Your bilirubin test results came back with both a total and direct value. But what is the difference between direct and indirect bilirubin, 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 [1].

Its yellow color is responsible for the yellow skin in jaundice, as well as the yellow color of urine and feces [1].

However, 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 [2, 3, 4, 5, 6, 7, 8, 9].

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 [10].

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 [10].

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

High bilirubin levels are linked with a lower incidence of many diseases and may provide increased protection against [10]:

  • Heart disease
  • Lupus
  • Fatty liver disease
  • Respiratory disease
  • Some types of cancer (colon, lung, head & neck)

What’s more, higher bilirubin levels provide other benefits, such as [10]:

  • Protection against oxidative stress
  • Improved immune response
  • Reduced mortality
  • Increased telomere length (a marker of longevity)

Limitations and Caveats

It is likely that higher bilirubin levels are beneficial for the prevention of

various diseases, but some evidence is contradictory.

Whether high bilirubin is beneficial or harmful may depend upon race, age, gender, or health status. More evidence is needed to elucidate this [10].

For a deeper look into the potential health benefits and risks of higher bilirubin levels, check out this post.

What is Jaundice?

Jaundice in Adults

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 about 2.3 mg/dL [11].

Jaundice in Newborns

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 probably why jaundice with high indirect bilirubin is common in babies [10].

Mild jaundice is not a cause for concern in the first few weeks of life. However, if bilirubin levels go over 30 mg/dL, permanent brain damage is possible [11, 10].

Interestingly, breastfeeding increases the chances of jaundice developing in babies. The high bilirubin actually protects the babies against oxidative stress, which protects them against certain diseases [10].

Bilirubin Test

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 [12].

The bilirubin test is normally included in a liver panel. Lab markers relevant to liver function include [13]:

  • Albumin
  • Total protein (TP)
  • The liver enzymes alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT)
  • Bilirubin
  • Prothrombin time (blood clotting time)

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 [12, 14].

Normal Range

Values can vary slightly between labs, but the following ranges are considered normal for adults [10, 12]:

  • 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.

Gender differences

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 [15]:

  • Men: 0.72 mg/dL
  • Women: 0.52 mg/dL
  • Overall: 0.62 mg/dL

Newborns and Children

In newborns and children, the normal values are different [16]:

  • 7-14 days: less than 15.0 mg/dL
  • 15 days to 17 years: up to 1.0 mg/dL

High Bilirubin Levels

High Indirect Bilirubin Levels

Indirect bilirubin rises if there is an unusual amount of red blood cell destruction (hemolysis). This can be the result of certain diseases, including [17, 12]:

  • Erythroblastosis fetalis
  • Hemolytic anemia
  • Hereditary spherocytosis
  • G6PD deficiency
  • Sickle cell disease
  • Hemoglobin E beta thalassemia
  • Immune system rejection of a blood transfusion

Indirect bilirubin can also increase when the liver is unable to adequately process (conjugate) bilirubin. This may occur in conditions such as [12, 18, 17]:

  • Cirrhosis (liver scarring)
  • Hepatitis (liver inflammation)
  • Genetic disorders (e.g. Gilbert syndrome, Crigler-Najjar syndrome)

High Direct Bilirubin Levels

Direct bilirubin may be too high if the liver is unable to get rid of bilirubin after conjugating it. This can happen in conditions such as [17, 12, 19]:

  • Hepatitis (liver inflammation)
  • Gallstones
  • Cancer in the pancreas or gallbladder
  • Inflammation or narrowing of the bile ducts
  • Dubin-Johnson Syndrome

Genetics of Bilirubin

UGT1A1

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 [10].

SLCO1B1

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 [17].

MRP2

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 [17].

Drugs that Increase Bilirubin

Some medications increase bilirubin either by causing liver damage or by increasing the breakdown of red blood cells (hemolysis). Certain drugs also inhibit the enzymes that conjugate bilirubin.

Drugs that Increase Indirect Bilirubin

Many medications can cause liver damage or increase hemolysis. The following is not a complete list. Check with your doctor, if in doubt [17, 20, 21].

  • Antibiotics (cephalosporins, penicillins, beta-lactamase inhibitors)
  • Methyldopa (for high blood pressure)
  • Antiarrhythmics (procainamide, quinidine)
  • Anticancer drugs (carboplatin, cisplatin, oxaliplatin, mitomycin, bleomycin, gemcitabine, Irinotecan)
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Antivirals (atazanavir, ribavirin)
  • Pyrrolizidine alkaloids (a toxic chemical found in many herbs)

Drugs that Increase Direct Bilirubin

Certain medications can cause cholestatic liver toxicity, also called stagnant liver. This condition leads to an accumulation of bile acids and direct bilirubin. Some drugs can also inhibit UGT1A1, the enzyme that conjugates bilirubin. The following is not a complete list. Check with your doctor, if in doubt [17].

  • Antibiotics (isoniazid, rifampicin, amoxicillin/clavulanic acid)
  • Phenylpropanolamine (decongestant)
  • Allopurinol (for lowering uric acid)
  • Cimetidine (reduces stomach acid)
  • Statins (fluvastatin, pravastatin, simvastatin)

Learn More

If you want to know more about how your genes affect your bilirubin levels, you can run your genetic data through SelfDecode.

Irregular Direct & Indirect Bilirubin Levels?

LabTestAnalyzer helps you make sense of your lab results and track them over time. It marks all your problematic labs and tells you how to get into the optimal range naturally. No need to do thousands of hours of research to understand your test results.

This post contains links from our sister companies, SelfDecode and LabTestAnalyzer. The proceeds from your purchase of these products are reinvested into our research and development, in order to serve you better. Thank you for your support.

Takeaway

Bilirubin tests help identify problems with the liver or red blood cells.

Indirect bilirubin is the unconjugated form of bilirubin in the blood. It is carried to the liver where it is conjugated to its direct form and excreted into the intestines. Indirect and direct bilirubin together makes up total bilirubin.

Indirect bilirubin may be too high if there is an unusual amount of red blood cell destruction (hemolysis). It can also be increased when the liver is unable to adequately process (conjugated) bilirubin. Meanwhile, direct bilirubin may be too high if the liver is unable to pass on the bilirubin after it has been conjugated.

About the Author

Jimmy Julajak, MSc

MS (Psychology)

Jimmy got his MSc from the University of Copenhagen.

Jimmy is a psychologist and researcher. He is particularly interested in the workings of the brain and strategies for improving brain health. He believes that people shouldn't hand over the responsibility for their health only to their doctors. His aim is to empower each person with easy-to-understand, science-based health knowledge.

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