Bilirubin is a yellowish-orange pigment that is a byproduct of the body’s constant process of recycling old cells. The form initially created is unconjugated bilirubin, which is not water-soluble. This molecule must be transformed and cleared efficiently from the body for safe excretion.
The Source of Bilirubin: Heme from Old Red Blood Cells
The starting point for bilirubin production is the breakdown of the body’s red blood cells. When these cells are destroyed, the hemoglobin they contain is released and split into the protein globin and the non-protein heme molecule. The globin portion is broken down into reusable amino acids, while the body must manage the heme component. Roughly 80% of all bilirubin produced daily originates from this ongoing breakdown. The remaining bilirubin comes from the turnover of other heme-containing proteins found throughout the body, such as myoglobin and various enzymes.
The Primary Site of Unconjugated Bilirubin Formation
The process of converting heme into unconjugated bilirubin takes place within specialized cells of the Reticuloendothelial System (RES). These cells are macrophages whose primary function is to engulf and recycle old or damaged blood cells. The major sites where these macrophages are concentrated, and where most unconjugated bilirubin is formed, are the spleen, the liver (specifically the Kupffer cells), and the bone marrow.
Once inside the macrophage, the heme molecule undergoes a two-step enzymatic conversion. The first step uses the enzyme heme oxygenase to convert heme into a green pigment called biliverdin. This reaction releases iron, which is recycled, and carbon monoxide. Next, the enzyme biliverdin reductase acts on the biliverdin, reducing it to the final product: unconjugated bilirubin.
The unconjugated bilirubin formed through this process is lipid-soluble, meaning it is not soluble in water. This insolubility is why it is often referred to as “indirect” bilirubin in clinical settings. Because of its structure, this form is potentially toxic if allowed to accumulate freely in the tissues.
How Unconjugated Bilirubin Travels in the Blood
Since unconjugated bilirubin is lipid-soluble, it cannot dissolve or travel freely in the bloodstream. To be safely transported from the macrophages in the RES to the liver, it must immediately bind to a carrier molecule. This carrier is albumin, the most abundant protein found in blood plasma. The unconjugated bilirubin forms a tight but reversible bond with albumin, creating a complex that circulates safely through the body. This binding mechanism prevents the water-insoluble pigment from depositing in various tissues. The albumin-bilirubin complex is then delivered to the liver cells for its final transformation into a water-soluble, excretable form.
Health Consequences of High Unconjugated Bilirubin
An excessive buildup of bilirubin in the blood is known as hyperbilirubinemia, and its most visible symptom is jaundice, a yellow discoloration of the skin and eyes. High levels of unconjugated bilirubin can occur if red blood cells are destroyed too rapidly, a condition called hemolysis, or if the liver’s ability to process the normal load is impaired.
High unconjugated bilirubin is a particular concern in newborns. The developing brains of infants are especially vulnerable because high levels of the unbound, lipid-soluble unconjugated bilirubin can cross the blood-brain barrier. When the amount of bilirubin exceeds the binding capacity of the available albumin, the free, unbound fraction can diffuse into the central nervous system. This deposition of unconjugated bilirubin in the brain tissue can lead to a condition known as kernicterus, which causes severe and permanent neurological damage. Clinicians monitor bilirubin levels closely in newborns to prevent this complication.