Bilirubin is a yellowish waste product that forms naturally in the body, primarily from the breakdown of old red blood cells. When these cells reach the end of their lifespan, the heme component of their hemoglobin is converted into bilirubin. Proper removal of bilirubin is important because its accumulation can lead to various health issues. The body’s ability to efficiently process and excrete bilirubin is a continuous and complex biological process.
Bilirubin Formation and Its Forms
Bilirubin forms mainly from the breakdown of heme. Approximately 80% of daily bilirubin comes from old red blood cells, with the rest derived from other heme-containing proteins in tissues like the liver and muscles. This process occurs within specialized cells of the reticuloendothelial system, including macrophages in the spleen, bone marrow, and Kupffer cells in the liver.
The initial product formed is unconjugated bilirubin, also known as indirect bilirubin. This form is not soluble in water and is therefore unable to be directly excreted from the body. To travel through the bloodstream, unconjugated bilirubin must bind to albumin, a protein that acts as a transporter. Once it reaches the liver, it undergoes further processing to become water-soluble, which is necessary for its eventual elimination.
The liver then converts unconjugated bilirubin into conjugated bilirubin, also known as direct bilirubin. This conversion involves attaching glucuronic acid to the bilirubin molecule, making it water-soluble. Conjugated bilirubin can then be excreted more easily from the body.
The Bilirubin Excretion Pathway
The journey of bilirubin for excretion begins with its uptake by the liver. Unconjugated bilirubin, bound to albumin, is transported to the liver, where it is absorbed by liver cells. Once inside the liver cells, an enzyme called uridine 5′-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase or UGT1A1) plays a role in attaching glucuronic acid molecules to the unconjugated bilirubin. This process, known as conjugation, transforms the water-insoluble unconjugated bilirubin into water-soluble conjugated bilirubin.
Following conjugation, conjugated bilirubin is actively secreted from liver cells into the bile. This digestive fluid then carries the conjugated bilirubin through a network of bile ducts. These ducts eventually lead to the small intestine, where bile and its contents are released.
Upon reaching the small intestine, conjugated bilirubin undergoes further transformation by gut bacteria. These bacteria deconjugate the bilirubin and convert it into urobilinogen. Approximately 80% of this urobilinogen is then converted into stercobilin, which gives feces their brown color and is excreted.
A smaller fraction of urobilinogen, around 20%, is reabsorbed into the bloodstream from the intestine and returns to the liver as part of the enterohepatic circulation. While some of this reabsorbed urobilinogen is recycled by the liver, a small percentage reaches the kidneys. In the kidneys, this urobilinogen is oxidized into urobilin, a yellow pigment that colors urine and is then excreted.
When Bilirubin Excretion Goes Wrong
When the body’s bilirubin excretion pathway is disrupted, bilirubin can accumulate in the bloodstream, leading to hyperbilirubinemia. The most apparent symptom is jaundice, characterized by a yellowing of the skin, eyes, and mucous membranes. Jaundice typically becomes noticeable when bilirubin levels exceed 2 to 3 mg/dL.
Impaired bilirubin excretion can arise from issues at different stages of the process: before the liver processes bilirubin, during its processing within the liver, or after it leaves the liver. For instance, increased breakdown of red blood cells can overwhelm the liver’s capacity to process bilirubin, leading to elevated levels. Conversely, problems within the liver itself, such as impaired conjugation, can also cause bilirubin to build up.
Adults with elevated bilirubin might experience jaundice and sometimes mild symptoms like fatigue or abdominal cramps. Severe accumulation can be a sign of underlying liver disease. In newborns, who have an immature liver, bilirubin accumulation is a particular concern because unconjugated bilirubin can cross the developing blood-brain barrier. This can lead to kernicterus, a serious condition where bilirubin accumulates in brain tissue, causing irreversible neurological damage.
Addressing Impaired Bilirubin Excretion
When impaired bilirubin excretion is suspected, healthcare providers rely on blood tests to measure bilirubin levels. These tests can distinguish between unconjugated and conjugated bilirubin, which helps identify the affected stage of the excretion pathway. Liver function tests are often performed concurrently to assess liver health and function.
Management of impaired bilirubin excretion focuses on addressing the underlying cause of the buildup. For example, if the issue stems from a liver condition, treatment targets that specific disease. In cases of neonatal jaundice, a common intervention is phototherapy, exposing the infant’s skin to specific wavelengths of light. This light helps convert unconjugated bilirubin into a water-soluble form that can be excreted in the urine without further processing by the liver.
In more severe instances, such as genetic conditions like Crigler-Najjar syndrome type 1, aggressive interventions like exchange transfusions or liver transplantation may be considered to prevent severe neurological damage. For less severe inherited conditions like Gilbert syndrome, no specific treatment is often needed, as the condition is benign and may only cause mild jaundice during times of stress. Patient education regarding factors that can exacerbate bilirubin levels, such as fasting or certain medications, is also an important aspect of management.