What are the causes of elevated total bilirubin without elevated Liver Function Tests (LFTs)?

From the Guidelines

Elevated total bilirubin without elevated liver function tests (LFTs) is most commonly caused by Gilbert's syndrome, a benign genetic condition affecting approximately 5-10% of the population. This condition is characterized by a deficiency in the enzyme UDP-glucuronosyltransferase, which impairs bilirubin conjugation in the liver, leading to mild unconjugated hyperbilirubinemia that often fluctuates with stress, fasting, or illness 1. Other causes of elevated total bilirubin without elevated LFTs include:

• Hemolytic disorders (such as sickle cell disease, thalassemia, or autoimmune hemolytic anemia), which cause increased bilirubin production due to accelerated red blood cell breakdown
• Ineffective erythropoiesis
• Certain medications that affect bilirubin metabolism, such as rifampin, probenecid, and atazanavir, which can compete with bilirubin for uptake or conjugation in the liver
• Crigler-Najjar syndrome, a rare condition that can also cause isolated hyperbilirubinemia

According to the most recent study 1, Gilbert's syndrome can be presumed by calculating the amount of conjugated bilirubin, which is normally less than 30% of the total bilirubin, in the absence of hemolysis. Isolated hyperbilirubinemia without other liver abnormalities generally doesn't require treatment unless it's secondary to an underlying condition. For Gilbert's syndrome, patients should be reassured about its benign nature, though they may experience mild jaundice during periods of stress or fasting.

In clinical practice, differentiating between the various potential etiologies of jaundice requires a detailed history, targeted physical examination, and pertinent laboratory studies, such as a hepatic profile, conjugated versus unconjugated bilirubinemia, and complete blood count 1. The results of these studies can help categorize the type of jaundice and guide further management.

It's worth noting that the most common causes of jaundice can vary depending on the population and geographic location, and that a thorough evaluation is necessary to determine the underlying cause of elevated total bilirubin without elevated LFTs 1. However, based on the most recent and highest quality study 1, Gilbert's syndrome is the most common cause of elevated total bilirubin without elevated LFTs, and patients with this condition can be reassured about its benign nature.

From the Research

Causes of Elevated Total Bilirubin without Elevated LFTs

• Elevated total bilirubin without elevated liver function tests (LFTs) can be caused by various conditions, including disorders of bilirubin metabolism such as Gilbert's syndrome 2.
• Gilbert's syndrome is a benign condition characterized by mildly elevated unconjugated bilirubin, which is present in approximately 5-10% of the population 2.
• Other conditions that can cause elevated total bilirubin without elevated LFTs include Crigler-Najjar syndrome, Rotor syndrome, and Dubin-Johnson syndrome 2.
• Acquired diseases such as alcoholic or non-alcoholic fatty liver disease, hepatotropic hepatitis, cirrhosis, or hepato-biliary malignancy can also cause elevated total bilirubin 2.

Diagnostic Tests for Gilbert's Syndrome

• The rifampin test can be used to diagnose Gilbert's syndrome, which involves measuring serum bilirubin levels before and after administration of rifampin 3, 4, 5.
• The test is based on the principle that rifampin increases unconjugated bilirubin levels in patients with Gilbert's syndrome 3, 4, 5.
• A shortened version of the rifampin test, which involves measuring bilirubin levels 2 hours after rifampin administration, has been proposed as a useful tool in diagnosing Gilbert's syndrome 6.

Interpretation of Rifampin Test Results

• The results of the rifampin test should be interpreted with caution, as the test is not specific for Gilbert's syndrome and can also cause an increase in unconjugated bilirubin levels in patients with chronic liver disease 3.
• The sensitivity and specificity of the rifampin test in diagnosing Gilbert's syndrome vary depending on the criteria used to interpret the results 4, 5.
• A rise in total serum bilirubin to >1.9 mg/dL after rifampin administration has been proposed as a diagnostic criterion for Gilbert's syndrome 4.
• Elevation of total serum bilirubin above 2.4 mg/dL after rifampin administration has been shown to be 93.8% sensitive and 93.3% specific for the diagnosis of Gilbert's syndrome 5.