Heme is an iron-containing molecule within hemoglobin that transports oxygen and gives blood its red color. The body breaks down substances into simpler forms through a process called catabolism. Heme catabolism is the specific pathway for breaking down heme from old or damaged red blood cells. This system recycles valuable components and safely removes potentially toxic substances.
The Heme Breakdown Pathway
The journey of heme degradation begins when red blood cells, after circulating for approximately 120 days, are removed by macrophages. This process occurs primarily in the spleen, liver, and bone marrow. Within these cells, hemoglobin is broken down, separating the protein parts from the iron-containing heme group, which is toxic if allowed to accumulate.
The breakdown of the heme molecule is a two-step enzymatic process. First, the enzyme heme oxygenase acts on the heme ring, breaking it open. This reaction creates a straight-chain molecule called biliverdin, which has a green color. During this step, iron is captured by ferritin for recycling, and carbon monoxide is exhaled.
Following its formation, the green biliverdin pigment undergoes a transformation. The enzyme biliverdin reductase converts it into a yellow-orange pigment known as bilirubin. This conversion is a reduction reaction, involving the addition of electrons to the biliverdin molecule. The resulting bilirubin is the final product of this initial breakdown phase.
Bilirubin Processing in the Liver
The bilirubin produced in macrophages is called unconjugated bilirubin. This form is not water-soluble, which makes it difficult to excrete and potentially toxic at high levels. To address this, unconjugated bilirubin binds to a carrier protein in the blood called albumin, allowing it to be safely transported to the liver.
Once it arrives at the liver, bilirubin is taken up by liver cells, known as hepatocytes, where conjugation occurs. The enzyme UDP-glucuronosyltransferase attaches glucuronic acid molecules to the bilirubin. This transforms the water-insoluble unconjugated bilirubin into a water-soluble form called conjugated bilirubin.
Making bilirubin water-soluble allows it to be mixed into bile, a digestive fluid produced by the liver. The conjugated bilirubin is then secreted from the hepatocytes into the small bile ducts within the liver, becoming a component of bile.
Excretion and Final Products
Conjugated bilirubin travels with bile from the liver and gallbladder into the small intestine. As the bile and its contents move into the large intestine, the bilirubin encounters a vast population of gut bacteria. These intestinal bacteria perform the next chemical conversion.
The bacteria in the large intestine deconjugate the bilirubin and then convert it into a colorless compound called urobilinogen. A small portion of the urobilinogen is reabsorbed from the intestine back into the bloodstream. This reabsorbed urobilinogen travels to the kidneys, where it is converted into urobilin, the pigment responsible for the yellow color of urine.
The majority of urobilinogen remains within the large intestine. The gut bacteria further process this urobilinogen, converting it into a brown pigment called stercobilin. This stercobilin mixes with digested food waste and is responsible for the characteristic brown color of feces.
Clinical Significance of Heme Catabolism
Disruptions in the heme catabolism pathway can lead to a buildup of bilirubin in the blood, a condition known as hyperbilirubinemia. The most visible sign is jaundice, a yellowing of the skin and the whites of the eyes. Jaundice is not a disease but an indicator of an underlying problem with red blood cell breakdown, liver function, or bile excretion. Measuring the levels of conjugated and unconjugated bilirubin can help identify the location of the issue.
Problems occurring before the liver are termed pre-hepatic. This type of jaundice is caused by conditions that lead to a rapid destruction of red blood cells, a process called hemolysis. This increase in heme breakdown overwhelms the liver’s capacity to process bilirubin, causing unconjugated bilirubin levels in the blood to rise.
Issues within the liver itself are known as hepatic causes. Liver damage from conditions like hepatitis or cirrhosis can impair the hepatocytes’ ability to conjugate bilirubin. This reduces the liver’s efficiency, leading to a buildup of unconjugated bilirubin. In newborns, neonatal jaundice is common because their liver enzymes are not yet fully mature.
Finally, problems that occur after the bilirubin has left the liver are called post-hepatic causes. This form of jaundice results from a blockage in the bile ducts, which prevents the flow of bile from the liver to the intestine. A common cause is gallstones. This blockage causes conjugated bilirubin, already processed by the liver, to back up and leak into the bloodstream.