Practice guidelines for the diagnosis and management of microcytic anemias due to genetic disorders of iron metabolism or heme synthesis

Abstract

During recent years, our understanding of the pathogenesis of inherited microcytic anemias has gained from the identification of several genes and proteins involved in systemic and cellular iron metabolism and heme syntheses. Numerous case reports illustrate that the implementation of these novel molecular discoveries in clinical practice has increased our understanding of the presentation, diagnosis, and management of these diseases. Integration of these insights into daily clinical practice will reduce delays in establishing a proper diagnosis, invasive and/or costly diagnostic tests, and unnecessary or even detrimental treatments. To assist the clinician, we developed evidence-based multidisciplinary guidelines on the management of rare microcytic anemias due to genetic disorders of iron metabolism and heme synthesis. These genetic disorders may present at all ages, and therefore these guidelines are relevant for pediatricians as well as clinicians who treat adults. This article summarizes these clinical practice guidelines and includes background on pathogenesis, conclusions, and recommendations and a diagnostic flowchart to facilitate using these guidelines in the clinical setting.

Hepcidin in the diagnosis of iron disorders

“…53 Because of the highly dynamic and multifactorial regulation, a key practical message is that, in a given individual, the correct interpretation of hepcidin levels requires accurate knowledge of the overall clinical context (Table 1 8 This genetic disease, due to mutations in the hepcidin inhibitor TMPRSS6 (encoding matriptase-2), 30 is characterized by IDA with inappropriately normal or high hepcidin levels. 54,55 Thus, oral iron is ineffective and parenteral administration is needed to achieve at least a partial response. In classical IDA, hepcidin is suppressed below the limit of detection in biological fluids.…”

“…pseudo-normal/elevated serum hepcidin in an appropriate clinical context can be considered virtually diagnostic of IRIDA, even without confirmation by TMPRSS6 sequencing (eg, in a young patient with unexplained IDA not responding to oral iron and with positive family history). Measurement of hepcidin may also help in the diagnosis of other atypical microcytic anemias due to rare genetic disorders of iron metabolism or heme synthesis (reviewed in Donker et al 55 ), although data are presently insufficient ( Table 1).…”

Modern iron replacement therapy: clinical and pathophysiological insights

“…Subjects homozygous for mutations in TMPRSS6, encoding the hepcidin inhibitor Matriptase-2, are affected by a rare genetic form of anemia named Iron Refractory Iron Deficiency Anemia (IRIDA, OMIM #206200) [64]. This condition should be suspected in patients presenting with IDA early in life, and poor or no response to oral iron without apparent cause [65,66]. Indeed, the biochemical hallmark of IRIDA is the presence of high (or inappropriately normal) serum hepcidin levels [25], which are pathogenetically relevant.…”

Toward Worldwide Hepcidin Assay Harmonization: Identification of a Commutable Secondary Reference Material

“…As a key player in iron metabolism, hepcidin holds great promise as the target of therapy and biomarker for diagnosis and monitoring of iron disorders (2 ). Hepcidin concentrations may be used for diagnosis of ironrefractory iron deficiency anemia (4,5 ), differentiation between iron deficiency anemia and anemia of chronic disease (2,6,7 ), guidance in safe iron supplementation (8 ), and as a companion diagnostic in novel therapies (9,10 ).…”