa ninguna diferencia significativa en el resultado perinatal de acuerdo al índice de ácidos biliares en orina/creatinemia. El rol de los ácidos biliares en el diagnóstico de la colestasia es poco claro, no parece existir a la luz de los conocimientos actuales un papel en la determinación de ácidos biliares en orina para estimar el riesgo perinatal que ese embarazo conlleva

Pruebas de función tiroidea en embarazadas normales, tercer trimestre y embarazadas con colestasis gravídica o con hepatitis aguda / Thyroid function tests in normal pregnancy women, third trimester and in women with intrahepatic cholestasis of pregnancy or with acute hepatitis in pregnancy

Background: Intrahepatic cholestasis of pregnancy (ICP) is a disease of unknown cause characterized by pruritus and biochemical cholestasis in the 3rd trimester of pregnancy. Its pathogenesis may be due to the interaction of abnormalities in the metabolism of estrogens and progesterone, while still unknown environmental factor (s) modulate the expressivity of a genetic predisposing trait. Aims: To verify if thyroid function tests (TFT) are altered in ICP as in other hepatic diseases and whether a dietary iodine deficiency could be involved. Material and methods: From 1983 to 1986, 13 normal pregnancies (3rd trimester), 26 ICP patients (with 30 pregnancies) and 4 patients with acute non-A non-B hepatitis in pregnancy, were studied. Serum T3, rT3, T4, fT4 and TSH (before and after TRH) were measured by RIA; in ICP patients, measurements were repeated in puerperium. Urinary 24 h iodine excretion was measured in normal pregnancies and in 6 ICP patients. Results: In normal pregnancies, T3 (3.00ñ0.22 nmol/L) and rT3 (0.40ñ0.03 nmol/L) were higher than the values detected in non-pregnant women; other TFT were unchanged. Urinary iodine excretion was normal in all individuals tested. Patients with acute hepatitis in pregnancy or with ICP had lower T3 than normal pregnancies (1.82ñ0.19 nmol/L in hepatitis; 2.24ñ0.12 nmol/L in ICP; p<0.01) and higher rT3 (0.80ñ0.25 nmol/L in hepatitis; 0.54ñ0.05 nmol/L in ICP; p<0.05), while other TFT were unchanged. None of them had clinical signs of hypo or hyperthyroidism. A "euthyroid sick syndrome" was detected in 2 ICP patients and in 2 acute hepatitis in pregnancy. In puerperium of ICP patients, T3 and rT3 returned to levels in non-pregnant women. Conclusions: In ICP patients, TFT show similar trends than in more severe hepatic and non-hepatic diseases. Although thyroid binding-globulin was not measured in our patients, the pattern of TFT suggests that an impaired peripheral (hepatic?) deiodination of T4 is responsible for these changes. The influence of a dietary iodine deficiency can be ruled out

Colestasia intrahepática del embarazo: manejo obstétrico y resultado perinatal / Intrahepatic cholestasis of pregnancy: obstetric management and perinatal result

Se estudian 131 pacientes con colestasia intrahepática del embarazo (CIE) que fueron admitidas en la unidad de feto de alto riesgo (FAR) de la maternidad del Hospital Félix Bulnes en el período de un año (08/96 - 08/97), las mismas que fueron evaluadas y evolucionadas de acuerdo a normas establecidas tanto en la unidad de FAR como durante su hospitalización en la unidad de tratamiento. Se encuentra una frecuencia de CIE de 2.1 por ciento con una mortalidad perinatal del 0 por ciento, se comparan las CIE puras y las con patología asociadas, siendo las más frecuentes anemia, SHE y RCIU, existiendo alto porcentaje de cesárea en este grupo. Se observó que la CIE sin patología asociada no afecta de manera importante las pruebas hepáticas, alteración de la UFP y no influye en el apgar del RN, siendo actualmente considerada una patología menos frecuente y menos grave que antes

Colestase intra-hepática da gravidez / Cholestasis in pregnancy

A colestase intra-hepática gestacional é uma doença hepática própria da gravidez. Chile, Escandinávia, norte da Europa e Bolívia são as regióes que apresentam maior prevalência desta doença, em cuja gênese estão envolvidos fatores genéticos e hormonais. A principal manifestação clínica é o prurido, que pode ser acompanhado de icterícia, esteatorréia, acolia e colúria. Algumas alteraóes das provas de função hepática são observadas...

Colestasis intrahepática del embarazo: una enfermedad en disminución / Intrahepatic cholestasis of the pregnancy: a dicreasing disease

Se revisan 232 pacientes con colestasis intrahepática del embarazo (CIE) que fueron controladas en el policlínico de Alto Riesgo Obstétrico de la Maternidad del Hospital Las Higueras de Talcahuano durante los años 1993, 1994 y 1995. Se encuentra una frecuencia de la enfermedad del 2,5 por ciento y una Mortalidad perinatal del 4,3 por ciento. Al separar las CIE con y sin patologías asociadas, se produce en las primeras una mayor cantidad de prematurez, recién nacidos de peso bajo, parto por cesárea y mortinatos (p < 0,05). Se compara la evolución de algunos parámetros clínicos de CIE en las tres últimas décadas, encontrándose una franca disminución de ellos

Síndrome de Alagille: un caso de evolución poco habitual / Alagille's syndrome: a case of unusual evolution

Se presenta la historia clínica de una niña con Síndrome de Alagille con la finalidad de jerarquizarlo como causa de colestasis neonatal y discutir presentación no habitual en esta paciente. Se trata de una niña de 21 meses en la que se diagnosticó el síndrome, a los 4 meses de edad, en su forma completa (colestasis crónica por escasez de conductos biliares, facies peculiar, embriotoxoma posterior, defecto de los arcos vertebrales y alteraciones cardiovasculares). Presentó una evolución no habitual con colestasis intensa que no se modificó con el tratamiento colerético, con gran repercusión nutricional y evolución a la insuficiencia hepatocítica e hipertensión portal. Se planteó el trasplante hepático como posibilidad terapéutica, no pudiendo realizarse. Falleció a los 21 meses comprobándose hemorragia pulmonar en la necropsia. Se destaca que el mejor conocimiento de esta enfermedad permitirá el diagnóstico precoz de la misma

Colestase intra-hepática en situs inversus do fígado / Intrahepatic cholestasis with situs inversus of the liver

Em nossa pesquisa bibliográfica näo encontramos nenhum trabalho sobre colestase intra-hepática em situs inversus do fígado. OBJETIVO. Relatar um caso de seguimento por um de nós (MM) durante aproximadamente, 14 anos após o desaparecimento da mencionada colestase. MÉTODOS. Foram estudados aspectos clínicos, realizados diversos testes laboratoriais e efetuados três exames ultra-sonográficos e uma tomografia computadorizada. Tentou-se realizar colangiografias transparieto-hepática e endoscópica. RESULTADOS. Quatro dias após a paciente ter sido submetida à prótese aórtica (com circulaçäo extracorpórea) surgiu icterícia, urina escura e fezes claras. As bilirubinas, fosfatase alcalina, gamaglutamil transferase e colesterol séricos estavam muito elevados. Os exames ultra-sonográficos e a tomografia sem evidências de obstruçäo extra-hepática. Neste exame, em especial, ficou caracterizada a existência de situs inversus do estômago e fígado. Näo houve êxito na realizaçäo das colangiografias. Os dados clínicos e laboratoriais referentes à colestase normalizaron após quatro meses. Boa evoluçäo após 14 abos. CONCLUSAO. O diagnóstico diferencial entre colestase intra e extra-hepática em pacientes com situs inversus do fígado pode, realmente, ser dificil, exigindo associar dados clínicos e vários exames complementares, entre os quais a colangiopancreatografia endoscópica retrógrada. A realizaçäo desse exame pode, porém, ser difícil nos mencionados pacientes