• Jaundice—a yellow or green/yellow hue to the skin, sclerae, and mucous membranes—becomes recognizable at serum total bilirubin levels of approximately 5 mg/dL (see table Common Causes of Pathologic Jaundice).
  
  
  

  Common Causes of Pathologic Jaundice

  
  
  
• Conjugated hyperbilirubinemia is defined as a direct-reacting fraction of serum bilirubin exceeding 30% to 40% of the total serum bilirubin.
• Unconjugated hyperbilirubinemia, the direct-reacting fraction is <15% of the total serum bilirubin. Patients with direct-reacting bilirubin between 15% to 30% are, therefore, indeterminate.

• Placental dysfunction
• Upper gastrointestinal (GI) tract obstruction (e.g., pyloric stenosis, duodenal web, stenosis, or atresia)
• Congenital hypothyroidism
• Infants of diabetic mothers

• Sepsis

• Cephalohematoma; bruising

• Inherited red cell enzyme or membrane structural defects (e.g., G6PD deficiency, phosphokinase deficiency, spherocytosis)
• Defect in hepatic bilirubin conjugation (Crigler-Najar syndrome, types I and II)

• Rh or ABO incompatibility

• Physiologic jaundice (almost always less than 14 days of age)
• Breast-feeding—associated jaundice
• Swallowed maternal blood; infant bleeding from clotting disorder (increased bilirubin load; see Trauma)
• Familial benign unconjugated hyperbilirubinemia (Lucey-Driscoll syndrome)

• Biliary atresia
• Biliary hypoplasia
• Congenital or acquired bile duct stenosis
• Choledochal cyst and other anomalies of the choledochopancreaticoductal junction
• Spontaneous perforation of the bile duct
• Bile or mucus plug or “biliary sludge”
• Gallstone
• Cystic dilatation of intrahepatic bile ducts (“Caroli disease”)
• Congenital hepatic fibrosis/polycystic kidney and liver disease

• Bacterial
  • Gram-negative sepsis
  • Urinary tract infection/pyelonephritis
• Viral
  • Cytomegalovirus (CMV)
  • Echovirus
  • HIV
  • Hepatitis B, C
• Toxoplasmosis
• Pneumocystis carinii
• Entamoeba histolytica
• Mycobacterium tuberculosis
• M. avium-intracellulare
• Syphilis

• Post-necrotizing enterocolitis
• Post-shock or post-asphyxia
• Medications
• Hyperalimentation

• Neuroblastoma
• Porta hepatis nodes

• Arteriohepatic dysplasia (Alagille syndrome)
• Progressive familial intrahepatic cholestasis (several types including Byler disease, MDR3 deficiency)
• Defects in bile acid metabolism
• Defects in amino acid metabolism
• Defects in lipid metabolism
  • Wolman disease (cholesterol ester storage disease)
  • Niemann-Pick disease
  • Gaucher disease
• Defects in carbohydrate metabolism
  • Galactosemia
  • Hereditary fructose intolerance
  • Glycogenosis type IV
  • Zellweger syndrome (cerebrohepatorenal)
• Defects in mitochondrial DNA and respiratory chain enzyme deficiencies
• Alpha₁-antitrypsin deficiency
• Cystic fibrosis
• Multiple acyl coenzyme A dehydrogenase deficiency
• Wilson disease (older child only)
• Inherited non-cholestatic conjugated jaundice syndromes (e.g., Dubin-Johnson and Rotor syndromes)
• Familial benign recurrent cholestasis—inborn errors of bile acid synthesis
• Hereditary cholestasis with lymphedema (Aegene syndrome)

• Sclerosing cholangitis

• Idiopathic neonatal hepatitis
• Neonatal iron storage disease
• Idiopathic hypopituitarism

Question: Does the patient have unexplained itching?
Significance: Suggests cholestatic liver disease (conjugated hyperbilirubinemia).

Question: Does the patient have a change in mental status, handwriting, or school performance?
Significance: Consider Wilson disease (generally children over 4 years of age).

Question: Is there a history of intravenous drug abuse or exposure to blood or blood products, especially prior to 1992?
Significance: The patient may have transfusion associated hepatitis, most likely hepatitis C.

Question: Is there a history of a sibling with prolonged jaundice or hepatic failure in infancy?
Significance: Because many of the causes of neonatal conjugated hyperbilirubinemia are due to recessive disorders, a sibling with prolonged neonatal jaundice, particularly if fatal and left undiagnosed, suggests an inborn error such as tyrosinemia, alpha₁-antitrypsin deficiency, etc. as the cause for the newborn patient’s jaundice.

Finding: Scratch marks
Significance: Possibly attributable to pruritus, suggesting cholestasis.

Finding: Spider angiomata, palmar erythema
Significance: Evidence of chronic liver disease.

Finding: Petechiae, purpura, microcephaly
Significance: Evidence of thrombocytopenia, possibly due to congenital TORCH infection.

Finding: Severe bruising, cephalohematoma
Significance: Increased bilirubin load.

Finding: Pallor
Significance: Indicative of severe anemia, possibly due to ongoing hemolysis as a cause of indirect hyperbilirubinemia.

Finding: Heart murmur
Significance: Alagille syndrome (classically peripheral pulmonic stenosis).

Finding: Hepatosplenomegaly
Significance: Congenital TORCH infection or of significant liver scarring and portal hypertension

Finding: Ascites
Significance: Hypoalbuminemia, generally implying significant chronic liver disease and synthetic dysfunction

Finding: Acholic stool
Significance: Severe cholestasis; in the newborn, suggestive but not pathognomic of biliary atresia; in the older child, may also suggest biliary obstruction due to a gallstone, mass, or other lesion obstructing the flow of bile.

Test: Total bilirubin with fractionation, preferably by HPLC into conjugated, unconjugated, and delta fractions (newborn or young infant).
Significance: If unconjugated hyperbilirubinemia, initiate work-up with:

Test: Serum aminotransferases (ALT, AST); GGT
Significance: Measures degree of liver inflammation and cholestasis

Test: Serum albumin, PT, PTT, fibrinogen, cholesterol
Significance: Measures degree of liver synthetic function; decrease in albumin, fibrinogen, or very low cholesterol and increases in PT, PTT implies significant liver disease.

Test: Stool color
Significance: Acholic (white) or very pale stools imply possibly obstructive lesion (such as biliary atresia).

Test: TORCH titers and VDRL
Significance: Congenital infection.

Test: Alpha₁-antitrypsin and Pi (protease inhibitor) type
Significance: Inherited homozygous deficient alleles.

Test: Sweat chloride
Significance: Cystic fibrosis.

Test: Urine and plasma amino acids and urine organic acids
Significance: Screens for inherited amino and organic acidopathies.

Test: Urine dipstick for glucose and Clinitest for reducing substances
Significance: Implying the presence of another sugar such as galactose.

Test: Urine for bile acid analysis
Significance: Assesses for inborn error of bile acid synthesis.

Test: Ultrasonography
Significance: Dilated hepatic ducts implying an obstructive lesion; presence of gallstones or a choledochal cyst.

Test: Hepatobiliary scintigraphy (DISIDA scan)
Significance: The presence of excretion of labeled tracer from the liver into the bowel effectively rules out biliary atresia; the absence of excretion does not necessarily rule in an obstructive disorder.

Test: Percutaneous liver biopsy
Significance: Allows with greater than 90% to 95% certainty the assessment of findings that may suggest extrahepatic obstruction, such as biliary atresia which merit surgical exploration and intraoperative cholangiogram.

Q: Because biliary atresia is an obstructive lesion, are the intrahepatic bile ducts dilated?
A: Never!

Q: What disorders are life-threatening?
A: Biliary atresia, galactosemia, hereditary fructose intolerance, tyrosinemia, sepsis, hypopituitarism, inborn error of bile acid metabolism, neonatal iron storage disease. In the infant with unconjugated hyperbilirubinemia, sepsis and hypothyroidism together with Crigler-Najar syndrome types I and II such as brisk hemolysis that causes a rapid rise of unconjugated bilirubin above 20 mg/dL. In the older child, suspected Wilson disease.

• Lack of excretion on hepatobiliary scintigraphy scan.
• Presence of choledochal cyst or dilated biliary ducts seen on ultrasound.
• Abnormal metabolic screen (urine and plasma, amino, or organic acids).
• Evidence of decompensated liver disease, e.g., PT >20 seconds; albumin <3.0, ascites, encephalopathy, bilirubin >20 mg/dL; ALT/AST >300, especially if associated with one or more of the previous criteria.

• Crigler-Najar type II syndrome must be treated promptly with phototherapy and phenobarbital to prevent kernicterus.
• Older children presenting with Wilson disease may present with significant hemolysis and, therefore, with a predominantly unconjugated hyperbilirubinemia but with significant parenchymal liver disease and even liver failure. Do not be fooled!

Balistreri WF. Neonatal cholestasis. J Pediatr 1985;106:171–184.

Lasker MR, Holzman R. Neonatal jaundice: when to treat, when to watch and wait. Postgrad Med 1996;99(3):187–193.

Mews C, Sinatra FR. Chronic liver disease in children. Pediatr Rev 1993;14(11):436–444.