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 in the liver to a water-soluble derivative that helps lipid emulsification and absorption
• Direct bilirubin: conjugated bilirubin plus bilirubin that is covalently bound to albumin (delta fraction)
• Direct bilirubin is higher than a measured conjugated bilirubin and has a longer half-life.
• Conjugated hyperbilirubinemia (direct hyperbilirubinemia): a conjugated bilirubin of >1 mg/dL

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, drug-induced liver injury

DIFFERENTIAL DIAGNOSIS

• Unconjugated hyperbilirubinemia
  • Congenital/anatomic
    • Placental dysfunction/insufficiency resulting in polycythemia (e.g., infants of diabetic mothers)
    • Upper gastrointestinal (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 syndrome
    • 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
• Conjugated hyperbilirubinemia
  • Extrahepatic
    • Extrahepatic biliary atresia
    • Choledochal cysts and other abnormalities of the choledochopancreatic ductal junction
    • Compression of bile duct from mass (malignancy, adenoma, focal nodular hyperplasia, or extrahepatic mass)
    • Spontaneous perforation of the bile duct
    • Bile or mucus plug or biliary sludge
    • Choledocholithiasis
  • Infectious etiologies
    • Bacterial: gram-negative sepsis, syphilis, urinary tract infection
    • Viral: cytomegalovirus; echovirus; herpes simplex virus; rubella; Epstein-Barr virus; HIV; hepatitis A, B, C, D, E
    • Parasitic: toxoplasmosis, entamoeba histolytica
    • Other: Pneumocystis carinii, Mycobacterium avium-intracellulare
  • Toxic, environmental, drugs
    • Postshock or postasphyxia (ischemic injury to liver)
    • Drugs: Many drugs can cause cholestatic hepatitis. Common medications include acetaminophen, valproate, chlorpromazine, Amanita toxin, oral contraceptive pills (OCPs), and others. The National Institutes of Health manage an online database of medications associated with drug induced liver injury (LiverTox.NIH.gov).
    • Hyperalimentation (total parenteral nutrition)
  • Neoplastic
    • Neuroblastoma, hepatic, biliary, pancreatic, duodenal, peritoneal
    • Infiltrative processes such as hemophagocytic lymphohistiocytosis (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: tyrosinemia
    • 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 Patient

• Phase 1: Determine if hyperbilirubinemia is unconjugated or conjugated.
• Phase 2: if unconjugated hyperbilirubinemia
  • Obtain complete blood count (CBC) and red blood cell (RBC) 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.
  • Peripheral smear
• Phase 3: if conjugated hyperbilirubinemia
  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltranspeptidase (GGT)
• Prothrombin time (PT)/partial thromboplastin time (PTT)/international normalized ratio (INR)
  • Ultrasound of the liver/pancreas/gallbladder and biliary tree to evaluate for biliary obstruction or mass
  • Ensure no synthetic liver dysfunction requiring urgent evaluation for acute liver failure.
  • 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: Taking any medications including over the counter and/or supplements?
• Significance: drug-induced liver injury
• Question: Right upper quadrant pain?
• Significance: biliary obstruction
• Question: History of isolated, intermittent jaundice with stress/illness and normal transaminases?
• Significance: Gilbert syndrome
• 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: Maternal history of IV drug abuse or exposure to blood or blood products, especially prior to 1992?
• Significance: viral hepatitis

PHYSICAL EXAM

• Finding: Boggy fluid collection on newborn head not crossing suture lines?
• Significance: cephalohematoma as source of unconjugated hyperbilirubinemia
• 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
• Finding: Xanthomata?
• Significance: cholesterol deposits that can be seen in chronic liver disease

DIAGNOSTIC TESTS & INTERPRETATION

• Test: total bilirubin with fractionation into unconjugated, conjugated fractions (or direct and indirect if conjugated bilirubin unavailable)
• Significance: conjugated versus unconjugated 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: sepsis evaluation (blood and urine and spinal fluid) if clinically indicated
  • Significance: Sepsis can impair conjugation and excretion of bilirubin.
  • Test: Genetic testing for UGT1A1 mutation (if severe, persistent hyperbilirubinemia)
  • Significance: Crigler-Najjar syndrome
• If 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) if clinically indicated
  • 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: Serum α 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: percutaneous liver biopsy
  • Significance: liver pathology—can evaluate for signs of biliary atresia, drug-induced liver injury, autoimmune hepatitis, sclerosing cholangitis, mitochondrial and genetic disorders
  • 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.

GENERAL MEASURES

• Treatment largely depends on etiology of jaundice.
• Infants with physiologic jaundice above accepted thresholds should be treated with phototherapy.
• In infants with confirmed biliary atresia, Kasai portoenterostomy is performed.
• Patients with Gilbert syndrome do not require continued follow up or treatment.
• Biliary obstruction may require ERCP for stone removal or stent placement; may also require cholecystectomy if gallstones present.
• Ursodeoxycholic acid is an exogenous bile acid that can help improve cholestasis and is frequently used in children with chronic cholestasis.
• Autoimmune hepatitis in older children and teenagers is treated with immunosuppression, often azathioprine and prednisone.

ISSUES FOR REFERRAL

• Any term infant with jaundice beyond 10 to 14 days of age or preterm infant beyond 21 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.
• Any patient with synthetic liver dysfunction should be directed to the emergency department for management of acute liver failure.
• Any patient with evidence of chronic liver disease should be referred to a pediatric gastroenterologist for further workup.
• Kasai portoenterostomy is more successful in treating infants with biliary atresia if performed at <8 weeks of age (prompt referral to pediatric gastroenterology is imperative).

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS

• Admission criteria
  • Infants with physiologic jaundice above accepted threshold should be admitted for phototherapy.
  • Any infant >2 months of age with jaundice should be admitted for biliary atresia evaluation.
  • Any patient with acute liver failure should be admitted for supportive care and further evaluation.
• Nursing
  • Daily weights are important in determining fluid status in children with chronic liver disease.
• Discharge criteria
  • Infants admitted for phototherapy can be discharged once total bilirubin is steadily decreasing and below threshold. Outpatient follow-up is key to ensure no significant rebound.
  • Discharge criteria for cholestasis and liver disease will depend on the etiology.
    • Infants with newly diagnosed biliary atresia who underwent Kasai procedure will be discharged once tolerating feeds and recovered from surgery.
    • Jaundice can take up to 3 months to resolve after Kasai procedure.
    • If a patient is admitted with a biliary obstruction, they can usually be discharged after obstruction is treated (ERCP vs. operative). Some children will need to remain admitted for cholecystectomy depending on local practices.
    • Children with acute liver failure may be discharged once there is an improvement in liver function.

ICD 10

• 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