Biliverdin and bilirubin are pigments central to the body’s recycling of red blood cells. Biliverdin is a green pigment, while bilirubin is yellow, and both are produced during the breakdown of heme—the iron-containing component of hemoglobin. This continuous process ensures that components of old cells are managed, and the levels of these pigments are indicators of how well this system is operating.
The Heme Breakdown Pathway
The journey from heme to bilirubin begins with the life cycle of red blood cells, which lasts approximately 120 days. At the end of their lifespan, these cells are removed from circulation by macrophages in the spleen, liver, and bone marrow. Inside these macrophages, hemoglobin is split into globin, a protein broken down into reusable amino acids, and heme, the iron-containing pigment.
The transformation of heme is a two-step enzymatic process. First, the enzyme heme oxygenase acts on the heme ring, breaking it open. This reaction releases iron for recycling and carbon monoxide, which is exhaled. The remaining structure is a green pigment called biliverdin. This stage is visible in the changing colors of a bruise, as the initial dark color gives way to a greenish hue.
The green biliverdin is almost immediately acted upon by a second enzyme, biliverdin reductase. This enzyme converts biliverdin into bilirubin, an orange-yellow pigment. This rapid conversion explains why the green stage of a bruise is brief, quickly transitioning to the yellow color caused by bilirubin. Approximately 4 milligrams of bilirubin per kilogram of body weight are produced daily.
The Role of the Liver and Excretion
Once produced, bilirubin is in a form known as unconjugated bilirubin. This version is not water-soluble, making it unable to travel freely in the bloodstream. To solve this, it binds to albumin, a protein in the blood plasma that transports it to the liver for processing.
The liver performs the function of making bilirubin excretable. Hepatocytes, the main cells of the liver, take up the unconjugated bilirubin from the albumin transporters. Inside the liver cells, an enzyme called glucuronyl transferase attaches glucuronic acid molecules to the bilirubin. This process, known as conjugation, transforms the bilirubin into a water-soluble form called conjugated bilirubin.
The water-soluble conjugated bilirubin is secreted from the liver as a component of bile, which flows into the small intestine. In the colon, gut bacteria convert it into colorless compounds called urobilinogen. A small portion of urobilinogen is reabsorbed and excreted by the kidneys as urobilin, which gives urine its yellow color. The rest is oxidized in the intestine to form stercobilin, the pigment that gives feces its brown color.
Clinical Significance and Jaundice
High levels of bilirubin in the blood cause jaundice, a condition marked by a yellowing of the skin and the whites of the eyes. Jaundice is not a disease but a sign of an underlying issue with bilirubin’s production, processing, or elimination. These issues trace back to three main problems: an unusually high rate of red blood cell breakdown, liver damage that impairs conjugation, or a blockage in the bile ducts that prevents excretion.
For example, conditions like hemolytic anemia cause rapid red blood cell destruction, overwhelming the liver with unconjugated bilirubin. Liver diseases like hepatitis or cirrhosis can damage hepatocytes and reduce their ability to perform conjugation. Obstructions in the biliary tract, such as from gallstones, can prevent conjugated bilirubin from flowing into the intestine.
Neonatal jaundice is a common form of this condition, affecting many newborns as their livers are not yet fully mature. A newborn’s liver cannot process bilirubin as efficiently as an adult’s, but this physiological jaundice usually resolves within a couple of weeks. For babies with very high levels, phototherapy with special blue lights helps break down bilirubin in the skin into a more easily excreted form.
Beyond Waste Products: Antioxidant Functions
For many years, biliverdin and bilirubin were viewed as metabolic waste products. However, research has uncovered that bilirubin is an effective antioxidant. Because bilirubin is fat-soluble, it can associate with cell membranes and protect lipids from oxidative damage. The body utilizes both water-soluble antioxidants, like glutathione, and lipid-soluble ones like bilirubin to protect different cellular components.
The protective mechanism involves a renewable cycle. When bilirubin neutralizes a reactive oxygen species, it becomes oxidized back into biliverdin. The enzyme biliverdin reductase then reduces the biliverdin back into bilirubin, ready to act as an antioxidant again. This recycling allows a small amount of bilirubin to have a protective effect against a much higher concentration of oxidants.
This discovery reframes the biological purpose of these pigments. The energy-intensive process of converting the water-soluble and easily excretable biliverdin into the potentially toxic bilirubin is justified by this antioxidant capability. Rather than being mere remnants of cellular breakdown, bilirubin and biliverdin are now understood to participate actively in defending the body’s cells against oxidative stress, a process linked to cellular aging and various diseases.