Bilirubin comes in both direct and indirect form. What’s the difference, what do they mean, and how are they tested? Find the answers here.
Your bilirubin test results came back with both a total and direct value. But what is the difference between the two, and what are the normal levels of each? Read on to learn the answers to these questions and more.
What is Bilirubin?
Bilirubin is a yellow compound produced during the normal breakdown of hemoglobin, the compound in red blood cells that allows them to carry oxygen. As red blood cells are broken down, the iron-containing part of hemoglobin (heme) is converted to bilirubin .
Its yellow color is responsible for the yellow skin in jaundice .
Direct & Indirect Bilirubin
Bilirubin passes through two phases. In the first phase, bilirubin binds to albumin, which allows it to be carried from the blood and into the liver. Bilirubin in this phase is called “indirect” or “unconjugated” bilirubin .
The second phase takes place in the liver. Here, the enzyme uridine diphosphate-glucuronosyltransferase (UGT1A1) attaches sugar molecules to the unconjugated bilirubin. This transformation makes bilirubin water-soluble; it can then be excreted in bile and eliminated in the stool . Bilirubin in this second phase is called “direct” or “conjugated” bilirubin.
Total bilirubin is the sum of your direct and indirect bilirubin levels.
Benefits of Bilirubin
Bilirubin is not just a waste product. In recent decades, science has been uncovering the beneficial roles bilirubin plays in our bodies. This research indicates that bilirubin acts as a powerful antioxidant and anti-inflammatory agent that may protect us from conditions such as heart disease, diabetes, cancer, and neurodegenerative diseases [3, 4, 5, 6, 7, 8, 9, 10].
However, there is some contradictory evidence. Some suggest that whether high bilirubin is beneficial or harmful may depend upon race, age, gender, or health status. Larger, well-designed studies are needed to shed more light on the subject .
For a deeper look into the potential health benefits and risks of higher bilirubin levels, check out this post.
Bilirubin is normally measured with a blood test. A healthcare professional will collect a blood sample from your vein and send it to a lab for analysis. The test determines your total and direct bilirubin levels. Indirect bilirubin is what is left after subtracting direct bilirubin from the total .
The bilirubin test is normally included in a liver panel or a complete metabolic panel.
How to Prepare
You should not eat or drink 4 hours before the test. Discuss with your doctor whether and when you need to stop taking any medications. Also, avoid taking vitamin C before the test, as it may interfere with your results [11, 12].
Values can vary slightly between labs, but the following ranges are considered normal for adults [2, 11]:
- Total bilirubin: 0.2 to 1.2 mg/dL
- Direct (conjugated) bilirubin: less than 0.3 mg/dL
- Indirect (unconjugated) bilirubin: about 0.2 to 1.2 mg/dL
Indirect bilirubin is calculated from direct and total figures, where indirect = total minus direct bilirubin. As such, the normal range given for indirect bilirubin is generally the same or very slightly lower than for total bilirubin.
In newborns and children, the normal values are different :
- 7-14 days: less than 15.0 mg/dL
- 15 days to 17 years: up to 1.0 mg/dL
Bilirubin levels are generally higher in men than in women. According to a survey of more than 176 million people in the U.S., the average total bilirubin levels are :
- Men: 0.72 mg/dL
- Women: 0.52 mg/dL
- Overall: 0.62 mg/dL
High Bilirubin Levels
High Indirect Bilirubin Levels
A result that’s higher than normal, doesn’t necessarily mean that you have a health condition needing treatment. Your doctor will interpret your results, taking into account your medical history, symptoms, and other test results.
Indirect (unconjugated) bilirubin levels can increase due to:
- Gilbert’s syndrome. This benign syndrome is due to an inherited gene mutation that mildly increases bilirubin levels. Up to 16 % of all people have this syndrome. Bilirubin levels may spike when exposed to stress [15, 16]
- Strenuous exercise. Athletes can normally have elevated bilirubin levels [17, 18]
- Abnormal red blood cell destruction (hemolysis) 
- A reaction to blood transfusion 
- Liver diseases such as cirrhosis and fatty liver [21, 22]
- Some rare genetic disorders (e.g. Crigler-Najjar syndrome) [23, 24]
- Antiviral drug atazanavir [25, 26]
Causes listed below are commonly associated with high indirect bilirubin levels. Work with your doctor or another health care professional to get an accurate diagnosis.
High Direct Bilirubin Levels
A high direct bilirubin often means that your body has a harder time removing bilirubin, either due to a liver problem, or blocked bile ducts. However, a result that’s higher than normal, doesn’t necessarily mean that you have a health condition needing treatment. Your doctor will interpret your results, taking into account your medical history, symptoms, and other test results.
Elevated direct (conjugated) bilirubin can be caused by a number of conditions, including:
- Liver disease, such as viral or autoimmune hepatitis, or alcoholic liver disease [27, 28, 29]
- Gallstones [30, 31]
- Gallbladder inflammation or tumors [32, 33]
- Inflamed pancreas (pancreatitis) or appendix (appendicitis) [34, 35, 36]
- Some rare genetic disorders [23, 24]
Causes shown here are commonly associated with high direct bilirubin levels. Work with your doctor or another health care professional to get an accurate diagnosis.
What is Jaundice?
When bilirubin levels rise, a condition known as jaundice may develop. This is a yellow discoloration of skin and eyes due to excess bilirubin building up in these tissues. Jaundice can occur in adults when bilirubin is higher than 2.3 mg/dL .
The UGT1A1 enzyme, which converts indirect bilirubin into direct bilirubin, is well-developed in the adult liver, but not in the livers of newborns. This is why jaundice with high indirect bilirubin is common in babies .
Genetics of Bilirubin
The primary gene responsible for the breakdown of bilirubin is UGT1A1, and variations in this gene determine how fast it is broken down. In Gilbert syndrome, which affects around 10% of the population, variants in UGT1A1 make the enzyme less efficient and cause moderate increases in indirect bilirubin levels .
SLCO1B1 is a gene that controls how well the liver takes up, metabolizes, and eliminates some drugs, toxins, hormones, and other compounds, including bilirubin. Variations in SLCO1B1 affect the rate and efficiency of bilirubin conjugation and, therefore, influence your indirect bilirubin levels .
MRP2 is a gene that affects how well the liver excretes certain compounds such as direct bilirubin. Variations in this gene can reduce excretion and lead to higher direct bilirubin levels .
Bilirubin tests are usually ordered to monitor liver health. Indirect bilirubin is the unconjugated form of bilirubin in the blood. It is carried from the blood to the liver where it is conjugated to its direct form and excreted into the intestines. Indirect and direct bilirubin together make up total bilirubin. Indirect bilirubin may be too high when the liver is unable to adequately process (conjugated) bilirubin or when there is abnormal destruction of red blood cells (hemolysis). Meanwhile, direct bilirubin may be too high if the liver is unable to pass on the bilirubin after it has been conjugated.