What is the Differential Diagnosis of Neonatal Unconjugated Hyperbilirubinemia?

Patient Presentation
A 3-day-old female came to clinic with jaundice.
She was a 39 week infant born by spontaneous vaginal delivery without complications who was discharged on day 2 of life with a transcutaneous bilirubin of 10.0 mg/dL.
She had been breastfeeding well, with several stools and many voids.
The past medical history shows she was born to a G2 P2 caucasian mother with blood type B+ with normal screening maternal laboratories and no problems during pregnancy or delivery.
Birth weight was 3080 grams.
The family history was negative for hematological, gastrointestinal or genetic problems.
The review of systems was negative.
The pertinent physical exam showed her vital signs to be normal with a current weight of 2990 grams (10-25%).
She was alert and active with no distress.
She was jaundiced from her head to her upper thighs. She had scleral icterus. Her abdominal examination was normal with no hepatosplenomegaly.
The laboratory evaluation showed a total bilirubin of 17.3 mg/dL and a direct bilirubin of 0.3 mg/dL.
The diagnosis of of neonatal unconjugated hyperbilirubinemia was made and she was admitted for phototherapy.
The patient’s clinical course showed her to improve after 24 hours of phototherapy and continuation of breastfeeding. She had many voids and stools during that time also.
Her bilirubin decreased to 14.6 mg/dL with the phototherapy. Six hours after discontinuing the phototherapy, it had decreased to 13.4 mg/dL. She was discharged to home with routine followup.

Bilirubin is a metabolite of heme degradation. Heme is oxidized to biliverdin which is then reduced to bilirubin. Bilirubin is then taken up into the liver and conjugated; conjugated bilirubin is then excreted through the gastrointestinal tract. Bilirubin can also be converted by a blue light at wavelength 450 nm into a water-soluble compound called lumirubin which is then excreted through the kidneys.
Hyperbilirubinemia occurs because of an increase in hemoglobin metabolites, decreased hepatic uptake, decreased hepatic conjugation and/or decreased excretion.

Unconjugated hyperbilirubinemia in the newborn is a normal occurance.
After birth the infant must rely on its own relatively immature liver to detoxify metabolites, the infant’s gastrointestinal tract also is not yet working as well for excretion, the infant is usually slightly fluid deficient before breastfeeding and/or bottle feeding are well established, and there is increased breakdown of red blood cells as the fetus has a higher hemoglobin than an infant and thus an infant is relatively hemoconcentrated.
If the infant is also further stressed because of intrapartum or post-partum complications such as hypoxia, infection, shock or other problems, the hyperbilirubinemia can be exacerbated.

The total bilirubin rises from 1.5 mg/dL to 6.5 mg/dL (+ or – 2.5 mg/dL) over the first 3-4 days of life.
Premature infants because of the relative immaturity of the liver usually have a higher maximum bilirubin that is ~30-50% more than full-term infants.
Visible jaundice (the yellowish staining of the skin and mucous membranes) on day 1 of life or a rate of total bilirubin rising > 5.0 mg/dL/24 hours is not normal and requires evaluation.
Evaluation for a possible pathological process usually includes: total bilirubin and indirect bilirubin (looking for total amounts and elevated unconjugated hyperbilirubinemia), complete blood count with blood smear (to look for evidence of hemolysis), reticulocyte count (to look for evidence of physiological response), direct Coombs test (to look for antibodies), and blood and Rh type (to compare for blood group incompatabilities).
Other tests depending on the clinical situation may include an APT test, sepsis evaluation, Glucose-6-phosphate deficiency screening, hemoglobin electrophoresis, prothrombin time, partial thromboplastin time, and thyroid function testing.

Treatment for hyperbilirubinemia may be necessary to prevent kernicterus or the staining of the basal ganglia, hippocampus and subthalamic nucleus of the brain. This in turn causes damage to the central nervous systems with signs of hyper- and hypo-tonia, seizures, abnormal deep tendon reflexes and other reflexes, developmental delay, cranial nerve deficits and movement abnormalities.
The level of bilirubin to begin treatment depends on gestation age, chronological age in hours/days, total bilirubin level and other risk factors such as acidosis, asphyxia, hypoalbuminemia (<3.0 g/dL), Glucose-6-phosphate deficiency, isoimmune hemolytic disease, lethargy, sepsis, and temperature instability.
Infants with lower weights are also at increased risk of hyperbilirubinemia requiring treatment.
Phototherapy is used most frequently for treatment. After phototherapy is begun, total bilirubin is checked within 4-6 hours looking for a 1-2 mg/dL decline (with total amount always remaining below the threshold for exchange transfusion). Sometimes exchange transfusions are necessary if phototherapy is failing or even before a trial of phototherapy if the bilirubin is very high.

Nomograms that assist in determining hyperbilirubinemia risk and possible treatment (phototherapy or exchange transfusion) are available from the American Academy of Pediatrics (see To Learn More below).

Conjugated hyperbilirubinemia is defined as the direct bilirubin being > 2.0 mg/dL or > 10% of the total serum bilirubin.

Learning Point
Causes of unconjugated hyperbilirubinemia include:

  • Transient jaundice
    • Normal physiologic jaundice
    • Breast-feeding jaundice (usually occurs in first week of life)
    • Breast-milk jaundice (usually occurs in weeks 2-3 of life)
    • Reabsorption of extravascular blood – severe caput or cephalohematoma
    • Polycythemia – twin-to-twin transfusion
  • Gastrointestinal problems
    • Increased enterohepatic circulation secondary to intestinal obstruction
      • Cystic fibrosis
      • Hirschsprung disease
      • Ileal atresia
      • Pyloric stenosis
      • Other causes of intestinal obstruction
    • Bilirubin metabolism problems
      • Crigler-Najjar syndrome
      • Gilbert syndrome
      • Hypothyroidism
      • Hypoxia
      • Lucey-Driscoll syndrome
  • Hematological problems
    • ABO incompability
    • Rh incompatability
    • Clotting disorders
    • Autoimmune disease
    • Hemoglobinopathies
    • Microangiopathies
    • Red cell enzyme defects – Glucose-6-phosphate deficiency, pyruvate kinase deficiency
    • Red cell membrane defects – spherocytosis, elliptocytosis
  • Miscellaneous
    • Acidosis
    • Dehydration
    • Hypoalbuminemia
    • Infant of a diabetic mother
    • Medication
    • Sepsis
    • Swallowed maternal blood

Questions for Further Discussion
1. What are the advantages and disadvantages of using a transcutaneous bilimeter to measure bilirubin levels?
2. What is the differential diagnosis of conjugated hyperbilirubinemia?
3. When is supplemental breast milk, formula or intravenous fluids indicated as part of treatment for hyperbilirubinemia?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Information prescriptions for patients can be found at MedlinePlus for this topic: Jaundice and at Pediatric Common Questions, Quick Answers for this topic: Jaundice.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

Bakerman P, Strausbauch P. Bakerman’s ABC’s of Interpretive Laboratory Data. 4th edit. Interpretive Laboratory Data, Scottsdale, AZ. 2002. pp.. 92-94.

Rudolph CD, et.al. Rudolph’s Pediatrics. 21st edit. McGraw-Hill, New York, NY. 2003:164-169.

American Academy of Pediatrics Clinical Practice Guideline. Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation. Pediatrics 2004:114;297-316. Available from the Internet at: http://aappolicy.aappublications.org/cgi/content/full/pediatrics;114/1/297 (rev. July 2004, cited 2/25/08).

Robertson J, Shilkofski N. The Harriet Lane Handbook. 17th. Edit. Mosby Publications: St. Louis. 2005:314-317, 467-470.

ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effectively and demonstrates caring and respectful behaviors.
    2. Essential and accurate information about the patients’ is gathered.
    3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
    4. Patient management plans are developed and carried out.
    7. All medical and invasive procedures considered essential for the area of practice are competently performed.
    8. Health care services aimed at preventing health problems or maintaining health are provided.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
    11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.

  • Practice Based Learning and Improvement
    13. Information about other populations of patients, especially the larger population from which this patient is drawn, is obtained and used.

    nsitivity and responsiveness to patients’ culture, age, gender, and disabilities are demonstrated.

  • Systems Based Practice
    24. Cost-effective health care and resource allocation that does not compromise quality of care is practiced.

    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa Children’s Hospital

    April 21, 2008