Heme Catabolism and Jaundice

Principal Sites of Heme Catabolism

The liver and spleen, where macrophages of the reticuloendothelial system break down old red blood cells after their $120\,\text{day}$ lifespan.

Bilirubin

The yellow end product of heme catabolism; $75\%$ originates from the hemoglobin of old red blood cells, with normal adult production ranging between $250\text{--}350\,\text{mg/day}$.

Heme degradation pathway

The multi-step catabolic pathway involving heme conversion in the reticuloendothelial system, uptake and conjugation in the liver, and excretion/transformation in the intestine.

Heme oxygenase

A microsomal P450 cytochrome enzyme that cleaves the $\alpha$ methenyl bridge of heme using $\text{O}_2$ and NADPH, yielding biliverdin, ferric iron ($\text{Fe}^{3+}$), and carbon monoxide ($\text{CO}$).

Biliverdin

A water-soluble green pigment formed from the oxidation of heme by heme oxygenase.

Biliverdin reductase

The enzyme that reduces the water-soluble green pigment biliverdin to yellow unconjugated bilirubin using NADPH.

Unconjugated bilirubin (Indirect bilirubin)

A water-insoluble yellow pigment transported in blood bound to plasma albumin; its measurement in the van den Bergh reaction requires the addition of methanol.

Conjugation of bilirubin

The hepatic pathway in which two glucuronate groups from UDP-glucuronic acid are transferred to bilirubin in two separate steps, producing water-soluble bilirubin diglucuronide.

UDP glucuronyl transferase

The hepatic enzyme responsible for conjugating bilirubin with glucuronic acid to form bilirubin diglucuronide.

Conjugated bilirubin (Direct bilirubin)

Bilirubin diglucuronide formed in hepatocytes; it is water-soluble, reacts directly with the diazo reagent in the van den Bergh test, and is secreted into bile.

Hepatic bilirubin secretion

The active transport of conjugated bilirubin from hepatocytes into biliary canaliculi, which represents the rate-limiting step in overall bilirubin metabolism.

Urobilinogen

A colorless compound produced in the intestine when intestinal bacteria deconjugate and reduce conjugated bilirubin.

Urobilin (stercobilin)

A brown pigment formed in the colon by the oxidation of urobilinogen, responsible for imparting the characteristic brown color to feces.

Enterohepatic circulation of urobilinogen

The process by which a portion of intestinal urobilinogen is reabsorbed into the portal blood, taken up by the liver, and re-excreted in bile.

Hyperbilirubinemia

An elevation of total plasma bilirubin level above $1\,\text{mg/dL}$ ($17\,\mu\text{mol/L}$).

Bilirubinuria

The pathological presence of conjugated bilirubin in urine, which darkens the urine to a deep orange-brown color.

Kernicterus

Severe, potentially fatal neural damage and brain injury in infants resulting from unconjugated bilirubin crossing the blood-brain barrier when levels exceed $20\text{--}25\,\text{mg/dL}$.

Jaundice

The yellow discoloration of skin, nail beds, and sclera caused by tissue deposition of bilirubin when plasma concentration exceeds $3\,\text{mg/dL}$ ($50\,\mu\text{mol/L}$).

Prehepatic (hemolytic) jaundice

Jaundice caused by excessive red blood cell destruction exceeding hepatic conjugation capacity; characterized by elevated indirect bilirubin, dark urine (from elevated urobilinogen), and dark stool (from elevated stercobilin).

Posthepatic (obstructive) jaundice

Jaundice caused by blockage of biliary ducts; characterized by elevated conjugated bilirubin, dark urine (containing conjugated bilirubin), absence of urine urobilinogen, and pale/clay-colored stool.

Hepatic (intrahepatic) jaundice

Jaundice due to hepatocyte dysfunction impairing bilirubin uptake, conjugation, or secretion; presents with elevated plasma levels of both conjugated and unconjugated bilirubin, dark urine, and pale stool.

Neonatal (physiologic) jaundice

A transient form of unconjugated hyperbilirubinemia occurring in $50\%$ of newborns due to developmental immaturity of UDP glucuronyl transferase.

Phototherapy

A medical light treatment used in neonatal jaundice to convert unconjugated bilirubin into soluble derivatives that are easily excreted in bile without conjugation.

Gilbert's syndrome

A harmless, asymptomatic genetic condition affecting up to $5\%$ of the population caused by a moderate deficiency in UDP glucuronyl transferase, leading to mild intermittent unconjugated hyperbilirubinemia.