Unconjugated Bilirubin: What High Levels Mean, Causes, Symptoms, and Treatment

Unconjugated bilirubin is one of the two main forms of bilirubin found in the blood. Unconjugated bilirubin is a yellow bile pigment produced during heme metabolism, specifically when heme from various heme proteins is broken down. Bilirubin is a yellow pigment produced when red blood cells break down. Heme proteins such as hemoglobin and myoglobin are broken down to produce bilirubin. The liver normally processes bilirubin so it can be removed from the body. Bilirubin metabolism involves the conversion of heme to biliverdin and then to bilirubin. When unconjugated bilirubin levels rise, it may signal a problem with red blood cell breakdown, bilirubin processing, or liver function. Excess bilirubin in the blood, known as hyperbilirubinemia, can result in jaundice and may indicate underlying clinical conditions related to impaired bilirubin conjugation or increased red blood cell breakdown. Abnormal bilirubin levels can indicate underlying health issues such as hemolysis, liver dysfunction, or inherited disorders, and are important for diagnosing specific conditions related to bilirubin metabolism. Plasma bilirubin levels are measured to assess bilirubin metabolism and liver function.

This guide explains what unconjugated bilirubin is, why it becomes elevated, symptoms to look for, how it is diagnosed, and what treatments may help.

What Is Unconjugated Bilirubin?

Bilirubin exists in two forms:

• Unconjugated (indirect) bilirubin: Not yet processed by the liver and not water-soluble

• Conjugated (direct) bilirubin: Processed by the liver and ready for excretion

Bilirubin uptake by the liver is a key step in the metabolic pathway that converts unconjugated to conjugated bilirubin. This process is known as hepatic uptake and is critical for effective bilirubin clearance from the bloodstream.

Unconjugated bilirubin becomes elevated when the body produces more bilirubin than the liver can process or when the liver has difficulty converting it. Impaired hepatic uptake, due to factors such as reduced liver blood flow or the effects of certain drugs, can also contribute to increased unconjugated bilirubin levels.

How Bilirubin Is Processed

The bilirubin pathway involves:

1. Old red blood cells are broken down.

2. Unconjugated bilirubin enters the bloodstream.

3. The liver converts it into conjugated bilirubin by attaching glucuronic acid to bilirubin during the conjugation process.

4. Conjugated bilirubin is excreted into bile and eliminated through stool.

During this process, bilirubin occurs in both unconjugated and conjugated forms.

The main product of conjugation is bilirubin diglucuronide, which is excreted in bile.

Any disruption in this pathway can raise bilirubin levels. Jaundice occurs when excess bilirubin accumulates in the blood, leading to yellowing of the skin and eyes. Underlying liver disease can further impair bilirubin processing and contribute to elevated bilirubin levels.

Read our guide on: How Ribbon Checkup Liver Tests Detect Early Problems.

Causes of High Unconjugated Bilirubin

High levels typically indicate either increased production of bilirubin or reduced liver processing. Increased bilirubin production, genetic disorders, and decreased conjugation are common causes of high unconjugated bilirubin. Decreased bilirubin clearance and impaired hepatic bilirubin uptake can also contribute to elevated levels. Severe unconjugated hyperbilirubinemia can have significant clinical implications, making early diagnosis and treatment essential to prevent complications.

1. Hemolysis (Increased Breakdown of Red Blood Cells)

Conditions that destroy red blood cells faster than normal cause a spike in unconjugated bilirubin.

Common causes include:

• Hemolytic anemia

• Sickle cell disease

• Thalassemia

• Autoimmune hemolytic anemia

• G6PD deficiency

• Reaction to medications

Serum bilirubin levels are measured in milligrams per deciliter (mg/dL) to assess the severity of hemolysis and hyperbilirubinemia.

2. Gilbert Syndrome (Most Common Cause)

A harmless genetic condition affecting up to 10 percent of people.

Features include:

• Mild, fluctuating elevation in unconjugated bilirubin. Mildly elevated unconjugated bilirubin is typical in Gilbert syndrome and may have possible health benefits, such as reduced cardiovascular risk.

• Jaundice during stress, fasting, dehydration, or illness

• Characterized by mild unconjugated hyperbilirubinemia and normal liver function

Normal liver function tests are typical in Gilbert syndrome, helping to distinguish it from other causes of elevated bilirubin.

Gilbert syndrome does not require treatment. Some studies suggest that mildly elevated bilirubin may be associated with a reduced risk of cardiovascular disease.

3. Liver Disorders Reduce Processing Ability

The liver may not be able to convert unconjugated bilirubin efficiently, especially in cases of liver dysfunction, which can reduce the ability to process unconjugated bilirubin.

Causes include:

• Hepatitis (viral or autoimmune)

• Alcohol-related liver disease

• Fatty liver disease (MASLD or MASH)

• Cirrhosis

Liver dysfunction is often accompanied by elevated liver enzymes such as alkaline phosphatase, which is an important marker for evaluating cholestasis and biliary obstruction.

4. Newborn Jaundice

Newborns often experience neonatal jaundice due to immature livers that cannot process bilirubin efficiently.

Physiologic jaundice is a common, mild jaundice in newborns, resulting from decreased bilirubin clearance by the immature liver. Visible jaundice typically appears when bilirubin levels exceed 2-3 mg/dL. Most cases resolve naturally, but severe cases require treatment to prevent complications. In newborns, the immature blood-brain barrier allows unconjugated bilirubin to cross into brain tissue, increasing the risk of neurological damage such as kernicterus. Maternal milk jaundice is a less common cause of prolonged jaundice in breastfed infants, related to increased enterohepatic circulation of bilirubin.

5. Medication-Related Causes

Some medications can impair bilirubin conjugation.

Examples:

• Rifampin

• Certain antivirals

• Some HIV medications

Some drugs can also affect the multidrug resistance associated protein (MRP2), impairing bilirubin excretion.

Symptoms of High Unconjugated Bilirubin

Symptoms depend on the cause and severity of the elevation.

Common symptoms include:

• Yellowing of the skin and eyes (jaundice)

• Fatigue

• Pale or slightly yellow stools

• Normal-colored urine (a key difference from conjugated bilirubin)

• Headaches or dizziness (in some cases)

In newborns, high levels may cause irritability, poor feeding, or lethargy. Severe elevations can result in bilirubin toxicity, especially in newborns, due to the accumulation of unconjugated bilirubin.

Unconjugated vs Conjugated Bilirubin: Key Differences

These differences help doctors identify the underlying cause.

Normal bilirubin levels in adults typically range from 0.1 to 1.2 mg/dL. Values above this range may indicate hyperbilirubinemia, which can signal liver dysfunction or other medical concerns.

How High Unconjugated Bilirubin Is Diagnosed

Testing typically includes: diagnosis often begins with a blood test, which requires a blood sample drawn from a vein. Routine blood testing can incidentally detect elevated bilirubin levels even in individuals without symptoms, helping with early diagnosis of underlying health conditions.

1. Blood Tests

• Total bilirubin

• Direct bilirubin

• Indirect bilirubin (calculated value)

• Liver enzyme tests (ALT, AST, ALP, GGT)

• Complete blood count (CBC)

• Reticulocyte count

Advanced testing can also measure bilirubin monoglucuronide, a water-soluble conjugate formed in the liver, to further evaluate bilirubin metabolism.

2. Additional Tests Based on Suspected Cause

• Coombs test (for autoimmune hemolysis)

• Genetic tests (for Gilbert syndrome)

• Ultrasound if liver disease is suspected

These help pinpoint whether the issue is red blood cell destruction or liver processing.

Treatment for High Unconjugated Bilirubin

Treatment depends on the cause. Some treatments focus on improving biliary excretion of bilirubin, which helps the liver process and eliminate conjugated bilirubin through the bile ducts. Treatment focuses on the underlying cause and monitoring liver health. In severe cases of congenital hyperbilirubinemia, such as Crigler-Najjar syndrome type I, liver transplantation may be considered as a curative therapy when other treatments are insufficient.

1. Hemolysis-Related Causes

Treatment may include:

• Steroids (autoimmune hemolysis)

• Changing medications

• Treating infections

• Blood transfusions (severe cases)

2. Gilbert Syndrome

No treatment is needed. Lifestyle steps can help:

• Staying hydrated

• Avoiding fasting

• Managing stress

3. Liver Disease Treatment

Manage underlying liver conditions such as:

• Hepatitis (antivirals, steroids, or immune treatment)

• Alcohol-related liver disease (alcohol cessation)

• Fatty liver disease (weight loss, diet changes, exercise)

4. Newborn Jaundice

Treatment may include:

• Phototherapy

• Increased feeding

• Exchange transfusion (rare, severe cases)

Complications and Prevention

Understanding the Main Risk: Kernicterus

• Very high bilirubin can sometimes reach the brain and cause harm. This condition is known as bilirubin encephalopathy (or kernicterus), which can lead to clinical manifestations such as hearing loss, vision problems, and movement disorders; prompt treatment is crucial to prevent permanent neurological damage.

• This can affect hearing, vision, and movement but the good news is that kernicterus is very rare when levels are checked regularly.

• Knowing this helps you stay proactive, not alarmed.

How You Can Help Prevent Problems

• Early testing is your strongest tool. Routine blood work—like liver function tests can spot issues before they become serious.

• For newborns: Their bilirubin levels are watched closely in the first days of life.

• If you’re breastfeeding and notice jaundice, you’re not alone. Sometimes simple adjustments or a quick conversation with a doctor can make a big difference.

If You’re an Adult with Higher Bilirubin

• Focusing on your liver health is key. This may mean working with your care team on medications, making supportive lifestyle changes, or—only in more advanced cases discussing transplant options.

• If hemolytic anemia is involved, treating the underlying cause helps bring bilirubin back under control.

When Elevated Bilirubin Is Genetic

• Gilbert syndrome: Usually mild and manageable. Staying aware and checking levels during illness or stress can help you feel more in control.

• Crigler-Najjar syndrome: A more serious lifelong condition, but many people manage it successfully with the right care—like light therapy, transfusions, or sometimes transplant. You don’t have to navigate it alone; your healthcare team is there to support you every step of the way.

Patient Education

Understanding unconjugated hyperbilirubinemia can help you take better care of your health and catch any issues early. This condition happens when your body has trouble processing bilirubin—a yellow substance that's normally broken down by your liver. Sometimes your body makes too much bilirubin, or your liver might have difficulty taking it up and processing it properly. When this happens, bilirubin can build up in your bloodstream. You might notice your skin or the whites of your eyes looking yellow, which is called jaundice, though this doesn't always occur.

When to Seek Medical Care

Seek evaluation if you experience:

• Persistent jaundice

• Fatigue or weakness

• Abdominal pain

• Unexplained weight loss

• Darkening of urine

• Family history of liver disease

Seek urgent care for:

• Severe jaundice

• Confusion

• Vomiting blood

• Intense abdominal pain

These symptoms may indicate serious liver or blood conditions.

The Bottom Line

Unconjugated bilirubin becomes elevated when red blood cells break down faster than normal or when the liver cannot process bilirubin efficiently. The most common causes are hemolysis, Gilbert syndrome, and liver disease.

Most cases are manageable, especially when identified early. Treatment focuses on the underlying cause and monitoring liver health.

If you notice jaundice or unexplained symptoms, a medical evaluation is important for proper diagnosis and care.

Want to check your bilirubin and liver enzyme levels from home?
You can take an at-home liver and metabolic panel test through Ribbon Checkup and get results in days.

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References

References

Aird, W. (2025, July 26). Elevated Unconjugated (Indirect) Bilirubin • The Blood Project. The Blood Project. https://www.thebloodproject.com/elevated-unconjugated-indirect-bilirubin/#:~:text=Indirect%20(unconjugated)%20hyperbilirubinemia%20occurs%20when%20there%20is,or%20decreased%20conjugation%20(as%20in%20Gilbert%20syndrome). 

Clinic, C. (2023, August 30). A bilirubin test measures bilirubin levels in your blood or in your urine. High bilirubin may indicate liver or biliary disease. Cleveland Clinic. https://my.clevelandclinic.org/health/diagnostics/17845-bilirubin 

Continental Hospitals. (2025). Continentalhospitals.com. https://continentalhospitals.com/diseases/unconjugated-hyperbilirubinemia/ 

Rossiaky, D. (2018, September 17). What Causes High Bilirubin? Healthline; Healthline Media. https://www.healthline.com/health/high-bilirubin 

Singh, A., Thoyaja Koritala, & Ishwarlal Jialal. (2023, February 20). Unconjugated Hyperbilirubinemia. Nih.gov; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK549796/ 

 

 

Frequently Asked Questions

Q: What does high unconjugated bilirubin mean?

A: High unconjugated bilirubin usually indicates increased red blood cell breakdown (hemolysis), reduced liver processing, or a benign condition like Gilbert syndrome.

Q: What causes high unconjugated bilirubin?

A: Common causes include hemolytic anemia, sickle cell disease, G6PD deficiency, Gilbert syndrome, hepatitis, fatty liver disease, cirrhosis, newborn jaundice, and certain medications.

Q: What symptoms come with high unconjugated bilirubin?

A: Typical symptoms include yellowing of the skin or eyes, fatigue, normal-colored urine, and sometimes mild abdominal discomfort. In newborns, symptoms include poor feeding or irritability.

Q: How is unconjugated bilirubin different from conjugated bilirubin?

A: Unconjugated bilirubin is unprocessed, not water-soluble, and does not darken urine. Conjugated bilirubin is processed by the liver, water-soluble, and causes dark urine and pale stools when elevated.

Q: Is Gilbert syndrome dangerous?

A: No. Gilbert syndrome is harmless and causes mild, fluctuating elevations in unconjugated bilirubin often during stress, illness, dehydration, or fasting.

Q: Can high unconjugated bilirubin be treated?

A: Treatment depends on the cause. Hemolysis: medications, treating infections, or transfusions. Liver disease: treating hepatitis, stopping alcohol, weight loss for fatty liver. Gilbert syndrome: no treatment needed. Newborn jaundice: phototherapy or increased feeding.

Q: Can high unconjugated bilirubin be reversed?

A: Yes, when the underlying cause is treatable—such as infections, anemia, or reversible liver inflammation. Genetic conditions like Gilbert syndrome remain lifelong but harmless.

Q: When is high unconjugated bilirubin serious?

A: It is concerning when accompanied by fatigue, abdominal pain, dark urine, rapid worsening jaundice, bleeding, or symptoms of liver disease.

Q: What tests check unconjugated bilirubin?

A: Diagnosis includes total, direct, and indirect bilirubin levels, CBC, reticulocyte count, liver enzymes, Coombs test, and imaging if liver disease is suspected.

Q: When should I see a doctor?

A: Seek care for persistent jaundice, weakness, unexplained weight loss, abdominal pain, or family history of liver disease. Seek emergency care for severe jaundice, confusion, or vomiting blood.