Pagophagia and restless legs syndrome are highly associated with iron deficiency and should be included in histories evaluating anemia
Published Nov 2, 2022 · M. Achebe, E. Mandell, Katherine Jolley
American Journal of Hematology
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Abstract
To the Editor: Iron deficiency (ID), as well as its more severe form iron deficiency anemia (IDA), is the most prevalent medical condition in the world. In an evaluation of global anemia burden, it was estimated that over 30% of the world's population is anemic, the majority due to ID. There are over 1.2 billion cases of IDA worldwide and ID without anemia may be more prevalent. IDA is most frequently encountered in women of child-bearing age, infants and adolescents. Its prevalence is higher in settings of lower socioeconomic status but no population is exempt. The vast majority of iron in the body serves for erythropoiesis, but iron is also crucial for numerous biologic functions, including respiration, energy production, DNA synthesis and cell proliferation. Therefore, the effects of ID are more far reaching than those of anemia alone. The US national health and nutrition examination survey NHANES-IV observed that up to 7% of infants aged 1–2 years and 9% of adolescent girls in the United States have ID without anemia. ID causes fatigue, decreased quality of life, slowed cognitive function and decreased work productivity. IDA is among the most prevalent contributors to decreases in disability-adjusted life years (DALYs) worldwide. In neonates, ID is associated with poor feeding and irritability, and in infants it causes detrimental neurological effects with potential long-term consequences. Making a diagnosis of ID is crucial to the individual and of significant impact on global health. According to the WHO, anemia is defined as hemoglobin <12 g/dL in women and <13 g/dL in men. Anemia is often an incidental finding on a routine complete blood count, making the diagnosis fairly straightforward. A diagnosis of ID is more difficult. Whereas many symptoms of ID are chronic, vague and nonspecific such as fatigue, brittle nails and hair loss, the diagnosis, especially in the absence of anemia, requires proactive clinical astuteness. In addition to the symptoms of anemia, a portion of iron-deficient individuals have pica, an abnormal compulsive craving for nonnutritive substances, such as clay, dirt, paper, rubber bands and others. Two strongly suggestive symptoms of ID are pica for ice, pagophagia and restless legs syndrome (RLS). Though the association of pagophagia and RLS with ID is well described in the literature, the prevalence of pagophagia and RLS in ID varies from 11% to 55% in studies and remains unclear. With the ever-increasing literature on the consequences of ID, particularly in neonates and infants, the potential harm of overlooking ID is obvious and there is the need for improved clinical detection. Unfortunately, these common and clinically significant symptoms, which predispose to serious dental morbidity, sleep deprivation and performance impairing fatigue, are often omitted from clinical histories. Estimates are at least 50% of those with ID are affected by one or both. The purpose of this study was to inform on the prevalence of these specific features of ID, pagophagia, and RLS and evaluate the association of these complications with laboratory indices of iron. Accordingly, we tested the relationship of iron indices (total iron binding capacity (TIBC), transferrin saturation (TSAT) and ferritin) with pagophagia and RLS. Medical records of 1000 consecutive, nonselected adults referred to a community hematology practice for evaluation of ID from October 2017 to September 2020 were evaluated. Those with normal iron parameters were excluded from this analysis. Abstracted variables included gender, age, etiology of ID when available, presence or absence of pagophagia and/or RLS, hemoglobin concentration (Hb), MCV, serum ferritin, TSAT and TIBC. Nine hundred and eighty-seven of 1000 records with complete information were analyzed. To maintain anonymity, birthdates were excluded from the analysis and age was transformed into a categorical variable, split by quartiles. A pairwise correlation test between iron indices was performed, which reported on significant correlations among most. In that some indices were strongly correlated with others, a LASSO model for pagophagia was enlisted (instead of logistic regression), offering all iron indices, gender and age as covariates. By fitting the LASSO model, highly correlated variables for the prediction model could be selected. Because TIBC and TSAT were highly correlated, only TIBC was chosen by LASSO. A logistic regression model using the LASSO-selected variables allowed the retrieval of odds ratios, confidence intervals (CIs) and P-values. RLS was handled in a similar fashion to pica. Of the 987 with ID, 886 (89.8%) were female, 399 (40.4%) had pagophagia and 398 (40.3%) has RLS. A combination of both pagophagia and RLS was observed in 220 (22.3%). The odds ratio for RLS was 2.82, suggesting a strong association with the presence of pagophagia, p < 0.001. The mean Hb for all subjects was 10.4 g/dL, MCV 79.4, TIBC 395.4, TSAT 11.2% and mean serum ferritin 37.9. In multivariable analyses, TIBC, MCV and gender were associated with pagophagia with a TIBC increment of 10 increasing the odds of pagophagia by 1.8% (p = 0.002). An MCV decrement of 5 femtoliters (fl) increased the odds of pagophagia by 3.8% (p < 0.001). The odds of a female having pagophagia were 2.66 times of a male (p < 0.001). In multivariable analyses with RLS as the outcome, TIBC was the only Received: 16 September 2022 Revised: 26 October 2022 Accepted: 27 October 2022