Porphyria
Basics
Description
- Porphyrias: group of inherited or acquired metabolic disorders involving heme biosynthesis (1,2)
- Symptoms mediated by overproduction of porphyrins or precursors in heme biosynthetic pathway (1,2)
- Heme biosynthesis (1)
- Involves eight enzymes (either cytoplasmic or mitochondrial) that are activated sequentially
- Occurs in all cells containing mitochondria but primarily in bone marrow (80%) and liver (15%)
- Essential for hemoglobin and formation of various cytochrome p450 (CYP450) isoenzymes
- Classification (1,2,3)
- See below for descriptions of each abbreviation.
- Acute porphyrias (AIP, VP, HCP, ADP)
- Inheritance: generally autosomal dominant (except ADP) with incomplete penetrance
- Clinical symptoms generally manifest during CYP450 induction (i.e., need for increased production by bone marrow or liver)
- Recurrent attacks (≥4 per year) occur in 3–5% of newly diagnosed patients.
- Chronic porphyrias (PCT, EPP, CEP, XLP)
- Inheritance: generally autosomal recessive (except PCT and XLP, see below)
- Chronic in nature; symptoms (mainly cutaneous) wax and wane over time.
- Do not present with acute attacks
- Can lead to progressive hepatic impairment
- Acute intermittent porphyria (AIP)
- Acute; autosomal dominant inheritance
- Deficient enzyme: no. 3 (porphobilinogen [PBG] deaminase, cytoplasmic, HMBS gene)
- ALA dehydratase deficiency porphyria (ADP)
- Acute; autosomal recessive inheritance
- Deficient enzyme: no. 2 (ALA dehydratase, cytoplasmic, ALAD gene)
- Congenital erythropoietic porphyria (CEP)
- Chronic; autosomal recessive inheritance
- Deficient enzyme: no. 4 (uroporphyrinogen III synthase, cytoplasmic, UROS gene)
- Rarely linked to GATA-1 (transcription factor) mutations on X chromosome
- Erythropoietic protoporphyria (EPP)
- Chronic; autosomal recessive inheritance
- Deficient enzyme: no. 8 (ferrochelatase, mitochondrial, FECH gene)
- Hereditary coproporphyria (HCP)
- Acute; autosomal dominant inheritance
- Deficient enzyme: no. 6 (coproporphyrinogen oxidase, mitochondrial, CPOX gene)
- Porphyria cutanea tarda (PCT)
- Chronic; 75% of cases acquired (type 1), whereas 25% of cases familial (type 2)
- Type 2: autosomal dominant inheritance but low clinical penetrance
- Deficient enzyme: no. 5 (uroporphyrinogen decarboxylase, cytoplasmic, UROD gene)
- Hepatoerythropoietic porphyria (HEP) caused by biallelic UROD gene mutations (homozygous recessive; extremely rare)
- Chronic; 75% of cases acquired (type 1), whereas 25% of cases familial (type 2)
- Variegate porphyria (VP)
- Acute; autosomal dominant inheritance
- Deficient enzyme: no. 7 (protoporphyrinogen type III oxidase, mitochondrial, PPOX gene)
- X-linked protoporphyria (XLP)
- Chronic; X-linked dominant inheritance
- Gain-of-function mutation in enzyme no. 1 (ALA synthase, mitochondrial, ALAS2 gene)
Epidemiology
- PCT: prevalence 1/5,000 to 1/25,000 (1)
- Most common porphyria overall
- Onset: ages 20 to 50 years
- AIP: prevalence 1/75,000 (1,2)
- Most common acute porphyria
- 1/1,000 prevalence in Sweden (founder effect)
- Onset: puberty to age 40 years
- EPP: prevalence 1/75,000 to 1/200,000 (1)
- Most common pediatric porphyria
- Onset: ages 1 to 4 years
- VP: prevalence 1/50,000 (1)
- 1/300 prevalence in South Africa (founder effect)
- Onset: puberty to age 30 years
- CEP: rare, ~150 cases reported (1)
- Onset: infancy to age 10 years
- XLP: prevalence 1/700,000 (3,4)
- Onset: childhood
- HCP: rare, <50 cases reported (1)
- Onset: after puberty
- ADP: rare, <10 cases reported (1)
- Onset: both childhood and adulthood
Etiology and Pathophysiology
- Symptoms mediated by overproduction of porphyrins or precursors (ALA, PBG) proximal to defect (1,2)
- Neuropsychiatric signs/symptoms: caused by ALA neurotoxicity, either with free radical generation or interactions with GABA receptors (2)
- Dermatologic signs/symptoms: caused by UV-induced oxidative damage induced by porphyrins (4,5)
- Hepatobiliary signs/symptoms: mediated by bile flow impairment or gallstones preventing clearance (5)
Risk Factors
- Attacks in acute porphyria commonly triggered by CYP450 inducers (2)
- Antibiotics (rifampin, macrolides, trimethoprim)
- Antiepileptics (barbiturates, phenytoin)
- Progesterone (hormonal contraception)
- Pregnancy increases risk of attacks but course generally well tolerated without adverse perinatal or neonatal outcomes.
- Other triggers: carbohydrate reduction (starvation, gastrointestinal upset), alcohol (particularly binge drinking), tobacco, viral infections
- PCT (1)
- Chronic alcohol or tobacco use
- Iron overload (e.g., hemochromatosis)
- Hepatitis C virus (HCV) or HIV infection
- Exogenous estrogen use
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Citation
Domino, Frank J., et al., editors. "Porphyria." 5-Minute Clinical Consult, 33rd ed., Wolters Kluwer, 2025. Medicine Central, im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816140/1.1/Porphyria.
Porphyria. In: Domino FJF, Baldor RAR, Golding JJ, et al, eds. 5-Minute Clinical Consult. Wolters Kluwer; 2025. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816140/1.1/Porphyria. Accessed November 4, 2024.
Porphyria. (2025). In Domino, F. J., Baldor, R. A., Golding, J., & Stephens, M. B. (Eds.), 5-Minute Clinical Consult (33rd ed.). Wolters Kluwer. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816140/1.1/Porphyria
Porphyria [Internet]. In: Domino FJF, Baldor RAR, Golding JJ, Stephens MBM, editors. 5-Minute Clinical Consult. Wolters Kluwer; 2025. [cited 2024 November 04]. Available from: https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816140/1.1/Porphyria.
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