Indirect (unconjugated) bilirubin

Indirect (unconjugated) bilirubin is the form of bilirubin produced by haemoglobin breakdown that the liver has not yet processed. It is not measured separately, but calculated as the difference between total and direct bilirubin. The most common cause of mildly raised indirect bilirubin is harmless Gilbert’s syndrome, and less often increased red blood cell breakdown.

Who the test is for

• people whose total bilirubin is raised, to see which form predominates;
• people with mild yellowing of the whites of the eyes, particularly if intermittent or occurring after fasting, illness or exertion;
• people with suspected increased red blood cell breakdown (haemolytic anaemia) and for its monitoring;
• people whose doctor is assessing whether the result suggests Gilbert’s syndrome.

What indirect bilirubin is and what it shows

Red blood cells live for about 120 days. When they break down, haemoglobin produces bilirubin that is not water-soluble, so it travels to the liver in the blood bound to albumin. Liver cells convert it into conjugated (direct) bilirubin, which is excreted in bile.

Indirect bilirubin rises when more is produced than the liver can process, for example in haemolysis, or when the liver takes it up and processes it more slowly, as in Gilbert’s syndrome. Because it is bound to albumin, it does not pass into urine, so urinalysis does not show it.

Preparation and sample

Blood is taken from a vein, and indirect bilirubin is calculated from total and direct bilirubin measured in the same sample. Fasting is not essential for bilirubin, but if glucose, lipids or PT are being tested from the same collection, come in the morning fasting. Do not fast longer than the usual overnight fast, and avoid strenuous training the day before, because prolonged fasting, exertion and insufficient fluids can temporarily raise indirect bilirubin, particularly in Gilbert’s syndrome. Tell staff which medicines you take.

How to interpret the result

Bilirubin is expressed in micromoles per litre (µmol/L), with a method-dependent reference interval printed on the report. Indirect bilirubin makes up most total bilirubin, so it is usually the form that rises when total bilirubin is mildly raised. A doctor considers the extent of the rise, whether the indirect form predominates and whether liver enzymes and the blood count are normal.

Gilbert’s syndrome

Gilbert’s syndrome is a common inherited trait, somewhat more common in men, in which the liver processes bilirubin more slowly because of reduced enzyme activity. Indirect bilirubin is therefore mildly raised or rises intermittently, particularly after fasting or with infection, exertion, stress, lack of sleep or insufficient fluids. Mild yellowing of the whites of the eyes may then be visible.

Repeatedly mildly raised indirect bilirubin, normal direct bilirubin, normal liver enzymes and a normal blood count without signs of haemolysis suggest Gilbert’s syndrome. Genetic testing is rarely needed. Gilbert’s syndrome does not damage the liver and requires no treatment, but tell your doctor you have it because it can affect tolerance of some medicines.

Haemolysis

When red blood cells break down faster than usual, more bilirubin is produced than the liver can process. Causes may be inherited, such as hereditary spherocytosis, G6PD enzyme deficiency, thalassaemia or sickle cell anaemia, or acquired, such as autoimmune haemolytic anaemia, some medicines and infections such as malaria. Alongside raised indirect bilirubin, anaemia is then often present, with raised reticulocytes and LDH.

Other causes

• breakdown of a large bruise or bleeding into tissue;
• severe vitamin B12 or folic acid deficiency, in which immature red blood cells break down within the bone marrow;
• some medicines, such as rifampicin or certain HIV medicines;
• Crigler–Najjar syndrome, a rare and more severe inherited disorder usually detected in childhood;
• newborn jaundice, common in the first days of life and usually resolving by itself.

With liver diseases such as hepatitis and cirrhosis, and with bile duct obstruction, both bilirubin forms usually rise and direct bilirubin predominates. Raised indirect bilirubin with normal direct bilirubin and normal liver enzymes therefore rarely means liver disease.

Seek medical attention immediately if jaundice develops suddenly with marked pallor, weakness, a rapid heartbeat or dark, reddish urine, or with abdominal pain and fever.

How to arrange testing

You can have blood taken without an appointment or referral at one of our branches across Croatia (listed under Contact). Prices for all tests and panels are available in the service price list. Because indirect bilirubin is calculated, it is determined together with total and direct bilirubin from the same sample. Total bilirubin is also part of the Extended liver health panel, with direct bilirubin added separately.

Frequently asked questions

What does raised indirect bilirubin mean?

Most often Gilbert’s syndrome, particularly if the rise is mild and other results are normal. Less often, increased red blood cell breakdown is responsible, so a doctor requests a blood count, reticulocytes and LDH if needed.

Is Gilbert’s syndrome dangerous?

No. It is a harmless inherited trait that does not damage the liver or shorten life. It is only important that a doctor knows about it when prescribing certain medicines.

How can indirect bilirubin be lowered?

Gilbert’s syndrome requires no treatment. Regular meals without prolonged fasting, enough fluids and sleep, and moderation with alcohol can reduce intermittent rises. In haemolysis, the underlying cause is treated.

Can indirect bilirubin rise because of fasting or dieting?

Yes. Prolonged fasting or a very low-calorie diet temporarily raises indirect bilirubin, particularly in Gilbert’s syndrome. Do not therefore fast longer than the usual overnight fast before testing.