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portion of children screened.4
Another issue of specificity is a modest increase in ZPP/H
oral iron dosing and timing by exploiting conditions that minimize iron-provoked hepcidin induction.14 It is also use- ful in the diagnosis of concomitant iron deficiency in patients with ACD in rheumatoid arthritis and inflammato- ry bowel disease, and in African children.15,16 It also allows for a rapid diagnosis of rare hereditary diseases, such as iron-refractory iron deficiency anemia (IRIDA) or ferro- portin disease due to hepcidin resistant mutations.17,18
Although several assays have been developed, a gold standard is still lacking, and efforts toward harmonization are ongoing. Nevertheless, the unique advantages of hep- cidin measurements can already be recognized , ranging from the use of hepcidin in diagnosing IRIDA to global health applications, such as guiding safe iron supplementa- tion in developing countries with a high infectious disease burden.
Summary
Table 1 lists the tests currently available for evaluating iron-restricted erythropoiesis in iron deficiency and in ACD.19-23 Important considerations in the choice of diagnos- tic tests should be the availability, affordability, sensitivity, specificity, and minimal time required for receiving POC results. Red cell indices described in the upper 4 rows are an excellent starting point, offering knowledge regarding the duration and severity of iron deficient erythropoiesis (IDA and ACD). Because of the low specificity of red cell indices, the next set of tests should include serum iron, transferrin and ferritin. Ideally, these tests should offer a clear distinction between IDA and ACD. However, in real life, and in particular in developing countries with popula- tions at the highest risk of anemia, IDA and ACD often coexist and the opposing directions of lab results make diagnosis difficult. This is the point where a third set of tests should be considered: ZPP/H, sTfR and hepcidin. Two of these three are the subjects of the present study by Kanuri et al. Their results show high sensitivity for IDA, but specificity could not be determined because of the design of studies pre-selecting only subjects with IDA documented by ferritin less than 12 ng/mL and an increased sTfR/log fer- ritin ratio.
In view of its high sensitivity and simplicity, ZPP/H is an excellent screening procedure which may deserve inclusion in the first set of POC tests of RBC indices. In particular, it is useful in excluding iron restricted erythropoiesis whether in IDA or ACD if results are within the normal range. Both sTfR24 and hepcidin measurements are able to identify IDA in the presence of ACD. They are not inexpensive, howev- er, and both require further efforts to turn them into univer- sally available and validated assays. Because the measure- ment of hepcidin is a direct reflection of the mechanism controlling iron homeostasis, its future development into a widely available diagnostic tool may offer a major advan- tage in our drive to understand the nature of iron deficiency diseases and their optimal management .
References
1. KassebaumNJ,JasrasariaR,NaghaviM,etal.Asystematicanalysisof global anemia burden from 1990 to 2010. Blood. 2014;123(5):615–624. 2. Kanuri G, Chichula D, Sawhne R, et al. Optimizing diagnostic bio- markers of iron deficiency anemia in community-dwelling Indian women and preschool children. Haematologica. 2018;103(12):1991-
1996.
in α and β thalassemia trait. However, the combined use of red cell distribution width (RDW) or mean corpuscular volume (MCV) and ZPP/H allows for discrimination between IDA and thalassemia trait in the vast majority of subjects.5,6
The main advantage of erythrocyte ZPP/H measuring is the low cost, POC testing and the simplicity with which these tasks can be performed. Erythrocyte ZPP/H can be best used as a primary screening test for assessing iron sta- tus, especially in patients likely to have uncomplicated iron deficiency. In addition to its primary application, it can be useful in monitoring response to iron therapy.
Hepcidin
Hepcidin, a liver-derived peptide hormone discovered in 2001, is a key regulator of systemic iron homeostasis.7 The central role of hepcidin in iron regulation has been exten- sively reviewed by Ganz8 and by Hentze et al.,9 and the use of serum hepcidin measurements in the diagnosis of iron disorders was reviewed in 2016 by Girelli et al.10
Hepcidin functions by inhibiting the entry to the plasma of iron acquired by intestinal absorption, the recycling of iron derived from catabolism of senescent red blood cells (RBC) in macrophages, and by mobilization of iron stored in the liver. The block of iron flow is achieved by the bind- ing of hepcidin to the iron transporter ferroportin, followed by its internalization and degradation.
Hepcidin production is increased by iron excess and by inflammation, and suppressed by both iron deficiency and increased erythropoiesis. Hepcidin production is flexible and changes within hours of introducing stimulatory or inhibitory messages such as iron administration or inflam- matory stimulation. Because several opposing messages may present simultaneously, hepcidin output will depend on the relative strength of each. For example, in severe iron deficiency, hepcidin production tends to remain low, even in the presence of inflammation. Similarly, in conditions of ineffective or expanded erythropoiesis, such as in non- transfusion-dependent thalassemias, signals released by bone marrow erythroid precursors tend to override those from replete iron stores.
One such erythroid signal, erythroferrone (ERFE), has been recently identified.11 ERFE is synthesized and secreted by erythroblasts in the marrow and extramedullary sites. The production of ERFE is induced by erythropoietin and is also proportional to the total number of responsive ery- throblasts. ERFE acts on hepatocytes to suppress the pro- duction of hepcidin by inhibiting hepatic BMP/SMAD sig- naling. By suppressing hepcidin, ERFE facilitates iron deliv- ery during stress erythropoiesis, but also contributes to iron overload in anemias with ineffective erythropoiesis.12
The measurement of hepcidin, unlike other tests used for evaluating iron status, is a direct reflection of the mecha- nism controlling iron homeostasis. This unique feature of hepcidin represents a major advantage in trying to eluci- date the nature of disease and its optimal management. It can be used as a guide for iron therapy. For example, it allows the prediction of favorable response to oral iron treatment among children living in countries with a high prevalence of infectious diseases,13 or the design of optimal
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