Causes of neonatal cholestasis
- Stephanie H Abrams, MD, MS
Stephanie H Abrams, MD, MS
- Assistant Professor of Pediatrics
- Baylor College of Medicine
- Robert J Shulman, MD
Robert J Shulman, MD
- Professor of Pediatrics
- Baylor College of Medicine
- Section Editors
- Steven A Abrams, MD
Steven A Abrams, MD
- Section Editor — Neonatology
- Professor of Pediatrics
- Baylor College of Medicine
- Elizabeth B Rand, MD
Elizabeth B Rand, MD
- Section Editor — Pediatric Hepatology
- Associate Professor of Pediatrics
- University of Pennsylvania School of Medicine
Neonatal cholestasis is defined serologically as the accumulation of components of bile in the bloodstream, most frequently manifested as conjugated hyperbilirubinemia in the newborn period. Cholestasis results from diminished bile flow and/or excretion, which can be the result of a number of different causes.
Causes of neonatal cholestasis can be divided into the following categories (table 1):
- Lien TH, Chang MH, Wu JF, et al. Effects of the infant stool color card screening program on 5-year outcome of biliary atresia in Taiwan. Hepatology 2011; 53:202.
- Singham J, Yoshida EM, Scudamore CH. Choledochal cysts: part 1 of 3: classification and pathogenesis. Can J Surg 2009; 52:434.
- Yamaguchi M. Congenital choledochal cyst. Analysis of 1,433 patients in the Japanese literature. Am J Surg 1980; 140:653.
- Todani T, Watanabe Y, Narusue M, et al. Congenital bile duct cysts: Classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst. Am J Surg 1977; 134:263.
- Diao M, Li L, Cheng W. Timing of surgery for prenatally diagnosed asymptomatic choledochal cysts: a prospective randomized study. J Pediatr Surg 2012; 47:506.
- Kim WS, Kim IO, Yeon KM, et al. Choledochal cyst with or without biliary atresia in neonates and young infants: US differentiation. Radiology 1998; 209:465.
- Caponcelli E, Knisely AS, Davenport M. Cystic biliary atresia: an etiologic and prognostic subgroup. J Pediatr Surg 2008; 43:1619.
- Jiexiong F, Minju L, Hongfeng T, et al. Clinical and pathological characteristics of cystic lesions of extrahepatic bile duct in neonates. Acta Paediatr 2003; 92:1183.
- Seeler RA, Hahn K. Jaundice in urinary tract infection in infancy. Am J Dis Child 1969; 118:553.
- Rooney JC, Hill DJ, Danks DM. Jaundice associated with bacterial infection in the newborn. Am J Dis Child 1971; 122:39.
- Wolf A, Pohlandt F. Bacterial infection: the main cause of acute cholestasis in newborn infants receiving short-term parenteral nutrition. J Pediatr Gastroenterol Nutr 1989; 8:297.
- Sondheimer JM, Asturias E, Cadnapaphornchai M. Infection and cholestasis in neonates with intestinal resection and long-term parenteral nutrition. J Pediatr Gastroenterol Nutr 1998; 27:131.
- Alagille D, Estrada A, Hadchouel M, et al. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr 1987; 110:195.
- Alagille D. Alagille syndrome today. Clin Invest Med 1996; 19:325.
- Sokol RJ, Heubi JE, Balistreri WF. Intrahepatic "cholestasis facies": is it specific for Alagille syndrome? J Pediatr 1983; 103:205.
- Kamath BM, Loomes KM, Oakey RJ, et al. Facial features in Alagille syndrome: specific or cholestasis facies? Am J Med Genet 2002; 112:163.
- Sokol RJ. Re: Article by Kamath et al.-"Facial features in Alagille Syndrome". Am J Med Genet A 2004; 124A:220.
- Kamath BM, Loomes KM, Oakey RJ, Krantz ID. Supernumerary digital flexion creases: an additional clinical manifestation of Alagille syndrome. Am J Med Genet 2002; 112:171.
- Kamath BM, Loomes KM, Piccoli DA. Medical management of Alagille syndrome. J Pediatr Gastroenterol Nutr 2010; 50:580.
- Kaye AJ, Rand EB, Munoz PS, et al. Effect of Kasai procedure on hepatic outcome in Alagille syndrome. J Pediatr Gastroenterol Nutr 2010; 51:319.
- Kamath BM, Yin W, Miller H, et al. Outcomes of liver transplantation for patients with Alagille syndrome: the studies of pediatric liver transplantation experience. Liver Transpl 2012; 18:940.
- Kronsten V, Fitzpatrick E, Baker A. Management of cholestatic pruritus in paediatric patients with alagille syndrome: the King's College Hospital experience. J Pediatr Gastroenterol Nutr 2013; 57:149.
- Cies JJ, Giamalis JN. Treatment of cholestatic pruritus in children. Am J Health Syst Pharm 2007; 64:1157.
- Zellos A, Roy A, Schwarz KB. Use of oral naltrexone for severe pruritus due to cholestatic liver disease in children. J Pediatr Gastroenterol Nutr 2010; 51:787.
- Chang Y, Golkar L. The use of naltrexone in the management of severe generalized pruritus in biliary atresia: report of a case. Pediatr Dermatol 2008; 25:403.
- Mansour-Ghanaei F, Taheri A, Froutan H, et al. Effect of oral naltrexone on pruritus in cholestatic patients. World J Gastroenterol 2006; 12:1125.
- Terg R, Coronel E, Sordá J, et al. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study. J Hepatol 2002; 37:717.
- Kamath BM, Piccoli DA, Magee JC, et al. Pancreatic insufficiency is not a prevalent problem in Alagille syndrome. J Pediatr Gastroenterol Nutr 2012; 55:612.
- Segal S, Berry GT. Disorders of galactose metabolism. In: The Metabolic and Molecular Bases of Inherited Disease, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York 1995. p.967.
- Wolman disease. In: OMIM Online Menedlian Inheritance in Man. Johns Hopkins University. Available at: http://www.ncbi.nlm.nih.gov/omim (Accessed on April 21, 2012).
- Novak, DA, Suchy, et al. Disorders of the liver and biliary system relevant to clinical practice. In: Oski's Pediatrics: Principles and Practice, McMillan JA (Ed), Lippincott, Williams and Wilkins, Philadelphia 1999. p.1714.
- Subramaniam P, Clayton PT, Portmann BC, et al. Variable clinical spectrum of the most common inborn error of bile acid metabolism--3beta-hydroxy-Delta 5-C27-steroid dehydrogenase deficiency. J Pediatr Gastroenterol Nutr 2010; 50:61.
- Hesham A-Kader H, Balistreri WF. Nontransplant alternatives for the treatment of patients with metabolic disease. Semin Liver Dis 1998; 18:255.
- Setchell KD, Heubi JE. Defects in bile acid biosynthesis--diagnosis and treatment. J Pediatr Gastroenterol Nutr 2006; 43 Suppl 1:S17.
- Molleston JP, Sokol RJ, Karnsakul W, et al. Evaluation of the child with suspected mitochondrial liver disease. J Pediatr Gastroenterol Nutr 2013; 57:269.
- Al-Hussaini A, Faqeih E, El-Hattab AW, et al. Clinical and molecular characteristics of mitochondrial DNA depletion syndrome associated with neonatal cholestasis and liver failure. J Pediatr 2014; 164:553.
- Dubern B, Broue P, Dubuisson C, et al. Orthotopic liver transplantation for mitochondrial respiratory chain disorders: a study of 5 children. Transplantation 2001; 71:633.
- Rake JP, van Spronsen FJ, Visser G, et al. End-stage liver disease as the only consequence of a mitochondrial respiratory chain deficiency: no contra-indication for liver transplantation. Eur J Pediatr 2000; 159:523.
- Chen ST, Su YN, Ni YH, et al. Diagnosis of neonatal intrahepatic cholestasis caused by citrin deficiency using high-resolution melting analysis and a clinical scoring system. J Pediatr 2012; 161:626.
- Yeh JN, Jeng YM, Chen HL, et al. Hepatic steatosis and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in Taiwanese infants. J Pediatr 2006; 148:642.
- Yasuda T, Yamaguchi N, Kobayashi K, et al. Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia. Hum Genet 2000; 107:537.
- Lee BH, Jin HY, Kim GH, et al. Nonalcoholic fatty liver disease in 2 siblings with adult-onset type II citrullinemia. J Pediatr Gastroenterol Nutr 2010; 50:682.
- Coakley RJ, Taggart C, O'Neill S, McElvaney NG. Alpha1-antitrypsin deficiency: biological answers to clinical questions. Am J Med Sci 2001; 321:33.
- Perlmutter DH. Alpha-1-antitrypsin deficiency. Semin Liver Dis 1998; 18:217.
- Sveger T. Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976; 294:1316.
- Francavilla R, Castellaneta SP, Hadzic N, et al. Prognosis of alpha-1-antitrypsin deficiency-related liver disease in the era of paediatric liver transplantation. J Hepatol 2000; 32:986.
- Vohra P, Haller C, Emre S, et al. Neonatal hemochromatosis: the importance of early recognition of liver failure. J Pediatr 2000; 136:537.
- Pan X, Kelly S, Melin-Aldana H, et al. Novel mechanism of fetal hepatocyte injury in congenital alloimmune hepatitis involves the terminal complement cascade. Hepatology 2010; 51:2061.
- Ekong UD, Melin-Aldana H, Whitington PF. Regression of severe fibrotic liver disease in 2 children with neonatal hemochromatosis. J Pediatr Gastroenterol Nutr 2008; 46:329.
- Smith SR, Shneider BL, Magid M, et al. Minor salivary gland biopsy in neonatal hemochromatosis. Arch Otolaryngol Head Neck Surg 2004; 130:760.
- Hayes AM, Jaramillo D, Levy HL, Knisely AS. Neonatal hemochromatosis: diagnosis with MR imaging. AJR Am J Roentgenol 1992; 159:623.
- Debray FG, de Halleux V, Guidi O, et al. Neonatal liver cirrhosis without iron overload caused by gestational alloimmune liver disease. Pediatrics 2012; 129:e1076.
- Tsunoda T, Inui A, Kawamoto M, et al. Neonatal liver failure owing to gestational alloimmune liver disease without iron overload. Hepatol Res 2014.
- Whitington PF, Malladi P. Neonatal hemochromatosis: is it an alloimmune disease? J Pediatr Gastroenterol Nutr 2005; 40:544.
- Whitington PF. Neonatal hemochromatosis: a congenital alloimmune hepatitis. Semin Liver Dis 2007; 27:243.
- Whitington PF, Kelly S. Outcome of pregnancies at risk for neonatal hemochromatosis is improved by treatment with high-dose intravenous immunoglobulin. Pediatrics 2008; 121:e1615.
- Heffron T, Pillen T, Welch D, et al. Medical and surgical treatment of neonatal hemochromatosis: single center experience. Pediatr Transplant 2007; 11:374.
- Timpani G, Foti F, Nicolò A, et al. Is exchange transfusion a possible treatment for neonatal hemochromatosis? J Hepatol 2007; 47:732.
- Sigurdsson L, Reyes J, Kocoshis SA, et al. Neonatal hemochromatosis: outcomes of pharmacologic and surgical therapies. J Pediatr Gastroenterol Nutr 1998; 26:85.
- Rand EB, Karpen SJ, Kelly S, et al. Treatment of neonatal hemochromatosis with exchange transfusion and intravenous immunoglobulin. J Pediatr 2009; 155:566.
- Whitington PF. Gestational alloimmune liver disease and neonatal hemochromatosis. Semin Liver Dis 2012; 32:325.
- Escolano-Margarit MV, Miras-Baldó MJ, Parrilla-Roure M, et al. Exchange transfusion as a possible therapy for neonatal hemochromatosis. J Pediatr Gastroenterol Nutr 2010; 50:566.
- Sheflin-Findling S, Annunziato RA, Chu J, et al. Liver transplantation for neonatal hemochromatosis: Analysis of the UNOS database. Pediatr Transplant 2015; 19:164.
- Leonis MA, Balistreri WF. Neonatal hemochromatosis: it's OK to say "NO" to antioxidant-chelator therapy. Liver Transpl 2005; 11:1323.
- Whitington PF, Hibbard JU. High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis. Lancet 2004; 364:1690.
- Baruteau J, Heissat S, Broué P, et al. Transient neonatal liver disease after maternal antenatal intravenous Ig infusions in gestational alloimmune liver disease associated with neonatal haemochromatosis. J Pediatr Gastroenterol Nutr 2014; 59:629.
- Sokol RJ, Durie PR. Recommendations for management of liver and biliary tract disease in cystic fibrosis. Cystic Fibrosis Foundation Hepatobiliary Disease Consensus Group. J Pediatr Gastroenterol Nutr 1999; 28 Suppl 1:S1.
- Colombo C, Battezzati PM, Strazzabosco M, Podda M. Liver and biliary problems in cystic fibrosis. Semin Liver Dis 1998; 18:227.
- Jang JY, Kim KM, Kim GH, et al. Clinical characteristics and VPS33B mutations in patients with ARC syndrome. J Pediatr Gastroenterol Nutr 2009; 48:348.
- Gissen P, Tee L, Johnson CA, et al. Clinical and molecular genetic features of ARC syndrome. Hum Genet 2006; 120:396.
- Eastham KM, McKiernan PJ, Milford DV, et al. ARC syndrome: an expanding range of phenotypes. Arch Dis Child 2001; 85:415.
- CRAIG JM, LANDING BH. Form of hepatitis in neonatal period simulating biliary atresia. AMA Arch Pathol 1952; 54:321.
- BILIARY ATRESIA
- OTHER OBSTRUCTIVE CAUSES
- Biliary cysts
- ALAGILLE SYNDROME
- Clinical features
- METABOLIC DISORDERS
- Disorders of lipid metabolism
- Disorders of bile acid metabolism
- Mitochondrial disorders
- Citrin deficiency
- ALPHA-1 ANTITRYPSIN DEFICIENCY
- GESTATIONAL ALLOIMMUNE LIVER DISEASE (NEONATAL HEMOCHROMATOSIS)
- Gestational therapy
- CYSTIC FIBROSIS
- PARENTERAL NUTRITION-ASSOCIATED LIVER DISEASE
- ARC SYNDROME
- IDIOPATHIC NEONATAL HEPATITIS