Basics
Description
- 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
Epidemiology
- 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
Genetics
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
Pathophysiology
- 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.
Etiology
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
Diagnosis
History
- Pregnancy and birth history
- History of consanguinity
- Family history/racial background
- Infectious exposure
- TPN exposure, prolonged history of NPO status
- Presence/absence of extrahepatic manifestations
- Signs and symptoms:
- Jaundice
- Hepatomegaly
- Pale-colored stools
- Dark-colored urine
- For specific diagnoses:
- Alagille syndrome: typical facies, heart murmur
- Congenital infections: low birth weight, microcephaly, rash, chorioretinitis
- Metabolic disorders: irritability, hypoglycemia, poor feeding, lethargy
Physical Exam
- Jaundice/scleral icterus
- Hepatomegaly
- Splenomegaly
- Cardiac murmurs
- Dysmorphic facial features
- Neurologic abnormalities
- Stool color
Diagnostic Tests & Interpretation
Lab
Clinical scenario must be taken into consideration to determine which of the following are appropriate:
- Fractionated serum bilirubin (total and direct)
- ALT, AST, alkaline phosphatase
- Gamma glutamyl transpeptidase (GGT)
- Serum albumin
- Prothrombin time/INR
- Glucose
- CBC
- Urine culture +/ ’ blood culture
- Urine-reducing substances
- Serum alpha-1 antitrypsin level and phenotype
- Serologies: CMV, HSV, enterovirus, hepatitis A and B
- Fat-soluble vitamin levels: A, D, and E
- Cortisol, TSH, T4
- Infant metabolic screen
- Plasma amino acids, urine organic acids, lactate/pyruvate
- Urine succinylacetone (tyrosinemia)
- Genetic testing for Alagille syndrome, PFIC (1 " 3), alpha-1 antitrypsin deficiency
- Serum and urine bile acids
Imaging
- Abdominal ultrasound (choledochal cyst, presence of gallbladder)
- Chest x-ray (for butterfly vertebrae with Alagille syndrome)
- Hepatobiliary scintigraphy (HIDA scan) after phenobarbital administrations for 5 days
- X-rays of skull and long bones (for congenital infections and peroxisomal disorders)
Diagnostic Procedures/Other
- Liver biopsy for histology, routine viral culture, immunohistochemistry, and electron microscopy as indicated
- Sweat chloride analysis
- MRCP
- Ophthalmologic exam (for posterior embryotoxin in Alagille syndrome, chorioretinitis)
- Intraoperative cholangiogram
- Echocardiogram (PPS in Alagille syndrome)
Differential Diagnosis
See "Etiology. " The provider must be able to distinguish neonatal cholestasis from physiologic or breast milk jaundice in infancy.
Alert
Most causes of neonatal cholestasis require expedited diagnosis and intervention:
- Biliary atresia
- Choledochal cyst
- Infection
- Metabolic disorders (e.g., galactosemia)
- Endocrine disorders (e.g., hypothyroidism, hypopituitarism)
Treatment
Medication
- Ursodeoxycholic acid (improvement in hepatic function and absorption of fat-soluble vitamins)
- Antihistamines and rifampin (for pruritus associated with cholestasis)
- Antibiotics and antivirals (when appropriate)
- ADEK vitamins (if fat-soluble vitamin deficiencies)
Issues for Referral
All neonates with cholestasis as defined earlier should have referrals to a pediatric gastroenterologist for further evaluation and management. If the provider suspects biliary atresia or metabolic disease, referral to the appropriate subspecialist should be prompt.
Additional Therapies
- Consider the need for speech therapy, occupational therapy, or physical therapy when appropriate.
- Nutritional support
Surgery/Other Procedures
- Intraoperative cholangiogram if suspect biliary atresia
- Kasai procedure (hepatoportoenterostomy) for biliary atresia
- Surgical referral for removal of choledochal cyst
- Biliary diversion for severe pruritus associated with Alagille syndrome and PFIC
- Liver transplantation
Inpatient Considerations
Initial Stabilization
- Sepsis must be identified and treated.
- Coagulopathy (prolonged INR) should be treated with vitamin K.
Ongoing Care
Diet
- Nutritional support needed. Typically, an elemental formula with high content medium-chain triglycerides is better absorbed in cholestasis.
- Consider need for nasogastric tube feeds.
- Special diets
- Supplementation with pancreatic enzymes (CF)
- Galactose-free (galactosemia)
Prognosis
Varies based on underlying diagnosis. Biliary atresia remains the most common indication for pediatric liver transplantation.
Complications
- End-stage liver disease (ascites, coagulopathy) and portal hypertension requiring liver transplantation
- Infection
- Failure to thrive
- Poor bone health
- Developmental delay
Additional Reading
- Benchimol EI, Walsh CM, Ling SC. Early diagnosis of neonatal cholestatic jaundice: test at 2 weeks. Can Fam Physician. 2009;55(12);1184 " 1192. [View Abstract]
- Emerick KM, Whitington PF. Neonatal liver disease. Pediatr Ann. 2006;35(4):280 " 286. [View Abstract]
- Moerschel SK, Cianciaruso LB, Tracy LR. A practical approach to neonatal jaundice. Am Fam Phys. 2008;77(9):1255 " 1262. [View Abstract]
- 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(2):115 " 128. [View Abstract]
Codes
ICD09
- 576.8 Other specified disorders of biliary tract
- 751.61 Biliary atresia
- 774.4 Perinatal jaundice due to hepatocellular damage
- 273.4 Alpha-1-antitrypsin deficiency
ICD10
- K83.1 Obstruction of bile duct
- Q44.2 Atresia of bile ducts
- P59.20 Neonatal jaundice from unspecified hepatocellular damage
- E88.01 Alpha-1-antitrypsin deficiency
SNOMED
- 433237003 Cholestasis in newborn (disorder)
- 77480004 Congenital biliary atresia (disorder)
- 69800000 neonatal hepatitis (disorder)
- 30188007 alpha-1-Antitrypsin deficiency (disorder)
FAQ
- Q: If my patient has an abnormal HIDA scan, does that mean he/she has biliary atresia?
- A: A HIDA scan can be abnormal in obstructive causes of cholestasis other than biliary atresia. A surgical evaluation via an intraoperative cholangiogram is the gold standard to diagnose biliary atresia.
- Q: What vitamin deficiencies are most common in infants with cholestasis?
- A: Infants with cholestasis often have malabsorption of fat-soluble vitamins (A, D, E, and K) and require supplementation.