Porphyrias

Heme synthesis pathway and overview

• Heme synthesis occurs in 8 enzymatic steps; a defect in one enzyme causes accumulation of the upstream intermediate, which drives toxicity.
• Acute (neurovisceral) porphyrias accumulate precursors (mainly ALA, the chief suspected neurotoxin, with PBG). AIP and ADP are early-step defects; HCP and VP are later-step (enzymes 6 and 7) and can also be cutaneous.
• Cutaneous porphyrias: defects in later steps lead to accumulation of porphyrins, which are photoactive and cause photosensitivity.
• Lead inhibits ferrochelatase (FECH) and ALA dehydratase, producing a porphyria-like biochemical picture.

Porphyria differentiation

Acute intermittent porphyria (AIP)

• Pathophysiology: PBG deaminase (HMBS) deficiency leads to accumulation of ALA and PBG.
• Triggers: cytochrome P450-inducing drugs (anti-epileptics such as phenobarbital, phenytoin, carbamazepine; sulfonamides; hormones such as OCPs, progesterones, ethinyl estradiol; alcohol), fasting (low caloric intake), infection, and hormonal cycling.
• Clinical features (ATTACK):
  • Abdominal pain (severe, colicky, without peritoneal signs).
  • Tachycardia, autonomic instability (hypertension, sweating).
  • Tea-colored urine (porphobilin oxidation in light).
  • Acute psychiatric symptoms: anxiety, agitation, psychosis, depression.
  • Constipation.
  • Kidney injury and electrolyte abnormalities (hyponatremia from SIADH).
• Diagnosis: ↑ urinary PBG (and ALA) during an acute attack on a random urine sample; PBG (and ALA) often remain elevated for years between attacks in patients with prior overt AIP; they may decline but rarely normalize, which is useful for diagnosis but complicates monitoring of recurrent attacks. Genetic testing confirms.
• Treatment of an acute attack:
  • IV hemin (Panhematin) 3 to 4 mg/kg/day for 4 days; inhibits ALAS1 (rate-limiting enzyme).
  • IV dextrose (high-carbohydrate load) suppresses ALAS1; glucose alone can suffice for a mild attack.
  • Identify and remove triggers.
  • Pain control: narcotics are safe (morphine, fentanyl); avoid NSAIDs in renal injury.
  • Antiemetics: ondansetron is safe; avoid metoclopramide (porphyrinogenic).
  • Treat SIADH-type (euvolemic) hyponatremia with fluid restriction, but assess volume status (replace volume if hypovolemic) and give hypertonic saline with controlled correction for severe or symptomatic hyponatremia.
• Long-term prevention:
  • Avoid triggers.
  • Givosiran (Givlaari): siRNA against hepatic ALAS1; FDA approved November 2019 for recurrent acute hepatic porphyria attacks; SQ monthly.
  • Severe refractory cases: liver transplantation.

Porphyria cutanea tarda (PCT)

• Most common porphyria; hepatic UROD activity decreased.
• Triggers and cofactors: HCV (especially in the US), HIV, alcohol, estrogens, smoking, iron overload, HFE mutations.
• Clinical: photosensitive blistering and vesicles on sun-exposed areas (hands, face), fragile skin, hypertrichosis (especially periorbital), hyperpigmentation, sclerodermatous changes.
• Diagnosis: ↑ urinary uroporphyrins; plasma porphyrin scan peaks at 619 nm; Wood lamp shows red-pink fluorescence of urine.
• Treatment:
  • Avoid triggers (alcohol, estrogens, iron supplements).
  • Treat HCV (direct-acting antivirals), which often resolves PCT.
  • Phlebotomy (reduces hepatic iron), 450 mL every 2 to 4 weeks until ferritin reaches the lower limit of normal (~15 to 20 ng/mL).
  • Low-dose hydroxychloroquine (100 mg twice weekly) as an alternative to phlebotomy.
  • Sun protection.

Erythropoietic protoporphyria (EPP)

• Painful photosensitivity WITHOUT blisters (key distinguishing feature); onset in childhood, so children avoid sunlight.
• FECH or ALAS2 (X-linked, XLP) mutations.
• Liver disease in 5 to 10% (protoporphyrin precipitates in bile, causing cholestatic injury and cirrhosis).
• Diagnosis: ↑ erythrocyte protoporphyrin is predominantly metal-free in EPP (>85%), which separates it from lead poisoning and iron deficiency (zinc-bound) but NOT from XLP, which also has high metal-free protoporphyrin (>15% zinc fraction). Distinguish EPP from XLP by fractionation and FECH versus ALAS2 genetic testing.
• Treatment:
  • Sun avoidance.
  • Afamelanotide (Scenesse): alpha-MSH analog that increases melanin for photoprotection; FDA approved October 2019.
  • β-carotene (historically used; efficacy not established, not recommended by current guidelines).
  • Liver disease management: cholestyramine, ursodiol; transplant for severe disease.

High yield (porphyrias)

• AIP: abdominal pain + neuro/psych + autonomic + dark urine; ↑ urine PBG (the 5 P's).
• AIP triggers: P450-inducing drugs (anti-epileptics, sulfa, OCP), fasting, alcohol.
• AIP acute treatment: hemin + IV dextrose (inhibit ALAS1); glucose alone for mild attacks.
• Givosiran (Givlaari): siRNA against ALAS1 for recurrent AIP attacks (FDA November 2019).
• PCT: most common porphyria; cutaneous blistering; HCV, alcohol, estrogen, and iron triggers; UROD deficiency.
• PCT treatment: phlebotomy + treat HCV + avoid triggers (or low-dose hydroxychloroquine).
• EPP: painful photosensitivity WITHOUT blisters; childhood onset; FECH deficiency; afamelanotide (FDA 2019).
• Erythrocyte protoporphyrin is elevated in EPP (free) and lead poisoning (zinc-bound); free vs zinc-bound distinguishes them, and XLP shows ↑ zinc protoporphyrin vs EPP.
• CEP: painless chronic blistering with severe scarring; UROS deficiency; allogeneic SCT for severe disease.
• Variegate porphyria (VP): mixed acute plus cutaneous; protoporphyrinogen oxidase; common in South African Afrikaners.