Porphyrias

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 article (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.

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 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): Acute intermittent porphyria is most common.
    • Chronic (often cutaneous): Porphyria cutanea tarda is most common.
  • Erythropoietic variants (rare)

Primary porphyrias (hereditary enzyme defect)

• Hepatic porphyrias
  • Acute hepatic porphyrias
    • Acute intermittent porphyria (autosomal dominant)
    • Porphyria variegata (autosomal dominant)
    • Hereditary coproporphyria (autosomal dominant)
    • Doss porphyria (autosomal recessive)
  • Chronic hepatic porphyrias
    • Porphyria cutanea tarda (autosomal dominant or acquired)
    • Hepatoerythropoietic porphyria (autosomal recessive)
  • Erythropoietic porphyrias
    • Congenital erythropoietic porphyria (Gunther disease, autosomal recessive)
    • Erythropoietic protoporphyria (autosomal dominant)

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; see metal toxicity)

• Epidemiology
  • Most common porphyria
  • Peak incidence: 40–70 years
  • Sex: ♂ > ♀
• Etiology
  • Defective uroporphyrinogen III decarboxylase (UROD)
    • Type I: acquired insufficiency (sporadic) of UROD in the context of hepatic damage
      • Mainly occurs in older men with chronic alcoholism and hepatic cirrhosis
    • Type II: inherited/familial (autosomal dominant) defective UROD
  • Susceptibility factors
    • Increased hepatic iron stores, hemochromatosis
    • Alcohol, smoking
    • Hepatitis C
    • HIV
    • Estrogen therapy
  • Sunlight exposure
• Pathophysiology
  • Defective UROD → uroporphyrin accumulation in the skin → sunlight-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
  • Avoid susceptibility factors and excessive sunlight.
  • Phlebotomy
  • Hydroxychloroquine or chloroquine

References:^[1][2][3]

• Epidemiology
  • Second most common porphyria
  • Peak incidence: ∼ 30 years
  • Sex: ♀ > ♂ (2:1)
• Etiology
  • Autosomal dominant
  • Mutation of porphobilinogen deaminase (PBG-D), previously known as uroporphyrinogen I synthase
  • Many patients with enzymatic defects associated with AIP remain asymptomatic unless an attack is triggered.
• Attacks are triggered by:
  • Certain drugs (especially inducers of hepatic CYPs): Several enzymes involved in heme biosynthesis are the CYP enzymes of cytochrome P450. Inducers of CYPs stimulate heme biosynthesis resulting in the accumulation of porphyrin intermediates.
    • Anticonvulsants (especially barbiturates, benzodiazepines, phenytoin)
    • Sulfonamides
    • Anesthetics
    • Hormone therapy
  • Alcohol
  • Smoking
  • Sex hormones, especially progesterone
  • Fasting: Increased intake of carbohydrates may alleviate symptoms.
  • Stress (e.g., surgery, infection)
• Pathophysiology: defective PBG-D → accumulation of porphobilinogen (PBG) and δ-aminolevulinic acid (ALA) → symptoms
• Clinical features
  • Fever
  • GI symptoms: severe abdominal pain, nausea, vomiting
  • Neurological abnormalities
    • Polyneuropathy: non-specific pain, weakness/fatigue, paresthesia, paresis
    • Seizures
  • 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.
• Therapy
  • Avoid triggers
  • Hemin
    • An iron-containing porphyrin that inhibits heme synthesis
    • Decreases activity of δ-aminolevulinate synthase → ↓ heme biosynthesis → ↓ intermediates
    • Dark, oily solution
  • Alternatives:
    • Heme arginate
    • Glucose loading

The skin is not involved in acute intermittent porphyria.

The 5 P's of acute intermittent porphyria: Painful abdomen, Polyneuropathy, Psychologic disturbances, Port wine-colored pee, Precipitated by triggers like drugs

1. Kasper DL, Fauci AS, Hauser SL, Longo DL, Lameson JL, Loscalzo J. Harrison's Principles of Internal Medicine. McGraw-Hill Education ; 2015
2. Poh-Fitzpatrick MB. Porphyria Cutanea Tarda. In: Elston DM, Porphyria Cutanea Tarda. New York, NY: WebMD. http://emedicine.medscape.com/article/1103643. Updated: May 8, 2017. Accessed: May 17, 2017.
3. Singal AK, Anderson KE, Schrier SL, Tirnauer JS. Porphyria Cutanea Tarda and Hepatoerythropoietic Porphyria: Clinical Manifestations and Diagnosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/porphyria-cutanea-tarda-and-hepatoerythropoietic-porphyria-clinical-manifestations-and-diagnosis.Last updated: October 5, 2015. Accessed: May 17, 2017.