CBB 37: Heme Metabolism
• Describe how heme synthesis is regulated in liver and erythrocyte-producing cells via the
rate-limiting step using the isoforms of ALA synthase
• Explain the mechanism by which leading poisoning, vitamin B6 deficiency, and a defect in
ALAS2 cause anemia
• Describe the general features of the porphyrias and the biochemical explanations for the
variety of symptoms seen in different versions
• Recite the specific enzyme deficiencies, symptoms, and complications associated with
acute intermittent porphyria and porphyria cutanea tarda
• Describe the process by which heme is ultimately eliminated from the body beginning with
the turnover of red blood cells and ending with the elimination of urobilin or stercobilin
• Describe the role of bilirubin UDP-glucuronosyltransferase in the catabolism of heme and
Crigler-Najjar and Gilbert Syndromes
• Explain the difference between unconjugated and conjugated bilirubin and how
measurement of these can be useful in the diagnosis of the cause jaundice
• Compare and contrast the following major types of jaundice: hemolytic, hepatocellular,
obstructive, and newborn.
Regulation of Heme Synthesis – ALA Synthase IsoformsRate-limiting enzyme: δ-aminolevulinic acid synthase (ALA synthase)
• Substrates: Glycine + Succinyl-CoA → δ-ALA
• Cofactor: Vitamin B6 (pyridoxal phosphate)
• Location: Mitochondria
Isoforms & Regulation:
Isoform Location Regulation Clinical Note
ALAS1
Liver & other
non-erythroid
tissues
Negative feedback by heme: ↓
transcription, ↑ mRNA degradation, ↓
mitochondrial import
Induced by ↑ demand for heme
(e.g., drugs metabolized by
CYP450, ethanol)
ALAS2 Erythroid cells
(bone marrow)
Not inhibited by heme; regulated by
iron availability (IRE in mRNA)
Deficiency → X-linked
sideroblastic anemia
Key Concept:
• In liver, heme accumulation suppresses ALAS1 to prevent excess synthesis.
• In erythroid cells, massive heme production is needed for hemoglobin → no heme
feedback inhibition.
Mechanisms of Anemia in Lead Poisoning, B6 Deficiency, ALAS2 Defect
Condition Mechanism Result
Lead
poisoning
Inhibits ALA dehydratase (2nd step) &
ferrochelatase (final step) → ↓ heme synthesis; ↑
ALA & protoporphyrin
Microcytic, hypochromic
anemia; neurotoxicity from ALA
buildup
Vitamin B6
deficiency
↓ cofactor for ALAS → ↓ δ-ALA production
Sideroblastic anemia (iron
present but not incorporated
into heme)
ALAS2 defect X-linked mutation → impaired erythroid δ-ALA
synthesis
X-linked sideroblastic anemia;
ringed sideroblasts in marrow
Clinical Pearl:
• ALA accumulation → neuropsychiatric symptoms (ALA structurally mimics GABA).
General Features of Porphyrias• Definition: Disorders of heme biosynthesis due to enzyme defects → accumulation of
pathway intermediates.
• Inheritance: Most are autosomal dominant (unlike most metabolic diseases).
• Pathophysiology:
o Before ring closure → ALA/porphobilinogen accumulate → neurovisceral
symptoms (abdominal pain, neuropathy, psychiatric changes).
o After ring closure → porphyrinogens accumulate → photosensitivity (ROS-
mediated tissue damage).
• Triggers: Drugs (↑ CYP450 demand), ethanol, fasting → ↑ ALAS1 activity → ↑ toxic
intermediates.
Key Porphyrias – Enzyme Defects, Symptoms, Complications
Porphyria Enzyme Deficiency Accumulated
Intermediate Symptoms Notes/Treatment
Acute
Intermittent
Porphyria
(AIP)
Porphobilinogen
deaminase
(hydroxymethylbilane
synthase)
ALA,
porphobilinogen
5 P’s: Painful
abdomen,
Polyneuropathy,
Psychiatric
changes, Port-wine
urine (darkens on
standing),
Precipitated by
drugs/alcohol
No photosensitivity;
treat with hemin &
glucose (↓ ALAS1)
Porphyria
Cutanea
Tarda (PCT)
Uroporphyrinogen
decarboxylase Uroporphyrin
Photosensitivity,
blistering skin
lesions, red-brown
urine
Most common
porphyria; 80%
sporadic; treat with
phlebotomy, avoid
triggers
Heme Degradation & Elimination Pathway
1. 2. 3. 4. RBC turnover (macrophages in spleen/liver) → heme released.
Heme oxygenase: Heme → biliverdin + Fe²⁺ + CO.
Biliverdin reductase: Biliverdin → unconjugated bilirubin (UCB).
Transport: UCB (water-insoluble) bound to albumin → liver.5. 6. 7. Conjugation: Bilirubin UDP-glucuronosyltransferase (UGT1A1) → bilirubin diglucuronide
(conjugated bilirubin, CB).
Excretion: CB → bile → intestine.
Gut bacteria: CB → urobilinogen.
o Stercobilin → feces (brown color).
o Urobilin → urine (yellow color).
o Some urobilinogen reabsorbed (enterohepatic circulation).
Bilirubin UDP-Glucuronosyltransferase & Related Syndromes
Syndrome Defect Severity Clinical Features
Crigler–Najjar
type I
Complete absence of
UGT1A1 Severe, fatal in infancy Very high UCB →
kernicterus
type II Crigler–Najjar
Partial deficiency Milder; responds to
phenobarbital ↑ UCB
Gilbert
syndrome Mild ↓ UGT1A1 activity Benign, intermittent jaundice
(stress, fasting) Slight ↑ UCB
Unconjugated vs Conjugated Bilirubin – Diagnostic Use
Type Solubility Bound to
Albumin? Lab Name Causes of Elevation
Unconjugated
(UCB) Insoluble Yes
Indirect
bilirubin
Hemolysis, impaired conjugation (UGT
defects, neonatal jaundice)
Conjugated (CB) Water-
soluble
No Direct
bilirubin
Biliary obstruction, hepatocellular
damage (impaired excretion)
Interpretation:
• ↑ UCB only → pre-hepatic (hemolysis) or conjugation defect.
• ↑ CB only → post-hepatic (obstructive).
• ↑ both → hepatocellular disease.
Types of Jaundice – Comparison TableType Primary Problem Bilirubin
Elevated Other Clues
Hemolytic (pre-
hepatic)
Excess RBC breakdown →
overload conjugation capacity
↑ UCB Anemia, ↑ LDH, ↑
reticulocytes
Hepatocellular Liver cell damage → impaired
conjugation & excretion ↑ UCB ± ↑ CB ↑ AST/ALT, hepatitis,
cirrhosis
Obstructive (post-
hepatic) Blocked bile flow ↑ CB Pale stools, dark urine,
pruritus, ↑ ALP
Newborn Low UGT activity + high RBC
turnover
↑ UCB Risk of kernicterus; treat
with phototherapy
Board-Style Pearls
• ALA synthase = rate-limiting step; B6-dependent.
• Lead poisoning → anemia + neuro symptoms from ALA buildup.
• Porphyrias:
o Before ring closure → neurovisceral (AIP).
o After ring closure → photosensitivity (PCT).
• UGT defects → unconjugated hyperbilirubinemia.
• CB in urine → water-soluble → dark urine in obstructive jaundice.
• UCB never appears in urine (albumin-bound, insoluble