Provisional standardization of hepcidin assays: creating a traceability chain with a primary reference material, candidate reference method and a commutable secondary reference material

Diepeveen, Laura E.; Laarakkers, Coby M.; Martos, Gustavo; Pawlak, Marta E; Uğuz, Fatih F; Verberne, Kim E S A; Swelm, Rachel P. L. van; Klaver, Siem M.; Haan, A.F.J. de; Pitts, Kelly R.; Bansal, Sukhvinder S.; Abbas, Ioana M.; Fillet, Marianne; Lefèbvre, Thibaud; Geurts-Moespot, Anneke; Girelli, Domenico; Castagna, Annalisa; Herkert, Matthias; Itkonen, Outi; Olbina, Gordana; Tomosugi, Naohisa; Westerman, Mark; Delatour, Vincent; Weykamp, Cas; Swinkels, Dorine W.

doi:10.1515/cclm-2018-0783

Cited by 47 publications

(75 citation statements)

References 27 publications

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“…These values can be used as for any other hepcidin assay worldwide that is standardized using the same secondary RM for calibration. 22 TA B L E 5 Results of linear regression models for hepcidin/ferritin ratio (pmol/µg) adjusted for age and time of blood sampling and stratified by sex 26.8%, with ß -0.057, CI -0.072 to -0.041 (P .000), ß 0.175, CI 0.023-0.326 (P .024), ß 0.432, CI 0.221-0.643 (P .000) for age, sampling time 12-3 PM and sampling time 3-6 PM, respectively. c For females, multivariate linear regression model with log-transformed hepcidin/ferritin ratio as the dependent variable and age (continuous variable) and sampling time as independent variables showed R 2 13.6%, with ß -0.042, CI -0.063 to -0.021 (P .000), ß 0.179, CI 0.026-0.384 (P .087), ß 0.250, CI -0.039-0.539 (P .089) for age, sampling time 12-3 PM and sampling time 3-6 PM, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…37 Our hepcidin assay was recently standardized using a second reference material (RM) that was value assigned by a provisional primary RM. 22 For additional information on the laboratory methods, see the Supporting Information.…”

Section: Laboratory Methodsmentioning

confidence: 99%

“…20,21 They have been constructed based on data from the general adult population (N∼3000), and have recently been converted to standardized reference ranges. 21,22 These data have revealed that in both men and women, serum hepcidin concentrations are strongly associated with serum ferritin 20,23 and only marginally with circulating iron (TSAT). 20 Serum hepcidin concentrations in men stay stable over age while in women concentrations are lower in premenopausal than in postmenopausal women.…”

Section: Introductionmentioning

confidence: 99%

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Standardized serum hepcidin values in Dutch children: Set point relative to body iron changes during childhood

Donker

Galesloot²,

Laarakkers

et al. 2019

Pediatric Blood & Cancer

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Background: Use of serum hepcidin measurements in pediatrics would benefit from standardized age-and sex-specific reference ranges in children, in order to enable the establishment of clinical decision limits that are universally applicable. Procedure:We measured serum hepcidin-25 levels in 266 healthy Dutch children aged 0.3-17 years, using an isotope dilution mass spectrometry assay, standardized with our commutable secondary reference material (RM), assigned by a candidate primary RM. Results:We constructed age-and sex-specific values for serum hepcidin and its ratio with ferritin and transferrin saturation (TSAT). Serum hepcidin levels and hepcidin/ferritin and TSAT/hepcidin ratios were similar for both sexes. Serum hepcidin and hepcidin/ferritin ratio substantially declined after the age of 12 years and TSAT/hepcidin ratio gradually increased with increasing age. Serum hepcidin values for Dutch children <12 years (n = 170) and >12 years (n = 96) were 1.9 nmol/L (median); 0.1-13.1 nmol/L (p2.5-p97.5) and 0.9 nmol/L; 0.0-9.1 nmol/L, respectively. Serum ferritin was the most significant correlate of serum hepcidin in our study population, explaining 15.1% and 7.9% of variance in males and females, respectively. Multivariable linear regression analysis including age, blood sampling time, iron parameters, ALT, CRP, and body mass index as independent variables showed a statistically significant negative association between age as a dichotomous variable (≤12 vs >12 years) and log-transformed serum hepcidin levels in both sexes. Conclusions:We demonstrate that serum hepcidin relative to indicators of body iron is age dependent in children, suggesting that the set point of serum hepcidin relative to stored and circulating iron changes during childhood. K E Y W O R D Schild, ferritin, hepcidin, pediatric reference ranges, transferrin saturation

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Section: Discussionmentioning

confidence: 99%

Section: Laboratory Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Standardized serum hepcidin values in Dutch children: Set point relative to body iron changes during childhood

Donker

Galesloot²,

Laarakkers

et al. 2019

Pediatric Blood & Cancer

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“…Age and gender differences in hepcidin concentrations are known. Within the mean age group of our study population, 30-35 years of age, (normal) hepcidin concentrations were reported to be higher on man than woman (36, 38). However reference data available is coming from Europe and no hepcidin reference levels are known for an African population.…”

Section: Discussionmentioning

confidence: 68%

“…Worldwide hepcidin concentrations are measured by various methods, which differ considerably in absolute hepcidin concentrations (35). Recently, secondary hepcidin reference material, that has been value assigned by a primary reference material, has become available (36). Standardization in February 2019 of a similar hepcidin assay as we used in 2012/2013 for our study, resulted in (only) 5.4 % increase of hepcidin concentrations (C. Laarakker and D. Swinkels unpublished data) (37).…”

Section: Discussionmentioning

confidence: 99%

Hepcidin and conventional markers to detect iron deficiency in severely anaemic HIV-infected patients in Malawi

Huibers

Calis

Allain

et al. 2019

Preprint

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phone: +265(0)883699070/ +31(0)616193631 35 Abstract 36 37 Introduction: Iron deficiency is a treatable cause of severe anaemia in low-and-middle-38 income-countries (LMIC). Diagnosing it remains challenging as peripheral blood markers 39 poorly reflect bone-marrow iron deficiency (BM-ID), especially in the context of HIV-40 infection.41 Methods: Severe anaemic (haemoglobin ≤70g/l) HIV-infected adults were recruited at 42 Queen Elizabeth Central Hospital, Blantyre, Malawi. BM-ID was evaluated. Accuracy of 43 blood markers including hepcidin alongside mean corpuscular volume, mean cellular 44 haemoglobin concentration, serum iron, serum ferritin, soluble transferrin receptor 45 (sTfR), sTfR -index, sTfR -ratio to detect BM-ID was valued by ROC area under the curve 46 (AUC ROC ).47 Results: Seventy-three patients were enrolled and 35 (48.0%) had BM-ID. Hepcidin and 48 MCV performed best; AUC ROC of 0.593 and 0.545. Other markers performed poorly 49 (ROC<0.5). The AUC ROC of hepcidin in males was 0.767 (sensitivity 80%, specificity 78%) 50 and in women 0.490 (sensitivity 60%, specificity 61%).51 Conclusion: BM-ID deficiency was common in severely anaemic HIV-infected patients 52 and is an important and potential treatable contributor to severe anaemia. Hepcidin was 53 the best, though still suboptimal, marker of BM-ID. Hepcidin, which is directly linked to 54 iron absorption, is a very promising marker to guide curative iron supplementation 55 policies in severely anaemic HIV-infected patients. 56 57 59 Introduction 60 Anaemia affects approximately a third of the world's population and substantially reduces the 61 disability-adjusted life years worldwide (1). Iron deficiency contributes to development of 62 anaemia and is diagnosed in more than half of all anaemic persons (2). Consequently, iron 63 supplements remain the backbone of prevention and treatment protocols for anaemia. 64Anaemia has an extensive list of potential causes. In sub-Saharan Africa, where this 65 condition is most common, its aetiology is even more complex and in these setting 66 aetiologies commonly co-incide requiring a multifactorial approach (3, 4). HIV may be the 67 cause of anaemia by its direct effect on BM cells, but can also increase the range of 68 aetiological factors to encompass opportunistic viral, bacterial and parasitic infections, 69 drugs such as Zidovudine and co-trimoxazole, micronutrient deficiencies and neoplastic 70 diseases (5, 6). 71The exact role of iron deficiency, one of the few potentially preventable and 72 treatable causes of anaemia, remains unclear due to its diagnostic challenges in HIV-73 infected patients in low resource settings (3, 4, 7). Peripheral blood markers, including 74 erythrocyte indices, serum iron, ferritin, and soluble transferrin receptor (sTfR), have 75 been evaluated but their accuracy is often negatively affected by inflammatory states and 76 renal and liver conditions, which are common in both the African and HIV-infected 77 populations (8-11). Previous studies therefore concluded that the ...

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Erythroferrone and hepcidin as mediators between erythropoiesis and iron metabolism during allogeneic hematopoietic stem cell transplant

et al. 2021

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Hematopoietic cell transplantation (HCT) brings important alterations in erythropoiesis and iron metabolism. Hepcidin, which regulates iron metabolism, increases in iron overload or inflammation and decreases with iron deficiency or activated erythropoiesis. Erythroferrone (ERFE) is the erythroid regulator of hepcidin. We investigated erythropoiesis and iron metabolism after allogeneic HCT in 70 patients randomized between erythropoietin (EPO) treatment or no EPO, by serially measuring hepcidin, ERFE, CRP (inflammation), soluble transferrin receptor (sTfR, erythropoiesis), serum iron and transferrin saturation (Tsat; iron for erythropoiesis) and ferritin (iron stores).We identified biological and clinical factors associated with serum hepcidin and ERFE levels. Serum ERFE correlated overall with sTfR and reticulocytes and inversely with hepcidin. Erythroferrone paralleled sTfR levels, dropping during conditioning and recovering with engraftment. Inversely, hepcidin peaked after conditioning and decreased during engraftment. Erythroferrone and hepcidin were not significantly different with or without EPO. Multivariate analyses showed that the major determinant of ERFE was erythropoiesis (sTfR, reticulocytes or serum Epo). Pretransplant hepcidin was associated with previous RBC transfusions and ferritin. After transplantation, the major determinants of hepcidin were iron status (ferritin at all time points and Tsat at day 56) and erythropoiesis (sTfR or reticulocytes or ERFE), while the impact of inflammation was less clear and clinical parameters had no detectable influence. Hepcidin remained significantly higher in patients with high compared to low pretransplant ferritin. After allogeneic HCT with or without EPO therapy, significant alterations of hepcidin occur between pretransplant and day 180, in correlation with iron status and inversely with erythroid ERFE. | INTRODUCTIONErythropoiesis and iron metabolism are closely related, as iron is critical for the production of red blood cells, and erythropoiesis is an essential actor in the regulation of hepcidin, the regulator of iron metabolism. 1 Hepcidin limits iron absorption by the gut and iron release by macrophages and hepatocytes through binding to and degradation of

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Provisional standardization of hepcidin assays: creating a traceability chain with a primary reference material, candidate reference method and a commutable secondary reference material

Cited by 47 publications

References 27 publications

Standardized serum hepcidin values in Dutch children: Set point relative to body iron changes during childhood

Standardized serum hepcidin values in Dutch children: Set point relative to body iron changes during childhood

Hepcidin and conventional markers to detect iron deficiency in severely anaemic HIV-infected patients in Malawi

Erythroferrone and hepcidin as mediators between erythropoiesis and iron metabolism during allogeneic hematopoietic stem cell transplant

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