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‣ D-bifunctional protein deficiency – a cause of neonatal onset seizures and hypotonia

Nascimento, J.; Mota, C.; Lacerda, L.; Pacheco, S.; Chorão, R.; Martins, E.; Garrido, C.
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em //2015 Português
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Background Peroxisomal disorders are classified in two major groups: (1) Peroxisome Biogenesis Disorders and (2) single Peroxisomal Enzyme/Transporter Deficiencies. D-bifunctional protein deficiency (DBP; OMIM #261515) included in this last group of rare diseases leads to an impaired peroxisomal beta-oxidation. D-bifunctional protein deficiencies are classified in four types based on the degree of activity of the 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase protein units. Case report/Result The authors present the first portuguese reported type II DBP deficiency patient, whose neonatal clinical picture is indistinguishable from a Zellweger spectrum disease. The clinical features and the neuroimaging findings of polymicrogyria raised suspicion of the diagnosis. After biochemical analysis, DBP deficiency was confirmed with the identification of p.Asn457Tyr (N457Y) mutation, present in homozygosity in HSD17B4 gene. Parents were found to be carriers of the mutated allele, confirming the patient homozygosity status and allowing prenatal diagnosis to future pregnancies. Conclusion D-bifunctional protein deficiency is a rare and severe disease and final diagnosis can only be accomplished after HSD17B4 gene sequencing. Treatment is generally of supportive nature...

‣ Diagnosis of alpha-1-antitrypsin deficiency by DNA analysis of children with liver disease

De TOMMASO,Adriana Maria Alves; ROSSI,Cláudio Lúcio; ESCANHOELA,Cecília Amélia Fazzio; SERRA,Heliane Guerra; BERTUZZO,Carmen Sílvia; HESSEL,Gabriel
Fonte: Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia - IBEPEGE ; Colégio Brasileiro de Cirurgia Digestiva - CBCD ; Sociedade Brasileira de Motilidade Digestiva - SBMD ; Federação Brasileira de Gastroenterologia - FBG; Sociedade Brasileira de Hepatologia - SBH; Sociedade Brasileira de Endoscopia Digestiva - SOBED Publicador: Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia - IBEPEGE ; Colégio Brasileiro de Cirurgia Digestiva - CBCD ; Sociedade Brasileira de Motilidade Digestiva - SBMD ; Federação Brasileira de Gastroenterologia - FBG; Sociedade Brasileira de Hepatologia - SBH; Sociedade Brasileira de Endoscopia Digestiva - SOBED
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2001 Português
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Background - Alpha-1-antitrypsin deficiency is a genetic disorder which is transmitted in a co-dominant, autosomal form. Alpha-1-antitrypsin deficiency affects mainly the lungs and the liver leading, in the latter case, to neonatal cholestasis, chronic hepatitis or cirrhosis. A precise diagnosis of Alpha-1-antitrypsin deficiency may be obtained by biochemical or molecular analysis. Objective - The purpose of this study was to use DNA analysis to examine the presence of an alpha-1-antitrypsin deficiency in 12 children suspected of having this deficiency and who showed laboratory and clinical characteristics of the disease. Patients and Methods - Twelve patients, aged 3 months to 19 years, who had serum alpha-1-antitrypsin levels lower than normal and/or had hepatic disease of undefined etiology were studied. The mutant alleles S and Z of the alpha-1-antitrypsin gene were investigated in the 12 children. Alpha-1-antitrypsin gene organization was analyzed by amplification of genoma through the polymerase chain reaction and digestion with the restriction enzymes Xmnl (S allele) and Taq 1 (Z allele). Results - Seven of the 12 patients had chronic liver disease of undefined etiology and the other five patients had low serum levels of alpha-1-antitrypsin as well as a diagnosis of neonatal cholestasis and/or chronic liver disease of undefined etiology. Five of the 12 patients were homozygous for the Z allele (ZZ) and two had the S allele with another allele (*S) different from Z. Conclusion - These results show that alpha-1-antitrypsin deficiency is relatively frequent in children with chronic hepatic disease of undefined etiology and/or low alpha-1-antitrypsin levels (41.6%). A correct diagnosis is important for effective clinical follow-up and for genetic counseling.

‣ Arteriohepatic dysplasia: Familial pulmonary arterial stenosis with neonatal liver disease

Watson, G. H.; Miller, V.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1973 Português
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A new syndrome is described of which the salient features are (1) congenital hypoplasia and stenoses of the pulmonary arteries, sometimes with associated cardiovascular malformations; (2) neonatal liver disease, commonly with obstructive jaundice and resembling biliary atresia or neonatal hepatitis, but sometimes apparent only as mild persistent hepatic dysfunction; and (3) various minor congenital anomalies, including an odd facies. There is a familial tendency suggesting autosomal dominant inheritance, with variable penetrance.

‣ Outcome of liver disease in children with Alagille syndrome: a study of 163 patients

Lykavieris, P; Hadchouel, M; Chardot, C; Bernard, O
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/2001 Português
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BACKGROUND AND AIMS—Various opinions have been expressed as to the long term prognosis of liver disease associated with Alagille syndrome (AGS).
PATIENTS AND METHODS—We reviewed the outcome of 163 children with AGS and liver involvement, investigated from 1960 to 2000, the end point of the study (median age 10 years (range 2 months to 44 years)) being death, liver transplantation, or the last visit.
RESULTS—At the study end point, of the 132 patients who presented with neonatal cholestatic jaundice, 102 remained jaundiced, 112 had poorly controlled pruritus, and 40 had xanthomas; cirrhosis was found in 35/76 livers, varices in 25/71 patients, and liver transplantation had been carried out in 44 patients (33%). Forty eight patients died, 17 related to complications of liver disease. Of 31 patients who did not present with neonatal cholestatic jaundice, five were jaundiced at the study end point, 17 had well controlled pruritus, and none had xanthomas; cirrhosis was found in 6/18 patients, varices in 4/11, and none underwent liver transplantation. Nine patients died, two of liver disease. In the whole series, actuarial survival rates with native liver were 51% and 38% at 10 and 20 years, respectively, and overall survival rates were 68% and 62%...

‣ Long term prognosis for babies with neonatal liver disease.

Deutsch, J; Smith, A L; Danks, D M; Campbell, P E
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /05/1985 Português
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A total of 123 patients with neonatal liver disease without extrahepatic bile duct obstruction or arteriohepatic dysplasia have been studied for six to 18 years. Idiopathic neonatal hepatitis, present in 73 babies, carried a high mortality due to liver failure (18%), septicaemia (6%), and associated defects (14%), especially in the first year of life (25%). Progression to chronic liver disease in non-familial idiopathic cases occurred in three of 40 reviewed patients. Only 12 of these children were completely healthy, the remainder having other permanent disabilities (57%). Four of nine familial cases of idiopathic neonatal hepatitis died in the first 12 months of life as did two of the four reviewed survivors. Progression to chronic liver disease or to death was a continuous process without any interval of recovery in all but one of these patients. Among patients with a presumed infective cause, cytomegalovirus infection caused a particularly benign form of neonatal hepatitis but was a frequent cause of brain damage or other disabilities. Babies who survived other infective liver diseases showed complete healing of the liver damage. Neonatal liver disease associated with alpha 1 antitrypsin deficiency progressed to death or chronic liver disease in three of nine patients and was not associated with a paucity of interlobular bile ducts.

‣ In Vivo Antisense Oligonucleotide Reduction of NPC1 Expression as a Novel Mouse Model for Niemann Pick Type C– Associated Liver Disease

Rimkunas, Victoria M.; Graham, Mark J.; Crooke, Rosanne M.; Liscum, Laura
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /05/2008 Português
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Niemann-Pick type C (NPC) is a fatal autosomal recessive lipidosis that is characterized by lysosomal storage of cholesterol and glycosphingolipids. Patients exhibit prolonged neonatal jaundice, hepatosplenomegaly, and progressive neurodegeneration that generally result in death by the teen years. Most clinical cases are caused by mutations in the NPC1 gene. Current mouse models of NPC are not well suited for studying the liver disease due to the rapidly progressing neurological disease. To facilitate study of NPC-associated liver dysfunction, we have developed a novel mouse model using antisense oligonucleotides to ablate NPC1 expression primarily in the liver. Here, we show that the NPC1 knockdown leads to a liver disease phenotype similar to that of patients with NPC and the NPCnih mouse model. Key features include hepatomegaly, lipid storage, elevated serum liver enzymes, and increased apoptosis.

‣ Bile salts and liver disease in childhood

Javitt, Norman B.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1974 Português
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Recognition of neonatal liver disease has been heavily dependent on the occurrence of jaundice. In most instances the jaundice is related to specific disturbances in bilirubin transport and other tests of liver function are normal. In contrast, hepatitis and other liver diseases not specifically affecting bilirubin transport often go undetected unless jaundice occurs.

‣ Neonatal liver failure due to deoxyguanosine kinase deficiency

Nobre, Susana; Grazina, Manuela; Silva, Francisco; Pinto, Carla; Gonçalves, Isabel; Diogo, Luísa
Fonte: BMJ Publishing Group Publicador: BMJ Publishing Group
Tipo: Artigo de Revista Científica
Publicado em 03/04/2012 Português
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Deoxyguanosine kinase (dGK) deficiency, a rare severe cause of mitochondrial DNA (mtDNA) depletion, has two forms of presentation: hepatocerebral syndrome and isolated hepatic disease. The authors report three cases with neonatal liver failure due to dGK deficiency. Consanguinity was present in all patients. One patient had a brother who died with a probable diagnosis of neonatal haemochromatosis. All patients had progressive cholestatic liver failure, hypoglycaemia, hyperlactacidaemia, elevated ferritin levels and nystagmus, since first day of life. Liver tissue study revealed: cholestasis, iron deposits, microvesicular steatosis and fibrosis/cirrhosis. Only one patient was submitted to liver transplantation. The other two died, at 2 and 5 months of age. mtDNA quantification and DGUOK gene study should be considered in infants/neonates with acute liver failure and systematically performed in patients with hepatocerebral presentation. Differential diagnosis with neonatal haemochromatosis is needed. Liver transplantation might be a therapeutic option. Early diagnosis is important for genetic counselling.

‣ Enteral bile acid treatment improves parenteral nutrition-related liver disease and intestinal mucosal atrophy in neonatal pigs

Jain, Ajay Kumar; Stoll, Barbara; Burrin, Douglas G.; Holst, Jens J.; Moore, David D.
Fonte: American Physiological Society Publicador: American Physiological Society
Tipo: Artigo de Revista Científica
Português
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Total parenteral nutrition (TPN) is essential for patients with impaired gut function but leads to parenteral nutrition-associated liver disease (PNALD). TPN disrupts the normal enterohepatic circulation of bile acids, and we hypothesized that it would decrease intestinal expression of the newly described metabolic hormone fibroblast growth factor-19 (FGF19) and also glucagon-like peptides-1 and -2 (GLP-1 and GLP-2). We tested the effects of restoring bile acids by treating a neonatal piglet PNALD model with chenodeoxycholic acid (CDCA). Neonatal pigs received enteral feeding (EN), TPN, or TPN + CDCA for 14 days, and responses were assessed by serum markers, histology, and levels of key regulatory peptides. Cholestasis and steatosis were demonstrated in the TPN group relative to EN controls by elevated levels of serum total and direct bilirubin and also bile acids and liver triglyceride (TG) content. CDCA treatment improved direct bilirubin levels by almost fourfold compared with the TPN group and also normalized serum bile acids and liver TG. FGF19, GLP-1, and GLP-2 were decreased in plasma of the TPN group compared with the EN group but were all induced by CDCA treatment. Intestinal mucosal growth marked by weight and villus/crypt ratio was significantly reduced in the TPN group compared with the EN group...

‣ Liver Disease in Mitochondrial Disorders

Lee, Way S.; Sokol, Ronald J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/2007 Português
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Liver involvement, a common feature in childhood mitochondrial hepatopathies, particularly in the neonatal period, may manifest as neonatal acute liver failure, hepatic steatohepatitis, cholestasis, or cirrhosis with chronic liver failure of insidious onset. There are usually significant neuromuscular symptoms, multisystem involvement, and lactic acidemia. The liver disease is usually progressive and eventually fatal. Current medical therapy of mitochondrial hepatopathies is largely ineffective, and the prognosis is usually poor. The role of liver transplantation in patients with liver failure remains poorly defined because of the systemic nature of the disease that does not respond to transplantation. Several specific molecular defects (mutations in nuclear genes such as SCO1, BCS1L, POLG, DGUOK, and MPV17 and deletion or rearrangement of mitochondrial DNA) have been identified in recent years. Prospective, longitudinal multicenter studies will be needed to address the gaps in our knowledge in these rare liver diseases.

‣ Liver disease in cystic fibrosis

Kobelska-Dubiel, Natalia; Klincewicz, Beata; Cichy, Wojciech
Fonte: Termedia Publishing House Publicador: Termedia Publishing House
Tipo: Artigo de Revista Científica
Português
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Cystic fibrosis-associated liver disease (CFLD) affects ca. 30% of patients. The CFLD is now considered the third cause of death, after lung disease and transplantation complications, in CF patients. Diagnostics, clinical assessment and treatment of CFLD have become a real challenge since a striking increase of life expectancy in CF patients has recently been observed. There is no elaborated “gold standard” in the diagnostic process of CFLD; clinical evaluation, laboratory tests, ultrasonography and liver biopsy are used. Clinical forms of CFLD are elevation of serum liver enzymes, hepatic steatosis, focal biliary cirrhosis, multilobular biliary cirrhosis, neonatal cholestasis, cholelithiasis, cholecystitis and micro-gallbladder. In children, CFLD symptoms mostly occur in puberty. Clinical symptoms appear late, when damage of the hepatobiliary system is already advanced. The CFLD is more common in patients with severe mutations of CFTR gene, in whom a complete loss of CFTR protein function is observed. CFLD, together with exocrine pancreatic insufficiency and meconium ileus, is considered a component of the severe CF phenotype. Treatment of CFLD should be complex and conducted by a multispecialist team (gastroenterologist, hepatologist...

‣ Hepatic ultrastructure in a neonatal piglet model of intestinal failure-associated liver disease (IFALD)

Hua, Zheng; Sergi, Consolato; Nation, Patrick N.; Wizzard, Pamela R.; Ball, Ron O.; Pencharz, Paul B.; Turner, Justine M.; Wales, Paul W.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica Formato: text/html
Português
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This study was designed to evaluate liver disease in neonatal piglets with surgical short bowel syndrome causing intestinal failure with partial parenteral nutrition dependence. The short bowel piglets had 75% surgical resection of distal small intestine, including all ileum and cecum, and were compared with sham controls, without resection, and to healthy sow-reared controls. After 18 days of combined parenteral and enteral nutrition in short bowel and sham piglets, liver tissue was collected for quantitative and semi-quantitative histological and ultrastructural evaluation. The short bowel piglets developed biochemical and histological cholestasis, not observed in sham and control piglets. Ultrastructural examination revealed bile canaliculus dilation with bile plugging, microvillus flattening and disappearance, but without abnormalities of the pericanalicular zone. Interestingly, these data are similar to bile canaliculus changes seen in human neonates with IFALD supporting an initial consideration of this model to elucidate the pathogenesis of IFALD.

‣ Detection of treatable neonatal liver disease by expanded newborn screening

Mackay, R.; Bratkovic, D.; Couper, R.; Davidson, G.; Fahy, R.; Fletcher, J.; Ranieri, E.
Fonte: Kluwer Academic Publ Publicador: Kluwer Academic Publ
Tipo: Artigo de Revista Científica
Publicado em //2008 Português
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Two neonates were identified at age 48 h by expanded newborn screening, with abnormal methionine and tyrosine concentrations, which were confirmed on repeat samples. Evidence of previously unsuspected liver disease was found at recall, and there was radiological and biochemical evidence of severe liver disease with hepatic synthetic failure. After inborn errors of metabolism (IEMs) were excluded, both were considered to have neonatal haemochromatosis, on the basis of raised ferritin, iron saturation, and very high α-fetoprotein and confirmed by a mildly hyperferritinaemic sibling in the first case, and raised ferritin and iron saturation in the second. However, it was not feasible to obtain tissue confirmation as the requirement for early therapy precluded biopsy. The babies were treated with antioxidants and iron-chelating agents, and the coagulopathy and hypoalbuminaemia were corrected. Both made a complete recovery and remain well after follow-up. Newborn screening programmes could consider advising clinicians, when tyrosine and methionine values are elevated, that once IEMs are excluded liver disease from other causes must be sought. Neonatal haemochromatosis is an example of one such disease that is potentially treatable.; R. J. Mackay...

‣ Análise metabolômica e histomorfométrica do fígado de ratas adultas em modelo experimental da síndrome dos ovários policísticos induzida por exposição neonatal a esteroides sexuais; Metabolomic and histomorphometric analysis of the liver of rat models of polycystic ovary syndrome induced by neonatal exposure to sex steroids.

Anzai, Alvaro
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 11/08/2015 Português
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A síndrome dos ovários policísticos (SOP) é um distúrbio endócrino complexo, associado a resistência insulínica, hiperinsulinemia, obesidade, acúmulo de gordura visceral e dislipidemia. Essas alterações podem levar a aumento de risco de doenças como "diabetes mellitus", doenças cardiovasculares, esteatose hepática ou até mesmo esteato-hepatite. Em ratas, o excesso de androgênios ou estrogênios no período neonatal induz a alterações metabólicas e reprodutivas similares às observadas na SOP em humanos. O objetivo deste estudo é analisar os efeitos da exposição neonatal à testosterona e ao estrogênio no fígado de ratas adultas. Para isso foram utilizadas 30 ratas, divididas em três grupos de 10 animais cada. Foi administrada por via subcutânea, entre 1 e 3 dias de vida, uma única dose dos seguintes compostos: 0,1 mL de óleo de oliva (veículo) - grupo Controle (n=10); propionato de testosterona (1,25 mg/0,1mL de veículo) - grupo Testosterona (n=10); benzoato de estradiol (0,5 mg/0,1mL de veículo) - grupo Estradiol (n=10), de acordo com o grupo a que pertenciam. Após cerca de 90 dias, os animais foram sacrificados, sendo retirados fragmentos do fígado que foram preparados para análise da metabolômica e da histomorfologia. Histologicamente...

‣ Disorders of the neonatal liver and bile ducts.

Rocha, Gustavo; Serviço de Neonatologia, Departamento de Pediatria, Hospital de São João/Faculdade de Medicina da Universidade do Porto, Porto.; Rocha, Paula; Proença, Elisa; Quintas, Conceição; Martins, Teresa; Pissarra, Susana; Guimarães, Hercíl
Fonte: Ordem dos Médicos Publicador: Ordem dos Médicos
Tipo: info:eu-repo/semantics/article; article; article; info:eu-repo/semantics/publishedVersion Formato: application/pdf
Publicado em 22/10/2010 Português
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Liver and biliary tract disorders in the neonate are relatively rare and often complex.To evaluate the incidence of neonatal liver and biliary tract disorders, main causes, clinical presentation, treatment and outcome. Material andClinical, imagiological, laboratory, pathological and autopsy data concerning all newborns with liver and biliary tract disorder admitted to the neonatal intensive care unit of five tertiary medical centers from the north of Portugal, between 1997 and 2006, were retrospectively analysed.77 neonates (incidence 0.5% - 77/14505 admissions); 44M/33F; gestational age 34 weeks (25-41); preterm 50 (65%); birthweight 1980 g (570-4130), < 1500 g 29 (38%). Several causes were identified and classified as infectious, metabolic, anatomic/structural, neoplastic, vascular, traumatic, immune, genetic and idiopathic. Clinical signs appeared between days 1 and 61 of life. Jaundice was the most frequent clinical sign (92%). Cholestasis occurred in 67 (87%) patients. Duration of hospital stay was 35 days (5-146); 18 patients (23%) were deceased. Autopsy study was diagnostic in 8 cases (10%).Nosocomial and intrauterine infection were the most common causes of liver and biliary tract disease. Several other rare causes represented an important challenge in diagnosis and treatment...

‣ Analysis of the histologic features in the differential diagnosis of intrahepatic neonatal cholestasis

BELLOMO-BRANDAO, Maria Angela; ESCANHOELA, Cecilia A. F.; MEIRELLES, Luciana R.; PORTA, Gilda; HESSEL, Gabriel
Fonte: W J G PRESS Publicador: W J G PRESS
Tipo: Artigo de Revista Científica
Português
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AIM: To compare the histologic features of the liver in intrahepatic neonatal cholestasis (IHNC) with infectious, genetic-endocrine-metabolic, and idiopathic etiologies. METHODS: Liver biopsies from 86 infants with IHNC were evaluated. The inclusion criteria consisted of jaundice beginning at 3 mo of age and a hepatic biopsy during the 1st year of life. The following histologic features were evaluated: cholestasis, eosinophilia, giant cells, erythropoiesis, siderosis, portal fibrosis, and the presence of a septum. RESULTS: Based on the diagnosis, patients were classified into three groups: group 1 (infectious; n = 18), group 2 (genetic-endocrine-metabolic; n = 18), and group 3 (idiopathic; n = 50). There were no significant differences with respect to the following variables: cholestasis, eosinophilia, giant cells, siderosis, portal fibrosis, and presence of a septum. A significant difference was observed with respect to erythropoiesis, which was more severe in group 1 (Fisher's exact test, P = 0.016). CONCLUSION: A significant difference was observed in IHNC of infectious etiology, in which erythropoiesis was more severe than that in genetic-endocrine-metabolic and idiopathic etiologies, whereas there were no significant differences among cholestasis...

‣ Analysis of the histologic features in the differential diagnosis of intrahepatic neonatal cholestasis

BELLOMO-BRANDAO, Maria Angela; ESCANHOELA, Cecilia A. F.; MEIRELLES, Luciana R.; PORTA, Gilda; HESSEL, Gabriel
Fonte: W J G PRESS Publicador: W J G PRESS
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
57.9342%
AIM: To compare the histologic features of the liver in intrahepatic neonatal cholestasis (IHNC) with infectious, genetic-endocrine-metabolic, and idiopathic etiologies. METHODS: Liver biopsies from 86 infants with IHNC were evaluated. The inclusion criteria consisted of jaundice beginning at 3 mo of age and a hepatic biopsy during the 1st year of life. The following histologic features were evaluated: cholestasis, eosinophilia, giant cells, erythropoiesis, siderosis, portal fibrosis, and the presence of a septum. RESULTS: Based on the diagnosis, patients were classified into three groups: group 1 (infectious; n = 18), group 2 (genetic-endocrine-metabolic; n = 18), and group 3 (idiopathic; n = 50). There were no significant differences with respect to the following variables: cholestasis, eosinophilia, giant cells, siderosis, portal fibrosis, and presence of a septum. A significant difference was observed with respect to erythropoiesis, which was more severe in group 1 (Fisher's exact test, P = 0.016). CONCLUSION: A significant difference was observed in IHNC of infectious etiology, in which erythropoiesis was more severe than that in genetic-endocrine-metabolic and idiopathic etiologies, whereas there were no significant differences among cholestasis...

‣ Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease.

Setchell, K D; Schwarz, M; O'Connell, N C; Lund, E G; Davis, D L; Lathe, R; Thompson, H R; Weslie Tyson, R; Sokol, R J; Russell, D W
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/11/1998 Português
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We describe a metabolic defect in bile acid synthesis involving a deficiency in 7alpha-hydroxylation due to a mutation in the gene for the microsomal oxysterol 7alpha-hydroxylase enzyme, active in the acidic pathway for bile acid synthesis. The defect, identified in a 10-wk-old boy presenting with severe cholestasis, cirrhosis, and liver synthetic failure, was established by fast atom bombardment ionization-mass spectrometry, which revealed elevated urinary bile acid excretion, a mass spectrum with intense ions at m/z 453 and m/z 510 corresponding to sulfate and glycosulfate conjugates of unsaturated monohydroxy-cholenoic acids, and an absence of primary bile acids. Gas chromatography-mass spectrometric analysis confirmed the major products of hepatic synthesis to be 3beta-hydroxy-5-cholenoic and 3beta-hydroxy-5-cholestenoic acids, which accounted for 96% of the total serum bile acids. Levels of 27-hydroxycholesterol were > 4,500 times normal. The biochemical findings were consistent with a deficiency in 7alpha-hydroxylation, leading to the accumulation of hepatotoxic unsaturated monohydroxy bile acids. Hepatic microsomal oxysterol 7alpha-hydroxylase activity was undetectable in the patient. Gene analysis revealed a cytosine to thymidine transition mutation in exon 5 that converts an arginine codon at position 388 to a stop codon. The truncated protein was inactive when expressed in 293 cells. These findings indicate the quantitative importance of the acidic pathway in early life in humans and define a further inborn error in bile acid synthesis as a metabolic cause of severe cholestatic liver disease.

‣ Glutathione S-transferases in neonatal liver disease.

Mathew, J.; Cattan, A. R.; Hall, A. G.; Hines, J. E.; Nelson, R.; Eastham, E.; Burt, A. D.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1992 Português
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AIMS: To investigate the distribution of alpha and pi class glutathione S-transferases (GST) in normal fetal, neonatal, and adult liver; and to examine changes in GST expression in neonatal liver disease. METHODS: alpha and pi class GST were immunolocalised in sections of formalin fixed liver tissue obtained from human fetuses (n = 21), neonates (n = 8), young children (n = 9) and adults (n = 10), and from neonates with extrahepatic biliary atresia (n = 15) and neonatal hepatitis (n = 12). Monospecific rabbit polyclonal antibodies were used with a peroxidase-antiperoxidase method. RESULTS: Expression of pi GST was localised predominantly within biliary epithelial cells of developing and mature bile ducts of all sizes from 16 weeks' gestation until term and in neonatal and adult liver. Coexpression of pi and alpha GST was seen in hepatocytes of developing fetal liver between 16 and 34 weeks' gestation. Although pi GST was seen in occasional hepatocytes up to six months of life, this isoenzyme was not expressed by hepatocytes in adult liver. By contrast, alpha GST continued to be expressed by hepatocytes in adult liver; this isoenzyme was also seen in some epithelial cells of large bile ducts in adult liver. No change was observed in the distribution of alpha GST in either neonatal hepatitis or extrahepatic biliary atresia. However...

‣ Diagnostic and therapeutic approach to cholestatic liver disease

Pérez Fernández,T.; López Serrano,P.; Tomás,E.; Gutiérrez,Mª L.; Lledó,J. L.; Cacho,G.; Santander,C.; Fernández Rodríguez,C. M.
Fonte: Revista Española de Enfermedades Digestivas Publicador: Revista Española de Enfermedades Digestivas
Tipo: info:eu-repo/semantics/article; journal article; info:eu-repo/semantics/publishedVersion Formato: text/html; application/pdf
Publicado em 01/01/2004 Português
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When cholestatic liver disease is present, liver ultrasound should be performed to ascertain if cholestasis is extrahepatic or intrahepatiic. 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 especific 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 hiperemesis 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 mid-dle-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...