Heme metabolism and bilirubin fractions
Heme breakdown occurs in macrophages. First, heme oxygenase converts heme into verdoglobin, and then into the green pigment biliverdin (releasing iron and carbon monoxide in the process). Next, the enzyme biliverdin reductase reduces it to indirect (free) bilirubin, which has a yellow-red color.
It is important to understand the biochemical differences between the fractions:
- Indirect bilirubin: is highly hydrophobic, which is why it travels in the blood only bound to albumin. Because of this binding to a large protein, it is not filtered by the kidneys. This form is extremely toxic because at high concentrations it penetrates the central nervous system and acts as an uncoupler of oxidative phosphorylation.
- Direct (conjugated) bilirubin: is formed in the endoplasmic reticulum of hepatocytes. Using the enzyme UDP-glucuronosyltransferase, UDP-glucuronic acid is attached to the molecule (forming mono- and diglucuronides). As a result, the pigment becomes hydrophilic, loses its toxicity, and is secreted into bile, or—in pathological conditions—is easily excreted in the urine.
Differential diagnosis of jaundice
Based on the mechanism of development, three groups of pathologies are distinguished. To make an accurate diagnosis, pigment levels in the blood, urine, and stool are evaluated.
- Hemolytic (suprahepatic). The cause is accelerated erythrocyte breakdown (oxidant poisoning, incompatible blood transfusion, hereditary microspherocytosis, or enzyme defects such as pyruvate kinase deficiency). The liver cannot cope with the massive influx of pigment. Blood levels of indirect bilirubin rise sharply (2–3 fold). Stool darkens due to excess stercobilin, and urine urobilin levels increase.
- Parenchymal (hepatocellular). Occurs in hepatitis of various origins, accompanied by fever and fatigue. Damaged hepatocytes take up pigment less effectively and lose the ability to excrete it into the intestine. Blood levels of direct and indirect bilirubin rise. Urine darkens because direct bilirubin is filtered by the kidneys, while stool becomes light (hypocholic).
- Obstructive (subhepatic or posthepatic). The problem lies in bile outflow due to gallstones or postoperative strictures. Direct bilirubin does not enter the intestine and returns to the bloodstream.
| Parameter | Hemolytic | Parenchymal | Obstructive |
|---|---|---|---|
| Blood (Bilirubin) | Sharp ↑ indirect | ↑ direct and indirect | ↑ direct and indirect |
| Urine color | Normal (no bilirubin) | Dark (direct bilirubin present) | «Dark beer» (direct bilirubin present) |
| Stool color | Intense (lots of stercobilin) | Light (little stercobilin) | Colorless / acholic (no stercobilin) |
Inherited jaundice
This group of pathologies is caused by genetic defects in proteins involved in intrahepatic bilirubin metabolism.
- Gilbert syndrome: impaired uptake of pigment from the blood. The problem lies in a defect of hepatocyte membrane transport proteins (ligandins) or reduced activity of UDP-glucuronosyltransferase.
- Crigler-Najjar syndrome: a severe defect in the primary structure of UDP-glucuronosyltransferase. The enzyme that conjugates bilirubin may be completely or partially absent.
- Rotor and Dubin-Johnson syndromes: excretory function is impaired. Due to a breakdown in ATP-dependent transport systems of the canalicular membrane, direct bilirubin cannot be properly secreted into bile.
Briefly: answers to topical questions
Which transport proteins are involved in the uptake of indirect bilirubin from the blood into the hepatocyte?
The transport proteins involved in the uptake of bilirubin from the blood into the hepatocyte are:
- ligandin
- protein Z
Bilirubin enters hepatocytes via the mechanism of facilitated diffusion.
How to remember the fractions: Indirect — insoluble in water, not filtered by kidneys, neurotoxic. Direct is the exact opposite.
Class and exam questions
Why does stool turn white (acholic) in obstructive jaundice?
Due to biliary tract obstruction, bile pigments do not enter the intestine at all. Consequently, stercobilin is not formed, which normally gives stool its brown color.
Can indirect bilirubin end up in the urine in severe hemolysis?
No. Indirect bilirubin circulates in the blood in a tight complex with albumin. This protein complex is too large to pass through a healthy renal filter.
What does «dark beer» urine indicate?
This is a sign of the presence of direct (water-soluble) bilirubin in the urine. This occurs in parenchymal or obstructive jaundice when the concentration of the direct fraction in the blood exceeds the renal threshold.
What else to study on this topic
- The mechanism of action of ALT and AST enzymes as markers of hepatocyte cytolysis.
- Erythrocyte glucose-6-phosphate dehydrogenase deficiencies and their link to hemolysis.
- ATP-dependent transport systems of hepatocyte membranes.
- The role of ligandin proteins in bilirubin uptake by liver cells.
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