Neonatal Cholestasis

BASICS

DESCRIPTION

Neonatal cholestasis is defined as a pathologic condition with reduced bile flow and/or hepatobiliary dysfunction. This occurs in the newborn period or within the first 3 months of life.
Further studies are needed on any infant with jaundice >2 weeks of age (or 3 weeks if breastfed).
Biochemical definition: serum direct (conjugated) bilirubin level >2 mg/dL or >20% of the total bilirubin concentration; some infants have only direct hyperbilirubinemia without other liver chemistry abnormalities at the onset of cholestasis (i.e., aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase [ALP], γ-glutamyl transpeptidase [GGT]). Note: Dubin-Johnson syndrome and Rotor syndrome are autosomal recessive noncholestatic conditions that only cause isolated direct hyperbilirubinemia without other liver chemistry abnormalities.

EPIDEMIOLOGY

Full-term infants: The most common causes in the 1st month are extrahepatic biliary atresia (EHBA), genetic disorders (e.g., α1-antitrypsin deficiency, progressive familial intrahepatic cholestasis [PFIC]), and idiopathic neonatal hepatitis.
Premature infants: must also consider sepsis and parenteral nutrition–associated cholestasis
The incidence is 1 in 2,500 live births (excluding infants with a history of parenteral nutrition).

ETIOLOGY

Most likely etiologies in infants <2 months of age:

Obstructive: biliary atresia, Alagille syndrome, gallstones/sludge, inspissated bile, choledochal cyst, neonatal sclerosing cholangitis, congenital hepatic fibrosis/Caroli disease
Idiopathic: idiopathic neonatal hepatitis
Infection: urinary tract infection, sepsis, cytomegalovirus (CMV), herpes simplex virus (HSV), syphilis, parvovirus B19, adenovirus, enterovirus
Metabolic/genetic: α1-antitrypsin deficiency, tyrosinemia, PFIC, cystic fibrosis (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

RISK FACTORS

Genetics

The cause of biliary atresia, neonatal hepatitis, and most other etiologies of neonatal cholestasis remains unknown. Known genetic causes include the following:

α1-Antitrypsin deficiency
- Autosomal codominant expression
- Mutations in SERPINA1 gene
- 10–15% of individuals develop hepatic disease.
- Z and M are the two alleles most commonly associated with liver disease. Only ZZ and SZ phenotypes cause significant liver disease in children.
Alagille syndrome
- Autosomal dominant, variable expressivity
- Mutations in JAG1 or NOTCH2 genes
PFIC
- Group of familial disorders: PFIC types 1 to 6
- Autosomal recessive
- Caused by mutations in genes ATP8B1 (type 1), ABCB11 (type 2), ABCB4 (type 3), TJP2 (type 4), NR1H4 (type 5), and MYO5B (type 6)
- Note: All have low/normal GGT levels other than type 3
Bile acid synthetic defects (BASDs)
- Most are autosomal recessive.
- Enzyme defects in the bile acid synthesis pathway lead to build-up of unusual bile acids/metabolites.
- Jaundice, elevated liver enzymes, coagulopathy, poor growth, vitamin deficiency
- Treatment with bile acids usually corrects all abnormalities of liver function.
CF
- Autosomal recessive
- CFTR gene mutation (most commonly ΔF508 deletion, which causes 70% of cases in the United States
Citrin deficiency: Neonatal-onset type II
- SLC25A13 gene mutation
- Transient cholestasis, diffuse fatty liver with hepatic fibrosis
- Seen almost exclusively in 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

PATHOPHYSIOLOGY

Neonatal cholestasis causes jaundice due 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, resulting in poor bile flow or excretion. In addition, there is inefficient enterohepatic circulation in the newborn period, which contributes to bilirubin accumulation.

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 biliary atresia 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
Panhypopituitarism
- Persistent hypoglycemia
- Septooptic dysplasia and optic nerve hypoplasia
- Micropenis in male infants

DIAGNOSIS

HISTORY

Pregnancy and birth history
History of consanguinity
Family history/racial background
Infectious exposure
Parenteral nutrition exposure, prolonged NPO status
Presence/absence of extrahepatic manifestations
Signs and symptoms:
- Jaundice
- Hepatomegaly
- Pale-colored/acholic stools
- Dark-colored urine
- For specific diagnoses:
  - Alagille syndrome: typical facies, murmur
  - Congenital infections: low birth weight, microcephaly, rash, chorioretinitis
  - Metabolic disorders: irritability, hypoglycemia, poor feeding, lethargy

PHYSICAL EXAM

Jaundice/scleral icterus
- Scleral icterus may not be obvious in infants if the total bilirubin is <5 mg/dL and may require a bright light in the exam room.
- Some etiologies, like PFIC, may not manifest early with jaundice.
Hepatomegaly
Splenomegaly
- May indicate portal hypertension from significant hepatic fibrosis/cirrhosis
- In younger newborns (<2 to 4 weeks of age), may suggest hemolysis or infection
Cardiac murmurs
Dysmorphic facial features with Alagille syndrome or metabolic/storage disorders
Ophthalmologic exam
- Posterior embryotoxon with Alagille syndrome
- Cataracts or chorioretinitis with “TORCH” (toxoplasmosis, other [HIV, syphilis], rubella, CMV and HSV) infections
- Cataracts with galactosemia
- Wandering eye movements with hypopituitarism
Tone for neurologic/muscular abnormalities
Extremities (arthrogryposis, lymphedema)
Genitalia (micropenis with panhypopituitarism)
Stool color
- Stool color cards and other promising equivalent tools or technologies may improve early detection of hepatobiliary disease at a low cost.
Skin rash with TORCH infections (“blueberry muffin” rash for congenital rubella); inspissation of bile from hemolytic disorders may also cause a “blueberry muffin” rash due to extramedullary hematopoiesis.

DIFFERENTIAL DIAGNOSIS

See “Etiology” section. 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: Early diagnosis is crucial.
Choledochal cyst or other obstruction of the bile duct
Infections (sepsis, disseminated intravascular coagulation [IDC], HSV, enterovirus)
Metabolic disorders (e.g., galactosemia)
Endocrine disorders (e.g., hypothyroidism, hypopituitarism)

DIAGNOSTIC TESTS & INTERPRETATION

Laboratory Evaluation

A team approach is needed to prioritize lab work with involvement of multiple subspecialties. The clinical scenario must be taken into consideration to determine which of the following are appropriate:

AST, ALT, ALP
GGT: Almost all causes of cholestasis involve elevated GGT. Few unique conditions present with low GGT—especially PFIC types 1, 2, and 4 and some BASDs. Note: Normal GGT values can be up to 200 in the 1st month of life and decline thereafter.
Prothrombin time/INR
Serum albumin
Glucose
Complete blood count (CBC)
Serologies for infectious disorders: CMV, enterovirus, hepatitis A and B, hepatitis B surface antigen, TORCH infections (toxoplasmosis, other [HIV, syphilis], rubella, CMV, HSV), Epstein-Barr virus, parvovirus B19, human herpesvirus 6, HIV, and others
Serum matrix metalloproteinase-7 (MMP-7) level may increase confidence in diagnosing EHBA when elevated.
Urine culture +/− blood culture
Serum α1-antitrypsin phenotype or mutation analysis
Genetic testing for Alagille syndrome, PFIC (types 1 to 6), or CF
Fractionated and total serum bilirubin; low bile acid concentrations are found in some BASD cases but are elevated in all other cholestatic diseases.
Serum and urine bile acids (Ursodeoxycholic acid must be discontinued for 7 days prior to urine specimen.)
Infant metabolic screen, plasma amino acids, urine organic acids, lactate/pyruvate ratio, and ammonia (if urea cycle dysfunction or liver failure are present)
Urine-reducing substances
Urine succinylacetone (for tyrosinemia)
RBC galactose-1-phosphate uridyltransferase (GALT)
Cortisol, TSH, free T₄
Fat-soluble vitamin levels: vitamin A and retinol binding protein, vitamin D, and vitamin E

Imaging

Abdominal ultrasound
- Dilated intrahepatic bile ducts indicate downstream obstruction, such as choledochal cyst, biliary duct stricture, or stones.
- Presence of gallbladder, asplenia, polysplenia, or annular pancreas
- Assessment of portal vein/hepatic artery and hepatic vein flow
Hepatobiliary scintigraphy (HIDA scan)
- Considered in infants when EHBA is suspected (after administration of phenobarbital for 5 days)
- Note: A negative HIDA scan is neither diagnostic for EHBA nor excludes EHBA due to hepatocyte uptake of technetium from hepatocellular injury. There have been case reports of positive excretion of technetium who later developed EHBA. EHBA is an evolving disease during the first few months of life. If there is a high suspicion for EHBA, consider repeating the test or proceeding with liver biopsy and/or intraoperative cholangiogram.
Magnetic resonance cholangiopancreatography (MRCP)
- May be considered to evaluate for EHBA in young infants with unclear cases in which the common bile duct is identified on HIDA scan, yet suspicion is high; negative testing does not rule out EHBA.
- May be helpful to rule out other conditions
Spinal radiograph (for butterfly vertebrae or hemivertebrae with Alagille syndrome)
Radiographs 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)
Intraoperative cholangiogram (gold standard for diagnosing EHBA)
- Close attention to contrast in the intrahepatic duct is essential in cases where Alagille syndrome is suspected due to hypoplasia of the bile duct.
Ophthalmologic exam
- Posterior embryotoxon with Alagille syndrome
- Chorioretinitis or cataracts
- Septooptic dysplasia and optic disc atrophy with panhypopituitarism
Echocardiogram (peripheral pulmonic stenosis in Alagille syndrome and others in EHBA)
Sweat chloride analysis

TREATMENT

MEDICATION

Ursodeoxycholic acid (improvement in hepatic function and absorption of fat-soluble vitamins)
Cholic or chenodeoxycholic acid for BASDs
Antihistamines or ileal bile acid transporter (IBAT) inhibitors (for pruritus associated with cholestasis—particularly with PFIC or Alagille syndrome)
Antibiotics and antivirals (when appropriate)
Vitamins A, D, E, and K (if fat-soluble vitamin deficiencies)

ISSUES FOR REFERRAL

All neonates with cholestasis require referral to a pediatric gastroenterologist for further evaluation and management. If biliary atresia or a metabolic disease is suspected, prompt referral to the appropriate subspecialist is required, such as geneticists, infectious disease specialists, endocrinologists, and/or pediatric general surgeons.

ADDITIONAL THERAPIES

Consider the need for speech therapy, occupational therapy, or physical therapy when appropriate.
Nutritional support

SURGERY/OTHER PROCEDURES

Liver biopsy
- Percutaneous route by gastroenterologist
- Open wedge by pediatric general surgeon
- Transjugular route by interventional radiologist
Intraoperative cholangiogram if EHBA is suspected.
Kasai procedure (hepatoportoenterostomy) for EHBA
Surgical referral for removal of choledochal cyst, common bile duct stones, bile duct stricture, or sclerosing cholangitis
Biliary diversion for severe pruritus associated with Alagille syndrome or PFIC
Liver transplantation
Other subspecialty consults as indicated

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS

Initial stabilization

Sepsis must be identified and treated.
Hypopituitarism may cause hypoglycemia during stress and/or a prolonged fasting period (i.e., during and after a liver biopsy or other procedures).
Evaluation for metabolic and/or genetic syndromes by metabolic or genetic specialists
Surgical intervention for obstructed common bile duct
Treatment of coagulopathy (increased INR) with vitamin K (to reduce risk of intracranial bleeding with significant cholestasis)

ONGOING CARE

DIET

Nutritional support is needed. Typically, an elemental formula with high content medium-chain triglycerides (MCTs) is better absorbed with cholestasis.
Consider need for nasogastric tube feeds.
Specialized 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
Failure to thrive, bone health, developmental delays

ADDITIONAL READING

Fawaz R , Baumann U , Ekong U , et al. Guideline for the evaluation of cholestatic jaundice in infants: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2017;64:154-168. doi:10.1097/MPG.0000000000001334 [PMID:27429428]
Selvakumar PK , Hupertz V , Mittal N , Kowdley KV , Alkhouri N . Pediatric cholestatic liver disease: successful transition of care. Cleve Clin J Med. 2019;86(7):454-464. doi:10.3949/ccjm.86a.18140 [PMID:31291179]

CODES

ICD 10

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

FAQ

Q: What history may be useful to identify cholestasis?
A: Direct observation of urine and stool color; acholic stools and dark urine suggest the presence of cholestasis and conjugated hyperbilirubinemia. Even experienced physicians often do not recognize stool color associated with biliary obstruction. Stool color cards or other promising technologies may improve early detection of hepatobiliary disease at a low cost.
Q: Does an abnormal HIDA scan always mean EHBA?
A: HIDA scans may be abnormal in obstructive causes of cholestasis other than EHBA. Surgical evaluation via an intraoperative cholangiogram is the gold standard to diagnose EHBA.
Q: Which 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.

Authors

Brett Hoskins, MD

Wikrom Karnsakul, MD