Enter your information to understand your indirect bilirubin levels.

The History of Indirect Bilirubin

The scientific understanding of bilirubin's two distinct forms began with 19th-century pathologist Rudolf Virchow's early chemical studies of pigments released from broken-down blood cells, work that laid the essential groundwork for later research into jaundice as a genuine chemical, rather than mysterious, phenomenon affecting the skin and eyes. The defining breakthrough came in 1913, when Dutch physician A.A. Hijmans van den Bergh discovered that a diazonium dye reagent reacted instantly with only part of the bilirubin present in a blood sample, while the remaining portion needed alcohol added first before it would react at all — he called this second, slower-reacting portion "indirect" bilirubin, a term still used in every laboratory report today, more than a century after his original careful observation was first published in the medical literature of the time.

What Indirect Bilirubin Actually Is

When red blood cells reach the end of their roughly 120-day natural lifespan and break down, the hemoglobin they once contained is converted into bilirubin, which is initially released in a form that doesn't dissolve in water at all — this raw, unprocessed form is what's called indirect bilirubin. Because it can't dissolve in blood plasma on its own, it must travel through the bloodstream tightly bound to albumin until it finally reaches the liver, where it's processed into a water-soluble form for later elimination from the body. An elevated indirect bilirubin level typically points to a problem occurring before or at that liver-processing step, most commonly either excessive red blood cell breakdown, known medically as hemolysis, or a common and usually entirely harmless inherited condition called Gilbert's syndrome, in which the liver's processing enzyme simply runs a bit slower than the average person's does.

How Indirect Bilirubin Is Measured

Indirect bilirubin isn't measured directly on its own — instead, laboratories first measure total bilirubin by adding an accelerant chemical, such as caffeine-benzoate or alcohol, which forces even the water-insoluble portion to finally react with the diazonium test reagent being used in that particular laboratory assay. They then separately measure direct bilirubin without that accelerant present, and simply subtract the direct result from the total to calculate the indirect value mathematically from those two separate numbers obtained. This subtraction-based approach, rooted directly in van den Bergh's original 1913 chemistry, remains the standard method used in clinical laboratories around the entire world today, largely unchanged in its basic underlying principle after all these years of use.

Scientists Behind the Science

A.A. Hijmans van den Bergh's 1913 diazo reaction gave physicians their very first chemical method for separating bilirubin into two clinically meaningful categories, a foundational achievement still underlying every bilirubin panel ordered anywhere in the world today. Decades earlier, in 1901, French physician Augustin Nicolas Gilbert had already described a mild, harmless hereditary condition causing intermittent jaundice, though its direct connection to reduced bilirubin-processing enzyme activity wasn't fully understood until biochemists studied the underlying liver enzyme pathway much more closely, many decades later, well into the mid-20th century and beyond that particular point in time.