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Chapter 33. Porphyria

Mark S. Tinklepaugh, MD

  • Pathophysiology:
    • Autosomal dominant defect in heme synthesis; 90% of gene carriers are asymptomatic; 80% of symptomatic patients are women from puberty to menopause
    • Heme is a porphyrin critical in the formation of hemoglobin and cytochrome P450 complex (drug metabolism)
    • Aminolevulinic acid (ALA) synthase is the enzyme involved in the rate-limiting step of heme formation:

      Glycine + succinyl CoA → ALA

    • ALA synthase is induced by feedback inhibition when heme requirements increase
    • Partial enzyme defect in heme pathway leads to buildup of ALA and other intermediaries leading to neurotoxicity, especially when need for heme (catabolism increased by menstrual hormones) or need for cytochrome P450 enzymes by inducing drugs
    • Classified as:
      • Erythropoietic porphyrias:
        • Günther disease and protoporphyria
        • Patients are children; no acute crises
      • Hepatic porphyrias:
        • Cutaneous porphyria
        • Acute porphyrias with related symptomatology (most often problematic with anesthesia):
          • Acute intermittent porphyria (AIP), most common form
          • Variegate porphyria (VP), protoporphyrinogen oxidase deficiency
          • Hereditary coproporphyria (HC), coproporphyrinogen oxidase deficiency
          • Plumboporphyria (PP), ALA dehydrase deficiency
  • Precipitating factors:
    • Clinical conditions:
      • Dehydration, fasting, infection, emotional stress, hormonal changes (menstruation/pregnancy), alcohol
    • Enzyme-inducing drugs:
      • Barbiturates, etomidate (Amidate®), ethanol, hydantoin anticonvulsants, phenytoin (Dilantin®), hormonal steroids (progesterone, estrogen)
  • Lab diagnosis:
    • Urgently: urinary porphyrin precursors (delta-ALA and porphobilinogen)
    • Porphyrins in urine and stool (uroporphyrin, coproporphyrin, protoporphyrin)
    • Specialized lab: enzyme activities, gene mutation
    • Chem 7: Hyponatremia due to SIADH, more common if neuro involvement
  • Treatment of crisis:
    • Analgesia (morphine), anxiolysis (benzodiazepine, phenothiazine)
    • D10% at 125 mL/h
    • Heme arginate 3–4 mg/kg per day IVSS over 30–40 minutes × 4 days; very effective on digestive symptoms; will prevent neurological symptoms, but not effective if already present. Possible thrombophlebitis
    • Other symptomatic treatment as needed (e.g., beta-blockers for tachycardia)

Table 33-1 Signs and Symptoms of Acute Porphyria
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Table 33-1 Signs and Symptoms of Acute Porphyria

Abdominal pain

Constipation, all the way through pseudoobstruction

95%

Dark urine

From reddish to black, within 10–30 min

70%
N/V, autonomic dysfunction (tachycardia, HTN)55–80%

Peripheral neuropathy, hemiplegia, quadriplegia, respiratory paralysis

Transfer to ICU

60%
CNS—cranial nerves, mental status changes30–55%
Electrolyte abnormalities (hyponatremia, hypokalemia, hyperchloremia)30–50%
Seizures20%

Cutaneous signs (in HC and VP)

Vesicles or bullae on face and hands (photosensitization) + hyperpigmentation/hypopigmentation

  • Identify patients by personal and familial history
  • Consider neurological evaluation to assess CNS/PNS and mental status
  • Premedicate to alleviate stress; midazolam acceptable
  • Avoid enzyme-inducing drugs
  • Treat preexisting infection and assess volume and electrolytes

  • Regional anesthesia not contraindicated; must consider autonomic instability, hypovolemia, and theoretical risk of exacerbation of peripheral neuropathies
  • Bupivacaine acceptable for both spinal and epidural anesthesia
  • General anesthesia: use safe drugs (see Table 33-2)

Table 33-2 Pharmacologic Considerations in Patients with Porphyria
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Table 33-2 Pharmacologic Considerations in Patients with Porphyria
Drug typeSafe drugsDrugs to avoid
Induction agentPropofol
  • Barbiturates
  • Etomidate
Inhalation agent
  • Nitrous oxide
  • Sevoflurane
  • Desflurane
  • Isoflurane
Enflurane
Analgesic
  • Fentanyl
  • Morphine
  • Sufentanil
  • Acetaminophen
    • ...

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