Recognizing an isolated hyperbilirubinemia pattern on a liver function panel

Learn how to recognize an isolated hyperbilirubinemia pattern of an abnormal liver function panel. Click here for more!
Last update26th Jan 2021

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:

  1. Overproduction of bilirubin
  2. Reduced uptake of bilirubin by the liver
  3. 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.

Figure 1. Bilirubin overproduction can be 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.

Figure 2. Reduced bilirubin uptake by the liver can be caused by heart failure, portosystemic shunts, certain 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.

Figure 3. Abnormal bilirubin conjugation can be caused by Gilbert’s syndrome, Crigler-Najjar syndrome, 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.

Table 1. Liver function testing abnormalities common with unconjugated hyperbilirubinemia.

What causes unconjugated hyperbilirubinemia?

Among the causes of unconjugated hyperbilirubinemia, there are three that are most common:

  1. Hemolytic anemia
  2. Drugs
  3. Gilbert’s syndrome

Let’s take a closer look at these conditions.

Hemolytic anemia

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.

Figure 4. Hemolytic anemia is associated with low hemoglobin levels, increased reticulocyte count, and elevated unconjugated bilirubin levels.

Drugs

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.

Figure 5. Certain medications can cause unconjugated hyperbilirubinemia including salicylates, sulphonamides, and rifampin.

Gilbert’s syndrome

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.

Figure 6. Gilbert’s syndrome is associated with mild jaundice at times of stress or infection, a positive calorie test, positive genetic testing (e.g., increased levels of unconjugated bilirubin with a low-calorie diet), and elevated unconjugated bilirubin levels.

How do we diagnose conjugated hyperbilirubinemia?

Now, let’s look at conjugated hyperbilirubinemia. In conjugated hyperbilirubinemia, conjugated and unconjugated bilirubin are both elevated.

Table 2. Liver function testing abnormalities common with conjugated hyperbilirubinemia.

Become a great clinician with our video courses and workshops

What causes conjugated hyperbilirubinemia?

Let’s discuss two possible causes of conjugated hyperbilirubinemia:

  1. Cholestasis
  2. Dubin-Johnson syndrome and Rotor's syndrome

Cholestasis

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.

Figure 7. Intrahepatic and extrahepatic cholestasis are both associated with elevated conjugated bilirubin, elevated unconjugated bilirubin, and elevated alkaline phosphatase (ALP).

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.

Figure 8. Both Dubin-Johnson syndrome and Rotor's syndrome are associated with elevated conjugated and unconjugated bilirubin levels along with normal alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels.

To conclude, let’s summarize the testing results we typically find with each condition associated with unconjugated and conjugated hyperbilirubinemia.

Table 3. Summary of testing results typical with several conditions that are associated with unconjugated and conjugated hyperbilirubinemia.

That’s it for now. If you want to improve your understanding of key concepts in medicine, and improve your clinical skills, make sure to register for a free trial account, which will give you access to free videos and downloads. We’ll help you make the right decisions for yourself and your patients.

Recommended reading

  • Chalasani, N, Younossi, Z, Lavine, JE, et al. 2012. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology142: 1592–1609. PMID: 22656328
  • Fuchs, S, Bogomolski-Yahalom, V, Paltiel, O, et al. 1998. Ischemic hepatitis: clinical and laboratory observations of 34 patients. J Clin Gastroenterol26: 183–186. PMID: 9600366
  • Lok, ASF and McMahon, BJ. 2007. Chronic hepatitis B. Hepatology45: 507–539. PMID: 17256718
  • Moussavian, SN, Becker, RC, Piepmeyer, JL, et al. 1985. Serum gamma-glutamyl transpeptidase and chronic alcoholism. Influence of alcohol ingestion and liver disease. Dig Dis Sci30: 211–214. PMID: 2857631
  • Myers, RP, Cerini, R, Sayegh, R, et al. 2003. Cardiac hepatopathy: clinical, hemodynamic, and histologic characteristics and correlations. Hepatology37: 393–400. PMID: 12540790
  • Rej, R. 1978. Aspartate aminotransferase activity and isoenzyme proportions in human liver tissues. Clin Chem24: 1971–1979. PMID: 213206
  • van de Steeg, E, Stránecký, V, Hartmannová, H, et al. 2012. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest122: 519–528. PMID: 22232210

About the author

Amer Wahed, MD FRCPath
Professor and Vice Chair (Clinical Pathology) and Associate Residency Program Director in the Department of Pathology and Laboratory Medicine at the University of Texas, Health Science Center at Houston, USA.
Author Profile

Become an expert

BMA Highly recommendedComenius EduMedia Siegel 2017
Highly commended by the British Medical Association
Awarded in the “digital” category of the BMA Book Awards - London 2017