porphyria

Last edited 11/2021 and last reviewed 03/2022

The porphyrias are a group of disorders caused by defects in the synthesis of haem.

Hepatic porphyrias:

• acute intermittent porphyria (AIP)
• variegate porphyria (VP)
• hereditary coproporphyria (HCP)
• aminolevulinic acid dehydratase porphyria (ADP), of which only six definite cases have been reported (1)
• porphyria cutanea tarda (PCT)

Erythropoietic porphyrias:

• erythropoietic porphyria (EP)
• erythropoietic protoporphyria (EPP)
• erythropoietic coproporphyria (ECP)

Hepatic / erythropoietic:

• hepatoerythropoietic porphyria (HEP)

In hepatic porphyrias there is excess hepatic production of porphobilinogen. In erythropoietic porphyrias there is increased production of porphyrins in red blood cells due to enzyme deficiency.

A useful classification divides porphyrias into acute and non-acute:

• porphyrias have been subdivided into hepatic and erythropoietic forms, according to the site of expression of the dysfunctional enzyme
  • although may be classified according to their clinical manifestations- as acute (neurovisceral) versus non-acute (cutaneous) porphyrias
• acute neurovisceral forms are characterized by overproduction of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), which are porphyrin precursors, at the initial steps of heme synthesis
• cutaneous porphyrias are characterized by accumulation of porphyrins, which are the precursors at the final steps of the synthesis
  
• in some of the acute porphyria types both neurovisceral and cutaneous symptoms may be present (2)

Notes:

• accumulated precursors are excreted in the urine, in the feces, or in both - according to their solubility -and measuring their level is the basis of porphyria biochemical diagnosis and typing
• heme
  • is the final product of the pathway
  • is essential for the synthesis of hematoproteins such as hemoglobin, myoglobin, microsomal cytochromes, catalase and others
    • all of which play an important role in oxygen transport and/or oxidation–reduction reactions
    • most of heme synthesis in human beings (80%) takes place in erythropoietic cells, while about 15% is produced in the liver parenchymal cells
  • the most important site of control is the first step in the synthesis, ALA formation
    • catalyzed by the enzyme ALA synthase (ALAS), which has two subtypes
      • ALAS1, the ubiquitous one, encoded on chromosome 3,
      • ALAS2, erythroid-specific, encoded on chromosome X
      • in the erythropoietic tissue, regulation of heme synthesis is influenced by erythroid differentiation and erythropoietin and iron availability
      • in the liver, ALAS1 is under negative feedback regulation by the intracellular heme pool
    • the levels of delta-aminolevulinate are elevated in all patients with porphyria because of the loss of feedback inhibition of d-ALA synthase by haem
    • haem usually prevents the translation of d-ALA synthase by activating a protein which binds to the 5'-untranslated region of the mRNA
    • in acute porphyrias the activity of porphobilinogen deaminase is either normal or low resulting in the accumulation of porphobilinogen (PBG). The combination of high d-ALA and PBG results in the abdominal pain and neuropsychiatric features
    • in non-acute porphyrias the acitivity of PBG deaminase is elevated and so PBG does no accumulate. There are specific defects in the the subsequent metabolism of proto-porphyrins. Accumulation of protoporphyris causes the photosensitivity

Reference:

• Edel Y, Mamet R. Porphyria: What Is It and Who Should Be Evaluated?. Rambam Maimonides Med J. 2018;9(2):e0013. Published 2018 Apr 19. doi:10.5041/RMMJ.10333
• Karim Z, Lyoumi S, Nicolas G, Deybach JC, Gouya L, Puy H. Porphyrias: a 2015 update. Clin Res Hepatol Gastroenterol. 2015;39:412–25