Iron in Porphyrias: Friend or Foe?

Buzzetti, Elena; Ventura, Paolo; Corradini, Elena

doi:10.3390/diagnostics12020272

Cited by 4 publications

(4 citation statements)

References 87 publications

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“…Moreover, an increase in aberrant FECH transcripts was reported in iron-depleted cells ( Barman-Aksozen et al, 2013 ). Then, iron deficiency might lead to less PPIX accumulation by inhibiting ALAS2 but should also increase PPIX level by inhibiting FECH action ( Buzzetti et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Microcytosis in Erythropoietic Protoporphyria

et al. 2022

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Partial deficiency of the last enzyme of the heme biosynthetic pathway, namely, ferrochelatase (FECH), is responsible for erythropoietic protoporphyria (EPP) in humans. This disorder is characterized by painful skin photosensitivity, due to excessive protoporphyrin IX (PPIX) production in erythrocytes. Although several papers report the presence of iron deficiency anemia in about 50% of EPP patients, there is still no a conclusive explanation of the why this occurs. In the present work, we explored hematological indices and iron status in 20 unrelated Italian EPP patients in order to propose a new hypothesis. Our data show that microcytosis is present in EPP patients also in the absence of anemia and iron deficiency with a link between PPIX accumulation and reduced MCV, probably indicating an indirect condition of heme deficiency. Patients studied had a downward shift of iron parameters due to increased hepcidin concentrations only in a state of repleted iron stores. Interestingly, hemoglobin synthesis was not limited by iron supply except in cases with further iron loss, in which concomitantly increased soluble transferrin (Tf) receptor (sTfR) levels were detected. The mechanisms involved in the iron uptake downregulation in EPP remain unclear, and the role of PPIX accumulation in microcytosis.

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Section: Introductionmentioning

confidence: 99%

Microcytosis in Erythropoietic Protoporphyria

et al. 2022

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“…The effects of iron supplementation therapy in EPP and XLP are controversial [4][5][6]. Early reports mention a beneficial effect of iron supplementation on EPP symptoms, as well as protoporphyrin and transaminase levels [123][124][125], whereas other authors warned against a worsening of cutaneous and hepatic symptoms [126][127][128].…”

Section: Erythropoietic and X-linked Protoporphyriamentioning

confidence: 99%

“…In line with the complexity of the processes involved, the role of iron in porphyrias and congenital sideroblastic anemias is multifarious [4][5][6]. This review aims at summarising the most important lines of evidence concerning the interplay between iron and heme metabolism, as well as the clinical and experimental aspects of the role of iron in inherited conditions of altered heme biosynthesis.…”

Section: Introductionmentioning

confidence: 99%

Iron Metabolism in the Disorders of Heme Biosynthesis

et al. 2022

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Given its remarkable property to easily switch between different oxidative states, iron is essential in countless cellular functions which involve redox reactions. At the same time, uncontrolled interactions between iron and its surrounding milieu may be damaging to cells and tissues. Heme—the iron-chelated form of protoporphyrin IX—is a macrocyclic tetrapyrrole and a coordination complex for diatomic gases, accurately engineered by evolution to exploit the catalytic, oxygen-binding, and oxidoreductive properties of iron while minimizing its damaging effects on tissues. The majority of the body production of heme is ultimately incorporated into hemoglobin within mature erythrocytes; thus, regulation of heme biosynthesis by iron is central in erythropoiesis. Additionally, heme is a cofactor in several metabolic pathways, which can be modulated by iron-dependent signals as well. Impairment in some steps of the pathway of heme biosynthesis is the main pathogenetic mechanism of two groups of diseases collectively known as porphyrias and congenital sideroblastic anemias. In porphyrias, according to the specific enzyme involved, heme precursors accumulate up to the enzyme stop in disease-specific patterns and organs. Therefore, different porphyrias manifest themselves under strikingly different clinical pictures. In congenital sideroblastic anemias, instead, an altered utilization of mitochondrial iron by erythroid precursors leads to mitochondrial iron overload and an accumulation of ring sideroblasts in the bone marrow. In line with the complexity of the processes involved, the role of iron in these conditions is then multifarious. This review aims to summarise the most important lines of evidence concerning the interplay between iron and heme metabolism, as well as the clinical and experimental aspects of the role of iron in inherited conditions of altered heme biosynthesis.

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“…In addition, most patients are affected by disturbances in the iron metabolism like low hemoglobin, ferritin, transferrin saturation, and iron accompanied by microcytic, hypochromic anemia ( Barman-Aksözen et al, 2015 ). Despite these indications for iron deficiency, earlier studies and case reports from patients with FECH deficient EPP demonstrated that administration of iron, while improving the anemia, also induced an increase in PPIX, phototoxicity and serum transaminases indicating induction of liver cell damage ( Holme et al, 2007 ; Buzzetti et al, 2022 ). The observed increase in PPIX under iron substitution is likely mediated by stimulated erythropoietic porphyrin synthesis via induction of ALAS2 translation by iron.…”

Section: Introductionmentioning

confidence: 99%

Heme Biosynthetic Gene Expression Analysis With dPCR in Erythropoietic Protoporphyria Patients

et al. 2022

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Background: The heme biosynthesis (HB) involves eight subsequent enzymatic steps. Erythropoietic protoporphyria (EPP) is caused by loss-of-function mutations in the ferrochelatase (FECH) gene, which in the last HB step inserts ferrous iron into protoporphyrin IX (PPIX) to form heme.Aim and method: The aim of this work was to for the first time analyze the mRNA expression of all HB genes in peripheral blood samples of patients with EPP having the same genotype FECH c.[215dupT]; [315-48T > C] as compared to healthy controls by highly sensitive and specific digital PCR assays (dPCR).Results: We confirmed a decreased FECH mRNA expression in patients with EPP. Further, we found increased ALAS2 and decreased ALAS1, CPOX, PPOX and HMBS mRNA expression in patients with EPP compared to healthy controls. ALAS2 correlated with FECH mRNA expression (EPP: r = 0.63, p = 0.03 and controls: r = 0.68, p = 0.02) and blood parameters like PPIX (EPP: r = 0.58 p = 0.06).Conclusion: Our method is the first that accurately quantifies HB mRNA from blood samples with potential applications in the monitoring of treatment effects of mRNA modifying therapies in vivo, or investigation of the HB pathway and its regulation. However, our findings should be studied in separated blood cell fractions and on the enzymatic level.

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Iron in Porphyrias: Friend or Foe?

Cited by 4 publications

References 87 publications

Microcytosis in Erythropoietic Protoporphyria

Microcytosis in Erythropoietic Protoporphyria

Iron Metabolism in the Disorders of Heme Biosynthesis

Heme Biosynthetic Gene Expression Analysis With dPCR in Erythropoietic Protoporphyria Patients

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