Overview of Hyperbilirubinemia

A Biological Imbalance Characterized by Jaundice

close up of jaundiced eyes
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Hyperbilirubinemia is the accumulation of bilirubin, a brownish-yellow compound that is formed when old or damaged red blood cells are broken down. Normally, bilirubin is chemically altered by the liver so that it can be safely excreted in stool and urine. However, if your red blood cells are being broken down at an abnormally high rate or your liver isn't functioning as it should, hyperbilirubinemia can occur. In infants, this can simply be due to the body's inability to perform the task of clearing bilirubin well in the first days of life. In anyone, however, the condition may be indicative of disease.


With hyperbilirubinemia, the excessive buildup of bilirubin can manifest with the characteristic symptoms of jaundice, including:

  • Yellowing of the skin and whites of the eyes
  • Darkening of urine, sometimes to a brownish tone
  • Pale, clay-colored stools
  • Extreme fatigue
  • Loss of appetite

Complications may occur, primarily in newborns, if bilirubin levels become toxic in the brain. This can lead to a condition known as kernicterus in which seizures, irreversible brain damage, and death can occur.


There are many different reasons why hyperbilirubinemia may occur. The causes can be broadly broken down by the type of bilirubin involved.

Unconjugated bilirubin is formed by the breakdown of red blood cells. It is neither water-soluble nor able to be excreted in urine.​ ​

Conjugated bilirubin is unconjugated bilirubin that has been altered by the liver to make it water-soluble and more readily passed in urine and bile.

Common causes of hyperbilirubinemia include:

  • Hemolytic anemia in which red blood cells are rapidly destroyed, often as a result of cancer (such as leukemia or lymphoma), autoimmune diseases (like lupus), or medications (such as acetaminophen, ibuprofen, interferon, and penicillin)
  • Liver diseases that prevent bilirubin from being converted into conjugated bilirubin, including viral hepatitiscirrhosis, and non-alcoholic fatty liver disease
  • Bile duct obstruction in which bilirubin cannot be delivered to the small intestine in bile, often as a result of cirrhosis, gallstones, pancreatitis, or tumors
  • A lack of digestive bacteria in newborns which prevents the breakdown of bilirubin (neonatal hyperbilirubinemia)


Hyperbilirubinemia can be diagnosed with a blood test. The test measures the level of total bilirubin (both unconjugated and unconjugated) and direct (conjugated) bilirubin in the blood. The indirect (unconjugated) bilirubin levels can be inferred from the total and direct bilirubin values.

Although labs will often use different reference ranges, generally, for older children and adults, the following ranges are considered normal:

  • Total bilirubin: 0.3 to 1.2 milligrams per deciliter (mg/dL)
  • Direct (conjugated) bilirubin: 0 to 0.3 mg/dL

In newborns, a normal value would be an indirect (unconjugated) bilirubin of below 5.4 mg/dL within the first 24 hours of birth.

Bilirubin is often included as part of a panel of tests which evaluate liver function and enzymes, including alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT) bilirubin.

A urinalysis may also be ordered to evaluate the level of bilirubin in your urine; doing so can help narrow the possible causes.

Differential Diagnoses

If your bilirubin levels are raised, your doctor will want to identify the underlying cause. It is important to remember that hyperbilirubinemia is not a disease per se but rather a characteristic of a disease.

To this end, the doctor will need to differentiate the causes, which may be broadly classified as follows:

  • Pre-hepatic, meaning that the problem occurred before the liver, namely as the result of the rapid breakdown of red blood cells
  • Hepatic, meaning that the problem occurred in the liver
  • Post-hepatic, meaning that the problem occurred after the liver, namely as the result of bile duct obstruction

Pre-hepatic causes are differentiated by the lack of bilirubin in the urine (since unconjugated bilirubin cannot be excreted in urine). In addition to a panel of red blood cell tests, your doctor may request a bone marrow biopsy or aspiration if cancer or other serious diseases are suspected. In terms of symptoms, the spleen would likely be enlarged, while the stool and urine color would be normal.

Hepatic causes are characterized by elevated liver enzymes and evidence bilirubin in the urine. Imaging tests such as an ultrasound or X-ray may be used to see if the liver is inflamed. A liver biopsy may be recommended if there is evidence of cirrhosis or liver cancer. Spleen enlargement would be expected.

Post-hepatic causes are characterized by normal unconjugated bilirubin levels and a normal spleen. A computed tomography (CT) scan may be used to identify gallstones, while an ultrasound and stool tests may be performed to detect abnormalities of the pancreas.

In the end, there is no single test that can differentiate the underlying causes of hyperbilirubinemia. Treatment would be directed by the diagnosed condition and can range from the termination of a toxic drug to surgery and long-term chronic therapy.

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