When interpreting the results of a liver testing panel, hepatocellular, cholestatic, or isolated hyperbilirubinemia patterns are all possible. Let’s take a closer look at the isolated hyperbilirubinemia pattern.
The hyperbilirubinemia pattern can be classified as unconjugated hyperbilirubinemia or conjugated hyperbilirubinemia. First, let’s discuss unconjugated hyperbilirubinemia.
How can unconjugated bilirubin become elevated?
There are three categories of unconjugated hyperbilirubinemia:
- Overproduction of bilirubin
- Reduced uptake of bilirubin by the liver
- Abnormal bilirubin conjugation
Overproduction of bilirubin
The first category results from the overproduction of bilirubin. This is often caused by hemolysis, dyserythropoiesis, or Wilson’s disease.
Reduced uptake of bilirubin by the liver
The second category involves reduced uptake of bilirubin by the liver. This can occur due to heart failure, portosystemic shunts, drugs (such as rifampin), or Gilbert’s syndrome.
Abnormal bilirubin conjugation
The third category involves abnormalities in bilirubin conjugation. This can be caused by Gilbert’s syndrome, Crigler-Najjar syndrome (a genetic disorder causing high levels of unconjugated bilirubin), hyperthyroidism, advanced cirrhosis, or maternal milk in neonates.
How do you diagnose unconjugated hyperbilirubinemia?
First, you’ll need to check the liver function tests. Liver disease and biliary disease are ruled out if liver enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) are normal.
What causes unconjugated hyperbilirubinemia?
Among the causes of unconjugated hyperbilirubinemia, there are three that are most common:
- Hemolytic anemia
- Gilbert’s syndrome
Let’s take a closer look at these conditions.
Individuals with hemolytic anemia have low levels of hemoglobin, increased reticulocyte count (also called polychromasia), and elevated levels of unconjugated bilirubin. A peripheral blood smear examination may be useful for this diagnosis.
Drugs such as salicylates, sulphonamides, and rifampin can competitively bind with albumin and result in unconjugated hyperbilirubinemia. Medication history is necessary to rule out any drugs that can affect bilirubin uptake.
Gilbert’s syndrome is a benign condition transmitted genetically as an autosomal dominant trait. Patients with Gilbert’s syndrome have reduced uptake and decreased conjugation of bilirubin in the liver. Patients may present with mild jaundice at times of stress such as during infection with the influenza virus.
One test that is useful for detecting Gilbert’s syndrome is the calorie test. The patient is put on a low-calorie diet for 48 hours and unconjugated bilirubin levels are measured before and after the calorie restriction. Increased levels of unconjugated bilirubin with a low-calorie diet is indicative of Gilbert’s syndrome. Genetic testing is sometimes required to confirm the diagnosis.
How do we diagnose conjugated hyperbilirubinemia?
Now, let’s look at conjugated hyperbilirubinemia. In conjugated hyperbilirubinemia, conjugated and unconjugated bilirubin are both elevated.
What causes conjugated hyperbilirubinemia?
Let’s discuss two possible causes of conjugated hyperbilirubinemia:
- Dubin-Johnson syndrome and Rotor's syndrome
Conjugated hyperbilirubinemia is most often caused by decreased bile formation or excretion associated with either intrahepatic or extrahepatic cholestasis. Cholestasis is also characterized by elevated levels of ALP, typically three times that of normal.
Dubin-Johnson syndrome and Rotor's syndrome
Rarely, conjugated hyperbilirubinemia may result from congenital defects such as Dubin-Johnson syndrome and Rotor's syndrome, which are genetic syndromes that cause defective canalicular excretion of bilirubin. In both Dubin-Johnson and Rotor's syndrome, levels of ALP as well as ALT and AST are all normal, which can help point to the presence of these rare disorders.
To conclude, let’s summarize the testing results we typically find with each condition associated with unconjugated and conjugated hyperbilirubinemia.
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