Iron Deficiency and Sleep/Wake Behaviors: A Scoping Review of Clinical Practice Guidelines-How to Overcome the Current Conundrum?

Abstract

Current evidence suggests that iron deficiency (ID) plays a key role in the pathogenesis of conditions presenting with restlessness such as attention deficit hyperactivity disorder (ADHD) and restless legs syndrome (RLS). In clinical practice, ID and iron supplementation are not routinely considered in the diagnostic work-up and/or as a treatment option in such conditions. Therefore, we conducted a scoping literature review of ID guidelines. Of the 58 guidelines included, only 9 included RLS, and 3 included ADHD. Ferritin was the most frequently cited biomarker, though cutoff values varied between guidelines and depending on additional factors such as age, sex, and comorbidities. Recommendations surrounding measurable iron biomarkers and cutoff values varied between guidelines; moreover, despite capturing the role of inflammation as a concept, most guidelines often did not include recommendations for how to assess this. This lack of harmonization on the interpretation of iron and inflammation biomarkers raises questions about the applicability of current guidelines in clinical practice. Further, the majority of ID guidelines in this review did not include the ID-associated disorders, ADHD and RLS. As ID can be associated with altered movement patterns, a novel consensus is needed for investigating and interpreting iron status in the context of different clinical phenotypes.

Keywords: attention deficit hyperactivity disorder; brain iron; central iron deficiency; clinical practice guidelines; iron deficiency; restless legs syndrome; restlessness; sleep disorders.

Figure 1

Effects of central iron deficiency (CID), as grouped by region of interest, brain, and spinal cord. CID refers to low iron levels in both the brain and spinal cord. Highlighted here are areas in the brain and spinal cord that are particularly susceptible to CID-induced changes in dopamine modulation. In the striatum, they are suspected to modulate motor outputs, while in the dorsal spinal cord, they are associated with sensory inputs. Data compiled from Silvani et al. [2] and Woods et al. [3]. A1 receptor: adenosine receptor; D1/D2 receptor: dopamine receptors; REM: rapid eye movement.

Figure 2

Study selection. Adapted from [88].

Figure 3

Recommended biomarkers for the diagnosis of NAID/IDA in the included general and pregnancy-specific guidelines [30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,48,51,52,53,54,55,57,58,64,65,67,68,70,71,72,73,74,75,76,77,78,80,81,85,86,87].

Figure 4

Recommended biomarkers for the diagnosis of NAID/IDA in the included disease-specific guidelines [47,49,50,56,59,60,61,62,63,66,69,79,82,83,84].

Figure 5

Serum ferritin cutoff values of the included general and pregnancy-specific guidelines. F: female; M: male [30,31,33,34,35,39,40,42,43,44,45,46,51,53,54,55,57,67,68,70,71,72,74,75,77,78,80,81,85,87].

Figure 6

Pediatric-specific serum ferritin cutoff values of the included general ID guidelines [30,31,35,37,38,40,41,42,43,48,52,58,64,65,72,73,74,76].