Porphyria cutanea tarda

Epidemiology & Risk Factors

• Most common disorder of heme biosynthesis; due to deficiency/inhibition of hepatic uroporphyrinogen decarboxylase (UROD).
  • Type 1 (Sporadic, ~80%): Acquired hepatic UROD inhibition triggered by iron overload, HCV, alcohol, or estrogens.
  • Type 2 (Familial, ~20%): Autosomal dominant mutation with reduced penetrance; affects UROD in all tissues.
• Strong associations (must screen for these):
  • Hepatitis C virus (HCV) (~50% of cases). c
  • HIV infection.
  • Alcohol use disorder.
  • Excess estrogen (OCPs, HRT).
  • Hemochromatosis / Iron overload (HFE mutations).
  • Tobacco smoking.

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Clinical Features

• Cutaneous Photosensitivity:
  • Painless vesicles, bullae, and skin fragility on sun-exposed areas (dorsum of hands, forearms, face, neck).
  • Minor trauma triggers erosions, ulcerations, and crusting.
  • Heals with scarring and milia (small white keratinous cysts).
• Chronic Skin Changes:
  • Facial hypertrichosis / hirsutism (malar/temporal areas).
  • Hyperpigmentation and sclerodermoid (thickened) skin plaques.
• Urine Changes:
  • Tea-colored or reddish-brown urine (darkens further upon exposure to sunlight/air).
• Note: Lack of neurovisceral symptoms (no acute abdominal pain or psychosis, distinguishing it from acute porphyrias).

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Diagnosis

• Initial / Screening Test:
  • Total urinary and plasma porphyrins (elevated).
  • Wood’s lamp examination of urine: Displays coral-red fluorescence (due to uroporphyrins).
• Confirmatory / Gold Standard:
  • Fractionated plasma/urine/fecal porphyrin assay: Shows marked elevation of uroporphyrin (isomer I & III) and heptacarboxyl porphyrin.
• Essential Secondary Workup (Mandatory in all new diagnoses):
  • HCV Ab and RNA, HIV serology.
  • Iron studies (serum iron, ferritin, TIBC, transferrin saturation) ± HFE genetic testing.
  • LFTs (transaminases, bilirubin).
• Skin Biopsy (rarely required, done if diagnosis is uncertain):
  • Subepidermal bullae with minimal inflammatory infiltrate and cell-free festooning of dermal papillae.

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Differential Diagnostics

• Pseudoporphyria:
  • Diff by identical clinical lesions but normal urine/plasma porphyrins.
  • Triggered by medications (e.g., naproxen, tetracyclines, furosemide) or chronic hemodialysis.
• Acute Intermittent Porphyria (AIP):
  • Diff by acute neurovisceral attacks (5 Ps: Painful abdomen, Polyneuropathy, Psychological disturbances, Port-wine urine, Precipitated by drugs/fasting) and NO cutaneous blisters; elevated urinary PBG and ALA.
• Variegate Porphyria (VP) / Hereditary Coproporphyria (HCP):
  • Diff by presence of both cutaneous blisters and acute neurovisceral attacks; confirmed by fecal porphyrin fractionation (elevated coproporphyrin/protoporphyrin).
• Bullous Pemphigoid (BP):
  • Diff by tense bullae on normal or erythematous skin (generalized, not sun-limited), pruritus, and direct immunofluorescence (DIF) showing linear IgG/C3 at the dermoepidermal junction; normal porphyrins.
• Pemphigus Vulgaris (PV):
  • Diff by flaccid bullae, (+) Nikolsky sign, prominent mucosal involvement, and intraepidermal acantholysis; normal porphyrins.

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Management

1. General & Preventive Measures:
   • Strict sun avoidance, broad-spectrum sunscreen (physical blockers like zinc oxide/titanium dioxide), and protective clothing.
   • Complete cessation of alcohol and smoking.
   • Discontinuation of exogenous estrogens (OCPs/HRT).
2. First-Line Targeted Therapy:
   • Serial Phlebotomy: First-line for pts with iron overload or elevated ferritin; removes hepatic iron stores (target ferritin: 20–50 ng/mL).
   • Low-Dose Antimalarials (Hydroxychloroquine or Chloroquine):
     • Used if phlebotomy is contraindicated (e.g., severe anemia, advanced cardiac disease) or as alternative first-line.
     • Low dose only (e.g., hydroxychloroquine 100 mg twice weekly); high doses can induce acute hepatotoxicity.
3. Treatment of Underlying Triggers:
   • Direct-acting antivirals (DAAs) for HCV.
   • Antiretroviral therapy (ART) for HIV.
   • Iron chelation (e.g., Deferasirox) if phlebotomy is contraindicated in hemochromatosis.

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Complications

• Secondary bacterial skin infections (cellulitis, impetigo).
• Permanent scarring, dyspigmentation, and alopecia.
• Increased long-term risk of Hepatocellular Carcinoma (HCC) (driven by concurrent HCV, iron overload, and chronic hepatic injury).