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01-05-2017 | Original Article

Disturbed iron metabolism in erythropoietic protoporphyria and association of GDF15 and gender with disease severity

Authors: Jasmin Barman-Aksoezen, Domenico Girelli, Caterina Aurizi, Xiaoye Schneider-Yin, Natascia Campostrini, Luca Barbieri, Elisabeth I. Minder, Gianfranco Biolcati

Published in: Journal of Inherited Metabolic Disease | Issue 3/2017

Abstract

Patients with erythropoietic protoporphyria (EPP) have reduced activity of the enzyme ferrochelatase that catalyzes the insertion of iron into protoporphyrin IX (PPIX) to form heme. As the result of ferrochelatase deficiency, PPIX accumulates and causes severe photosensitivity. Among different patients, the concentration of PPIX varies considerably. In addition to photosensitivity, patients frequently exhibit low serum iron and a microcytic hypochromic anemia. The aims of this study were to (1) search for factors related to PPIX concentration in EPP, and (2) characterize anemia in EPP, i.e., whether it is the result of an absolute iron deficiency or the anemia of chronic disease (ACD). Blood samples from 67 EPP patients (51 Italian and 16 Swiss) and 21 healthy volunteers were analyzed. EPP patients had lower ferritin (p = 0.021) and hepcidin (p = 0.031) concentrations and higher zinc–protoporphyrin (p < 0.0001) and soluble-transferrin-receptor (p = 0.0007) concentrations compared with controls. This indicated that anemia in EPP resulted from an absolute iron deficiency. Among EPP patients, PPIX concentrations correlated with both growth differentiation factor (GDF) 15 (p = 0.012) and male gender (p = 0.015). Among a subgroup of patients who were iron replete, hemoglobin levels were normal, which suggested that iron but not ferrochelatase is the limiting factor in heme synthesis of individuals with EPP.

Allen J, Backstrom KR, Cooper JA, Cooper MC, Detwiler TC, Essex DW, Fritz RP, Means RT, Meier PB, Pearlman SR, Roitman-Johnson B, Seligman A (1998) Measurement of soluble transferrin receptor in serum of healthy adults. Clinical Chemistry 44.1: 35-39

Baker H (1971) Erythropoietic protoporphyria provoked by iron therapy. Proc R Soc Med 64:610–611PubMedPubMedCentral

Balwani M, Bloomer J, Desnick R (2014) Erythropoietic protoporphyria, autosomal recessive. In: Pagon RR, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean JLH, Ledbetter N, Mefford HC, Smith RJH, Stephens K (eds) GeneReviews. University of Washington, Seattle

Barman-Aksozen J, Beguin C, Dogar AM, Schneider-Yin X, Minder EI (2013) Iron availability modulates aberrant splicing of ferrochelatase through the iron- and 2-oxoglutarate dependent dioxygenase Jmjd6 and U2AF(65.). Blood Cells Mol Dis 51:151–161CrossRefPubMed

Barman-Aksozen J, Minder EI, Schubiger C, Biolcati G, Schneider-Yin X (2015) In ferrochelatase-deficient protoporphyria patients, ALAS2 expression is enhanced and erythrocytic protoporphyrin concentration correlates with iron availability. Blood Cells Mol Dis 54:71–77CrossRefPubMed

Bossi K, Lee J, Schmeltzer P, Holburton E, Groseclose G, Besur S, Hwang S, Bonkovsky HL (2015) Homeostasis of iron and hepcidin in erythropoietic protoporphyria. Eur J Clin Investig 45:1032–1041CrossRef

Campostrini N, Castagna A, Zaninotto F, Bedogna V, Tessitore N, Poli A, Martinelli N, Lupo A, Olivieri O, Girelli D (2010) Evaluation of hepcidin isoforms in hemodialysis patients by a proteomic approach based on SELDI-TOF MS. J Biomed Biotechnol 2010:329646CrossRefPubMedPubMedCentral

Cook JD, Finch CA (1979) Assessing iron status of a population. Am J Clin Nutr 32:2115–2119PubMed

Delaby C, Lyoumi S, Ducamp S, Martin-Schmitt C, Gouya L, Deybach JC, Beaumont C, Puy H (2009) Excessive erythrocyte PPIX influences the hematologic status and iron metabolism in patients with dominant erythropoietic protoporphyria. Cell Mol Biol (Noisy-le-grand) 55:45–52

Eyster E, Mayer K, McKenzie S (1968) Traumatic hemolysis with iron deficiency anemia in patients with aortic valve lesions. Ann Intern Med 68:995–1004CrossRefPubMed

Fleming RE, Sly WS (2001) Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease. Proc Natl Acad Sci U S A 98:8160–8162CrossRefPubMedPubMedCentral

Ganz T (2013) Systemic iron homeostasis. Physiol Rev 93:1721–1741CrossRefPubMed

Goodnough LT (2012) Iron deficiency syndromes and iron-restricted erythropoiesis (CME). Transfusion 52:1584–1592CrossRefPubMed

Gouya L, Puy H, Robreau AM, Bourgeois M, Lamoril J, Da Silva V, Grandchamp B, Deybach JC (2002) The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH. Nat Genet 30:27–28CrossRefPubMed

Gulec S, Anderson GJ, Collins JF (2014) Mechanistic and regulatory aspects of intestinal iron absorption. Am J Physiol Gastrointest Liver Physiol 307:G397–G409CrossRefPubMedPubMedCentral

Han AP, Fleming MD, Chen JJ (2005) Heme-regulated eIF2alpha kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and beta-thalassemia. J Clin Invest 115:1562–1570CrossRefPubMedPubMedCentral

Holme SA, Worwood M, Anstey AV, Elder GH, Badminton MN (2007) Erythropoiesis and iron metabolism in dominant erythropoietic protoporphyria. Blood 110:4108–4110CrossRefPubMed

Holme SA, Whatley SD, Roberts AG, Anstey AV, Elder GH, Ead RD, Stewart MF, Farr PM, Lewis HM, Davies N, White MI, Ackroyd RS, Badminton MN (2009) Seasonal palmar keratoderma in erythropoietic protoporphyria indicates autosomal recessive inheritance. J Investig Dermatol 129:599–605CrossRefPubMed

Hsiao EC, Koniaris LG, Zimmers-Koniaris T, Sebald SM, Huynh TV, Lee SJ (2000) Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury. Mol Cell Biol 20:3742–3751CrossRefPubMedPubMedCentral

Kempf T, Zarbock A, Widera C, Butz S, Stadtmann A, Rossaint J, Bolomini-Vittori M, Korf-Klingebiel M, Napp LC, Hansen B, Kanwischer A, Bavendiek U, Beutel G, Hapke M, Sauer MG, Laudanna C, Hogg N, Vestweber D, Wollert KC (2011) GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat Med 17:581–588CrossRefPubMed

Kirkwood B, Sterne J (2003) Essential medical statistics, 2nd edn. Wiley, Oxford

Koniaris LG (2003) Induction of MIC-1/growth differentiation factor-15 following bile duct injury. J Gastrointest Surg 7:901–905CrossRefPubMed

Lecha M, Puy H, Deybach JC (2009) Erythropoietic protoporphyria. Orphanet J Rare Dis 4:19CrossRefPubMedPubMedCentral

Lyoumi S, Abitbol M, Andrieu V, Henin D, Robert E, Schmitt C, Gouya L, de Verneuil H, Deybach JC, Montagutelli X, Beaumont C, Puy H (2007) Increased plasma transferrin, altered body iron distribution, and microcytic hypochromic anemia in ferrochelatase-deficient mice. Blood 109:811–818CrossRefPubMed

McClements BM, Bingham A, Callender ME, Trimble ER (1990) Erythropoietic protoporphyria and iron therapy. Br J Dermatol 122:423–424CrossRefPubMed

Milligan A, Graham-Brown RA, Sarkany I, Baker H (1988) Erythropoietic protoporphyria exacerbated by oral iron therapy. Br J Dermatol 119:63–66CrossRefPubMed

Minder EI, Schneider-Yin X (2008) Porphyrins, porphobilinogen, and δ–aminolevulinic acid. In: Blau N, Duran M, Gibson KM (eds) Laboratory guide to the methods in biochemical genetics. Springer, Berlin, pp 751–780CrossRef

Minder EI, Schneider-Yin X, Mamet R, Horev L, Neuenschwander S, Baumer A, Austerlitz F, Puy H, Schoenfeld N (2010) A homoallelic FECH mutation in a patient with both erythropoietic protoporphyria and palmar keratoderma. J Eur Acad Dermatol Venereol 24:1349–1353CrossRefPubMed

Moore AG, Brown DA, Fairlie WD, Bauskin AR, Brown PK, Munier ML, Russell PK, Salamonsen LA, Wallace EM, Breit SN (2000) The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. J Clin Endocrinol Metab 85:4781–4788PubMed

Murphy WG (2014) The sex difference in haemoglobin levels in adults—mechanisms, causes, and consequences. Blood Rev 28:41–47CrossRefPubMed

Musallam KM, Taher AT, Duca L, Cesaretti C, Halawi R, Cappellini MD (2011) Levels of growth differentiation factor-15 are high and correlate with clinical severity in transfusion-independent patients with beta thalassemia intermedia. Blood Cells Mol Dis 47:232–234CrossRefPubMed

Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, Vaulont S (2001) Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci U S A 98:8780–8785CrossRefPubMedPubMedCentral

Osada M, Park HL, Park MJ, Liu JW, Wu G, Trink B, Sidransky D (2007) A p53-type response element in the GDF15 promoter confers high specificity for p53 activation. Biochem Biophys Res Commun 354:913–918CrossRefPubMedPubMedCentral

Schneider-Yin X, Minder EI (2013) In: Ferreira GC (ed) Erythropoietic protoporphyria and X-linked dominant protoporphyria. World Scientific Publishing Company, Singapore, pp 299–328

Schneider-Yin X, Harms J, Minder EI (2009) Porphyria in Switzerland, 15 years experience. Swiss Med Wkly 139:198–206PubMed

Sears DA, Anderson PR, Foy AL, Williams HL, Crosby WH (1966) Urinary iron excretion and renal metabolism of hemoglobin in hemolytic diseases. Blood 28:708–725PubMed

Simpson RJ, McKie AT (2009) Regulation of intestinal iron absorption: the mucosa takes control? Cell Metab 10:84–87CrossRefPubMed

Skikne BS, Flowers CH, Cook JD (1990) Serum transferrin receptor: a quantitative measure of tissue iron deficiency. Blood 75:1870–1876PubMed

Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, Moroney JW, Reed CH, Luban NL, Wang RH, Eling TE, Childs R, Ganz T, Leitman SF, Fucharoen S, Miller JL (2007) High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 13:1096–1101CrossRefPubMed

Tanno T, Noel P, Miller JL (2010) Growth differentiation factor 15 in erythroid health and disease. Curr Opin Hematol 17:184–190PubMedPubMedCentral

Tong S, Marjono B, Brown DA, Mulvey S, Breit SN, Manuelpillai U, Wallace EM (2004) Serum concentrations of macrophage inhibitory cytokine 1 (MIC 1) as a predictor of miscarriage. Lancet 363:129–130CrossRefPubMed

Turnbull A, Baker H, Vernon-Roberts B, Magnus IA (1973) Iron metabolism in porphyria cutanea tarda and in erythropoietic protoporphyria. Q J Med 42:341–355PubMed

Wahlin S, Floderus Y, Stal P, Harper P (2011) Erythropoietic protoporphyria in Sweden: demographic, clinical, biochemical and genetic characteristics. J Intern Med 269:278–288CrossRefPubMed

Whatley SD, Ducamp S, Gouya L, Grandchamp B, Beaumont C, Badminton MN, Elder GH, Holme SA, Anstey AV, Parker M, Corrigall AV, Meissner PN, Hift RJ, Marsden JT, Ma Y, Mieli-Vergani G, Deybach JC, Puy H (2008) C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. Am J Hum Genet 83:408–414CrossRefPubMedPubMedCentral

Whatley SD, Mason NG, Holme SA, Anstey AV, Elder GH, Badminton MN (2010) Molecular epidemiology of erythropoietic protoporphyria in the U.K. Br J Dermatol 162:642–646CrossRefPubMed

Zimmers TA, Jin X, Hsiao EC, Perez EA, Pierce RH, Chavin KD, Koniaris LG (2006) Growth differentiation factor-15: induction in liver injury through p53 and tumor necrosis factor-independent mechanisms. J Surg Res 130:45–51CrossRefPubMed

Title: Disturbed iron metabolism in erythropoietic protoporphyria and association of GDF15 and gender with disease severity
Authors: Jasmin Barman-Aksoezen
Domenico Girelli
Caterina Aurizi
Xiaoye Schneider-Yin
Natascia Campostrini
Luca Barbieri
Elisabeth I. Minder
Gianfranco Biolcati
Publication date: 01-05-2017
Publisher: Springer Netherlands
Published in: Journal of Inherited Metabolic Disease / Issue 3/2017
Print ISSN: 0141-8955
Electronic ISSN: 1573-2665
DOI: https://doi.org/10.1007/s10545-017-0017-7

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