Tissue stage and blood transport
Heme degradation begins in the cells of the reticuloendothelial system, predominantly in the spleen and bone marrow. The heme oxygenase system operates in the endoplasmic reticulum (ER) of these cells. With the participation of oxygen (O$_2$) and the NADPH+H$^+$ cofactor, it breaks down hemoglobin into an intermediate compound, verdoglobin, and then forms biliverdin, a green pigment. During this reaction, ferric iron ions (Fe$^{3+}$), the protein moiety (globin), carbon monoxide (CO), and the oxidized form of the coenzyme NADP$^+$ are released.
Next, the enzyme biliverdin reductase comes into play, which, using the same NADPH+H$^+$ cofactor, reduces green biliverdin to red-yellow bilirubin. The resulting pigment is toxic and extremely poorly soluble in water. To safely reach the liver, it binds in the bloodstream to a transport protein — albumin. This complex is called indirect (unconjugated) bilirubin. Due to its tight binding with the protein, it is unable to give a direct reaction with the laboratory diazo reagent.
Hepatic stage: uptake and conjugation
Upon reaching the liver via the bloodstream, indirect bilirubin is taken up by hepatocytes. This process proceeds via facilitated diffusion with the obligatory participation of special intracellular carrier proteins — ligandin and protein Z.
Inside the hepatocyte, specifically in the membranes of the endoplasmic reticulum, the pigment is detoxified. Bilirubin itself acts as the substrate, and two molecules of UDP-glucuronic acid serve as the functional group donor. The reaction is catalyzed by UDP-glucuronosyltransferase enzymes.
- UDP-glucuronosyltransferase I attaches the first molecule to form bilirubin monoglucuronide.
- UDP-glucuronosyltransferase II completes the process, forming bilirubin diglucuronide.
The final product is direct (conjugated) bilirubin, which loses its toxicity, becomes water-soluble, and is secreted into the bile via active transport. The activity of conjugation enzymes can be induced (increased) by ethanol or medications, such as phenobarbital.
Intestinal stage and excretion pathways
With the flow of bile, direct bilirubin enters the duodenum, where the final stage of its metabolism begins. Here, under the influence of intestinal microflora enzymes, glucuronic acid is cleaved off. The liberated bilirubin is reduced by bacteria to colorless tetrapyrroles — urobilinogens (specifically, stercobilinogen is formed).
The excretion of metabolites proceeds via two main pathways:
- Via feces (95%). The major part of urobilinogen moves along the large intestine. Upon contact with atmospheric oxygen, it is oxidized, turning into a brown pigment — stercobilin (urobilin), which gives feces their characteristic color. A substantial amount of pigment is excreted this way daily — from 200 to 300 mg.
- Via urine (5%). A small portion of urobilinogen is absorbed from the intestine into the portal vein system. Having passed through the liver and entered the systemic circulation, the pigment is filtered by the kidneys. In the urine, upon contact with oxygen, it is oxidized to straw-yellow urobilin, determining the normal color of urine. Only trace amounts — from 1 to 6 mg of pigment — are excreted via this pathway daily.
Briefly: answers to topical questions
What types of jaundice exist in disorders of bilirubin metabolism?
There are three main types of jaundice depending on the mechanism of development.
- Prehepatic (hemolytic) — occurs due to hyperproduction of indirect bilirubin resulting from massive erythrocyte breakdown (hemolysis).
- Hepatic (parenchymal) — develops in liver diseases accompanied by hepatocyte damage, which disrupts the uptake, conjugation, and excretion of bilirubin.
- Posthepatic (obstructive) — caused by impaired bile outflow (obstruction of the biliary tract).
How is the enterohepatic circulation of bile pigments carried out?
The enterohepatic circulation of bile pigments is the cycle of urobilinogen between the intestine and the liver. Part of the urobilinogen is absorbed from the intestine into the blood (portal vein), then enters the liver, from where it is re-secreted into the bile. Partially, urobilinogen enters the systemic circulation and is filtered by the kidneys, being excreted in the urine.
Color change of pigments: Hemoglobin (red) → Biliverdin (green) → Bilirubin (yellow-red) → Stercobilin (brown).
Class and exam questions
Why did indirect bilirubin get this name?
In the blood, this type of bilirubin is transported in a tight complex with albumin. Due to the protein shell, it cannot directly interact with the diazo reagent in laboratory tests.
Why does bilirubin need conjugation in the liver?
Free (indirect) bilirubin is toxic and insoluble in water. The addition of UDP-glucuronic acid in hepatocytes makes it water-soluble (direct) and safe, allowing the body to excrete it into the bile.
What determines the normal color of urine and feces?
The color of feces is determined by the pigment stercobilin (brown), formed during the oxidation of stercobilinogen. The color of urine is due to urobilin (straw-yellow), which is formed when filtered urobilinogen contacts oxygen.
What else to study on this topic
- Structure and functions of the heme oxygenase system
- Mechanisms of enterohepatic circulation of bile pigments
- Specificity of UDP-glucuronosyltransferase types I and II
- Induction of liver enzymes by medications
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