Jaundice

Basics
DESCRIPTION

Jaundice is derived from the French word jaune, which means yellow.

Jaundice: A yellow or green/yellow hue to the skin, sclera, and mucous membranes that can be appreciated
at serum bilirubin levels >2 mg/dL. Intensity of color is related directly 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 bilirubinof >2 mg/dL or >20% of the
total bilirubin.
ETIOLOGY

The most common causes of pathologic jaundice:

Newborn period: Biliary atresia, idiopathic neonatal hepatitis, 1-antitrypsin deficiencyinfection

Older child: Autoimmune hepatitis, viral hepatitis, Wilson disease, biliary obstruction

Diagnosis
Approach to the patient:

Step 1: Determine if the hyperbilirubinemiais unconjugated or conjugated.

Step 2: If unconjugated hyperbilirubinemia:

1. Obtain CBC and indices.
2. Reticulocyte count
3. Coombs test: If Coombs test is positive, the diagnosis is isoimmune; if Coombs test is negative, then
consider polycythemia, extravascular bleed, or RBC structural or enzyme defects.

Step 3: If conjugated hyperbilirubinemia:

1. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), -glutamyltranspeptidase (GGT)
2. PT/PTT/International normalized ratio
3. Ultrasound of the liver/pancreas/gallbladder and biliary tree
4. 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).
SIGNS AND SYMPTOMS

History

Unexplained itching: Cholestatic liver disease (conjugated hyperbilirubinemia)

History of poor school performance, change in mental status, handwriting: Wilson disease

History of other family members having prolonged jaundice, hepatic failure, or sudden death in infancy: Suggests
an underlying inborn error of metabolism such as tyrosinemia, galactosemia, or a fatty acid oxidation defect.

History of IV drug abuse or exposure to blood or blood products, especially prior to 1992: The patient may have
transfusion-associated hepatitis (e.g., hepatitis C).
Physical Exam

Scratch marks: Pruritus secondary to cholestasis

Spider angiomata, palmar erythema: Chronic liver disease

Petechiae, purpura, microcephaly, thrombocytopenia: Congenital TORCHinfection

Heart murmur: Alagille syndrome (peripheral pulmonic stenosis)

Splenomegaly: Suggests acute hemolysis (in unconjugated hyperbilirubinemia) or chronic liver disease and portal
hypertension (conjugated hyperbilirubinemia)

Ascites: Suggests portal hypertension

Acholic stool: Severe cholestasis or biliary obstruction

TESTS

LABORATORY

Total with fractionation into unconjugated, conjugated bilirubin, and delta fractions: Direct versus
indirect hyperbilirubinemia.

If unconjugated hyperbilirubinemia, investigation is initiated with:

CBC with indices, reticulocyte count, and peripheral blood smear for RBC morphology: Polycythemia in neonate,
hemolysis or other red cell evidence of increased destruction

Coombs test: Isoimmune and autoimmune hemolytic anemia

PT/PTT/International normalized ratio, platelet count: Coagulopathy associated with hemorrhage that causes an
increased bilirubin load

Sepsis evaluation (blood, urine, and spinal fluid): Sepsis can impair conjugation and excretion of bilirubin, result in
poor feeding with bile sludging and subsequent formation of gallstones.

Free T3, T4, and thyroid-stimulating hormone: Congenital hypothyroidism

Serum aminotransferases (alanine aminotransferase, aspartate aminotransferase): Ongoing liver

inflammation/destruction

Alkaline phosphatase/glutamyltranspeptidase: Biliary tree obstruction/cholestasis

Serum albumin, PT, PTT fibrinogen, cholesterol: Liver synthetic function

Stool color: Acholic (white) stools suggest biliary atresia due to the lack of bile salts in the stool.

1-Antitrypsin serum levels and Pi phenotype: Serum 1-antitrypsin levels will be low in inherited protease
inhibitor deficiency:
1. Levels can be falsely elevated due to the fact that 1-antitrypsin is an acute-phase reactant.

Urine dipstick for glucose and reducing substances: Positive reducing substances seen in galactosemia and
hereditary fructose intolerance

Urine for bile acid analysis: Inborn error of bile acid metabolism
IMAGING

Ultrasound:
1. A noninvasive method to examine the overall liver appearance, size, and density
2. Allows for examination of the biliary tree and gallbladder to rule out choledochal cysts, sludge/stones, and
ductal dilatation indicating possible obstruction

Hepatobiliary scintigraphy (HIDA scan): Tracer secretion into the duodenum excludes biliary atresia or
extrahepatic biliary obstruction
DIAGNOSTIC PROCEDURES

Percutaneous liver biopsies: Liver pathologyhepatocyte and other cell histology, fibrosis, and pathologic features
DIFFERENTIAL DIAGNOSIS

Unconjugated hyperbilirubinemia:
1. 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

2. Infectious:

Sepsis

3. Trauma/Delivery complications:

Cephalohematoma/bruising

Delayed cord clamping, twintwin transfusion, maternalfetal transfusion leading to

polycythemia

Intrauterine hypoxia (secondary to cocaine abuse, high altitude) resulting in polycythemia

Induction of labor with oxytocin

Prematurity

4. Genetic/Metabolic:

Inherited red cell enzyme, membrane defects (e.g., spherocytosis, glucose 6-phosphate
dehydrogenase deficiency, phosphokinase deficiency, elliptocytosis)

Red cell abnormalities (sickle cell anemia, thalassemia)

Defect in hepatic bilirubin conjugation (e.g., Crigler-Najjar types I and II, Gilbert)

Inborn errors of metabolism

Cystic dilation of the intrahepatic bile ducts

Congenital hepatic fibrosis/polycystic kidney and liver disease

5. Allergic/Inflammatory/Immunologic:

Isoimmunization (ABO, Rh, Kell, other incompatibility)

6. Functional:

Physiologic jaundicepeaks during the day

Breast-feedingassociated 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:
1. 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

2. Infectious etiologies:

Bacterial: Gram-negative sepsis, UTI

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

M. avium-intracellulare

Syphilis

3. Toxic/Environmental/Drugs
4. Postnecrotizing enterocolitis
5. Postshock or post-asphyxia (ischemic injury to liver)

Drugs: Acetaminophen, valproate, chlorpromazine, Amanita toxin

Hyperalimentation (total parenteral nutrition)

6. Tumor:

Neuroblastoma, hepatic, biliary, pancreatic, duodenal, peritoneal

Portal hepatis nodes

7. Genetic/Metabolic:

Arteriohepatic dysplasia (Alagille syndrome)

Progressive familial intrahepatic cholestasis (including Byler disease 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 mitochondrial DNA and respiratory chain defects

1-Antitrypsin deficiency

Cystic fibrosis

Multiple acyl coenzyme A dehydrogenase deficienc

Wilson disease (older children

Inherited noncholestatic conjugated jaundice syndromes (e.g., Dubin-Johnson and Rotor

syndrome

Hereditary cholestasis with lymphedema (Aegenaes syndrome)

8. Inflammatory/Immunologic/Endocrine:

Idiopathic neonatal hepatitis

Neonatal iron storage disease

Idiopathic hypopituitarism

Autoimmune hepatitis (children and adolescents)

Sclerosing cholangitis (children and adolescents, unless neonatal form)

Treatment
Clinical pearls:

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.

Follow-up Recommendations

DISPOSITION
FOLLOWUP-DISPOSITION-Issues-for-Referral
When to refer:

Any infant with jaundice beyond 1014 days of age should have a fractionated bilirubin sent.
1. Any infant with conjugated hyperbilirubinemia should be referred immediately to a pediatric
gastroenterologist for further workup.

Frequently Asked Questions

Q: Are there any characteristic findings in neonatal jaundice that are specifically concerning?

A: These findings are concerning until proven otherwise:

Development of 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 ethnic/social factors associated with higher bilirubin levels?

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, breast-feeding. Factors that have been
associated with lower serum levels in neonates include maternal smoking, black race, and certain drugs, such
as phenobarbital.