Porphyria is a topic covered in the 5-Minute Clinical Consult.

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  • 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)
  • 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)


  • 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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