Iron in Porphyrias: Friend or Foe?

Abstract

Iron is a trace element that is important for many vital processes, including oxygen transport, oxidative metabolism, cellular proliferation, and catalytic reactions. Iron supports these functions mainly as part of the heme molecule. Heme synthesis is an eight-step process which, when defective at the level of one of the eight enzymes involved, can cause the development of a group of diseases, either inherited or acquired, called porphyrias. Despite the strict link between iron and heme, the role of iron in the different types of porphyrias, particularly as a risk factor for disease development/progression or as a potential therapeutic target or molecule, is still being debated, since contrasting results have emerged from clinical observations, in vitro studies and animal models. In this review we aim to deepen such aspects by drawing attention to the current evidence on the role of iron in porphyrias and its potential implication. Testing for iron status and its metabolic pathways through blood tests, imaging techniques or genetic studies on patients affected by porphyrias can provide additional diagnostic and prognostic value to the clinical care, leading to a more tailored and effective management.

Keywords: anemia; heme; hepcidin; iron; porphyrias.

Figure 1

Iron Metabolism in the Human Body. Abbreviations: DMT-1, divalent metal transporter 1; Dcytb, duodenal cytochrome B; HO: heme oxygenase; Ft, ferritin; Fpn, ferroportin; Heph, hephaestin; Tf, transferrin; EPL, erythrophagolysomes; Cp, ceruloplasmin, ferroxidase activity; Hb, hemoglobin; HPX, hemopexin; HPG, haptoglobin; NTBI, non transferrin-bound iron; TfR1, transferrin receptor 1; ALAS, aminolevulinate synthase.

Figure 2

Summary of heme synthetic pathway, types of porphyrias and iron influences within the cell (cytosolic and mitochondrial compartments). Heme synthesis starts in mitochondria, with the condensation of succinyl-CoA with the amino acid glycine, activated by pyridoxal phosphate by ALA synthase, the rate-limiting enzyme of heme synthesis. ALA then enters the cytoplasm, where, in the presence of ALA dehydratase, porphobilinogen and water molecules are formed. Four PBG molecules are joined by PBG deaminase as hydroxymethylbilane. Linear tetrapyrrole cyclizes to form a ring known as uroporphyrinogen III with the participation of uroporphyrinogen III synthase. Through the activity of uroporphyrinogen III decarboxylase (UROD), coproporphyrinogen III is generated. In mitochondria CPG is then transformed into protoporphyrinogen, which is then further oxidized to protoporphyrins. Finally, iron is incorporated to generate heme. In each specific form of porphyria (in blue) the activity of a specific enzyme (in red) in the heme biosynthetic pathway is defective and leads to accumulation of pathway intermediates. Iron (Fe2+) is involved in ALAS2 regulation via the IRE-IRP system, in FECH activity and possibly in UROD activity. Abbreviations: ALA, 5-aminolevulinic acid; ALAS, 5-aminolevulinic acid synthase; ALA-D, 5-aminolevulinic acid dehydratase; PBG, porphobilinogen; HMB, hydroxymethylbilane; PBG-D, porphobilinogen deaminase; UroPIII, uroporphyrinogen III; UROS, uroporphyrinogen III synthase; CPPIII, coproporphyrinogen III; UROD, uroporphyrinogen III decarboxylase (UROD); CPOX, coproporphyrinogen oxidase ProtoIX, protoporphyrinogen IX, PPOX, protoporphyrinogen oxidase; PPIX, protoporphyrin IX (PPIX); FECH, ferrochelatase. XLPP, X-linked protoporphyria; ALADDP, 5-aminolevulinic acid dehydratase deficiency porphyria; AIP, acute intermittent porphyria; CEP, congenital erythropoietic porphyria; PCT, porphyria cutanea tarda; HEP, hepato-erythropoietic porphyria; HCP, hereditary coproporphyria; VP, variegate porphyria; EPP, erythropoietic protoporphyria. IRP, iron regulatory protein; Ox, oxidative stress.