What is porphyria?

What is Porphyria

Porphyrias are a group of rare inherited metabolic disorders caused by deficiencies in specific enzymes of the heme biosynthesis pathway, resulting in toxic accumulation of porphyrins and their precursors, which manifest clinically as either acute neurovisceral attacks or chronic cutaneous photosensitivity. 1

Disease Classification

Porphyrias are categorized into two main clinical groups based on their predominant manifestations 2:

Acute Hepatic Porphyrias (Neurovisceral)

• Acute Intermittent Porphyria (AIP) - autosomal dominant, most common acute form, presents with abdominal pain and neurological symptoms 1
• Variegate Porphyria (VP) - autosomal dominant, can have both neurovisceral and cutaneous symptoms 1
• Hereditary Coproporphyria (HCP) - autosomal dominant, similar mixed presentation 1
• ALA-dehydratase deficiency porphyria - autosomal recessive, extremely rare with only six documented cases 1, 3

Cutaneous Porphyrias (Photosensitivity)

• Porphyria Cutanea Tarda (PCT) - most common porphyria overall, typically sporadic (non-hereditary), presents with bullous skin lesions on sun-exposed areas 1, 4
• Erythropoietic Protoporphyria (EPP) - autosomal recessive, causes acute painful photosensitivity without scarring 1, 5
• X-linked Erythropoietic Protoporphyria (XLEPP) - X-linked, similar photosensitivity presentation 1
• Congenital Erythropoietic Porphyria (CEP) - autosomal recessive, extremely rare (1 in 1,000), severe bullous lesions with hemolytic anemia 1, 3

Pathophysiology

The underlying mechanism involves enzyme deficiencies at specific steps in the eight-enzyme heme biosynthesis pathway 6, 3:

• In acute porphyrias: Accumulation of neurotoxic precursors, particularly delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), causes the neurovisceral symptoms 1, 6, 7
• In cutaneous porphyrias: Accumulated porphyrins are photosensitizing compounds that react with light, damaging sun-exposed skin 7, 4

Clinical Presentations

Acute Neurovisceral Attacks

• Severe abdominal pain (hallmark symptom) 1, 6, 7
• Nausea and vomiting 6, 7
• Tachycardia and hypertension 7
• Neuropsychiatric symptoms ranging from mild confusion to severe psychosis 6, 7
• Peripheral neuropathy that can progress to paralysis and respiratory failure if untreated 7
• Hyponatremia 7
• Seizures in severe cases 6, 7
• Critical pitfall: Most carriers of acute porphyria mutations (low clinical penetrance) never develop symptoms; only a small minority experience attacks 1, 6

Cutaneous Manifestations

• Bullous skin lesions and fragile skin on sun-exposed areas (PCT, VP, HCP, CEP) 1, 4
• Acute painful photosensitivity without scarring (EPP, XLEPP) 1, 5
• Dark urine (PCT) 4

Diagnostic Approach

Biochemical testing must always precede genetic testing and is essential for diagnosis, as clinical features alone are insufficient. 2

First-Line Testing for Suspected Acute Attack

• Random urinary porphobilinogen (PBG) - if significantly elevated, confirms acute porphyria 1, 2
• Urinary/plasma ALA and PBG - normal results rule out acute porphyria when proper collection conditions are met 1
• Critical caveat: ALA is less specific than PBG; elevated ALA also occurs in lead intoxication and hereditary tyrosinemia 1
• Avoid urinary total porphyrins as first-line - unhelpful and potentially misleading for acute porphyrias 1

Sample Collection Requirements

• Protect all samples from light (cover tubes with aluminum foil) to prevent falsely low results 1
• Use morning or spot urine samples, normalize results to creatinine 1
• Interpret cautiously if urinary creatinine <2 mmol/L (falsely elevated results) 1
• PBG degrades within 24 hours at room temperature 1

Comprehensive Diagnostic Evaluation

• Demonstration of characteristic patterns of heme precursors in urine, feces, and blood 1, 2
• Consult expert porphyria centers or specialist laboratories for complete diagnostic workup and interpretation 1, 2
• Genetic testing useful for family counseling after biochemical diagnosis established 2, 5

Epidemiology and Inheritance

• All porphyrias combined affect fewer than 200,000 people in the United States 3
• PCT prevalence: approximately 1 in 10,000 (most common) 3
• AIP prevalence: approximately 1 in 20,000 (most common acute form) 3
• EPP prevalence: 1 in 50,000 to 75,000 3
• Most acute porphyrias are autosomal dominant with low clinical penetrance 1
• PCT is typically sporadic (non-hereditary) in most patients 1, 5

Key Clinical Pearls

• 90% of symptomatic acute porphyria patients are women, with attacks rare before menarche or after menopause 5
• 90% of patients experience only one or few attacks in their lifetime 5
• Acute attacks typically become symptomatic in early adulthood 2
• Approximately 50% of women with AIP experience an attack during pregnancy and/or puerperium, most severe in early pregnancy 8
• PCT resolves with iron depletion; most patients have hepatic siderosis 4