Physiology of Heme Metabolism and Acute Intermittent Porphyria
Overview
Heme is a complex iron-containing porphyrin that serves as the prosthetic group for numerous vital proteins including hemoglobin, myoglobin, cytochromes, and various enzymes. The biosynthesis of heme involves an elegant eight-step enzymatic pathway that begins in the mitochondria, continues in the cytoplasm, and returns to the mitochondria for completion. Understanding heme metabolism is crucial for comprehending disorders like the porphyrias, particularly acute intermittent porphyria, which results from enzymatic defects in this pathway. The tight regulation of heme synthesis ensures adequate production while preventing accumulation of toxic intermediates.
Heme Biosynthesis Pathway
Overview of the Eight-Step Pathway
The heme biosynthetic pathway involves eight enzymatic steps occurring in two cellular compartments:
Mitochondrial Steps: 1. ALA synthase (ALAS): Rate-limiting enzyme 2. Ferrochelatase: Final step inserting iron
Cytoplasmic Steps: 3. ALA dehydratase (ALAD) 4. Porphobilinogen deaminase (PBGD/HMBS) 5. Uroporphyrinogen III synthase (UROS) 6. Uroporphyrinogen decarboxylase (UROD) 7. Coproporphyrinogen oxidase (CPOX) 8. Protoporphyrinogen oxidase (PPOX)
Step-by-Step Synthesis
Step 1: ALA Formation
- Enzyme: δ-aminolevulinic acid synthase (ALAS)
- Substrates: Glycine + Succinyl-CoA
- Product: δ-aminolevulinic acid (ALA)
- Location: Mitochondrial matrix
- Regulation: Rate-limiting step, inhibited by heme
- Cofactor: Pyridoxal phosphate (Vitamin B6)
Step 2: Porphobilinogen Formation
- Enzyme: ALA dehydratase (ALAD/PBGS)
- Substrate: 2 molecules of ALA
- Product: Porphobilinogen (PBG)
- Location: Cytoplasm
- Inhibition: Lead poisoning affects this enzyme
Step 3: Hydroxymethylbilane Formation
- Enzyme: Porphobilinogen deaminase (PBGD/HMBS)
- Substrate: 4 molecules of PBG
- Product: Hydroxymethylbilane
- Deficiency: Causes acute intermittent porphyria
Step 4: Uroporphyrinogen III Formation
- Enzyme: Uroporphyrinogen III synthase
- Substrate: Hydroxymethylbilane
- Product: Uroporphyrinogen III
- Alternative: Non-enzymatic formation of uroporphyrinogen I
Step 5: Coproporphyrinogen III Formation
- Enzyme: Uroporphyrinogen decarboxylase
- Product: Coproporphyrinogen III
- Process: Sequential decarboxylation of acetate groups
Step 6: Return to Mitochondria
- Transport: Coproporphyrinogen III enters mitochondria
- Enzyme: Coproporphyrinogen oxidase
- Product: Protoporphyrinogen IX
Step 7: Protoporphyrin IX Formation
- Enzyme: Protoporphyrinogen oxidase
- Product: Protoporphyrin IX
- Process: Oxidation removing 6 hydrogen atoms
Step 8: Heme Formation
- Enzyme: Ferrochelatase (heme synthase)
- Substrates: Protoporphyrin IX + Fe²⁺
- Product: Heme (ferroprotoporphyrin IX)
- Inhibition: Lead also affects this enzyme
Regulation of Heme Synthesis
Tissue-Specific Regulation
Hepatic Regulation: - Primary control: ALAS1 (hepatic isoform) - Negative feedback: Heme inhibits ALAS1 - Transcriptional: Heme represses ALAS1 gene - Post-translational: Heme promotes ALAS1 degradation - Inducers: Cytochrome P450 inducing drugs
Erythroid Regulation: - Isoform: ALAS2 (erythroid-specific) - Control: Iron regulatory proteins (IRPs) - Iron-dependent: 5' iron-responsive element - Coordinated: With globin synthesis
Factors Affecting Synthesis
Upregulation: - hypoxia: Increases erythropoiesis - Erythropoietin: Stimulates RBC production - Iron availability: Essential cofactor - Drug metabolism: P450 induction
Downregulation: - Heme excess: Feedback inhibition - Iron deficiency: Limits final step - Inflammation: Via hepcidin - Heavy metals: Lead, mercury
Heme Catabolism
Overview of Degradation
Heme catabolism occurs primarily in the reticuloendothelial system:
Step 1: Heme to Biliverdin
- Enzyme: Heme oxygenase
- Products: Biliverdin, CO, Fe²⁺
- Location: Endoplasmic reticulum
- Isoforms: HO-1 (inducible), HO-2 (constitutive)
Step 2: Biliverdin to Bilirubin
- Enzyme: Biliverdin reductase
- Product: Unconjugated bilirubin
- Transport: Bound to albumin
Step 3: Hepatic Processing
- Uptake: Via OATP transporters
- Conjugation: UDP-glucuronosyltransferase (UGT1A1)
- Product: Conjugated bilirubin
- Excretion: Into bile
Step 4: Intestinal Metabolism
- Bacterial action: Produces urobilinogen
- Fate: Reabsorption or excretion
- Final products: Stercobilin (feces), urobilin (urine)
Clinical Significance of Catabolism
- Jaundice: Bilirubin accumulation
- Gilbert Syndrome: UGT1A1 deficiency
- Crigler-Najjar syndrome: Severe UGT1A1 deficiency
- Dubin-Johnson syndrome: Excretion defect
Clinical Correlations
Disorders of Heme Synthesis
The porphyrias result from enzymatic defects:
Hepatic Porphyrias: - Acute intermittent porphyria (AIP) - Variegate porphyria (VP) - Hereditary coproporphyria (HCP) - ALA dehydratase porphyria (ADP)
Erythropoietic Porphyrias: - Congenital erythropoietic porphyria (CEP) - Erythropoietic protoporphyria (EPP)
Mixed Porphyrias: - Porphyria cutanea tarda (PCT)
Other Clinical Conditions
- Lead poisoning: Inhibits ALAD and ferrochelatase
- Iron deficiency anemia: Limits heme synthesis
- Sideroblastic anemia: ALAS2 mutations
- Erythropoietic porphyria: Photosensitivity
Acute Intermittent Porphyria
Definition and Epidemiology
Acute intermittent porphyria (AIP) is the most common acute hepatic porphyria: - Inheritance: Autosomal dominant - Gene: HMBS gene (formerly PBGD) - Prevalence: 5-10 per 100,000 - Penetrance: Low (~10-20%) - Demographics: More common in females, onset typically 20-40 years
Pathophysiology
Enzymatic Defect: - Enzyme: Porphobilinogen deaminase (third step) - Activity: 50% reduction in heterozygotes - Consequence: Accumulation of ALA and PBG
Neurotoxicity Mechanisms: - ALA neurotoxicity: Structure similar to GABA - Oxidative stress: From porphyrin precursors - Heme deficiency: In nervous tissue - Autonomic neuropathy: Explains GI symptoms
Precipitating Factors: - Drugs: Barbiturates, sulfonamides, antiepileptics - Hormones: Estrogen, progesterone - Fasting: Induces hepatic ALAS1 - Stress: Surgery, infection - Alcohol: Enzyme induction
Clinical Manifestations
Acute Attack Features:
Abdominal Symptoms (85-95%): - Severe abdominal pain: Colicky, no peritoneal signs - Nausea and vomiting - 03 Spaces/Medical Hub/🏥 Clinical Rotations/Clinical Consult/Constipation: From autonomic neuropathy - Abdominal distension
Neurological Symptoms: - Peripheral neuropathy: Motor > sensory - Muscle weakness: Can progress to paralysis - Seizures: 10-20% of attacks - Mental symptoms: Anxiety, confusion, psychosis
Autonomic Features: - Tachycardia: Most common sign - 03 Spaces/Medical Hub/📝 Exam Prep/Medicine Notebook/Hypertension: During attacks - Postural hypotension - Urinary retention
Other Features: - Dark urine: Port wine urine on standing - 03 Spaces/Medical Hub/🏥 Clinical Rotations/Clinical Consult/Hyponatremia: From SIADH - No cutaneous manifestations (unlike other porphyrias)
Diagnosis
Biochemical Testing:
During Acute Attack: - Urine PBG: Markedly elevated (>10x normal) - Urine ALA: Also elevated - Watson-Schwartz test: Historical screening - Quantitative testing: Preferred over qualitative
Between Attacks: - May have normal or mildly elevated levels - Genetic testing: Confirms diagnosis - Family screening: Important for carriers
Differential Diagnosis: - Surgical abdomen: Many undergo unnecessary surgery - Lead poisoning: Also elevates ALA - Guillain-Barré Syndrome - Psychiatric disorders
Management
Acute Attack Treatment:
Specific Therapy: - Hemin/Hematin: 3-4 mg/kg IV daily × 4 days - Mechanism: Downregulates ALAS1 - Early administration: Better outcomes - Alternative: Heme arginate (Europe)
Supportive Care: - Pain management: 03 Spaces/Medical Hub/📘 Med terms dictionary/Glossary/Opioids safe, avoid triggers - Hydration: With dextrose to suppress ALAS1 - Electrolyte correction: Monitor sodium - Antiemetics: For nausea - Beta-blockers: For autonomic symptoms
Seizure Management: - Safe options: Gabapentin, levetiracetam - Avoid: Most traditional antiepileptics - Magnesium: May help
Prevention of Attacks:
Lifestyle Modifications: - Avoid triggers: Drug list education - Regular meals: Prevent fasting - Stress management - Medical alert: Bracelet/card
Prophylactic Measures: - GnRH agonists: For cyclic attacks - Prophylactic hemin: Severe recurrent attacks - Liver transplantation: Curative but rare
Long-term Monitoring: - Renal function: Risk of CKD - Liver imaging: Risk of 03 Spaces/Medical Hub/📝 Exam Prep/General Surgery SS Notes/SGE Notes INISS/HPB/Liver/Hepatocellular Carcinoma - Neuropathy assessment - Bone health: Osteoporosis risk
Prognosis
Attack Outcomes: - Mortality: <5% with modern treatment - Recovery: Usually complete - Residual neuropathy: In severe cases - Psychological impact: Common
Long-term Complications: - 03 Spaces/Medical Hub/🏥 Clinical Rotations/Clinical Consult/Chronic Kidney Disease: 40-60% develop - 03 Spaces/Medical Hub/📝 Exam Prep/Medicine Notebook/Hypertension: Often persistent - 03 Spaces/Medical Hub/📝 Exam Prep/General Surgery SS Notes/SGE Notes INISS/HPB/Liver/Hepatocellular Carcinoma: Increased risk - Peripheral neuropathy: May be permanent
Special Considerations
Pregnancy: - Risk: Hormonal changes may trigger - Management: Hemin safe if needed - Outcomes: Generally good with care
Surgery: - Preoperative: Dextrose loading - Anesthesia: Careful drug selection - Monitoring: For postoperative attacks
Safe Medications: - Analgesics: Morphine, fentanyl - Antibiotics: Penicillins, cephalosporins - Other: Acetaminophen, aspirin
Clinical Pearls
- Heme synthesis requires eight enzymes, deficiency of any causes porphyria
- ALA synthase is the rate-limiting enzyme regulated by heme feedback
- Lead poisoning mimics AIP by inhibiting ALAD but also causes basophilic stippling
- The "purple urine" of porphyria develops on standing due to PBG oxidation
- Hemin therapy should be started early in acute attacks - don't wait for confirmation
- Many AIP patients undergo unnecessary appendectomy before diagnosis
- Carbohydrate loading suppresses hepatic ALAS1 and can abort mild attacks
- Check sodium levels - SIADH is common during acute attacks
- Motor neuropathy in AIP can mimic Guillain-Barré Syndrome
- Safe drug lists should be provided to all AIP patients