Jaundice, Pediatric

Basics

Description

Jaundice: a yellow or green/yellow hue to the skin, sclerae, and mucous membranes which can be appreciated at serum bilirubin levels >2 mg/dL. Intensity of color is directly related to the serum bilirubin level.
Unconjugated bilirubin: 80% is due to hemoglobin turnover and 20% is from degradation of hepatic and renal heme proteins. It is a hydrophobic compound that must be carried to the liver by albumin for processing.
Conjugated bilirubin: conjugated to glucuronic acid in the liver, a water-soluble derivative that helps lipid emulsification and absorption
Conjugated hyperbilirubinemia (direct hyperbilirubinemia): a conjugated bilirubin of >2 mg/dL or >20% of the total bilirubin

Epidemiology

The most common causes of pathologic jaundice are as follows:

Newborn period: biliary atresia, idiopathic neonatal hepatitis,α-1-antitrypsin deficiency, infection
Older child: autoimmune hepatitis, viral hepatitis, Wilson disease, biliary obstruction

Diagnosis

Differential Diagnosis

Unconjugated hyperbilirubinemia
- Congenital/anatomic
  - Placental dysfunction/insufficiency resulting in polycythemia (e.g., infants of diabetic mothers)
  - Upper GI tract obstruction (e.g., pyloric stenosis, duodenal web, atresia)
  - Congenital hypothyroidism
- Infectious
  - Sepsis
- Trauma/delivery complications
  - Cephalohematoma/bruising
  - Delayed cord clamping, twin " twin transfusion, maternal " fetal transfusion leading to polycythemia
  - Intrauterine hypoxia (secondary to cocaine abuse, high altitude) resulting in polycythemia
  - Induction of labor with oxytocin
  - Prematurity
- Genetic/metabolic
  - Inherited red cell enzyme, membrane defects (e.g., spherocytosis, glucose-6-phosphate dehydrogenase [G6PD] deficiency, phosphokinase deficiency, elliptocytosis)
  - Hemoglobinopathies (sickle cell anemia, thalassemia)
  - Defect in hepatic bilirubin conjugation (e.g., Crigler-Najjar types I and II, Gilbert)
  - Inborn errors of metabolism
- Allergic/inflammatory/immunologic
  - Isoimmunization (ABO, Rh, Kell, other incompatibility)
- Functional
  - Physiologic jaundice
  - Breastfeeding-associated jaundice
  - Swallowed maternal blood
  - Increased bilirubin load due to infant bleeding from a clotting disorder
  - Familial benign unconjugated hyperbilirubinemia in mother and neonate (Lucey-Driscoll syndrome)
Conjugated hyperbilirubinemia
- Extrahepatic
  - Extrahepatic biliary atresia
  - Choledochal cysts and other abnormalities of the choledochopancreatic ductal junction
  - Spontaneous perforation of the bile duct
  - Bile or mucous plug or biliary sludge
  - Gallstones
- Infectious etiologies
  - Bacterial: gram-negative sepsis, urinary tract infection
  - Viral: cytomegalovirus; echovirus; herpes simplex virus; rubella; Epstein-Barr virus; HIV; hepatitis A, B, C, D, and E
  - Toxoplasmosis
  - Pneumocystis carinii
  - Entamoeba histolytica
  - Mycobacterium tuberculosis
  - Mycobacterium avium-intracellulare
  - Syphilis
- Toxic, environmental, drugs
  - Post shock or post-asphyxia (ischemic injury to liver)
  - Drugs: acetaminophen, valproate, chlorpromazine, Amanita toxin, and others
  - Hyperalimentation (total parenteral nutrition)
- Neoplastic
  - Neuroblastoma, hepatic, biliary, pancreatic, duodenal, peritoneal
  - Infiltrative processes such as HLH
  - Langerhans cell histiocytosis
- Genetic/metabolic
  - Arteriohepatic dysplasia (Alagille syndrome)
  - Progressive familial intrahepatic cholestasis (including FIC1, BSEP, and MDR3 deficiency)
  - Benign recurrent intrahepatic cholestasis
  - Defects in bile acid metabolism
  - Defects in amino acid metabolism
  - Defects in lipid metabolism: Wolman disease, Niemann-Pick disease, Gaucher disease
  - Defects in carbohydrate metabolism: galactosemia, hereditary fructose intolerance, glycogenosis type IV
  - Defects in fatty acid oxidation
  - Defects in mitochondrial DNA and respiratory chain defects
  - α-1-antitrypsin deficiency
  - Cystic fibrosis
  - Wilson disease (older children)
  - Inherited noncholestatic conjugated jaundice syndromes (e.g., Dubin-Johnson and Rotor syndrome)
  - Hereditary cholestasis with lymphedema (Aagenaes syndrome)
- Inflammatory/immunologic/endocrine:
  - Idiopathic neonatal hepatitis
  - Congenital alloimmune hepatitis
  - Idiopathic panhypopituitarism
  - Autoimmune hepatitis (children and adolescents)
  - Sclerosing cholangitis (children and adolescents, unless neonatal form)

Approach to the Patient

Phase 1: Determine if hyperbilirubinemia is unconjugated or conjugated.
Phase 2: if unconjugated hyperbilirubinemia
- Obtain CBC and indices.
- Reticulocyte count
- Coombs test: If test is positive, the diagnosis is isoimmune; if test is negative, then consider polycythemia, extravascular bleed, or RBC structural or enzyme defects.
Phase 3: if conjugated hyperbilirubinemia
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST), ³-glutamyltranspeptidase (GGT)
  - PT/PTT/international normalized ratio (INR)
- Ultrasound of the liver/pancreas/gallbladder and biliary tree
- Rule out those etiologies of conjugated hyperbilirubinemia that may adversely affect the outcome if diagnosis is delayed (biliary atresia, tyrosinemia, galactosemia, inborn error of bile acid synthesis, hereditary fructose intolerance, panhypopituitarism, and others).

History

Question: Unexplained itching?
Significance: Cholestatic liver disease (conjugated hyperbilirubinemia)
Question: History of poor school performance, change in mental status, handwriting?
Significance: Wilson disease
Question: History of other family members having prolonged jaundice, hepatic failure, or sudden death in infancy?
Significance: Suggests an underlying inborn error of metabolism such as tyrosinemia, galactosemia, or a fatty acid oxidation defect
Question: History of IV drug abuse or exposure to blood or blood products, especially prior to 1992?
Significance: The patient may have transfusion-associated hepatitis (e.g., hepatitis C).

Physical Exam

Finding: Scratch marks?
Significance: Pruritus secondary to cholestasis
Finding: Spider angioma, palmar erythema?
Significance: Chronic liver disease
Finding: Petechiae, purpura, microcephaly, thrombocytopenia?
Significance: Congenital TORCH infection
Finding: Heart murmur?
Significance: Alagille syndrome (peripheral pulmonic stenosis)
Finding: Splenomegaly?
Significance: Suggests acute hemolysis (in unconjugated hyperbilirubinemia) or chronic liver disease and portal hypertension (conjugated hyperbilirubinemia)
Finding: Ascites?
Significance: Suggests portal hypertension
Finding: Acholic stool?
Significance: Severe cholestasis or biliary obstruction

Diagnostic Tests & Interpretation

Percutaneous liver biopsies: Liver pathology " in infants with cholestasis, the most common patterns are giant cell hepatitis, bile duct proliferation, and bile duct paucity. A pattern of duct proliferation, bile plugs, portal expansion, and fibrosis suggests biliary obstruction, most likely biliary atresia.
Intraoperative cholangiogram is indicated for infants with a liver biopsy suggestive of biliary obstruction and possible biliary atresia. If the cholangiogram is consistent with biliary atresia, the surgeon will perform the Kasai portoenterostomy.
Total bilirubin with fractionation into unconjugated, conjugated, and delta fractions
Significance: Direct versus indirect hyperbilirubinemia

If unconjugated hyperbilirubinemia, investigation is initiated with the following:

Test: CBC with indices, reticulocyte count, and peripheral blood smear for RBC morphology
Significance: Polycythemia in neonate, hemolysis, or other conditions associated with increased destruction of red cells
Test: Coombs test
Significance: Isoimmune and autoimmune hemolytic anemia
Test: PT/PTT/INR, platelet count
Significance: Coagulopathy associated with hemorrhage that causes an increased bilirubin load

If neonatal conjugated hyperbilirubinemia, investigation is initiated with the following:

Test: Serum aminotransferases (ALT, AST)
Significance: Ongoing liver inflammation
Test: Alkaline phosphatase and GGT
Significance: Biliary tree obstruction, bile duct injury, or cholestasis
Test: PT/INR, PTT, serum albumin, fibrinogen
Significance: Liver synthetic function
Test: Sepsis evaluation (blood and urine and spinal fluid)
Significance: Sepsis can impair conjugation and excretion of bilirubin
Test: Free T3, T4, and thyroid-stimulating hormone
Significance: Congenital hypothyroidism
Test:α-1-Antitrypsin serum levels and PI phenotype
Significance: Serumα-1-antitrypsin levels will be low in inherited protease inhibitor deficiency.
Test: Urine dipstick for glucose and reducing substances
Significance: Positive reducing substances are seen in galactosemia and hereditary fructose intolerance.
Test: Urine for bile acid analysis
Significance: Inborn error of bile acid metabolism
Metabolic workup may be performed depending on clinical setting, including plasma amino acids, urine organic acids, succinylacetone, lactate, pyruvate, and other tests as indicated.
In an older child presenting with conjugated hyperbilirubinemia, the most common causes are biliary obstruction due to gallstones, viral hepatitis, and autoimmune hepatitis.

Imaging

Ultrasound
- A noninvasive method to examine the overall liver appearance, size, and density
- Allows for examination of the biliary tree and gallbladder to rule out choledochal cysts, sludge/stones, and ductal dilatation indicating possible obstruction
- Infants with biliary atresia/splenic malformation syndrome may have other findings including polysplenia, asplenia, and preduodenal portal vein with azygous continuation.
Hepatobiliary scintigraphy (HIDA scan): Tracer secretion into the duodenum excludes biliary atresia or extrahepatic biliary obstruction.

Treatment

General Measures

Treat Crigler-Najjar syndrome promptly with phototherapy and phenobarbital to prevent kernicterus.
Older children with Wilson disease may present with profound hemolysis and may have predominantly unconjugated hyperbilirubinemia with severe parenchymal liver disease and fulminant liver failure.

Issues for Referral

Any infant with jaundice beyond 10 " 14 days of age should have a fractionated bilirubin sent.
Any infant with conjugated hyperbilirubinemia should be referred immediately to a pediatric gastroenterologist for further workup.

Additional Reading

American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114(1):297 " 316. [View Abstract]
Brumbaugh D, Mack C. Conjugated hyperbilirubinemia in children. Pediatr Rev. 2012;33(7):291 " 302. [View Abstract]
Cohen RS, Wong RJ, Stevenson DK. Understanding neonatal jaundice: a perspective on causation. Pediatr Neonatol. 2010;51(3):143 " 148. [View Abstract]
Kelly DA, Davenport M. Current management of biliary atresia. Arch Dis Child. 2007;92(12):1132 " 1135. [View Abstract]
Mack CL, Feldman AG, Sokol RJ. Clues to the etiology of bile duct injury in biliary atresia. Semin Liver Dis. 2012;32(4):307 " 316. [View Abstract]
Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med. 2008;358(9):920 " 928. [View Abstract]
Watchko JF. Hyperbilirubinemia in African American neonates: clinical issues and current challenges. Semin Fetal Neonatal Med. 2010;15:176 " 182. [View Abstract]

Codes

ICD09

782.4 Jaundice, unspecified, not of newborn
774.6 Unspecified fetal and neonatal jaundice
774.2 Neonatal jaundice associated with preterm delivery
277.4 Disorders of bilirubin excretion
751.61 Biliary atresia

ICD10

R17 Unspecified jaundice
P59.9 Neonatal jaundice, unspecified
P59.0 Neonatal jaundice associated with preterm delivery
E80.6 Other disorders of bilirubin metabolism
Q44.2 Atresia of bile ducts

SNOMED

18165001 Jaundice (finding)
387712008 Neonatal jaundice (disorder)
73749009 Neonatal jaundice associated with preterm delivery (disorder)
9326001 Conjugated hyperbilirubinemia (disorder)
77480004 Congenital biliary atresia (disorder)

FAQ

Q: Are there any findings in neonatal jaundice that are specifically concerning?
A: These findings are concerning until proven otherwise:
- Jaundice before 36 hours of life
- Persistent jaundice beyond 10 days of life
- Serum bilirubin concentration >12 mg/dL
- Elevation of direct bilirubin >2 mg/dL or 20% of total bilirubin at any time
Q: Are there any specific factors associated with higher bilirubin levels in neonates?
A: Factors that have been associated with high serum bilirubin levels are low birth weight, certain ethnic groups (Asian, Native American, Greek), delayed meconium passage after birth, and breastfeeding. G6PD deficiency has also been associated with a higher risk of neonatal jaundice. Factors that have been associated with lower serum levels in neonates include maternal smoking and certain drugs such as phenobarbital. Of note, African American neonates have a lower risk of jaundice overall but are overrepresented in the U.S. Kernicterus Registry. This finding is due partially to a higher incidence of G6PD deficiency in males.
Q: Where does the term "jaundice " come from?
A: Jaundice is derived from the French word jaune, which means "yellow. "

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