eMedicine Specialties > Gastroenterology > Systemic Disease

Hyperbilirubinemia, Unconjugated: Differential Diagnoses & Workup

Author: Sandeep Mukherjee, MB, BCh, MPH, FRCPC, Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center
Coauthor(s): Nuri Ozden, MD, Assistant Professor, Department of Internal Medicine, Meharry Medical College
Contributor Information and Disclosures

Updated: Nov 19, 2009

Differential Diagnoses

Iron Deficiency Anemia
Pernicious Anemia
Toxicity, Lead

Other Problems to Be Considered

Increased production of bilirubin

In ineffective erythropoiesis (ELB production), a marked increase in ELB formation has been documented in diseases associated with ineffective erythropoiesis such as iron deficiency anemia, pernicious anemia, thalassemia, erythropoietic porphyria, and lead poisoning.

Neonatal jaundice, physiologic

While no specific test exists for physiologic jaundice, other causes of jaundice should be considered in infants with one or more of the following: (1) jaundice occurring within 24 hours of birth, (2) serum concentrations of unconjugated bilirubin of 11-12 mg/dL in infants who are formula-fed or 14-15 mg/dL in infants who are breastfed, (3) increased levels of conjugated bilirubin (>2 mg/dL), or (4) jaundice persisting for more than 2 weeks.

For full-term infants with no evidence of hemolysis, the American Academy of Pediatrics recommends initiating phototherapy according to a threshold for serum bilirubin that depends on the infant's age, as follows: (1) 15 mg/dL at age 25-48 hours, (2) 18 mg/dL at age 49-72 hours, and (3) 20 mg/dL at age 72 hours or older. Unfortunately, these values are not based on large prospective studies, and they may not apply to all infants. These recommendations should not be extrapolated to preterm or ill infants because of a higher risk of toxic effects in these infants. Bilirubin concentration is merely a marker of possible neurotoxic effects and should be evaluated as part of the infant's overall condition.10

The American Academy of Pediatrics has established guidelines for the diagnosis and treatment of hyperbilirubinemia in newborns. These guidelines are available through the American Academy of Pediatrics (see Management of Hyperbilirubinemia in the Healthy Term Newborn).

Neonatal jaundice, nonphysiologic

Regarding maternal serum jaundice (Lucey-Driscoll syndrome), jaundice begins earlier and is more severe compared to maternal milk jaundice.

Workup

Laboratory Studies

  • Increased production of bilirubin, ineffective erythropoiesis (ELB production) - Marked increase in fecal urobilinogen excretion and a normal or near-normal red blood cell life span
  • Impaired conjugation of bilirubin
    • Crigler-Najjar syndrome type I: Results of liver tests, except high serum unconjugated bilirubin levels, are normal. Serum bilirubin levels range from 20-50 mg/dL. Conjugated bilirubin is absent from serum, and bilirubin is not present in urine.
    • Crigler-Najjar syndrome type II (Arias syndrome): Serum bilirubin levels range from 7-20 mg/dL. This disorder may be distinguished definitively from type I by chromatographic analysis of pigments excreted in bile. In type II, bile contains significant amounts of conjugated bilirubin, although the proportion of bilirubin monoglucuronide in bile is increased.
    • Gilbert syndrome: Hyperbilirubinemia is the only serum biochemical abnormality. Serum bilirubin concentrations range from 1-5 mg/dL. Two provocative tests, energy deprivation and nicotinic acid administration, have been used. However, a significant number of false-positive and false-negative results limit the value of these tests in patients with marginal elevation of serum bilirubin concentration. A polymerase chain reaction assay has also been introduced to identify TA repeats and may be used as a screening test.

Imaging Studies

  • Impaired conjugation of bilirubin, Crigler-Najjar syndrome type I: The gallbladder is visualized using oral cholecystography despite very high serum bilirubin levels because excretion of nonglucuronidated organic anions is normal.
  • Japanese researchers have reported that patients with schizophrenia associated with Gilbert syndrome have specific changes of signal intensities on fluid-attenuated inversion-recovery magnetic resonance images. This suggests that schizophrenia with associated Gilbert syndrome may produce changes in the fronto-temporal cortex, limbic system, and basal ganglia.

Other Tests

  • Impaired conjugation of bilirubin, Crigler-Najjar syndrome type I: Bile collected through duodenal aspiration is light yellow because of small amounts of unconjugated bilirubin. Bilirubin conjugates are nearly absent from the bile.

Histologic Findings

In impaired conjugation of bilirubin, Crigler-Najjar syndrome type I, liver histology findings are normal.

More on Hyperbilirubinemia, Unconjugated

Overview: Hyperbilirubinemia, Unconjugated
Differential Diagnoses & Workup: Hyperbilirubinemia, Unconjugated
Treatment & Medication: Hyperbilirubinemia, Unconjugated
Follow-up: Hyperbilirubinemia, Unconjugated
Multimedia: Hyperbilirubinemia, Unconjugated
References
Further Reading
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References

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Keywords

unconjugated hyperbilirubinemia, hemolysis, Gilbert syndrome, jaundice, bilirubin levels, high bilirubin, bilirubin level, elevated bilirubin, serum bilirubin, acute hemolytic crisis, paroxysmal nocturnal hemoglobinuria, unconjugated bilirubin, Crigler-Najjar syndrome, Gilbert syndrome, dyserythropoietic, physiologic jaundice, breast milk jaundice

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Contributor Information and Disclosures

Author

Sandeep Mukherjee, MB, BCh, MPH, FRCPC, Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center
Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Coauthor(s)

Nuri Ozden, MD, Assistant Professor, Department of Internal Medicine, Meharry Medical College
Nuri Ozden, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy
Disclosure: Nothing to disclose.

Medical Editor

Ann Ouyang, MBBS, Professor, Department of Internal Medicine, Pennsylvania State University College of Medicine; Attending Physician, Division of Gastroenterology and Hepatology, Milton S Hershey Medical Center
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Oscar S Brann, MD, FACP, Associate Clinical Professor, Department of Medicine, University of California at San Diego; Consulting Staff, Mecklenburg Medical Group
Oscar S Brann, MD, FACP is a member of the following medical societies: American Gastroenterological Association
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

 
 
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