Published onChildren's Doctor
A full-term, breast-feeding, 2-week-old baby is noted to be jaundiced at the initial visit. Per guidelines by the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition, an evaluation for cholestasis should be initiated in any jaundiced infant at 2 weeks of age, with measurement of a total and direct bilirubin. However, breast-fed infants who can be reliably monitored and who have an otherwise normal history (no light-colored stools or dark urine) and physical exam may be followed clinically until 3 weeks of age, when a total and direct bilirubin should be obtained if jaundice persists. The patient had elevated bilirubin levels and was referred to the Division of Gastroenterology, Hepatology and Nutrition at Children’s Hospital.
Newborn jaundice is a common pediatric problem, as approximately 50% of term and 80% of preterm infants develop jaundice in the first week of life. Most instances are benign, and the challenge for clinicians is to determine when further evaluation is needed.
The majority of neonatal jaundice is due to unconjugated bilirubin and is a result of neonatal physiology. Newborns produce 6 to 8 mg/kg of bilirubin daily (twice the adult rate). This level typically declines to adult levels within two weeks after birth, coinciding with the resolution of physiologic jaundice. In contrast, conjugated hyperbilirubinemia in infancy — defined as a conjugated or direct fraction of bilirubin either >1mg/dL or 20 percent of the total bilirubin level — indicates neonatal cholestasis jaundice and requires prompt evaluation. Referral to a pediatric gastroenterologist is indicated if conjugated hyperbilirubinemia is noted beyond 2 weeks of life, as early detection and timely diagnosis are important for treatment and prognosis.
Neonatal cholestasis jaundice affects roughly 1 in 2500 infants and would warrant a referral to the Fred and Suzanne Biesecker Pediatric Liver Center at CHOP. While a variety of disorders can present with cholestasis in the newborn period, the majority of the initial evaluation is focused on biliary obstruction, and particularly biliary atresia, because outcome and treatment are time sensitive. The differential for neonatal cholestasis should be guided by the patient’s history, physical exam, and laboratory studies. The initial workup should focus on conditions most amenable to treatment.
- Structural diseases
- Cystic fibrosis
- Idiopathic neonatal hepatitis
- Alagille syndrome
- Progressive familial intrahepatic cholestasis
- Bile acid synthesis defects
- Mitochondrial disorders
Biliary atresia is the most common indication for pediatric liver transplant. It is a progressive, fibro-obliterative disease of unclear etiology characterized by complete obstruction of the extrahepatic bile ducts, proliferation of intrahepatic bile ducts on liver biopsy, and marked intrahepatic fibrosis. Early diagnosis and surgical management with a Kasai hepatoportoenterostomy are key, as outcome correlates to the infant’s age at the time of operation. However, the onset of jaundice can be insidious, as infants with biliary atresia tend to look well initially. As physiologic jaundice occurs frequently in newborns, it can be difficult to identify children with biliary atresia on initial presentation, and there is a need for effective screening with access to timely specialist referrals.
Primary screening tests are stool color and serum total and direct bilirubin level. Acholic or pale stools can be seen in biliary obstruction, and community-based screening programs using stool color cards can be effective. For example, in Taiwan, with its relatively high incidence of biliary atresia, new parents receive stool color cards. This program led to earlier diagnosis and performance of Kasai with an associated improved 3-year jaundice-free survival rate.
As conjugated bilirubinemia is often the earliest indicator of cholestasis, studies have looked at potentially screening for conjugated bilirubin levels. A bilirubin screening program in the United Kingdom reported that no infants with a normal bilirubin level had liver disease, while 11 of 12 infants with an elevated conjugated bilirubin level on repeat were ultimately diagnosed with liver disease. More recently, a retrospective study of infants with biliary atresia indicated that 34 out of 61 infants with biliary atresia had an elevated direct or conjugated bilirubin level within the first 96 hours of life. Current efforts are focused on further determining the efficacy of universal newborn bilirubin screening strategies.
Overall, neonatal cholestasis is a clinical manifestation of a diverse spectrum of disorders. Conjugated hyperiblirubnemia is never physiologic and should prompt immediate evaluation with referral to a pediatric gastroenterologist.
References and suggested reading
Chen SM, Chang MH, Du JC, et al; Taiwan Infant Stool Color Card Study Group. Screening for biliary atresia by infant stool color card in Taiwan. Pediatrics. 2006;117(4):1147–1154.
Harpavat S, Finegold MJ, Karpen SJ. Patients with biliary atresia have elevated direct/conjugated bilirubin levels shortly after birth. Pediatrics. 2011;128(6):e1428-33.
Lien TH, Chang MH, Wu JF, et al; Taiwan Infant Stool Color Card Study Group. Effects of the infant stool color card screening program on 5-year outcome of biliary atresia in Taiwan. Hepatology. 2011;53(1):202-208.
Wang KS. Newborn screening for biliary atresia. Pediatrics. 2015:136(6):e1663-1669
Moyer V, Freese DK, Whitington PF, et al. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Guideline for the evolution of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2004;39(2)115-128.
The Pediatric Transplant Center at CHOP addresses all of the transplant needs of children and families, from evaluation through long-term, post-surgical care. We have programs for heart, heart/lung, lung, kidney, and liver transplants, and perform more than 100 transplants each year. To refer a patient, contact us at 877-ORGAN50 (674-2650).
Contributed by: Henry C. Lin, MD