What is the Differential Diagnosis of Direct Hyperbilirubinemia?

Patient Presentation
A 4-day-old male was transferred to a regional children’s hospital for direct hyperbilirubinemia.
The infant was full term, was discharged at 2 days of life, and returned that morning to his private medical doctor’s office for routine followup.
Mother reports that he had been breastfeeding sluggishly, was urinating well and had stools that were yellow-colored.
The past medical history showed a normal pregnancy and delivery.
The family history was negative for congenital, metabolic, or gastrointestinal abnormalities.
The review of systems was negative.
The pertinent physical exam showed a jaundiced infant with a slightly protuberant abdomen.
The vital signs and growth parameters were normal.
He was jaundiced over the entire body including the eyes and he had no prominent cutaneous abdominal vasculature.
His liver was palpable 2-3 cm below the right costal margin and there was no splenomegaly or obvious masses.
The laboratory evaluation showed a total bilirubin of 17.1 mg/dL with a direct bilirubin of 7.1 mg/dL.
The gamma-glutamyltransferase was elevated at 580 U/L (normal up to 94 U/L). Alanine aminotransferase was 46 (normal up to 35 U/L) and the aspartate aminotransferase was 87 (normal up to 35 U/L). Coagulation studies were normal.
He had a normal complete blood count, electrolytes, and neonatal screen.
Later blood and urine cultures were negative including for cytomegalovirus and toxoplasmosis.
Other testing was negative including a sweat test for cystic fibrosis, syphilis, hepatitis A and B and alpha-1-anti-trypsin levels.
The radiologic evaluation of an ultrasound of the right upper quadrant showed a small gallbladder and a normal intra and extrahepatic biliary tree, and hepatobiliary scan revealed no excretion of radiotracer into the biliary tree or bowel.
He had a liver biopsy that showed moderate to severe fibrosis with proliferation of the bile ducts that was compatible with the diagnosis of of biliary atresia.
The patient’s clinical course showed that he underwent a Kasai procedure (i.e. hepatoportal enterostomy) at 10 days of life. He had some hepatomegaly until 18 months of age which then resolved.
At 3 years of life he is doing well without hepatomegaly, jaundice or abnormal growth.

Case Image

Figure 70 – Transverse ultrasound image of the liver at
the level of the main portal vein shows the liver and intrahepatic
and extrahepatic biliary tree to be unremarkable. The gall bladder
(not shown) was small and collapsed, although the patient had been
fasting for 12 hours before the exam.

Case Image

Figure 71 – Serial images from a hepatobiliary scan
obtained up to 5 minutes after the injection of radiotracer show
prompt uptake of radiotracer by the liver but no excretion of
radiotracer into the biliary tree, gall bladder, or bowel.

Case Image

Figure 72 – Delayed image from a hepatobiliary scan
obtained at 24 hours after injection of radiotracer again fails to
show excretion of radiotracer into the biliary tree, gall bladder, or
bowel. A diagnosis of biliary atresia was therefore made.

Biliary atresia occurs in 1 in 5000 – 12,000 live births worldwide. Its cause is unknown.
Biliary atresia was universally fatal until the Kasai procedure was introduced. Liver transplantation can be used if the Kasai fails.
Patients that have surgery early (< 60 days old) and who have a lower bilirubin level after the Kasai procedure appear to have a much better long-term prognosis.

Learning Point
Direct or conjugated hyperbilirubinemia is defined as direct bilirubin > 2.0 mg/dL and is > 10% of the total bilirubin.
Age at presentation, appearing well or ill, and other associated signs such as hepatomegaly or elevated gamma-glutamyltransferase can assist in the prioritization of the differential diagnosis.

The differential diagnosis of direct hyperbilirubinemia includes:

  • Structural abnormalities
    • Alagille syndrome
    • Biliary atresia
    • Choledochal cyst
    • Gallstones
  • Genetic/Metabolic abnormalities
    • Alpha-1-anti-trypsin deficiency
    • Cystic fibrosis
    • Fructose intolerance
    • Galactosemia
    • Glycogen storage disease
    • Gaucher’s disease
    • Niemann Pick
    • Neonatal hemochromatosis
    • Porphyria
    • Tyrosinemia
    • Wolman disease
  • Infectious diseases
    • Intrauterine infection
    • Urinary tract infection
    • Sepsis
    • Adenovirus
    • Coxsackie virus
    • Cytomegalovirus
    • Hepatitis B
    • Herpes
    • Listeriosis
    • Rubella
    • Syphilis
    • Toxoplasmosis
  • Other
    • Autoimmune hepatitis
    • Bile plug syndrome
    • Dubin-Johnson syndrome
    • Rotor syndrome
    • Hypopituitarism
    • Hypothyroidism
    • Idiopathic neonatal/giant cell hepatitis
    • Total parenteral nutrition

To review the differential diagnosis of indirect or unconjugated hyperbilirubinemia see What is the Differential Diagnosis of Neonatal Unconjugated Hyperbilirubinemia?

Questions for Further Discussion
1. What evaluation should be considered in an infant with direct hyperbilirubinemia?
2. What causes chronic hepatitis in a child?
3. What are the indications for liver transplantation?

Related Cases

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

Evidence-based medicine information on this topic can be found at the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Bile Duct Diseases and 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.

Illingworth RS. Common Symptoms of Disease in Children. Blackwell Scientific Publications: Oxford. 1988:127-35.

Rudolph CD, et.al. Rudolph’s Pediatrics. 21st edit. McGraw-Hill, New York, NY. 2003:1479.

Kirk JM. Neonatal jaundice: a critical review of the role and practice of bilirubin analysis.
Ann Clin Biochem. 2008:Sep;45(Pt 5):452-62.

Roach JP, Bruny JL. Advances in the understanding and treatment of biliary atresia.
Curr Opin Pediatr. 2008:Jun;20(3):315-9.

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.
    9. Patient-focused care is provided by working with health care professionals, including those from other disciplines.

  • 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.

  • Interpersonal and Communication Skills

    19. The health professional works effectively with others as a member or leader of a health care team or other professional group.

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