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 and excretion of porphyrins and their precursors (δ-aminolevulinic acid and porphobilinogen), which manifest clinically as acute neurovisceral attacks and/or cutaneous photosensitivity depending on which enzyme is deficient. 1
Pathophysiology
- The disorders result from abnormal functioning of enzymes in the heme biosynthetic pathway, causing accumulation of specific metabolites upstream of the enzymatic defect 1
- In acute hepatic porphyrias, neurotoxic precursors (particularly δ-aminolevulinic acid and porphobilinogen) accumulate and cause neurological damage 2, 3
- In cutaneous porphyrias, porphyrins accumulate in the skin and react with light, causing photosensitivity in sun-exposed areas 3, 4
Classification by Clinical Presentation
Acute Neurovisceral Porphyrias
- Acute Intermittent Porphyria (AIP): Most common acute porphyria, autosomal dominant inheritance, presents with abdominal pain and neurological symptoms 1, 2
- Variegate Porphyria (VP): Autosomal dominant, can present with both neurovisceral attacks and cutaneous symptoms 1, 3
- Hereditary Coproporphyria (HCP): Autosomal dominant, similar to VP with both potential manifestations 1, 3
- ALA-dehydratase Deficiency Porphyria: Autosomal recessive, extremely rare with only six documented cases 1, 5
Cutaneous Porphyrias
- Porphyria Cutanea Tarda (PCT): Most common porphyria overall, usually sporadic (non-hereditary) in most populations, presents with bullous skin lesions 1, 2
- Erythropoietic Protoporphyria (EPP): Autosomal recessive, causes acute painful photosensitivity without scarring, often presents in childhood 1, 2
- Congenital Erythropoietic Porphyria (CEP): Autosomal recessive, severe bullous skin lesions and hemolytic anemia, often evident in newborns 1
- X-linked Erythropoietic Protoporphyria (XLEPP): X-linked inheritance, acute painful photosensitivity 1
Clinical Manifestations
Acute Neurovisceral Symptoms
- Severe abdominal pain (most common presenting symptom), nausea, vomiting, constipation 2, 3
- Neuropsychiatric symptoms including confusion, anxiety, hallucinations, and in severe cases, seizures and psychosis 3, 6
- Peripheral neuropathy (motor-predominant, axonal) that can progress to paralysis and respiratory failure if untreated 3, 6
- Autonomic dysfunction with tachycardia, hypertension, and hyponatremia 2, 3
- 90% of symptomatic patients are women, with attacks rare before menarche or after menopause 2
- 90% of patients experience only one or few attacks in their lifetime 2
Cutaneous Symptoms
- Bullous skin lesions with skin fragility on sun-exposed areas (PCT, VP, HCP, CEP) 1, 3
- Acute painful photosensitivity without scarring (EPP, XLEPP) 1, 2
Age of Onset
- Erythropoietic porphyrias (CEP, EPP) often present in newborns or children 1
- Acute porphyrias (AIP, VP, HCP) typically become symptomatic in early adulthood 1
- PCT most often presents in adults or older age 1
Long-Term Complications
- Liver disease including primary liver cancer and acute liver failure 1, 2
- Chronic kidney disease and renal failure 1, 2
- Hypertension, osteoporosis, vitamin D deficiency, and anemia 1, 2
Genetic Considerations
- Most porphyrias are hereditary with autosomal dominant, autosomal recessive, or X-linked inheritance patterns 1
- Critical caveat: Autosomal dominant porphyrias have low clinical penetrance—pathogenic variants are frequently found in the general population without causing metabolic or clinical disease 1
- PCT is predominantly a sporadic, non-hereditary disease in most populations 1
- Genetic testing has limited diagnostic value in symptomatic patients and should not be used for screening without prior biochemical confirmation 1, 2