Porphyrias

Porphyrias: Heme Synthesis & Intro - Pathway Puzzles

• Porphyrias: Inherited disorders from enzyme defects in heme biosynthesis pathway. Each defect is a "puzzle piece".
• Heme: Essential iron-porphyrin for hemoglobin, myoglobin, cytochromes. Synthesis in mitochondria & cytosol.
• Key Steps: Glycine + Succinyl CoA $\xrightarrow{\text{ALAS}}$ $\delta$-ALA $\rightarrow$ Porphobilinogen (PBG) $\rightarrow \dots \rightarrow$ Protoporphyrin IX + $Fe^{2+}$ $\xrightarrow{\text{Ferrochelatase}}$ Heme.

⭐ ALA synthase (ALAS) is the rate-limiting enzyme in heme synthesis and is feedback inhibited by heme.

• Defect $\rightarrow$ ↑ specific precursor $\rightarrow$ unique porphyria type & symptoms.

Porphyrias: Classification - Symptom Sorting

• Primary Site of Defect:
  • Hepatic: Defect in liver (e.g., AIP, PCT, VP, HCP).
  • Erythropoietic: Defect in bone marrow (e.g., CEP, EPP).
• Clinical Presentation (Symptom-Based):
  • Acute (Neurovisceral): Severe abdominal pain, neuropathy, psychiatric symptoms. Urine may darken.
    • Examples: AIP, ADP, VP, HCP.
  • Cutaneous (Photosensitive): Skin fragility, blisters, scarring on sun-exposed areas.
    • Examples: PCT, EPP, CEP.
  • Mixed: VP & HCP exhibit both neurovisceral and cutaneous features.

⭐ Acute porphyrias (e.g., AIP) are characterized by neurovisceral symptoms, while non-acute/cutaneous porphyrias (e.g., PCT) primarily manifest with photosensitivity.

Porphyrias: Acute (AIP) - Neurovisceral Vexations

• Acute Intermittent Porphyria (AIP): Most common acute type. Autosomal dominant.
  • Defect: ↓ Hydroxymethylbilane synthase (HMBS) / Porphobilinogen deaminase (PBGD).
  • Accumulation: Porphobilinogen (PBG) & Aminolevulinic acid (ALA).
• Clinical (Neurovisceral Attacks):
  • 📌 AIP's 5 P's: Pain (severe abdominal), Peripheral neuropathy, Psychological disturbances, Pee (port-wine colored), Precipitated by drugs (barbiturates, sulfonamides), stress, fasting.
• Diagnosis (Acute Attack):
  • ↑↑ Urinary PBG (key) & ALA.
  • DNA testing confirms.

  ⭐ Elevated urinary porphobilinogen (PBG) is pathognomonic for acute attacks of AIP, HCP, and VP.

• Management:
  • Acute: IV Hemin (3-4 mg/kg IV daily for 4 days), glucose.
  • Avoid precipitants.
• Flowchart: AIP Pathogenesis

Porphyrias: Cutaneous (PCT) - Dermal Dramas

• Most common porphyria; adult onset.
• Defect: Uroporphyrinogen decarboxylase (UROD). Accumulation of uroporphyrinogen.
• Clinical: Photosensitivity (blisters, erosions, fragility on sun-exposed areas), hyperpigmentation, hypertrichosis. No acute attacks.
• Triggers: 📌 IAESH (Iron, Alcohol, Estrogen, Hepatitis C, Smoking), HIV.
• Diagnosis:
  • ↑ Urine uroporphyrins (Type I > III); pink/red urine, coral-pink fluorescence (Wood's lamp).
  • ↑ Plasma porphyrins (peak ~620 nm).
  • ↑ Fecal isocoproporphyrin.
  • Normal ALA/PBG.
• Management: Phlebotomy (ferritin <50 ng/mL), low-dose hydroxychloroquine/chloroquine. Avoid triggers, sun protection.

⭐ Porphyria Cutanea Tarda (PCT) is the most common porphyria, characterized by photosensitive skin lesions and elevated uroporphyrins in urine.

High‑Yield Points - ⚡ Biggest Takeaways

• Porphyrias: Inherited enzyme defects in heme synthesis pathway.
• Acute Intermittent Porphyria (AIP): PBG deaminase defect; neurovisceral symptoms (pain, neuropathy), port-wine urine, no photosensitivity. Triggered by drugs.
• Porphyria Cutanea Tarda (PCT): Uroporphyrinogen decarboxylase defect; most common; photosensitivity, blisters, tea-colored urine.
• Erythropoietic Protoporphyria (EPP): Ferrochelatase defect; photosensitivity (non-blistering), risk of gallstones, liver disease.
• Lead poisoning inhibits ALA dehydratase & ferrochelatase, mimicking porphyria.
• AIP treatment: glucose, hemin. Avoid precipitants for all.