What are the clinical features and diagnosis of porphyria?

Porphyria: Clinical Features and Diagnosis

Porphyrias are rare inborn errors of metabolism caused by abnormal functioning of heme biosynthesis enzymes, presenting with various clinical manifestations ranging from acute neurovisceral attacks to chronic skin symptoms, requiring biochemical testing for definitive diagnosis as clinical features alone are insufficient for establishing the diagnosis. 1

Types and Clinical Presentations

Acute Hepatic Porphyrias

• Include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and the rare aminolevulinic acid dehydratase deficiency porphyria (ADP) 1, 2
• Typically become symptomatic in early adulthood 1
• Present with acute neurovisceral attacks characterized by:
  • Severe abdominal pain (most common presenting symptom) 1, 2
  • Neuropsychiatric symptoms 1
  • Chest, back, or extremity pain 2
  • Hyponatremia (most common electrolyte abnormality) and hypomagnesemia 2
  • Seizures (occur in 20-30% of acute attacks) 2
• VP and HCP may additionally present with skin photosensitivity 1, 3

Cutaneous Porphyrias

• Include porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLP), and congenital erythropoietic porphyria (CEP) 3, 4
• Present with skin manifestations:
  • Bullae on sun-exposed areas 1
  • Acute painful photosensitivity 1
  • Hypertrichosis and scarring 5
• PCT most often presents in adults or older age 1
• EPP typically presents in children 1
• CEP often presents in newborns 1

Long-term Complications

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

Diagnostic Approach

First-line Diagnostic Testing

• Biochemical testing is essential and must precede genetic testing 1
• Diagnosis depends on demonstration of typical patterns of heme precursors in: 1
  • Urine
  • Feces
  • Blood

Specific Tests for Acute Porphyrias

• Check random urinary porphobilinogen (PBG) for rapid diagnosis 2
• Measure urinary 5-aminolevulinic acid (ALA) and PBG 3
  • Increased ALA alone in ADP
  • Increased ALA and PBG in other acute porphyrias

Diagnostic Pitfalls to Avoid

• Secondary abnormalities of porphyrin accumulation and excretion occur in many disorders more common than porphyrias 1
• Elevated porphyrins can occur in patients without porphyria in: 3
  • Liver diseases
  • Iron deficiency
  • Lead intoxication
• Inadequate pre-analytical precautions can lead to incorrect diagnosis 1
• Poor analytical quality and inappropriate interpretation of test results may lead to misdiagnosis 1

Role of Genetic Testing

• Should not be used for diagnostic screening without prior biochemical testing showing increased porphyria-related markers 1
• Useful adjunct for genetic counseling of asymptomatic family members in acute porphyrias 1
• Important to note that autosomal dominant porphyrias have low clinical penetrance 1
• Pathogenic variants may be observed in the general population without associated disease 1

Inheritance Patterns

• Most porphyrias are hereditary, with various inheritance patterns: 1
  • Autosomal dominant (AIP, VP, HCP)
  • Autosomal recessive (ADP, CEP, HEP)
  • X-linked (XLP)
• PCT is usually sporadic and non-hereditary in most populations 1

Diagnostic Recommendations

• For suspected porphyria, consult with an expert center or porphyria specialist laboratory 1
• Non-expert laboratories should perform correct first-line diagnostic markers and recommend further analysis at expert laboratories when needed 1
• A complete diagnostic evaluation should include: 1
  • Biochemical testing to confirm diagnosis
  • Genetic testing to determine the specific type of porphyria
  • Complete medical history and physical examination

Early and accurate diagnosis is crucial for appropriate management and prevention of long-term complications in these rare disorders 6. The wide array of clinical presentations at different stages of life makes porphyrias relevant for many different clinical specialties, particularly hepatologists, gastroenterologists, and dermatologists 1.