OFFICIAL ABP TOPIC:

Understand the differential diagnosis and evaluation of jaundice beyond the neonatal period

BACKGROUND

Jaundice refers to the yellow discoloration of the skin, sclerae, and mucous membranes caused by elevated serum bilirubin levels. It typically becomes clinically apparent when the total bilirubin concentration exceeds 2–3 mg/dL (34–51 µmol/L). While pediatricians encounter jaundice most often in neonates, it is important to be aware of the various causes of jaundice beyond the neonatal period to guide appropriate evaluation.

DIFFERENTIAL DIAGNOSIS OF JAUNDICE

Unconjugated hyperbilirubinemia results from hemolysis, impaired hepatic bilirubin uptake, or bilirubin conjugation defects. Conjugated hyperbilirubinemia (conjugated bilirubin >1 mg/dL or >20% of total bilirubin) is associated with underlying hepatocellular dysfunction, cholestasis, or biliary obstruction. Mixed hyperbilirubinemia can also occur in conditions like sickle cell disease or hemolysis with concurrent liver dysfunction.

Unconjugated Hyperbilirubinemia

• Bilirubin overproduction
  • Hemolysis (e.g., sickle cell disease, G6PD deficiency, hereditary spherocytosis)
  • Dyserythropoiesis: disordered red blood cell production (e.g., thalassemias, megaloblastic anemia)
  • Blood extravasation (e.g., trauma, hematomas, pulmonary hemorrhage)
• Impaired hepatic bilirubin uptake
  • Caused by drugs (e.g., rifampin, probenecid)
  • Reduced hepatic blood flow (e.g., heart failure, portosystemic shunts)
• Impaired bilirubin conjugation
  • Gilbert syndrome: Mild, intermittent jaundice triggered by stress or fasting; benign condition requiring no treatment
  • Crigler-Najjar syndrome:
    • Type I: Severe jaundice due to absent UDP-glucuronosyltransferase (UGT) enzyme activity
    • Type II: Partial UGT deficiency
  • Drugs that inhibit UGT: HIV protease inhibitors, ketoconazole

Conjugated Hyperbilirubinemia

• Hepatocellular injury: e.g., viral hepatitis, drug-induced liver injury, autoimmune hepatitis
• Extrahepatic cholestasis: biliary obstruction (e.g., biliary atresia, choledochal cysts, gallstones), pancreatitis
• Intrahepatic cholestasis:
  • Inherited disorders:
    • Dubin-Johnson syndrome: Black liver, impaired bilirubin excretion, elevated coproporphyrin I fraction
    • Rotor syndrome: Normal liver biopsy, elevated urinary coproporphyrins
    • Progressive familial intrahepatic cholestasis
  • Hepatitis (viral, alcoholic, autoimmune, nonalcoholic fatty liver disease)
  • Primary biliary cholangitis
  • Drugs and toxins
  • Total parenteral nutrition
  • Sepsis or systemic infection
  • Infiltrative disorders (e.g., amyloidosis, tuberculosis, sarcoidosis, malignancy)
  • End-stage liver disease

Jaundice Without Hyperbilirubinemia

Jaundice without hyperbilirubinemia is usually due to carotenemia, typically in infants and toddlers who eat a lot of orange or yellow vegetables such as carrots. In carotenemia, the sclerae are not discolored and the skin has a yellow-orange tint, more noticeable on the palms and soles.

EVALUATION OF JAUNDICE

History should include age of symptom onset, family history of jaundice, anemia, or liver disease, dietary history, including fava beans if G6PD deficiency is suspected, travel history, and exposure to medications and toxins. Dark urine and pale stools suggest impaired bilirubin excretion and biliary obstruction. Pruritus may be from cholestasis and the accumulation of bile acids.

PHYSICAL EXAM

• Skin and sclerae: Examine closely under adequate light. The palms and soles may be easier to evaluate for jaundice or pallor in patients with dark skin. Mild jaundice might only be visible in the sclerae.
• Pallor, tachycardia, and hypotension: May suggest anemia, hemolysis, or blood loss.
• Hepatomegaly or liver tenderness: Suggests hepatitis or other liver disease.
• Splenomegaly: May be due to splenic sequestration in sickle cell disease, portal hypertension, or autoimmune hemolysis.

LAB TESTING

• Measure total and fractionated bilirubin to classify hyperbilirubinemia as conjugated or unconjugated.
• If hyperbilirubinemia is unconjugated:
  • Obtain CBC, reticulocyte count, AST/ALT, and PT/PTT.
  • If evidence of hemolysis or anemia:
    • Obtain direct antiglobulin (Coombs) test and peripheral blood smear.
    • Consider testing for G6PD deficiency based on risk factors (e.g., male, African or Mediterranean descent, hemolytic episode triggered by oxidative drugs or infection).
  • If NO hemolysis or anemia:
    • Suspect Gilbert syndrome if mild elevation (<5 mg/dL) and no other lab abnormalities.
    • Consider Crigler-Najjar syndrome if marked elevation.
• If hyperbilirubinemia is conjugated: Assess for liver dysfunction with liver function tests (AST, ALT, ALP, GGT), albumin, and coagulation studies (PT, PTT, INR).
  • Isolated conjugated hyperbilirubinemia: Likely Dubin-Johnson or Rotor syndrome.
  • Hepatocellular injury: Disproportionate elevation in ALT/AST compared with ALP.
  • Cholestasis: Disproportionate elevation in ALP compared with AST/ALT.
  • Low albumin: Suggests chronic process; normal albumin suggests acute process such as viral hepatitis.
  • ALP and GGT: Elevated in biliary obstruction.

IMAGING

• Imaging is usually not needed for unconjugated hyperbilirubinemia.
• Obtain RUQ ultrasound if signs of cholestasis or liver injury are present.

ADDITIONAL TESTING

• Consider liver biopsy if the diagnosis is unclear after evaluation.
• Genetic testing: ABCC2 mutations for Dubin-Johnson syndrome, SLCO1B1/SLCO1B3 for Rotor syndrome.
• Urinary coproporphyrin analysis: Elevated coproporphyrin I fraction in Dubin-Johnson versus high total coproporphyrins in Rotor syndrome.

REFERENCES

https://www.uptodate.com/contents/evaluation-of-jaundice-caused-by-unconjugated-hyperbilirubinemia-in-children

https://www.uptodate.com/contents/classification-and-causes-of-jaundice-or-asymptomatic-hyperbilirubinemia

https://www.uptodate.com/contents/inherited-disorders-associated-with-conjugated-hyperbilirubinemia