Approach to neonatal cholestasis
- 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, Department of Pediatrics
- Dell Medical School at the University of Texas at Austin
- Elizabeth B Rand, MD
Elizabeth B Rand, MD
- Section Editor — Pediatric Hepatology
- Professor of Pediatrics
- University of Pennsylvania School of Medicine
Neonatal cholestasis is generally defined as prolonged conjugated hyperbilirubinemia that occurs in the newborn period. It results from diminished bile flow and/or excretion, which can be caused by a number of disorders. Neonatal cholestasis lasting more than two weeks affects approximately 1 in 2500 births (excluding infants with intestinal failure-associated liver disease), but estimates vary depending on the definition used to define cholestasis [1,2].
This topic review provides an approach to patients with neonatal cholestasis. The pathogenesis and management of neonatal unconjugated hyperbilirubinemia and common causes of neonatal cholestasis are discussed separately. (See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn" and "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants" and "Causes of cholestasis in neonates and young infants".)
Cholestasis is defined as an impairment in the excretion of bile, which can be caused by defects in intrahepatic production or transmembrane transport of bile, or mechanical obstruction to bile flow. The biochemical features of cholestasis reflect the retention of components of bile in the serum (eg, bilirubin, bile acids, and/or cholesterol). The pattern and severity of each of these abnormalities varies with the underlying disorder. Elevated conjugated bilirubin is the predominant characteristic in most of the causes of neonatal cholestasis.
Conjugated hyperbilirubinemia in a neonate is defined as a serum conjugated bilirubin concentration greater than 1.0 mg/dL (17.1 micromol/L) if the total serum bilirubin is <5.0 mg/dL (85.5 micromol/L) or greater than 20 percent of the total serum bilirubin if the total serum bilirubin is >5.0 mg/dL (85.5 micromol/L). An elevated conjugated bilirubin is an abnormal finding and requires additional evaluation . The threshold is somewhat higher, usually a serum conjugated bilirubin greater than 2.0 mg/dL (34.2 micromol/L), for defining clinically significant hyperbilirubinemia in infants with intestinal failure-associated liver disease (which is also known as parenteral nutrition-associated liver disease). (See "Intestinal failure-associated liver disease in infants", section on 'Definition'.)
The terms "conjugated bilirubin" and "direct bilirubin" are often used interchangeably because conjugated bilirubin can be estimated by the "direct" reaction with a diazo reagent (van den Bergh reaction). However, direct-reacting bilirubin overestimates conjugated bilirubin, particularly when the concentrations of total serum bilirubin are high . (See "Clinical aspects of serum bilirubin determination", section on 'Measurement of serum bilirubin'.)
- Dick MC, Mowat AP. Hepatitis syndrome in infancy--an epidemiological survey with 10 year follow up. Arch Dis Child 1985; 60:512.
- Balistreri WF. Neonatal cholestasis. J Pediatr 1985; 106:171.
- Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2004; 39:115.
- Davis AR, Rosenthal P, Escobar GJ, Newman TB. Interpreting conjugated bilirubin levels in newborns. J Pediatr 2011; 158:562.
- Winfield CR, MacFaul R. Clinical study of prolonged jaundice in breast- and bottle-fed babies. Arch Dis Child 1978; 53:506.
- Kelly DA, Stanton A. Jaundice in babies: implications for community screening for biliary atresia. BMJ 1995; 310:1172.
- el-Youssef M, Whitington PF. Diagnostic approach to the child with hepatobiliary disease. Semin Liver Dis 1998; 18:195.
- McLin VA, Balistereri WF. Approach to neoonatal cholestasis. In: Pediatric Gastrointestinal Disease: Pathopsychology, Diagnosis, Management, 4th, Walker WA, Goulet O, Kleinman RE, et al (Eds), BC Decker, Ontario 2004. p.1079.
- Sivan Y, Merlob P, Nutman J, Reisner SH. Direct hyperbilirubinemia complicating ABO hemolytic disease of the newborn. Clin Pediatr (Phila) 1983; 22:537.
- Burton EM, Babcock DS, Heubi JE, Gelfand MJ. Neonatal jaundice: clinical and ultrasonographic findings. South Med J 1990; 83:294.
- Manolaki AG, Larcher VF, Mowat AP, et al. The prelaparotomy diagnosis of extrahepatic biliary atresia. Arch Dis Child 1983; 58:591.
- Hirfanoglu IM, Unal S, Onal EE, et al. Analysis of serum γ-glutamyl transferase levels in neonatal intensive care unit patients. J Pediatr Gastroenterol Nutr 2014; 58:99.
- Wright K, Christie DL. Use of gamma-glutamyl transpeptidase in the diagnosis of biliary atresia. Am J Dis Child 1981; 135:134.
- Maggiore G, Bernard O, Hadchouel M, et al. Diagnostic value of serum gamma-glutamyl transpeptidase activity in liver diseases in children. J Pediatr Gastroenterol Nutr 1991; 12:21.
- Kanegawa K, Akasaka Y, Kitamura E, et al. Sonographic diagnosis of biliary atresia in pediatric patients using the "triangular cord" sign versus gallbladder length and contraction. AJR Am J Roentgenol 2003; 181:1387.
- Tan Kendrick AP, Phua KB, Ooi BC, et al. Making the diagnosis of biliary atresia using the triangular cord sign and gallbladder length. Pediatr Radiol 2000; 30:69.
- Farrant P, Meire HB, Mieli-Vergani G. Ultrasound features of the gall bladder in infants presenting with conjugated hyperbilirubinaemia. Br J Radiol 2000; 73:1154.
- Lee CH, Wang PW, Lee TT, et al. The significance of functioning gallbladder visualization on hepatobiliary scintigraphy in infants with persistent jaundice. J Nucl Med 2000; 41:1209.
- Majd M, Reba RC, Altman RP. Hepatobiliary scintigraphy with 99mTc-PIPIDA in the evaluation of neonatal jaundice. Pediatrics 1981; 67:140.
- Iinuma Y, Narisawa R, Iwafuchi M, et al. The role of endoscopic retrograde cholangiopancreatography in infants with cholestasis. J Pediatr Surg 2000; 35:545.
- Derkx HH, Huibregtse K, Taminiau JA. The role of endoscopic retrograde cholangiopancreatography in cholestatic infants. Endoscopy 1994; 26:724.
- Wilkinson ML, Mieli-Vergani G, Ball C, et al. Endoscopic retrograde cholangiopancreatography in infantile cholestasis. Arch Dis Child 1991; 66:121.
- Shirai Z, Toriya H, Maeshiro K, Ikeda S. The usefulness of endoscopic retrograde cholangiopancreatography in infants and small children. Am J Gastroenterol 1993; 88:536.
- Guelrud M, Jaen D, Mendoza S, et al. ERCP in the diagnosis of extrahepatic biliary atresia. Gastrointest Endosc 1991; 37:522.
- Ohnuma N, Takahashi T, Tanabe M, et al. The role of ERCP in biliary atresia. Gastrointest Endosc 1997; 45:365.
- Norton KI, Glass RB, Kogan D, et al. MR cholangiography in the evaluation of neonatal cholestasis: initial results. Radiology 2002; 222:687.
- Miyazaki T, Yamashita Y, Tang Y, et al. Single-shot MR cholangiopancreatography of neonates, infants, and young children. AJR Am J Roentgenol 1998; 170:33.
- Jaw TS, Kuo YT, Liu GC, et al. MR cholangiography in the evaluation of neonatal cholestasis. Radiology 1999; 212:249.
- Han SJ, Kim MJ, Han A, et al. Magnetic resonance cholangiography for the diagnosis of biliary atresia. J Pediatr Surg 2002; 37:599.
- Fox VL, Cohen MB, Whitington PF, Colletti RB. Outpatient liver biopsy in children: a medical position statement of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 1996; 23:213.
- Penna FJ, Leão E. Duodenal intubation in the differential diagnosis of obstructive jaundice in infants. Arq Gastroenterol 1982; 19:143.
- Larrosa-Haro A, Caro-López AM, Coello-Ramírez P, et al. Duodenal tube test in the diagnosis of biliary atresia. J Pediatr Gastroenterol Nutr 2001; 32:311.
- Faweya AG, Akinyinka OO, Sodeinde O. Duodenal intubation and aspiration test: utility in the differential diagnosis of infantile cholestasis. J Pediatr Gastroenterol Nutr 1991; 13:290.