Heme and bilirubin metabolism

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Heme and Bilirubin Metabolism

1. Heme Biosynthesis

Heme synthesis involves eight enzymatic steps converting glycine and succinyl-CoA to heme. These eight enzymes are encoded by nine genes (two genes encode the first enzyme, ALA-synthase). The pathway is split between mitochondria (first and last three enzymes) and cytosol (middle four enzymes).

Step	Enzyme	Location	Product
1	ALA-synthase (ALAS1/ALAS2)	Mitochondria	δ-Aminolevulinic acid (ALA)
2	ALA-dehydratase	Cytosol	Porphobilinogen (PBG)
3	HMB-synthase (PBG-deaminase)	Cytosol	Hydroxymethylbilane
4	Uroporphyrinogen III synthase	Cytosol	Uroporphyrinogen III
5	Uroporphyrinogen decarboxylase	Cytosol	Coproporphyrinogen III
6	Coproporphyrinogen oxidase	Mitochondria	Protoporphyrinogen IX
7	Protoporphyrinogen oxidase	Mitochondria	Protoporphyrin IX
8	Ferrochelatase	Mitochondria	Heme

Key points:

ALA-synthase is the rate-limiting enzyme. It condenses glycine (activated by pyridoxal phosphate) + succinyl-CoA → ALA.
ALAS1 (housekeeping, chromosome 3p21.1) is induced in the liver by drugs, steroids, and chemicals.
ALAS2 (erythroid-specific, chromosome Xp11.2): loss-of-function → X-linked sideroblastic anemia (XLSA); gain-of-function → X-linked erythropoietic protoporphyria (XLP).
~85% of daily heme synthesis occurs in erythroid precursors (for hemoglobin); hepatocytes account for most of the remainder (primarily for CYP450 enzymes).

— Harrison's Principles of Internal Medicine 22E, p. 3386; Tietz Textbook of Laboratory Medicine 7e

2. Heme Catabolism: Heme → Biliverdin → Bilirubin

Heme catabolism pathway: Heme → Biliverdin → Bilirubin → Urobilinogen → Urobilin

Figure 46-6A — Medical Physiology (Boron & Boulpaep)

Heme is degraded in the reticuloendothelial system (macrophages in spleen, liver, bone marrow):

Heme oxygenase (HO-1 inducible, HO-2 constitutive) cleaves the α-methene bridge of the porphyrin ring using NADPH + 3O₂, releasing:
- Biliverdin-IXα (green tetrapyrrole)
- CO (carbon monoxide — signaling molecule with vasodilatory, anti-apoptotic, anti-inflammatory effects via p38 MAPK, NF-κB, sGC)
- Fe²⁺ (ferrous iron — recycled via transferrin; sequestered by ferritin to prevent Fenton reaction ROS)
Biliverdin reductase reduces biliverdin → bilirubin-IXα (yellow pigment) using NADPH.

Heme degradation overview with downstream CO, iron, and bilirubin effects

Sources of bilirubin:

65–80% from hemoglobin of senescent red cells (RBC lifespan ~120 days)
~15% from myoglobin, cytochromes, and other hemoproteins
~10–15% from "ineffective erythropoiesis" (premature destruction of RBC precursors)

— Medical Physiology (Boron & Boulpaep), p. 1410

3. Bilirubin Transport and Hepatic Uptake

Bilirubin secretion: from systemic circulation through hepatocyte to intestine and kidney

Figure 46-6B — Medical Physiology (Boron & Boulpaep)

Unconjugated (indirect) bilirubin is:

Lipophilic and water-insoluble → cannot be excreted in urine or bile directly
Bound reversibly to albumin in plasma (normally ~0.5 mg/dL total bilirubin, mostly unconjugated)
Taken up by hepatocytes via OATP1B1 and OATP1B3 (organic anion transporting polypeptides) at the basolateral membrane

4. Hepatic Conjugation

Inside the hepatocyte endoplasmic reticulum, the enzyme UGT1A1 (UDP-glucuronosyltransferase 1A1) conjugates bilirubin with glucuronic acid:

Bilirubin monoglucuronide (BMG)
Bilirubin diglucuronide (BDG) — predominant form in bile

Conjugated bilirubin is water-soluble and can be excreted. It cannot be reabsorbed by biliary or intestinal epithelia once secreted.

Clinically important UGT1A1 defects:

Disorder	UGT1A1 Activity	Bilirubin type	Features
Gilbert syndrome	Mildly reduced (~30%)	Unconjugated ↑	Benign, common; exacerbated by fasting/stress
Crigler-Najjar type I	Absent	Unconjugated ↑↑↑	Kernicterus, fatal without liver transplant
Crigler-Najjar type II	Severely reduced	Unconjugated ↑↑	Less severe; responds to phenobarbital

— Medical Physiology, p. 1410

5. Biliary Secretion and Intestinal Fate

Conjugated bilirubin is exported from the hepatocyte into the bile canaliculus via MRP2 (ABCC2) — an ATP-dependent efflux pump. It then flows through bile ducts → gallbladder → small intestine.

In the terminal ileum and colon:

Intestinal bacteria (β-glucuronidases) deconjugate bilirubin glucuronides → free bilirubin
Microbial enzymes reduce bilirubin → urobilinogen (colorless)
Urobilinogen → stercobilin (brown pigment of feces) in the colon
~20% of urobilinogen is reabsorbed (enterohepatic circulation) → re-excreted in bile; small fraction reaches kidney → oxidized to urobilin (yellow pigment of urine)

6. Clinical Correlations: Jaundice

Jaundice (icterus) appears when serum bilirubin rises to 1.5–3 mg/dL. Normal total bilirubin is ≤1 mg/dL.

Classification of Hyperbilirubinemia

Type	Mechanism	Bilirubin	Urine Bilirubin	Urine Urobilinogen	Stool Color
Pre-hepatic (hemolytic)	↑ RBC destruction	Unconjugated ↑	Absent (albumin-bound)	↑↑	Normal/dark
Hepatocellular	Liver disease (hepatitis, cirrhosis)	Mixed ↑	Present	Variable	Pale
Post-hepatic (obstructive)	Bile duct obstruction	Conjugated ↑	Present (dark urine)	Absent	Pale/clay-colored

Diagnostic Approach

Evaluation of the patient with jaundice — Harrison's diagnostic flowchart

Figure 49-1 — Harrison's Principles of Internal Medicine, Evaluation of jaundice

Key inherited direct hyperbilirubinemia syndromes:

Dubin-Johnson syndrome — defective MRP2; conjugated bilirubin cannot be exported into canaliculus; black liver pigment; benign
Rotor syndrome — defective OATP1B1/1B3 re-uptake; conjugated bilirubin leaks into plasma

7. Laboratory Measurement of Bilirubin

The Jendrassik-Gróf method is the most common clinical assay:

Diazotized sulfanilic acid reacts with bilirubin's pyrrole rings to form colored phenyl-azo adducts (absorbance at 600 nm)
Direct bilirubin = conjugated bilirubin that reacts without a dissociating agent
Total bilirubin = reacts after adding caffeine-benzoate (displaces albumin-bound unconjugated bilirubin)
Indirect bilirubin = total − direct (≈ unconjugated bilirubin)

— Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 527

8. Neonatal Jaundice

Physiological neonatal jaundice results from:

↑ RBC turnover (fetal hemoglobin replacement)
Immature UGT1A1 conjugation capacity
Enhanced enterohepatic circulation (higher intestinal β-glucuronidase activity)

Treatment with phototherapy converts bilirubin to photoisomers and oxidation products that are less lipophilic and can be excreted without hepatic conjugation (photoisomers → bile; oxidation products → urine).

Extreme unconjugated hyperbilirubinemia → kernicterus (bilirubin deposition in basal ganglia and brainstem nuclei, causing brain damage).

Summary Pathway

Hemoglobin (senescent RBCs, ~80%)
        ↓  [Macrophages - RES]
      Heme
        ↓  Heme Oxygenase (NADPH, O₂)  →  CO + Fe²⁺
   Biliverdin
        ↓  Biliverdin Reductase (NADPH)
  Unconjugated Bilirubin (lipophilic)
        ↓  [Bound to albumin in plasma]
     Liver (OATP1B1/1B3 uptake)
        ↓  UGT1A1 (ER)
  Conjugated Bilirubin (water-soluble)
        ↓  MRP2/ABCC2
       Bile → Intestine
        ↓  Bacterial β-glucuronidase + reduction
    Urobilinogen
    ↙              ↘
Stercobilin         Reabsorbed → Re-excreted in bile
(feces, brown)      Small fraction → Kidney → Urobilin (urine, yellow)

Sources: Medical Physiology (Boron & Boulpaep), p. 1409–1411 | Harrison's 22E, pp. 3386–3387 | Henry's Clinical Diagnosis and Management by Laboratory Methods | Tietz Textbook of Laboratory Medicine 7e

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