Start Saying “Conjunctival Icterus”


A 3-day-old neonate born at 36 weeks’ gestation is being evaluated. His mother had a history of gestational diabetes. He was born vaginally, with a birthweight of 3.5 kg. He has been breastfeeding every 2 to 3 hours since discharge from the hospital 24 hours after birth. On physical examination, his weight is 3.1 kg. He has jaundice, a high-pitched cry, weak suck, and mild generalized hypotonia.

What is the most likely cause of this patient’s presentation?

Bilirubin Metabolism

  • Unconjugated bilirubin (UCB) binds albumin in the bloodstream on its way to the liver. UCB can become unbound if albumin is saturated or if it’s displaced by certain drugs (e.g., sulfa, streptomycin, CTX, ibuprofen, chloramphenicol); free bilirubin can cross the blood-brain barrier and cause CNS toxicity. 
  • Jaundice occurs because bilirubin binds elastin, which is found predominantly in the skin (including the lingual frenulum). In the eye, elastin is predominantly found in the innermost layer of the conjunctiva (the subepithelial lamina propria) and the contiguous episclera. Thus, when we see yellowing of the eyes in patients with jaundice, we should use the term “conjunctival icterus”—”scleral icterus” is a misnomer!


The DDx for hyperbilirubinemia is broad, but generally divided into indirect and direct forms. Non-pathologic forms are always indirect; pathologic forms are either indirect or direct. 

Unconjugated hyperbilirubinemia


  • Physiologic jaundice
    • Results from increased bilirubin production (more RBCs with shorter lifespan), increased hematocrit relative to body weight, and immature conjugation enzymes. 
    • Only occurs in first week of life
  • Lactation/breastfeeding failure jaundice (previously known as breastfeeding jaundice)
    • Results from caloric deprivation, leading to increased enterohepatic circulation. 
    • Typically occurs in the first week of life
  • Human milk jaundice
    • Occurs because breastmilk contains β-glucuronidase and fatty acids that inhibit conjugating enzymes. 
    • Typically occurs in the second week of life, but may last 3 months

Increased production of bilirubin: 

  • Hemolytic disease
    • Hemolytic disease of the fetus and newborn (HDFN), which includes ABO/Rh incompatibility
    • G6PD deficiency
    • Pyruvate kinase deficiency
    • Elliptocytosis
    • Spherocytosis
  • Birth trauma
    • Cephalohematoma
    • Excessive bruising
  • Polycythemia

Impaired conjugation: 

  • Crigler-Najjar syndrome
  • Gilbert syndrome
  • OAT-P2 polymorphism

Increased enterohepatic circulation: 

  • Intestinal obstruction

Conjugated hyperbilirubinemia 

Impaired excretion of bilirubin (i.e., cholestasis): 

  • Biliary atresia
  • Choledochal cyst
  • Dubin-Johnson syndrome
  • Rotor syndrome

Inherited disorders: 

  • Alagille syndrome
  • Alpha-1 antitrypsin deficiency
  • Progressive familial intrahepatic cholestasis
  • Galactosemia
  • Tyrosinemia (type 1)

Should I say “direct” or “conjugated”? 

The words “conjugated bilirubin” and “direct bilirubin” are often used interchangeably because conjugated bilirubin (CB) can be estimated by the “direct” reaction with a diazo reagent (van den Bergh reaction); however, direct-reacting bilirubin includes both CB and the delta fraction, which represents bilirubin bound to albumin. 

In a jaundiced infant, the threshold for initiating a clinical evaluation for cholestasis is CB >1.0 mg/dL.

  • In contrast, in adults with isolated hyperbilirubinemia, up to 30% of indirect hyperbilirubinemia may be direct fraction whereas direct hyperbilirubinemia is at least 50% direct fraction. 

Bilirubin toxicity

Acute bilirubin encephalopathy is acute neurologic changes resulting from bilirubin toxicity, which has 3 general phases in neonates: 

  • First 48h: poor suck, high-pitched cry, stupor, hypotonia, seizure
  • First week: hypertonic extensors, opisthotonos, retrocollis, fever
  • After first week: hypertonia

If not corrected, hyperbilirubinemia eventually leads to bilirubin-induced neurologic dysfunction (BIND) with injuries to the basal ganglia and brainstem. BIND has 2 general phases: 

  • First year: hypotonia, tonic neck reflexes, developmental delay
  • After first year: choreoathetotic cerebral palsy, ballismus, tremor, upward gaze, dental dysplasia, sensorineural hearing loss, cognitive impairment

Kernicterus is defined as the chronic neurologic changes that result from bilirubin toxicity.

Source: Neuropathology

Risk assessment

Bilitool is a risk assessment tool based on the AAP’s 2004 revised guidelines on the prevention and management of hyperbilirubinemia in newborn infants of 35 or more weeks of gestation. The guidelines include multiple nomograms with recommendations for hour-specific treatment thresholds. On the nomogram pictured below, infants are designated as “higher risk” because of the potential negative effects of the conditions listed on albumin binding of bilirubin, the blood-brain barrier, and the susceptibility of the brain cells to damage by bilirubin.

In determining an infant’s follow-up needs and neurotoxicity risk level, it’s imperative to consider the following risk factors:

  • Hyperbilirubinemia risk factors:
    • TSB/TcB in high-risk zone
    • Jaundice in first 24 hours
    • ABO incompatibility with positive direct Coombs, known hemolytic disease, or elevated end-tidal CO
    • Gestational age of 35-36 weeks
    • Prior sibling had phototherapy
    • Cephalohematoma or bruising
    • Exclusive breastfeeding, especially with poor feeding or weight loss
  • Neurotoxicity risk factors:
    • Isoimmune hemolytic disease
    • G6PD deficiency
    • Asphyxia
    • Significant lethargy
    • Temperature instability
    • Sepsis
    • Acidosis
    • Albumin <3.0 g/dL


Phototherapy converts bilirubin into water-soluble lumirubin, which is excreted in urine or bile without conjugation. 

  • Fun facts: Bilirubin is yellow, so it is strongly absorbed by blue light at the 460-490 nm wavelength range. Sunlight also includes this wavelength range, but contains the harmful range (<400 nm) of UV light that can cause sunburn and potential for skin malignancies. Thus, unfiltered sunlight should not be used for phototherapy.  

Initiating phototherapy should be based on total bilirubin, age in hours, and the presence of risk factors, as discussed above; however, there are no guidelines for the use of phototherapy in infants <35wk gestational age.

  • Choosing Wisely Campaign: Do not initiate phototherapy in term or late preterm well-appearing infants with neonatal hyperbilirubinemia if total bilirubin is below the level at which the AAP guidelines recommend treatment. 

Expect total bilirubin to decline 0.5 mg/dL per hour over the first 4-8 hours. Discontinue phototherapy when approximately 2 mg/dl below the threshold for initiation

  • Rebound hyperbilirubinemia is rare following the discontinuation of phototherapy. 

Interestingly, phototherapy is not the most effective way to remove bilirubin rapidly. This distinction belongs to exchange transfusion, a potentially life-saving emergency procedure that is expensive, time-consuming, and requires clinical expertise because of its multiple potential complications.

  • In general, exchange transfusion is only used to treat symptomatic infants with BIND and when intensive phototherapy fails to effectively reduce total bilirubin levels in infants severe hyperbilirubinemia. 


Returning to the opening question, the most likely explanation for this neonate’s jaundice, hypotonia, and poor suck is acute bilirubin encephalopathy. 

Blog post based on Med-Peds Forum talk by Ann Ding, PGY4, and Sam Masur, PGY4

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