Heme catabolism: general characteristics
The breakdown of heme occurs in the cells of the reticuloendothelial system — predominantly in the spleen, bone marrow, and liver. The reactions take place in the endoplasmic reticulum involving the heme oxygenase system. During sequential transformations, heme loses iron and a carbon atom (in the form of CO), forming the green pigment biliverdin, which is reduced to bilirubin by the action of biliverdin reductase.
The resulting bilirubin is hydrophobic, incapable of dissolving in plasma, and is designated as unconjugated (indirect) bilirubin. In the blood, it is transported in a complex with albumin to hepatocytes.
Bilirubin metabolism in the liver
The entry of bilirubin into the hepatocyte occurs via facilitated diffusion involving transport proteins. In the smooth endoplasmic reticulum, bilirubin undergoes conjugation with UDP-glucuronic acid under the action of UDP-glucuronosyltransferase.
- First, bilirubin monoglucuronide is formed.
- Then — bilirubin diglucuronide.
Conjugated (direct) bilirubin is hydrophilic, water-soluble, and is secreted by active transport as part of bile into the duodenum.
Intestinal stage and pigment excretion
In the intestine, under the action of microflora enzymes, bilirubin glucuronides are hydrolyzed: glucuronic acid and bilirubin are released, which is reduced to colorless urobilinogen.
- Part of the urobilinogen is reabsorbed in the ileum, enters the portal vein, and is re-excreted by the liver.
- A small amount enters the systemic circulation and is excreted by the kidneys as urobilin, a urine pigment.
- In the large intestine, urobilinogen is oxidized to stercobilinogen and stercobilin, the main fecal pigment.
Hyperbilirubinemia and jaundice
Normally, total blood bilirubin does not exceed reference values. An increase in its concentration — hyperbilirubinemia — occurs when there is:
- excessive production of bilirubin exceeding the conjugating capacity of the liver;
- impaired uptake, conjugation, or excretion of bilirubin by hepatocytes;
- obstruction of the biliary tract;
- genetic defects in enzymes and carrier proteins.
When the blood bilirubin concentration increases approximately 2.5-fold, the pigment is deposited in tissues, staining the sclera, mucous membranes, and skin yellow, thus forming jaundice.
Hemolytic jaundice
Develops as a result of enhanced erythrocyte hemolysis — in glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, hemoglobinopathies, and autoimmune hemolytic conditions.
- Blood levels of indirect (unconjugated) bilirubin increase.
- The flow of bilirubin into the intestine increases, leading to enhanced formation of urobilinogen and stercobilin.
- Urobilin content in urine is elevated; stool is intensely colored.
Parenchymal (hepatocellular) jaundice
Occurs upon hepatocyte damage by hepatitis viruses, hepatotropic poisons, or in cirrhosis. The capacity of cells to take up, conjugate, and excrete bilirubin is reduced.
- Both fractions — direct and indirect bilirubin — increase in the blood.
- Conjugated bilirubin and urobilinogen appear in the urine.
- The stercobilin content in stool decreases, and stool becomes light-colored.
Obstructive (mechanical) jaundice
Caused by impaired bile outflow due to obstruction of the bile ducts (by a gallstone or tumor).
- Blood direct bilirubin levels rise sharply, and in prolonged cholestasis, indirect bilirubin rises as well.
- Conjugated bilirubin is detected in the urine, and urine darkens.
- Stercobilin in stool is reduced or absent — stool is clay-colored (acholic).
- Impaired bile influx reduces lipid emulsification, leading to steatorrhea and impaired absorption of fat-soluble vitamins.
Neonatal jaundice
Physiological jaundice is caused by enhanced breakdown of erythrocytes containing HbF and the replacement of fetal hemoglobin with HbA, as well as delayed induction of glucuronosyltransferase. Hepatocytes have a limited capacity to take up and conjugate bilirubin.
The danger is posed by unconjugated bilirubin: it crosses the blood-brain barrier, acts as an uncoupler of oxidative phosphorylation, and exerts a neurotoxic effect (kernicterus).
Treatment approaches:
- prescription of phenobarbital and other barbiturates to induce glucuronosyltransferase synthesis;
- phototherapy with blue light — bilirubin is oxidized and converted into a water-soluble photoisomer, which is excreted by the kidneys.
Inherited jaundice
Associated with genetic defects in proteins and enzymes of bilirubin metabolism:
- Gilbert syndrome — impaired bilirubin uptake by hepatocytes and reduced glucuronosyltransferase activity; indirect bilirubin is elevated.
- Crigler–Najjar syndrome — defect in the primary structure of UDP-glucuronosyltransferase; pronounced unconjugated hyperbilirubinemia.
- Dubin–Johnson syndrome — defect in proteins that excrete direct bilirubin into the bile; conjugated bilirubin is elevated.
Key points
- Heme catabolism occurs in the reticuloendothelial system via biliverdin to unconjugated bilirubin.
- In the liver, bilirubin is conjugated with glucuronic acid with the participation of UDP-glucuronosyltransferase.
- In the intestine, bilirubin is converted into urobilinogen, stercobilin, and urobilin.
- Hemolytic jaundice — elevated indirect bilirubin during enhanced erythrocyte breakdown.
- Parenchymal jaundice — elevation of both fractions upon hepatocyte damage.
- Obstructive jaundice — elevated direct bilirubin, clay-colored stools, steatorrhea.
- Neonatal jaundice is treated with phenobarbital and phototherapy.
- Gilbert, Crigler–Najjar, and Dubin–Johnson syndromes are inherited defects of bilirubin metabolism.