Porphyrias: Causes

Pathogenesis (disease development)

Heme is a component of hemoglobin (red blood pigment) in erythrocytes (red blood cells), myoglobin (red muscle pigment), and cytochromes (enzymes that are important in the breakdown of drugs, among other things). It consists of a porphyrin in the middle of which there is an iron ion. The formation of heme takes place mainly in the bone marrow and to a small extent in the liver. Eight enzymes are involved in the formation of heme. In porphyria, there is an enzyme defect, which means that heme cannot be formed as regularly. Instead, there is an accumulation of intermediate products of heme biosynthesis (heme precursors such as porphobilinogen (PBG) and delta-aminolevulinic acid (ALA)) in the organs, especially in the skin and liver. Which organs are affected in their function depends on which of the eight enzymes is defective. The porphyrins are not only stored, but also excreted in the stool and urine. An orange or red colored urine is therefore a sign of some forms of porphyria. Heme biosynthesis with the corresponding enzymes and the related porphyria.

Step Substance name Enzyme involved in the reaction step Associated porphyria
Succinyl-CoA and glycine (= starting materials).
1 ↓ ALA synthase X-linked protoporphyria
5-aminolevulinic acid (ALA)
2 ↓ ALA dehydratase ALA dehydratase deficiency porphyria
Porphobilinogen
3 ↓ Porphobilinogen deaminase Acute intermittent porphyria
Hydroxymethylbilane
4 ↓ Uroporphyrinogen synthase Congenital erythropoietic porphyria
Uroporphyrinogen III
5 ↓ Uroporphyrinogen decarboxylase Porphyria cutanea tarda
Coproporphyrinogen III
6 ↓ Coproporphyrinogen oxidase Hereditary coproporphyria
Protoporphyrinogen IX
7 ↓ Protoporphyrinogen oxidase Porphyria variegata
Protoporphyrin IX
8 ↓ Ferrochelatase Protoporphyria
Hem

Etiology (causes)

Biographical causes

  • Genetic burden from parents, grandparents – Primary porphyrias result from a gene mutation. This can be passed on, skipping generations.
    • In acute intermittent porphyria (AIP), the enzyme porphobilinogen deaminase is defective (3rd enzyme in heme biosynthesis; mutation on chromosome 11).
    • In porphyria cutanea tarda (PCT), the enzyme uroporphyrinogen III decarboxalysis is defective (5th enzyme in heme biosynthesis). This form can be passed heterozygous, meaning the gene defect is on one of the two paired chromosomes, or homozygous, meaning the gene defect is on both chromosomes.
    • In erythropoietic porphyria (EPP), the last enzyme of heme biosynthesis is defective. This is where the iron ion is normally incorporated.
  • Hormonal changes – menstruation (in the second phase of the cycle/luteal phase), gravidity (in the first weeks of pregnancy or immediately after birth) [acute porphyrias].

Primary porphyrias

An attack/burst in the setting of acute porphyrias may be triggered by the following factors:

Behavioral triggers

  • Diet
    • Carbohydrate deficiency due to (crash) diets
    • Hunger states – attention must be paid to regular eating
  • Pleasure food
    • Alcohol
  • Psycho-social situation
    • Stress

Disease-related triggers

  • Infections

Operations

Medications – porphyria centers of excellence provide information on the compatibility or suitability of medications.

Environmental pollution – intoxications (poisonings).

  • Organic solvents, such as those found in painting companies and dry cleaning.

An attack/flash in cutaneous porphyrias can be triggered by the following factors:

Behavioral triggers

  • Stimulants
    • Alcohol
  • (Sun) light exposure – applying suntan lotion is of no use, as the damaging wavelengths are in the visible range of light and sunscreen only has a protective effect in the UV range; textiles with UV protection factor and protective films also do not help

Secondary porphyrias

Coproporphyrias

Behavioral causes

  • Nutrition
    • Hunger states – attention must be paid to regular eating

Causes related to disease

  • Bilirubin transport disorders
  • Hemochromatosis (iron storage disease).
  • Infections
  • Liver diseases
  • Leukemias

Environmental pollution – intoxications

  • Toxic chemicals (hepatotoxic/liver damaging).

Protoporphyrinemias

Behavioral causes

  • Stimulants
    • Alcohol (liver damaging)

Causes related to disease

  • Hemolytic anemias

Environmental pollution – intoxications

  • Lead poisoning