Neonatal Cholestasis



  • Neonatal cholestasis is defined as elevated conjugated bilirubin levels that occur in the newborn period. It typically indicates hepatobiliary dysfunction.
  • Further studies are needed on any infant who is jaundiced beyond 2 weeks old (or 3 weeks if breastfed).
  • Biochemical definition: serum conjugated bilirubin >20% of the total bilirubin concentration or direct bilirubin >2 mg/dL


  • Full-term infants: Most common causes in the 1st month are extrahepatic biliary atresia (EHBA), idiopathic neonatal hepatitis, alpha-1 antitrypsin deficiency, and progressive familial intrahepatic cholestasis (PFIC).
  • Premature infants: must consider sepsis and TPN-associated cholestasis
  • Incidence of neonatal cholestasis is 1 in 2,500 live births (excluding infants with history of parenteral nutrition).

Risk Factors


Causes of biliary atresia, neonatal hepatitis, and most other etiologies of neonatal cholestasis remain unknown.

Known genetic causes include the following:

  • Alpha-1 antitrypsin deficiency
    • Autosomal codominant expression
    • Mutations in SERPINA1 gene
    • 10–15% of individuals develop hepatic disease.
    • 2 alleles most commonly associated with liver disease: Z and M
  • Alagille syndrome
    • Autosomal dominant, variable expressivity
    • Mutations in JAG1 and NOTCH2 gene
  • PFIC
    • Group of familial cholestatic disorders: PFIC-1, 2, and 3. Note PFIC 1 and 2 have low GGT values.
    • Autosomal recessive
    • Caused by mutations in FIC1, ATP8B1, ABCB11, and ABCB4 genes


  • Neonatal cholestasis is jaundice secondary to elevated conjugated bilirubin levels in the newborn period.
  • Typically, infants are not jaundiced at birth but develop cholestasis within days to weeks of life. In utero, the placenta and maternal liver perform the necessary hepatic functions for the infant. The liver slowly matures throughout the 1st year of life to reach full hepatic metabolism potential.
  • Neonatal cholestasis can be caused by a variety of mechanisms of hepatobiliary dysfunction that results in poor bile flow or excretion. In addition, there is inefficient enterohepatic circulation in the newborn period, which contributes to bilirubin accumulation.


Most likely etiologies in <2-month-old infant:

  • Obstructive: biliary atresia, gallstones/sludge, inspissated bile, choledochal cyst, neonatal sclerosing cholangitis, congenital hepatic fibrosis/Caroli disease, Alagille syndrome
  • Idiopathic: idiopathic neonatal hepatitis
  • Infection: UTI, sepsis, cytomegalovirus (CMV), herpes simplex virus (HSV), syphilis, parvovirus B19, adenovirus, enterovirus
  • Metabolic/genetic: alpha-1 antitrypsin deficiency, tyrosinemia, PFIC, cystic fibrosis (CF), galactosemia, lipid storage disease, bile acid synthesis defects, mitochondrial hepatopathy, peroxisomal disorders
  • Endocrine: hypothyroidism, panhypopituitarism
  • Toxic: parenteral nutrition–associated cholestasis, drug-induced
  • Miscellaneous: hypoperfusion/shock

Commonly Associated Conditions

  • 10% of infants with biliary atresia also have another major congenital defect (other than laterality defects, see below).
  • Biliary atresia splenic malformation (BASM): syndromic form of BA with laterality defects
    • Situs invertus
    • Polysplenia or asplenia
    • Malrotation
    • Congenital heart disease
  • Alagille syndrome
    • Syndromic appearance (triangular face, deep set eyes, broad nose)
    • Cardiac anomalies, typically peripheral pulmonary stenosis (PPS)
    • Butterfly vertebrae
    • Ophthalmologic findings: posterior embryotoxon

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