What is porphyria?

Porphyria: A Group of Rare Metabolic Disorders

Porphyria is a group of rare inborn errors of metabolism caused by abnormal functioning of heme biosynthesis enzymes, resulting in various clinical presentations ranging from acute neurovisceral attacks to chronic skin manifestations depending on the specific enzyme deficiency. 1

Types and Classification

Porphyrias can be classified into two main categories:

1. Acute (Neurovisceral) Porphyrias:

   • Acute Intermittent Porphyria (AIP)
   • Variegate Porphyria (VP)
   • Hereditary Coproporphyria (HCP)
   • ALA-dehydratase Deficiency Porphyria (ADP) - extremely rare

2. Cutaneous Porphyrias:

   • Porphyria Cutanea Tarda (PCT) - most common type
   • Congenital Erythropoietic Porphyria (CEP)
   • Erythropoietic Protoporphyria (EPP)
   • X-linked Erythropoietic Protoporphyria (XLEPP)

Some types (VP and HCP) can present with both acute and cutaneous manifestations 2.

Clinical Presentation

Acute Porphyrias

• Neurovisceral symptoms: Severe abdominal pain, nausea, vomiting, tachycardia
• Neurological manifestations: Peripheral neuropathy, seizures, mental changes
• Other features: Hypertension, hyponatremia
• Severe cases: Can progress to paralysis, respiratory failure, coma, and death if untreated 2

Cutaneous Porphyrias

• PCT: Fragile skin, bullae on sun-exposed areas, dark urine
• EPP: Non-scarring stinging and burning sensations in sun-exposed skin
• CEP: Severe bullous skin lesions, often presenting in newborns 1, 3

Pathophysiology

Each porphyria represents a defect in one of the eight enzymes in the heme biosynthesis pathway, leading to:

• Accumulation of heme precursors (porphyrins and porphyrin precursors)
• In acute porphyrias: neurotoxic precursors (particularly ALA) cause symptoms
• In cutaneous porphyrias: photosensitizing porphyrins react with light causing skin damage 4, 2

Diagnosis

Diagnosis requires biochemical testing, as clinical features alone are not specific enough to establish a porphyria diagnosis. 1

Key diagnostic steps:

1. Biochemical testing: Measurement of porphyrins and precursors in urine, feces, and blood

   • For acute attacks: Urinary/plasma ALA and PBG (porphobilinogen)
   • For cutaneous symptoms: Plasma, urine, and fecal porphyrin patterns 1, 5

2. Genetic testing: Should only be performed after biochemical confirmation

   • Important for family screening and genetic counseling
   • Not recommended as first-line diagnostic test 1, 5

Common Pitfalls in Diagnosis

• Secondary porphyrinuria: Abnormal porphyrin patterns can occur in conditions other than porphyria (more common than true porphyria)
• Inadequate sample collection: Proper handling of samples is crucial; dilute urine may lead to false negatives
• Incomplete testing: Different porphyrias require different tests; consultation with specialist laboratories is recommended
• Premature genetic testing: Genomic testing should not be used for screening without prior biochemical confirmation 1, 5

Treatment

Treatment depends on the type of porphyria:

Acute Porphyrias

• Trigger avoidance: Medications that induce cytochrome P450 enzymes, alcohol, fasting
• Acute attack management:
  • Carbohydrate loading (300g/day orally or 10% glucose IV)
  • Pain management with safe analgesics
  • Correction of electrolyte abnormalities
  • Hemin therapy: Intravenous hemin for severe attacks 5, 6
  • Givosiran for recurrent attacks (4+ per year) 5

Cutaneous Porphyrias

• PCT: Therapeutic phlebotomy to decrease iron levels, low-dose hydroxychloroquine 3
• EPP/XLEPP: Sun protection, beta-carotene
• CEP: Blood transfusions, bone marrow transplantation in severe cases

Long-term Complications

Depending on the type of porphyria, patients may develop:

• Liver disease (including primary liver cancer and acute liver failure)
• Chronic kidney disease and renal failure
• Hypertension
• Osteoporosis
• Vitamin D deficiency
• Anemia 1

Inheritance Patterns

• Autosomal dominant: AIP, VP, HCP, PCT (familial form)
• Autosomal recessive: CEP, HEP, ADP
• X-linked: XLEPP
• Sporadic: PCT (most common form) 1, 7

Monitoring and Follow-up

Regular monitoring is essential:

• Recurrent attack patients: Every 3-6 months
• Sporadic attack patients: At least annually
• Latent carriers: Every 1-3 years 5

Proper diagnosis and management of porphyria are crucial for preventing severe complications and improving quality of life for affected individuals.