• Clinical science

Porphyrias

Abstract

Porphyrias are a group of inherited or (rarely) acquired metabolic disorders in which defective enzymes impair the biosynthesis of heme in the liver and/or bone marrow. All porphyrias are characterized by the accumulation of porphyrin, or intermediates of its biosynthesis, which can cause a variety of symptoms depending on the organs involved (e.g., skin, liver, CNS). Porphyria cutanea tarda (PCT) is the most common form and presents with chronic, blistering cutaneous photosensitivity and tea-colored urine. The second most common form, acute intermittent porphyria (AIP), is characterized by life-threatening attacks of severe abdominal pain, constipation, tachycardia, and neuropsychiatric abnormalities. Attacks are generally triggered by certain drugs, alcohol, infections, or fasting. The diagnosis is confirmed by detecting metabolic heme precursors in urine, which often appear reddish. An important acquired form of porphyria is lead poisoning, which is discussed in another learning card (see metal toxicity). Patients with a known porphyria should avoid potential triggers. Management consists of supportive care; acute attacks should be treated with hemin to reduce heme production.

General information

Description

  • Porphyrias are a group of inherited or (rarely) acquired metabolic disorders in which defective enzymes impair the biosynthesis of heme in the liver and/or bone marrow.

Pathophysiology

  • (Trigger →) ↓ enzyme activity in heme biosynthesis → intermediates of heme production accumulate
    • → Deposited into different tissue, such as the skin and/or liver → symptoms
    • → Increased urinary and fecal elimination → metabolite detection
  • The specific intermediates that accumulate depends on which enzymes are affected in the heme biosynthesis pathway.

Classification

Porphyrias can be classified based on inheritance or organ of accumulation.

  • Inheritance: primary (inherited) or secondary (acquired)
  • Organ of accumulation:
    • Hepatic (more common)
      • Acute (often systemic): AIP is most common
      • Chronic (often cutaneous): PCT is most common
    • Erythropoietic variants (rare)

Primary porphyrias (hereditary enzyme defect)

Secondary porphyria (acquired)

  • Secondary coproporphyria (caused by e.g., intoxication, hepatic diseases, blood disorders, infections, starvation)
  • Secondary protoporphyrinemia; (caused by e.g., anemia, alcohol, or chronic heavy metal poisoning)

Porphyria cutanea tarda (PCT)

  • Epidemiology
    • Most common porphyria
    • Peak incidence: 40–70 years
    • Sex: >
  • Etiology
  • Pathophysiology
    • Defective UROD porphyrin accumulation in the skinsunlight-dependent skin damage (chronic photosensitivity)
  • Clinical findings
    • Cutaneous manifestations
      • Increased fragility of sun-exposed skin blistering and impaired healing (blistering photosensitivity)
      • Healing results in scarring and milia formation
      • Hypertrichosis
      • Hyperpigmentation
      • Scleroderma-like changes (especially forehead and scalp)
    • Commonly occurs on:
      • Dorsum of the hand
      • Face and neck
      • Extensor surface of the forearm
  • Diagnosis
    • Urinary tests: uroporphyrin (tea-colored urine)
    • Blood tests: porphyrins, possibly abnormal LFTs
  • Therapy

References:[1][2][3]

Acute intermittent porphyria (AIP)

  • Epidemiology
    • Second most common porphyria
    • Peak incidence: ∼ 30 years
    • Sex: > (2:1)
    • Especially common in Great Britain and Scandinavian countries
  • Etiology
  • Attacks are triggered by:
  • Pathophysiology: defective PBG-Daccumulation of porphobilinogen (PBG) and δ-aminolevulinic acid (ALA) → symptoms
  • Clinical features
    • Fever
    • GI symptoms: severe abdominal pain, nausea, vomiting
    • Neurological abnormalities
    • Psychiatric abnormalities; : hallucinations, disorientation, anxiety, insomnia
    • Autonomic dysfunction; : tachycardia; , hypertension
    • Red-purple urine
    • In contrast to some porphyrias, the skin is not involved
  • Diagnosis
    • Initial diagnosis of AIP is based on clinical findings. A high index of suspicion is necessary.
    • Urinary tests (especially during attacks): PBG and ALA
      • Urine may turn brown, dark red, or purple when exposed to sunlight.
    • Lactate blood level
      • Recent studies have shown dysfunction of oxidative phosphorylation (OXPHOS) in patients with AIP, resulting in elevated lactate blood levels.
      • Therefore, AIP is a relevant DDx in patients with elevated lactate levels.
  • Therapy
    • Avoid triggers
    • Hemin
      • Decreases activity of δ-aminolevulinate synthaseheme biosynthesis → ↓ intermediates
      • Dark, oily solution
    • Alternatives:
      • Heme arginate
      • Glucose loading

The skin is not involved!

The 5 P's: Painful abdomen, Polyneuropathy, Psychologic disturbances, Purple pee, Precipitated by triggers like drugs

Erythropoietic porphyrias

Congenital erythropoietic porphyria (Gunther disease)

Erythropoietic protoporphyria