Colestasis neonatal


Arq Gastroenterol 1999 Oct-Dec;36(4):185-94
[Prolonged neonatal cholestasis: prospective study].
Prado ET, Araujo M de F, Campos JV
Departamento de Pediatria da Faculdade de Ciencias Medicas da Santa Casa de Sao Paulo-FCMSCSP.
Due to the urgency in choosing either clinical treatment or immediate surgical intervention, the study of the prolonged neonatal cholestasis involves two basic aims: the differential diagnosis between biliary atresia and neonatal hepatitis and the research into the associated etiological agents. So, in a prospective trial carried out in the 70's, 77 children with prolonged neonatal cholestasis were studied in order to establish the differential diagnosis between biliary atresia and neonatal hepatitis, followed by the evaluation of 108 children towards a pathogenesis of the prolonged neonatal cholestasis. The results of the differential diagnosis showed that within 18 items examined only 8 proved to be good biliary atresia indicators. They are as follows (in decreasing order): ductular proliferation (portal tracts), fibrosis (portal tracts), cholestasis (portal tracts), stools colour--acholia, hepatomegaly, canalicular cholestasis (lobule), infiltrate (portal tracts), giant cells (lobule). These eight items were then gathered in a sole indicator of great discriminative power, with a confidence level of 99%. The figures regarding the pathogenesis are: rubella virus 0%, herpes simplex virus 0%, listeriosis 0%, cytomegalovirus 2.2%, hepatitis B virus 2.4%, toxoplasmosis 2.8%, alpha-1-antitrypsin deficiency 13.1%, syphilis 21.1%, autoantibodies against the liver 58.4%. Such work thus revealed that those eight most important factors when differentiating biliary atresia from neonatal hepatitis remain as fundamental indicators and, when employed alongside other diagnostic methods, can help in the assembling of a multifactorial strategy less and less invasive and more precise. The pathogenic study, with its heavy dependency on time and place, has become more complete with the introduction of new diagnostic methods, evolving to the ideal progressive reduction of idiopathic processes.

J Pediatr Surg 2000 Apr;35(4):545-9
The role of endoscopic retrograde cholangiopancreatography in infants with cholestasis.
Iinuma Y, Narisawa R, Iwafuchi M, Uchiyama M, Naito M, Yagi M, Kanada S, Otaki M, Yamazaki S, Honma T, Motoyama H, Baba Y
Department of Pediatric Surgery, Niigata University School of Medicine, Niigata City, Japan.
BACKGROUND/PURPOSE: Endoscopic retrograde cholangiopancreatography (ERCP) was assessed in the diagnosis of cholestatic liver disease in infants. METHODS: ERCP was performed in 50 infants who had prolonged cholestasis. Their ages ranged from 25 to 274 days (mean, 69 days), and their weight ranged from 2.6 to 6.7 kg (mean, 4.7 kg). Incomplete visualization of the biliary tree or visualization of only the pancreatic duct was followed by exploratory laparotomy. In those in whom the biliary tree was visualized completely, the caliber of the bile duct was compared with that of the pancreatic duct. RESULTS: ERCP was completed in 43 patients (success rate, 86%) without complications. In the 7 patients in whom ERCP failed, 6 had biliary atresia (BA) diagnosed by exploratory laparotomy. The other patient had congenital biliary dilatation (CBD). In 29 of the 43 patients, the biliary tree was seen partially or only the pancreatic duct was visualized. These patients had BA diagnosed by laparotomy. Complete visualization of the biliary tree was obtained in 14 patients. Of these, 9 had neonatal hepatitis (NH), 2 had a paucity of intrahepatic bile ducts (PIBLD), and 3 had CBD. In all of the patients with NH, cholestasis improved spontaneously. The 2 patients with PIBLD had biopsy-proven disease. The caliber of the bile duct was larger than that of the pancreatic duct in NH. This relationship was not observed in PIBLD. CONCLUSIONS: ERCP is safe in infants. It is useful in the diagnosis of prolonged cholestasis.

Clin Nucl Med 1999 Sep;24(9):655-9
The use of hepatocyte extraction fraction to evaluate neonatal cholestasis.
Tolia V, Kottamasu SR, Tabassum D, Simpson P
Department of Pediatrics, Children's Hospital of Michigan, Detroit, USA.
PURPOSE: Hepatobiliary scintigraphy is used routinely to evaluate infants with neonatal cholestasis. Hepatobiliary scintigraphy determines biliary patency by detecting radioactivity in the bowel on imaging, in duodenal and gastric aspirates, or all of these. During hepatobiliary scintigraphy, the hepatocyte extraction fraction (HEF) is calculated by deconvolution analysis. Normal values of HEF are more than 90%. It is believed that HEF may predict hepatic dysfunction, because, during hepatobiliary scintigraphy, the radiopharmaceutical used in this test is extracted by the hepatocytes from the blood stream. Therefore, a low value of HEF is seen with more severe hepatocellular disease. The goal of this study was to determine whether HEF has any correlation with synthetic liver function, whether HEF can differentiate obstructive from nonobstructive lesions that cause neonatal cholestasis, and whether HEF can predict the outcome of the different causes of neonatal cholestasis. METHODS: A retrospective analysis of 68 hepatobiliary scintigraphy results was done in patients with neonatal cholestasis for a period covering 6 years. RESULTS: The HEF was available in 67 of these 68 patients, with a median value of 25% (range, 3.3% to 100%). The results of synthetic liver function tests (i.e., albumin and prothrombin time) were normal in all infants with neonatal cholestasis. No significant correlation was detected between HEF and the serum levels of total and direct bilirubin, albumin, alkaline phosphatase, and prothrombin time by exploratory data analysis (R = 0.08; small, P > 0.2). The HEF values in different causes of neonatal cholestasis were compared: extrahepatic biliary atresia, neonatal hepatitis, and a miscellaneous category consisting of alpha1-antitrypsin deficiency, ischemic hepatitis, paucity of bile ducts, and others. The outcomes of these diseases were assessed as resolution, continuing disease, transplantation, or death, but no predictive correlation was found with HEF. CONCLUSIONS: A single determination of HEF is of no value in assessing synthetic liver function (as assessed by albumin and prothrombin time), specific diagnoses, and outcomes in patients with neonatal cholestasis. Therefore, a low isolated value of HEF should not be considered suggestive of poor prognosis and outcome in these patients.

BMJ 1999 Aug 21;319(7208):B [Texto completo]
Single screening test for neonatal cholestasis is not yet feasible from blood spots.

BMJ 1999 Aug 21;319(7208):471-7 [Texto completo]
Published erratum appears in BMJ 1999 Nov 6;319(7219):1253
Screening of newborn infants for cholestatic hepatobiliary disease with tandem mass spectrometry.
Mushtaq I, Logan S, Morris M, Johnson AW, Wade AM, Kelly D, Clayton PT
Biochemistry Unit, Institute of Child Health, University College London, London WC1N 1EH.
OBJECTIVE: To assess the feasibility of screening for cholestatic hepatobiliary disease and extrahepatic biliary atresia by using tandem mass spectrometry to measure conjugated bile acids in dried blood spots obtained from newborn infants at 7-10 days of age for the Guthrie test. SETTING: Three tertiary referral clinics and regional neonatal screening laboratories. DESIGN: Unused blood spots from the Guthrie test were retrieved for infants presenting with cholestatic hepatobiliary disease and from the two cards stored on either side of each card from an index child. Concentrations of conjugated bile acids measured by tandem mass spectrometry in the two groups were compared. MAIN OUTCOME MEASURES: Concentrations of glycodihydroxycholanoates, glycotrihydroxycholanoates, taurodihydroxycholanoates, and taurotrihydroxycholanoates. Receiver operator curves were plotted to determine which parameter (or combination of parameters) would best predict the cases of cholestatic hepatobiliary disease and extrahepatic biliary atresia. The sensitivity and specificity at a selection of cut off values for each bile acid species and for total bile acid concentrations for the detection of the two conditions were calculated. RESULTS: 218 children with cholestatic hepatobiliary disease were eligible for inclusion in the study. Two children without a final diagnosis and five who presented at <14 days of age were excluded. Usable blood spots were obtained from 177 index children and 708 comparison children. Mean concentrations of all four bile acid species were significantly raised in children with cholestatic hepatobiliary disease and extrahepatic biliary atresia compared with the unaffected children (P<0.0001). Of 177 children with cholestatic hepatobiliary disease, 104 (59%) had a total bile acid concentration >33 micromol/l (97.5th centile value for comparison group). Of the 61 with extrahepatic biliary atresia, 47 (77%) had total bile acid concentrations >33 micromol/l. Taurotrihydroxycholanoate and total bile acid concentrations were the best predictors of both conditions. For all cholestatic hepatobiliary disease, a cut off level of total bile acid concentration of 30 micromol/l gave a sensitivity of 62% and a specificity of 96%, while the corresponding values for extrahepatic biliary atresia were 79% and 96%. CONCLUSION: Most children who present with extrahepatic biliary atresia and other forms of cholestatic hepatobiliary disease have significantly raised concentrations of conjugated bile acids as measured by tandem mass spectrometry at the time when samples are taken for the Guthrie test. Unfortunately the separation between the concentrations in these infants and those in the general population is not sufficient to make mass screening for cholestatic hepatobiliary disease a feasible option with this method alone.
Publication Types:
  Multicenter study

J Pediatr Endocrinol Metab 1999 Jul-Aug;12(4):549-53
Parenteral nutrition-associated cholestasis in preterm neonates: evaluation of ursodeoxycholic acid treatment.
Levine A, Maayan A, Shamir R, Dinari G, Sulkes J, Sirotta L
Division of Gastroenterology and Nutrition, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
BACKGROUND/OBJECTIVE: Parenteral nutrition is an integral part of the care of premature infants. Cholestatic liver disease is a frequent complication of prolonged parenteral nutrition, especially in premature infants. It has been suggested that ursodeoxycholic acid may alter the course of parenteral nutrition-associated cholestasis in children and adults. We attempted to determine the efficacy of ursodeoxycholic acid in premature infants with parenteral nutrition-associated cholestasis. METHODS: Retrospective chart review of all infants receiving ursodeoxycholic acid for parenteral nutrition-associated cholestasis in a 40 bed neonatal intensive care unit. Efficacy of ursodeoxycholic acid was evaluated by response of bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase over a treatment period of at least 1 month. RESULTS: Six infants with parenteral nutrition-associated cholestasis who had received ursodeoxycholic acid for one month were identified. Doses of ursodeoxycholic acid ranged from 15-30 mg/kg/day. Cholestasis appeared at a mean age of 47 +/- 17 (mean +/- SD) days after a mean of 42 +/- 15 days of parenteral nutrition. Transaminase levels decreased in three, and either increased or did not change in the other three infants. Bilirubin levels decreased in all infants. Alkaline phosphatase showed a non significant trend to decreased levels. Consistent improvement in all infants was noted only after 10 days of full enteral nutrition. No toxicity was found during ursodeoxycholic acid treatment. CONCLUSIONS: Ursodeoxycholic acid treatment in premature infants appears to be safe, and leads to an early sustained decrease in bilirubin levels by two weeks of therapy. The response of transaminase levels was not sustained in our small cohort.

J Pediatr 1999 Jun;134(6):795 [Texto completo]
Transient neonatal cholestasis and perinatal asphyxia.
Vajro P, Paludetto R, DeCurtis M
Publication Types:
  Comment on: J Pediatr 1998 Oct;133(4):563-7

J Pediatr 1998 Oct;133(4):563-7
Transient neonatal cholestasis: origin and outcome.
Jacquemin E, Lykavieris P, Chaoui N, Hadchouel M, Bernard O
Departement de Pediatrie, Hopital de Bicetre, Le Kremlin Bicetre, France.
We studied, retrospectively, 92 children who were first seen with neonatal cholestasis and who were followed up until liver test results normalized. Among the 92 children, 81 displayed factors responsible for chronic and/or acute perinatal distress. Onset of jaundice was recorded at a mean age of 7 days, and mean duration was 3.5 months. Stools, initially discolored in 39 children, were normally colored at a mean age of 1.7 months. Hepatomegaly present in 90 children resolved at a mean age of 13 months. Liver test results were normal at the age of 1 year in 83 children and normalized at a mean age of 10 months. Liver histologic examination, performed in 70 children, showed moderate portal and lobular fibrosis, multinucleated giant hepatocytes, and hematopoietic foci; findings in follow-up liver biopsy specimens from 15 children were normal or improved. Spontaneously resolving forms of neonatal cholestasis may result from the association of several factors, including immaturity of bile secretion and perinatal disease leading to hepatic hypoxia or ischemia.
  Comment in: J Pediatr 1999 Jun;134(6):795

Braz J Med Biol Res 31( 7) 1998 [Texto completo en formato PDF]
Histological diagnosis of neonatal cholestasis Brazilian Journal of Medical
and Biological Research (1998) 31: 911- 919 ISSN 0100- 879X

Histopathological diagnosis of intra-and extrahepatic neonatal cholestasis 
Departamentos de 1 Pediatria, 2 Cirurgia and 3 Patologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil J. L. Santosą, H. Almeida˛, C. T. S. Cerski 3 and T. R. Silveira 

The histopathology of the liver is fundamental for the differential diagnosis between intra- and extrahepatic causes of neonatal cholestasis. However, histopathological findings may overlap and there is dis-agreement among authors concerning those which could discriminate between intra- and extrahepatic cholestasis. The most valuable hepatic histopathological variables for the dis-crimination between intra- and extrahepatic  cholestasis, in decreasing order of importance, were periportal ductal proliferation, portal ductal proliferation, portal expansion, cholestasis in neoductules, foci of myeloid metaplasia, and portal- portal bridges. References Data indicating EHC Data indicating IHC Kasai et al. (25) Portal fibrosis, portal ductal proliferation, More marked hepatocytic degenerative neoductule cholestasis, Kupffer cell alterations and giant cell transformation cholestasis, severe portal expansion, marked lobular fibrosis with disarray of the lobular architecture even before the age of 6 months Present study Periportal ductal proliferation, Foci of myeloid metaplasia portal ductal proliferation, portal expansion, cholestasis in neoductules, portal cholestasis, portal- portal bridges 


Indian Pediatr 1996 Sep;33(9):753-62
Neonatal cholestasis syndrome in India--a diagnostic and therapeutic challenge.
Bhave SA, Bavdekar AR, Pandit AN
Department of Pediatrics, K.E.M. Hospital Research Center, Pune.

Indian Pediatr 1996 Sep;33(9):729-34
Neonatal cholestasis syndrome: an appraisal at a tertiary center.
Yachha SK, Khanduri A, Kumar M, Sikora SS, Saxena R, Gupta RK, Kishore J 

Department of Gastroenterology (Pediatric GE), Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow.
OBJECTIVE: To know the magnitude, etiology and clinical profile, the efficacy of various investigations and the outcome in patients with neonatal cholestasis syndrome (NCS). DESIGN: Prospective evaluation of 60 consecutive infants with NCS (mean age 3.9 +/- 1.9 months; 49 males) over a period of 3.5 years. SETTING: Tertiary level referral gastroenterology center in North India. METHODS: Liver function tests, urine examination, serum antibodies against Cytomegalovirus (CMV), Rubella and Toxoplasma; abdominal ultrasonography, hepatobiliary scintigraphy and liver biopsy were done. In appropriate setting, laparotomy and surgical corrections were done for biliary tract disorders. RESULTS: NCS constituted 19% of pediatric liver diseases. Considerable delay in presentation was observed [mean delay, extrahepatic biliary atresia (EHBA) = 4 +/- 2.0 months, neonatal hepatitis (NH) = 2.2 +/- 1.3 months]. Thirty three (55%) infants had EHBA, 14 (23%) NH (4 CMV, 2 galactosemia, 1 urinary tract infection and 7 idiopathic), 2 (3%) paucity of intralobular bile ducts and 11 (18%) were of indeterminate etiology. Liver biopsy was the most accurate (96.4%) investigation in discriminating between EHBA and NH. Of the 18 operated infants with EHBA (portoenterostomy-15 and hepatico-jejunostomy-3), 10 were alive (mean follow up = 22.8 +/- 8.6 months) of which 4 were completely asymptomatic. CONCLUSIONS: (i) NCS is an important cause of liver disease in Indian children. (ii) It requires prompt referral, quick investigative approach and targeted management. (iii) Liver biopsy is highly accurate in differentiating EHBA and NH. (iv) infants with EHBA and compensated status of liver should undergo corrective surgery irrespective of age at presentation.

Clin Perinatol 1996 Jun;23(2):321-52
Neonatal hepatobiliary disorders.
Andres JM
Department of Pediatrics, University of Florida College of Medicine, Shands Hospital, Gainesville, USA.
Neonatal hepatobiliary disorders are now better understood due primarily to new discoveries in molecular genetics, virology, and immunology. Because they are almost always pathologic and require early intervention, the neonatologist must recognize infants with these hepatocellular and ductal cholestatic problems occurring in the first few weeks of life. This article focuses mainly on new developments regarding neonatal metabolic disorders and their potential for gene therapy; perinatal infections, especially those caused by hepatitis B virus, hepatitis C virus, and human immunodeficiency virus; and recent concepts of neonatal hepatitis and biliary atresia, including a review of predictors that influence outcome for infants undergoing Kasai portoenterostomy and liver transplantation.
Publication Types:
  Review, tutorial

Trop Gastroenterol 1996 Apr-Jun;17(2):61-9
Neonatal cholestasis.
Arora NK
Department of Paediatrics, AIIMS, New Delhi.
Publication Types:
  Review, tutorial

Rev Gastroenterol Peru 1995 Jan-Apr;15(1):27-33
[Neonatal cholestasis in the Children's Health Institute: evaluation of obstructive cholangiopathy syndrome in children].
Rivera-Medina J, Aguado-Quevedo R, Rodriguez-Huapaya J, Palacios-Salas M, Gonzales-Benavides J, Alarcon-Olivera A
Servicio de Gastroenterologia, Instituto de Salud del Nino.
In order to establish a clinical or laboratory difference 52 Clinical charts of patients that were attended at the Gastroenterologic Unit at the Children's Hospital in Lima-Peru since January 1988 to December 1992, with the diagnosis of Neonatal Cholestasis were reviewed. 14 of them were discharged; at the end we have reviewed 23 cases of biliary atresia, 8 of neonatal hepatitis and 7 with congenital choledochal cyst. All patients went through sonography, scintigraphy and liver biopsy. No statistical differences were found in symptomatology, as well as jaundice, feces color or coluria. We concluded that the most accurate way to predict a diagnosis is through the sonography, scintigraphy and liver biopsy.

Pediatr Clin North Am 1994 Oct;41(5):943-66
Neonatal cholestasis. New approaches to diagnostic evaluation and therapy.
Shah HA, Spivak W
Department of Pediatrics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.
Neonatal cholestasis remains a major diagnostic challenge despite increasing knowledge regarding its pathogenesis. The time constraint and urgency in the investigational process is underscored by the age-dependent success rate of the surgical corrective procedures for EHBA. Appropriate interpretation of imaging and pathologic studies requires a pediatric center familiar with the entities causing neonatal cholestasis. When liver failure or progressive hepatic dysfunction is likely to occur, early referral to a liver transplant center is recommended. Despite the increasing experience and excellent results of pediatric liver transplantation, at this point, surgical corrective procedures such as the Kasai procedure remain the first line of treatment for most patients with EHBA.
Publication Types:
  Review, academic

J Pediatr 1994 Sep;125(3):379-84
A new cause of progressive intrahepatic cholestasis: 3 beta-hydroxy-C27-steroid dehydrogenase/isomerase deficiency.
Jacquemin E, Setchell KD, O'Connell NC, Estrada A, Maggiore G, Schmitz J, Hadchouel M, Bernard O
Department of Pediatrics, Hopital de Bicetre, Le Kremlin Bicetre, France.
There have been a few reports of infants with severe neonatal cholestasis related to a defect in primary bile acid synthesis. To assess the importance of such deficiency among children with progressive intrahepatic cholestasis (Byler disease), screening for inborn errors in bile acid synthesis was performed by fast atom bombardment ionization-mass spectrometry of urine samples from 30 affected children. Bile acid analysis revealed a specific fast atom bombardment ionization-mass spectrometry profile for 3 beta-hydroxy-C27 steroid dehydrogenase/isomerase deficiency in five children who had jaundice, hepatosplenomegaly, and fatty stools beginning at ages ranging from 4 to 46 months. None of them had pruritus. Liver function tests showed persistently normal serum gamma-glutamyltransferase activity, low serum cholesterol and vitamin E levels, normal serum bile acid concentrations despite raised serum bilirubin levels, and decreased prothrombin time and clotting factor V. In four of the cases a similar disease was observed in siblings. Liver function returned to normal after oral ursodeoxycholic acid therapy. We conclude that 3 beta-hydroxy-C27-steroid dehydrogenase/isomerase deficiency should be considered when idiopathic cholestatic liver disease with clinical features akin to Byler disease is characterized by the association of normal serum gamma-glutamyltransferase activity, normal serum bile acid concentration, absence of pruritus, and a return to normal liver function during ursodeoxycholic acid therapy. Early identification of these children is essential because they benefit from bile acid therapy and might thus avoid the need for liver transplantation.



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