Neonatal Cholestasis



  • Neonatal cholestasis is defined as elevated conjugated bilirubin levels that occur in the newborn period and often extends during the infancy. 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 (TB) 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, α1-antitrypsin deficiency, and progressive familial intrahepatic cholestasis (PFIC).
  • Premature infants: must consider sepsis and total parenteral nutrition (TPN)-associated cholestasis
  • Incidence of neonatal cholestasis is 1 in 2,500 live births (excluding infants with history of parenteral nutrition).



Causes of biliary atresia (BA), neonatal hepatitis, and most other etiologies of neonatal cholestasis remain unknown. Known genetic causes include the following:

  • α1-Antitrypsin deficiency
    • Autosomal codominant expression
    • Mutations in SERPINA1 gene
    • 10–15% of individuals develop hepatic disease.
    • Two alleles most commonly associated with liver disease: Z and M
  • Alagille syndrome
    • Autosomal dominant, variable expressivity
    • Mutations in JAG1 and NOTCH2 gene
  • PFIC and bile acid synthetic defects (BASDs)
    • Group of familial cholestatic disorders: PFIC1, PFIC2, and PFIC3. Note PFIC1, PFIC2, and some types of BASD have low γ-glutamyl transpeptidase (GGT) values.
    • Autosomal recessive
    • Caused by mutations in FIC1, ATP8B1, ABCB11, and ABCB4 genes
  • Cystic fibrosis (CF)
    • Autosomal recessive
    • CFTR gene mutations, most common ΔF508 deletion (causes 70% of cases in United States)
  • Citrin deficiency: neonatal-onset type II
    • SLC25A13 gene mutation
    • Transient cholestasis, diffuse fatty liver with hepatic fibrosis
    • Almost exclusively Asian infants
  • Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome
    • Autosomal recessive: VPS33B gene mutation
    • Multiple joint contractures, renal dysfunction, bleeding tendency, affected infants die during infancy
    • Normal GGT
  • Aagenaes syndrome
    • Autosomal recessive
    • Congenital hypoplasia of lymph vessels
      • Lymphedema of legs, cholestasis, hepatic cirrhosis


  • 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 infant <2 months of age:

  • Obstructive: BA, 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: α1-antitrypsin deficiency, tyrosinemia, PFIC, CF, galactosemia, lipid storage disease, bile acid synthesis defects, mitochondrial hepatopathy, peroxisomal disorders, neonatal/infantile intrahepatic cholestasis caused by citrin deficiency (NICCD)
  • Endocrine: hypothyroidism, panhypopituitarism
  • Toxic: parenteral nutrition–associated cholestasis, drug-induced
  • Immune mediated: gestational alloimmune liver disease (GALD)
  • Miscellaneous: hypoperfusion/shock


  • 10% of infants with BA 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 inversus
    • Polysplenia or asplenia
    • Malrotation
    • Congenital heart disease
  • Alagille syndrome
    • Syndromic appearance (triangular face, deep set eyes, broad nose)
    • Cardiac anomalies, typically pulmonic stenosis
    • Butterfly vertebrae
    • Ophthalmologic findings: posterior embryotoxon
  • Panhypopituitarism
    • Persistent hypoglycemia
    • Septooptic dysplasia and optic nerve hypoplasia

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