Absent Iron Research Articles

Redefining Iron Deficiency in Patients With Chronic Heart Failure.

A serum ferritin level <15 to 20 μg/L historically identified patients who had absent bone marrow iron stores, but serum ferritin levels are distorted by the systemic inflammatory states seen in patients with chronic kidney disease or heart failure. As a result, nearly 25 years ago, the diagnostic ferritin threshold was increased 5- to 20-fold in patients with chronic kidney disease (ie, iron deficiency was identified if the serum ferritin level was <100 μg/L, regardless of transferrin saturation [TSAT], or 100 to 299 μg/L if TSAT was <20%). This guidance was motivated not by the findings of studies of total body or tissue iron depletion, but by a desire to encourage the use of iron supplements to potentiate the response to erythropoiesis-stimulating agents in patients with renal anemia. However, in patients with heart failure, this definition does not reliably identify patients with an absolute or functional iron-deficiency state, and it includes individuals with TSATs (≥20%) and serum ferritin levels in the normal range (20-100 mg/L) who are not iron deficient, have an excellent prognosis, and do not respond favorably to iron therapy. Furthermore, serum ferritin levels may be distorted by the use of both neprilysin and sodium-glucose cotransporter 2 inhibitors, both of which may act to mobilize endogenous iron stores. The most evidence-based and trial-tested definition of iron deficiency is the presence of hypoferremia, as reflected by as a TSAT <20%. These hypoferremic patients are generally iron deficient on bone marrow examination, and after intravenous iron therapy, they exhibit an improvement in exercise tolerance and functional capacity (when meaningfully impaired) and show the most marked reduction (ie, 20%-30%) in the risk of cardiovascular death or total heart failure hospitalizations. Therefore, we propose that the current ferritin-driven definition of iron deficiency in heart failure should be abandoned and that a definition based on hypoferremia (TSAT <20%) should be adopted.

High Prevalence of Iron Deficiency Among Daratumumab-Treated Newly Diagnosed Multiple Myeloma Patients

Background: Iron deficiency (ID), a common cause of anemia, is often overlooked among patients with hematologic malignancies given alternative etiologies. Daratumumab is an anti-CD38 monoclonal antibody used in the management of multiple myeloma (MM). Approximately 45% of patients on daratumumab are anemic. In a study of 22 patients with relapsed refractory AL amyloidosis treated with daratumumab, 40% developed iron deficiency requiring IV iron replacement. It is unclear whether iron deficiency in this setting is specific to AL amyloidosis, or whether it is universally seen with daratumumab treatment. In this study we evaluated iron deficiency parameters, including bone marrow iron stores, in MM patients treated with daratumumab. Methods: We conducted a retrospective study to evaluate the prevalence of ID among newly diagnosed MM patients who were treated uniformly in a phase II study with the combination of daratumumab, ixazomib, lenalidomide and dexamethasone conducted at our center. Laboratory values of ferritin, hemoglobin and MCV were extracted from the medical records at trial enrollment and at 1-year from treatment initiation. ID was defined as ferritin &amp;lt;30 mcg/L. Bone marrow iron stores were assessed at pre-trial and 1-year from therapy initiation by Prussian blue stain of bone marrow clot sections, with grade 0 (absent iron) or grade 1 (trace to low iron) considered as depleted iron storage. Results: Among 54 included patients, 2 (3.7%) had ferritin &amp;lt;30 mcg/L at trial-enrollment, while 27 (50%) developed ID within 1 year and 33 (61%) became iron deficient during their treatment course. All patients (100%) had lower ferritin at 1 year compared to pre-trial value. The median reduction of ferritin at 1-year was 109 (IQR: 41-239 mcg/L), a decrease by 75% (IQR:56- 86%) from baseline value. Fifteen patients (28%) received IV or oral iron replacement, and 4 were already on iron-repletion before the 1-year landmark assessment. The median ferritin improved from 16 to 84 mcg/L (p&amp;lt;.0001) following iron replacement. Forty patients (74%) had improved hemoglobin at 1-year compared to baseline correlated to disease response to therapy. The median increment in hemoglobin was 1.1 (IQR: -0.3 - 2.7 g/dL). Hemoglobin at 1-year was higher in patients having ferritin ≥ 30 mcg/L compared to the ID group: 13.5 (IQR: 12.3-14.1 g/dL) vs 12.8 (IQR: 12.3-13.4 g/dL), p=.05. BM samples from pre-trial (n=37) and 1-year on-trial (n=36) were available for iron staining. Depleted iron storage was more frequent at1-year compared to baseline (63.9% vs 40.5%, p&amp;lt;.05). The median ferritin was lower in patients with iron depleted versus non-iron depleted BM: 58 (IQR: 31-120 mcg/L) vs 243 (IQR: 125-486 mcg/L) at baseline, p=.0002; 27 (IQR: 16-41 mcg/L) vs 59 (IQR: 19-245 mcg/L) at 1-year landmark, p=.07. Comparisons of laboratory markers at initiation and after 1-year on daratumumab trial are listed in Table 1. Conclusions: Our study demonstrated a high prevalence of ID among patients receiving daratumumab-based treatment for newly diagnosed MM. While some decrease in ferritin over treatment course may be caused by myeloma disease control and improved systemic inflammation, this study should increase awareness for ID among MM patients treated with daratumumab. Future studies are needed to better understand the possible role of daratumumab in the pathogenesis of ID in MM and other plasma cell disorders.

'Ironing out the risk': Assessing the effect of plateletpheresis donation frequency on iron stores in South-Asian male donors.

Repeated blood donation is a well-known cause of iron deficiency among donors. However, present scientific literature lacks comprehensive evidence regarding the impact of regular plateletpheresis procedures on body iron reserves. In this study, we aimed to detect and correlate iron deficiency (using iron indices) with the frequency of platelet donations. Additionally, we also analysed the correlation between other iron and haematological indices with serum ferritin to determine cost-effective parameters that may serve as an initial screening approach to determine which donors should be subjected to serum ferritin testing. A total of 180 male participants from our platelet donor registry were enrolled in this observational cross-sectional study. Enrolment questionnaires were administered to eligible donors, and biological samples were collected during plateletpheresis donation. Biological tests such as complete blood count, reticulocyte indices, iron indices, vitamin B12 and folate were performed. Donors with ≥12 donations per year showed the highest prevalence of low ferritin (serum ferritin: 15-30 ng/mL) and absent iron stores (serum ferritin <15 ng/mL) (41.3% and 26.7%, respectively). Ferritin showed a significant negative correlation with recent (r = -0.346) and lifetime donations (r = -0.196). The efficacy of other indices for identifying iron depletion was much better using a serum ferritin value <15 ng/mL. Regular plateletpheresis donations can lead to varying severities of non-anaemic iron deficiency. Blood centres must regularly monitor frequent plateletpheresis donors (especially donors with more than 11 donations in a calendar year) and ideally maintain their serum ferritin above 30 ng/mL.

Review and assessment of the donor safety among plasma donors.

Review and assessment of the donor safety among plasma donors.

Impact of donor ferritin testing on iron deficiency prevention and blood availability in France: A cohort simulation study.

Implementing a ferritin testing policy for whole blood (WB) donors may prevent iron deficiency (ID, ferritin <26 ng/mL) and anaemia, but may induce donation losses. As part of a national prevention plan in France, we aimed to estimate its impact on ID, anaemias and WB donations among donors at high risk of ID. A micro-simulation model was developed to evaluate different scenarios compared to the current situation without ferritin testing as a reference scenario. The following scenarios were simulated: a minimum scenario with a 6-month deferral for donors with absent iron store (AIS, ferritinemia <15 ng/ml), a main scenario with additional delayed invitations for donors with ferritinemia 15-25 ng/ml and a supplementation scenario with additional iron supplementation for 50% of the donors with AIS. In the main scenario, 52,699 WB donations per year were estimated to be lost after 1 year (-8%), falling to 27,687 (-4.7%) after 5 years. IDs and anaemias were reduced by 13.6% and 29.3%, respectively, after 1 year. The supplementation scenario increased the number of prevented IDs and anaemias to 24.1% and 35.4%, respectively, after 1 year, and halved the number of anaemias at 5 years. The latter scenario also had the least impact on the number of donations (-3.2% after 5 years). A ferritin testing policy resulting in delayed donations for ID donors is effective in reducing IDs and anaemias, but significantly impacts the number of donations, thereby posing a self-sufficiency challenge.

Prevalence of Iron Deficiency in Endurance Runners: A Cross-Sectional Study of the Detroit Free Press Marathon and Half-Marathon Athletes

Background Iron deficiency, with or without anemia, may be more prevalent in endurance athletes than the general population. Marathon and half-marathon runners, a subset of these endurance athletes, are at risk for iron deficiency via several mechanisms, such as increased demand, foot-strike hemolysis, sweat, and others. The prevalence of iron deficiency among marathon and half-marathon runners in the United States has not been studied. Methods We performed a cross-sectional study to identify the prevalence of iron deficiency in runners participating in the Detroit Free Press Marathon or Half-Marathon on October 17, 2021. Eligible participants were screened at the pre-race expo, at which time they filled out questionnaires and had blood samples taken. The questionnaires included items such as demographic information, exercise and dietary habits, bleeding history, and symptoms. The blood samples were tested the same day for hemoglobin, hematocrit, ferritin, serum iron, total iron binding capacity (TIBC) and iron saturation. Participants received their laboratory results and a $30 Amazon gift card via email for participating. For the purpose of our study, we defined severe iron deficiency as ferritin <15 ng/mL, or ferritin <35ng/mL and iron saturation <16%. This was likely consistent with absent iron storage and similar to previous definitions used in studies examining other endurance athletes. As clinicians, we agreed upon clinical iron deficiency as ferritin <30 ng/mL, or ferritin <100 ng/mL and iron saturation < 20%. This was likely consistent with low iron stores, at-risk iron stores, or iron deficiency in some populations. This definition is also likely to prompt treatment and/or investigation. Data were analyzed using chi-squared analysis, Student's t-test, ANOVA and logistic regression using SPSS v. 28.0. Results Of 277 participants, the mean age was 40.6 ± 13.6 years, and 38.6% (n=107) were male. Most of our participants identified as white (n=219, 79.1%). All participants were residents of the United States; 213 participants (80.1%) were from Michigan. The majority of our participants registered for the half marathon: 185 (66.8%) half marathon, 87 (31.4%) marathon, and three (1.1%) unknown. The prevalence of clinical iron deficiency was significantly higher in females than males, 47.6% versus 15%, respectively (p<0.001). The same trend was found for severe iron deficiency, 14.7% in females vs. 2.8% in males (p=0.001). These results were independent of anemia status. On univariable analysis, factors associated with iron deficiency (clinical and/or severe) included younger age, race entered, history of anemia, heavy menstrual bleeding, blood thinner use, ≥15 hours of exercise per week, restrictive dietary habits, and lightheadedness. For multivariable analysis, we ran separate models by sex (Table). Conclusion Iron deficiency is prevalent in marathon and half-marathon runners and is associated with several risk factors, which differ by sex. Patients who participate in endurance sports and/or training should be screened accordingly. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Work-up of Patients with Decreased Hemoglobin A2 Identified by Capillary Zone Electrophoresis: A North American Institutional Experience.

Isolated low hemoglobin A2 (HbA2) is rarely encountered in our clinical practice using capillary zone electrophoresis. The study goal was to characterize the work-up at our institution of patients with low HbA2. Patients with low HbA2 and a control cohort with normal capillary zone electrophoresis were identified and relevant information extracted from the medical record. Of 44 patients with isolated decreased HbA2, 28 (64%) had corresponding complete blood count/ferritin values. Compared to control patients, patients with low HbA2 were more likely to have iron deficiency and demonstrated a more microcytic, hypochromic blood picture. However, 46% (13/28) of patients with low HbA2 and ferritin for evaluation did not have iron deficiency. Only 2 patients had genetic testing. This study redemonstrates the association between low HbA2 and iron deficiency and reinforces the need for iron indices to interpret capillary zone electrophoresis results. Our study population showed incomplete or absent iron studies in most cases.

Random Forest Clustering Identifies Three Subgroups of β-Thalassemia with Distinct Clinical Severity

In this work, we aimed to establish subgroups of clinical severity in a global cohort of β-thalassemia through unsupervised random forest (RF) clustering. We used a large global dataset of 7910 β-thalassemia patients and evaluated 19 indicators of phenotype severity (IPhS) to determine their contribution and relatedness in grouping β-thalassemia patients into clusters using RF analysis. RF clustering suggested that three clusters with minimal overlapping exist (classification error rate: 4.3%), and six important IPhS were identified: the current age of the patient, the mean serum ferritin level, the age at diagnosis, the age at first transfusion, the age at first iron chelation, and the number of complications. Cluster 3 represented patients with early initiation of transfusion and iron chelation, considerable iron overload, and early mortality from heart failure. Patients in Cluster 2 had lower serum ferritin levels, although they had a higher number of complications manifesting overtime. Patients in Cluster 1 represented a subgroup with delayed or absent transfusion and iron chelation, but with a high morbidity rate. Hepatic disease and cancer were dominant causes of death in patients in Cluster 1 and 2. Our findings established that patients with β-thalassemia can be clustered into three groups based on six parameters of phenotype severity.

Utility of reticulocyte haemoglobin content and immature reticulocyte fraction in early diagnosis of latent iron deficiency in whole blood donors.

The present study was planned to assess the clinical utility of reticulocyte haemoglobin content (CHr) and immature reticulocyte fraction (IRF) in the early detection of latent iron deficiency in blood donors. The prospective longitudinal observational study was conducted using the purposive sampling method. Written informed consent was obtained and donors were allocated into the first-time (FTD) and regular donor (RD) group. The enrolled blood donors (n= 205 in each group) were followed up for two subsequent whole blood donations. Haemoglobin (Hb), CHr, IRF and serum ferritin values were recorded at enrolment and two follow-ups. The sensitivity of CHr in detecting iron-deficient erythropoiesis (serum ferritin values ≤ 26 μg/dl) was 45% and 56.7%, specificity 96.7%, positive predictive value (PPV) 85.6% and 90.8% and negative predictive value (NPV) 80.1% and 78.7%, respectively in FTD and RD cohorts. The sensitivity of IRF was 45.1% and 44.8%, specificity 93.4% and 97.1%, PPV 74.8% and 90.4% and NPV 79.6% and 74.5%, respectively in both the cohorts. The sensitivity of CHr in detecting absent iron stores (serum ferritin values ≤ 15 μg/dl) was 66.2% and 74.4%, specificity 92% and 90.6%, PPV 56.7% and 68.7% and NPV 94.5% and 92.8% among FTD and RD cohort, respectively. The sensitivity of IRF was 72.7% and 65.3%, specificity 90.3% and 94.3%, PPV 54.4% and 76% and NPV 95.4% and 90.8%, respectively in both the cohorts. Reticulocyte hemoglobin content and IRF can be used along with complete blood count for early detection of iron deficiency in blood donors using the same blood sample at no extra cost.

Individualized risk trajectories for iron-related adverse outcomes in repeat blood donors.

Despite a fingerstick hemoglobin requirement and 56-day minimum donation interval, repeat blood donation continues to cause and exacerbate iron deficiency. Using data from the REDS-II Donor Iron Status Evaluation study, we developed multiclass prediction models to estimate the competing risk of hemoglobin deferral and collecting blood from a donor with sufficient hemoglobin but low or absent underlying iron stores. We compared models developed with and without two biomarkers not routinely measured in most blood centers: ferritin and soluble transferrin receptor. We generated and analyzed "individual risk trajectories": estimates of how each donors' risk developed as a function of the time interval until their next donation attempt. With standard biomarkers, the top model had a multiclass area under the receiver operator characteristic curve (AUC) of 77.6% (95% CI [77.3%-77.8%]). With extra biomarkers, multiclass AUC increased to 82.8% (95% CI [82.5%-83.1%]). In the extra biomarkers model, ferritin was the single most important variable, followed by the donation interval. We identified three risk archetypes: "fast recoverers" (<10% risk of any adverse outcome on post-donation day 56), "slow recoverers" (>60% adverse outcome risk on day 56 that declines to <35% by day 250), and "chronic high-risk" (>85% risk of the adverse outcome on day 250). A longer donation interval reduced the estimated risk of iron-related adverse outcomesfor most donors, but risk remained high for some. Tailoring safeguards to individual risk estimates could reduce blood collections from donors with low or absent iron stores.

Dietary Advice Improves Non-Anemic Iron Deficiency

Source: Parkin PC, Borkhoff CM, Macarthur C, et al. Randomized trial of oral iron and diet advice versus diet advice alone in young children with non-anemic iron deficiency [published online ahead of print February 3, 2021]. J Pediatr. 2021. doi:10.1016/j.jpeds.2021.01.073Investigators from multiple Canadian institutions conducted a randomized trial to compare the effect of oral iron supplementation versus diet advice alone on neurodevelopmental outcomes in children. Parents of children with health supervision visits at 1 of 8 primary care practices in Toronto, Canada, during the study period were eligible. Children were included if they were 12-40 months of age and met criteria for non-anemic iron deficiency (NAID), defined as a hemoglobin ≥110 g/L and serum ferritin <14 μg/L. Children were excluded if they had a developmental condition, were born at a gestational age of <35 weeks or birth-weight of <2,500 grams, had acute illness, had previous anemia or iron deficiency, were receiving iron, or had a c-reactive protein ≥10 mg/L. Child demographics were collected at baseline.Participants were randomized to receive either liquid ferrous sulfate (6 mg elemental iron/kg/day) or liquid placebo in 2 divided doses daily by mouth for 4 months. All parents received diet advice on improving iron status via a written guide. Parents and researchers were blinded to treatment arm. Participants received a developmental assessment of gross motor and cognitive at baseline as well as 4 and 12 months after baseline using the Mullen Scales of Early Learning (MSEL).The primary outcome was MSEL scores 4 and 12 months after baseline. Secondary outcomes included serum ferritin values at 4 and 12 months. The investigators used an intention-to-treat analysis to assess the effect of intervention arm on outcomes, adjusting for baseline score, baseline ferritin, and unbalanced demographic characteristics across treatment arms.There were 60 participants randomized. Participants had a mean age of 24.2 months. Serum ferritin and mean MSEL scores were similar across treatment groups at baseline. The mean between-group difference in MSEL scores at 4 months was 1.1 points (95% CI, -4.2, 6.5) and at 12 months was 4.1 points (95% CI, -1.9, 10.1). The mean between-group difference in serum ferritin at 4 months was 16.9 μg/L (95% CI, 6.5, 27.2) and at 12 months was 3.9 μg/L (95% CI, -7.3, 15.1).The investigators conclude that there is no important between-group difference in neurodevelopmental outcomes in young children NAID treated with ferrous sulfate plus diet advice versus diet advice alone, though serum ferritin values are higher among those who received ferrous sulfate 4 months later.Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.NAID is found in an estimated 11% of US children ages 6 months to 5 years.1 Approximately 25% to 42% of NAID eventually contributes to anemia in this age group.1 Duration, severity, and age onset of NAID may impact neurocognitive skills, breath-holding spells, restless leg syndrome, attention-deficit, pagophagia (ice craving), and athletic performance.2The definitive diagnostic study for NAID is absent iron staining on bone marrow biopsy, an invasive study.3 Although serum ferritin is specific and usually aligned with total body iron stores, normal thresholds vary with age and assay types. Serum ferritin levels rise during and for days to weeks after acute or chronic infection, injury, exercise, and inflammatory conditions.1-3 Consensus among health organizations as to definitions of NAID based on serum ferritin and other biomarkers vary.1-3Strengths of the current study include randomization and longitudinal data. Limitations include a small, homogeneous, well-educated cohort with self-reported medication compliance, adverse effects, and dietary intake. Even though iron supplementation was prescribed for 4 months, both groups had similarly improved ferritin levels after 12 months and equivalent hemoglobin levels throughout. CRP levels were not obtained at 4 and 12 months’ time points to determine the accuracy of the ferritin levels.1-3 Red blood cell indices, transferrin saturation, reticulocyte hemoglobin content, soluble transferrin receptor, and hepcidin—which are available serum biomarkers to help differentiate low iron stores from NAID—were not assessed.1Non-anemic iron deficiency due to inadequate iron intake in children ages 6 months to 5 years seems resolvable with written nutrition education within 12 months. More research is needed to determine whether low serum ferritin levels are associated with neurodevelopmental outcomes. (See AAP Grand Rounds. 2021;45[3]:27.)4The AAP recommends universal screening for anemia with measurement of hemoglobin concentration at approximately 12 months of age.3 Although the association of iron deficiency anemia in infancy and later cognitive deficits is supported by a number of prior studies, the same cannot be said of NAID.3 Unfortunately, the results of the current study are also inconclusive. Perhaps if low-dose ferrous sulfates (3 mg/kg elemental iron/day) had been used, compliance would have improved, potentially leading to differences in neurodevelopmental outcomes. (See AAP Grand Rounds. 2017;38[4]39.)5

Prevalence, risk factors, and ferritin testing to mitigate iron depletion in male plateletpheresis donors.

Most single-donor platelet (SDP) donors transition to plateletpheresis after prior red blood cell (RBC) donation. Recruitment may follow identification of a high platelet count, a marker associated with iron depletion (ID). SDP donors may have underrecognized risk for iron depletion. To assess the prevalence of ID, we performed ferritin testing on male plateletpheresis donors with hemoglobin levels less than 13.5 g/dL. Multivariable logistic regression identified risk factors for low ferritin (LF; ferritin ≤26 ng/mL) and absent iron stores (AIS; ferritin <12 ng/mL). To assess the impact of notifying donors of LF results, we compared donation behavior of "Test" subjects before and after sending an LF notification letter to that of "Control" subjects before and after increasing the minimum hemoglobin for male donors. An electronic survey to Test donors inquired about iron supplementation practices. Prevalence of LF was 50% and AIS was 23%, with increase in risk associated with more frequent SDP donation, both controlling for RBC donation and in donors with no recent RBC donations. Donation frequency after intervention declined less in 1272 Test donors (19%, from 13.9 to 11.2 annualized donations) than in 878 Control donors (49%, from 12.3 to 6.3 donations). Only 20% of Test donors reported taking supplemental iron when they received the LF letter; 64% of those not taking iron initiated iron supplementation following the letter. Donors were responsive to notification of LF and attendant messaging on iron supplementation. Ferritin testing potentially benefits donor health and a stable platelet supply.

Diagnosing Absolute Iron-Deficiency Anemia in Patients on Hemodialysis in a Tertiary Care Centre: A Retrospective Chart Review

Introduction: The gold standard for the diagnosis of absolute iron-deficiency anemia (IDA) in hemodialysis patients is a bone marrow aspirate with iron staining. Many clinicians use peripheral iron indices instead because they are non-invasive. Previous studies suggested that a serum ferritin &lt; 200 ng/mL was a reliable indicator of absolute iron deficiency in the hemodialysis population. However, the sensitivity of serum ferritin for the diagnosis of IDA in hemodialysis patients is poor. Methods: The primary objective of this study was to identify the optimal ferritin value to diagnose patients with absolute iron deficiency, as assessed on bone marrow aspiration, in the renal dialysis population. Secondary endpoints included the rate of clinically relevant findings on gastrointestinal investigation according to iron status. Research Ethics Board approval was obtained from Queen's University for this retrospective chart review. Hematopathology laboratory records were used to determine all individuals who had bone marrow examination at Kingston Health Sciences tertiary referral center between 2008 January 1 and 2018 August 21. This list was cross-referenced with the Nephrology dialysis database to identify the pre-specified study cohort; those who were receiving concurrent hemodialysis or peritoneal dialysis. Iron deficiency was defined as reduced or absent iron stores on bone marrow aspirate with Perl's Prussian blue stain. Anemia was defined as hemoglobin &lt;130 g/L in males and &lt;120 g/L in females. Additional parameters collected included ferritin (normal range 22 - 275 ng/mL male and 4 - 205 ng/mL female), transferrin saturation (TSAT, normal range 20-55%), vitamin B12, folate, albumin, CRP and thyroid function tests. Peripheral iron indices over six months were analyzed; statistical analysis was performed with t-tests and Mann-Whitney U tests. ROC curves were generated to determine the sensitivity and specificity of various threshold values for serum ferritin and TSAT. Results: Between 2008 January 1 and 2018 August 21, 4234 patients underwent bone marrow examination, of whom 28 had received renal dialysis replacement therapy at some point. Fifteen patients concurrently at the time of bone marrow testing receiving hemodialysis form the study population (Table 1). Among these fifteen patients, 6 (40%) were female, median age was 70.5 (range 39 - 80) years and all were anemic (Hb range 73 - 110 g/L). Four of these individuals were absolutely iron-deficient with reduced or absent iron stores by bone marrow evaluation. The mean ferritin and TSAT values for individuals with absolute iron deficiency by bone marrow aspiration was 273.5 ng/mL (n=4; median 224.5 ng/mL; range 158-539 ng/mL) and 22.0% (n=3; median 20%; range 20-26%), respectively. All four commenced erythropoietin stimulating agents; two received oral iron supplementation. Eight patients, including two of those determined to be absolutely iron deficient on bone marrow, had endoscopic investigation. Two were identified to have sources of gastrointestinal bleeding, both with ferritin values in the 100-200 range (106 and 189 ng/mL). With the limited sample size, the sensitivity and specificity of ferritin to identify absolute iron deficiency in this hemodialysis population was 50% and 85%, respectively, at a threshold of 198 ng/mL. Discussion: Ferritin and TSAT are not sensitive markers for absolute iron deficiency in hemodialysis patients. Bone marrow examination is performed in a minority. The small sample size in this study precludes definitive determination of an optimal ferritin cut-off to diagnose iron deficiency in the dialysis population. Uncertainty about actual iron status may result in alternative invasive testing, such as colonoscopy, to investigate the cause of their anemia. Newer tests such as reticulocyte hemoglobin content and percent hypochromic red blood cells are more accurate and may guide diagnosis and management of IDA in hemodialysis patients. However they are not always routinely available. Further studies are needed to compare the utility of these peripheral iron indices to the gold standard bone marrow examination in a larger population, to allow identification of patients with absolute or functional IDA, and minimize invasive and potentially unnecessary investigation. Disclosures Hay: AbbVie: Research Funding; Kite: Research Funding; Janssen: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; MorphoSys: Research Funding; Roche: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Takeda: Research Funding.

Iron status and risk factors for iron depletion in a racially/ethnically diverse blood donor population.

The optimal approach for reducing iron depletion (ID) in blood donors may vary depending on biologic or behavioral differences across donors. More than 12,600 successful whole blood donors were enrolled from four US blood centers for ferritin testing. The study population was enriched for racial/ethnic minorities (1605 African American, 1616 Asian, 1023 Hispanic). Subjects completed questionnaires on ID risk factors. Logistic regression identified predictors of absent iron stores (AIS; ferritin <12 ng/mL) and low ferritin (LF; ferritin <26 ng/mL). Across all subjects, 19% had AIS and 42% had LF, with a sharp increase in risk observed with increasing donation intensity and among women a large decrease in risk in those more than 50 years old. When other factors were controlled for, African American and Asian donors showed 20% to 25% decreased risk for AIS compared to non-Hispanic Caucasian donors, while Hispanic donors had 25% higher risk. Daily iron supplementation reduced risk for LF and AIS by 30% to 40%, respectively, while the benefit from less frequent use was lower (7%-19% protection). Regular antacid use was associated with at least 20% increment to risk. Use of oral contraceptives or estrogen in females reduced risk by 16% to 22%, while males who reported supplemental testosterone use had a 50% to 125% greater risk for LF and AIS. This study confirms high prevalence of LF and AIS in US donors and the principal risk factors of age, sex, and donation frequency. Additional demographic and behavioral risk factors of secondary importance might allow for refinement of ID mitigation strategies.

Association of blood donation with iron deficiency among adolescent and adult females in the United States: a nationally representative study.

Blood donation results in a loss of iron stores, which is particularly concerning for young female blood donors. This study examines the association of blood donation and iron deficiency among adolescent and adult females in the United States. A cross-sectional analysis was performed using data from the 1999-2010 National Health and Nutrition Examination Survey (NHANES). Females who reported their blood donation history in the preceding year and had serum ferritin (SF) measurements were included. Analyses were weighted and stratified by adolescents (16-19 years; n = 2419) and adults (20-49 years; n = 7228). Adjusted prevalence ratios (aPRs) were estimated by multivariable Poisson regression. Standard errors were estimated by Taylor series linearization. Geometric mean SF levels (ng/mL) were lower in blood donors compared to nondonors among adolescents (21.2 vs. 31.4; p < 0.001) and among adults (26.2 vs. 43.7; p < 0.001). The prevalence of absent iron stores (SF < 12 ng/mL) was higher in blood donors compared to nondonors among adolescents (22.6% vs. 12.2%; aPR = 2.03 [95% confidence interval (CI) = 1.45-2.85]) and among adults (18.3% vs. 9.8%; aPR = 2.06 [95% CI = 1.48-2.88]). Additionally, the prevalence of iron deficiency anemia (SF < 26 ng/mL and hemoglobin < 12.0 g/dL) was also higher in blood donors compared to nondonors among adolescents (9.5% vs. 6.1%; aPR = 2.10 [95% CI = 1.13-3.90]) and among adults (7.9% vs. 6.1%; aPR = 1.74 [95% CI = 1.06-2.85]). Similar results were observed in a sensitivity analysis restricted to adolescents aged 16 to 18 years. Blood donation is associated with iron deficiency among adolescent and adult females in the United States. These national data call for further development and implementation of blood donation practices aimed toward mitigating iron deficiency.

Paraclinical cardiac findings of children with breath-holding Spells in Taleghani Hospital of Gorgan, Iran, during 2014–2016

Context: Breath-holding spells (BHSs) are episodes of brief, involuntary cessation of breathing that occur in children in response to stimuli such as anger, frustration, fear, or injury. It occurs in about 0.1%–4.6% of healthy children. Although the etiology is not known, autonomic dysfunction and increased vagal tonus leading to cardiac arrest and cerebral anoxia are considered to play a role. Increase of QT dispersion increases the risk of sudden death. Because of this, children are always referred to cardiac clinics. Aims: Our aim was to evaluate According to these problems, our aim was the evaluation of ECG and Echocardiography findings in children diagnosed with BHSs in Taleghani Hospital in Gorgan. Settings and Design/ Methods and Material: All patients diagnosed with BHSs were enrolled in this study. In the first step, demographic characteristics and echocardiography and electrocardiogram (ECG) findings were obtained from the patients. Statistical Analysis Used: For statistical analysis, the demographic variables and ECG and echocardiography information of the patients were analyzed using frequency, percentage, and statistical tests such as Chi-square. Results: Sixty-three (9%) children were male and 36 (1%) children were female. Thirty-eight (9%) children were aged between 1 and 2 years, and this group was the most common age group. The most common type of attack was cyanotic (68/5%); 24 (1%) children had a positive family history, 78 (8%) had incomplete or absent iron supplementation, and 68% of children had anemia. Five (6%) children had long QT in ECG and five (6%) had abnormal echocardiography. There was a significant correlation between echocardiography findings and age, whereas there was no significant relationship between ECG findings with age, echocardiography findings with sex, and type of attack with age and sex. Conclusions: Although BHS among children with LQTS are relatively rare and occur at similar frequency as the general population, they can be the presenting symptom for a heart rhythm disorder.

Ferritin testing to characterize and address iron deficiency in young donors.

Iron deficiency is observed in blood donors who meet hemoglobin requirements for donation. Frequent donation results in negative iron balance, and teenage donors may thus be at risk for adverse health consequences. Blood Systems implemented ferritin testing on all successful 16- to 18-year-old (teen) donations. Low ferritin (LF) was defined as less than 20 ng/mL in females and less than 30 ng/mL in males. Donors with LF were deferred from red blood cell (RBC) donations (12 months for females, and 6 for males) and counseled to take low-dose iron for 60 days. A ferritin value less than 26 ng/mL indicated iron-deficient erythropoiesis and less than 12 ng/mL absent iron stores. Over 16 months, 110,417 teen donations were tested and represented 10.5% of all successful donations. The rate of absent iron stores was 9.0% (1.9% male; 15.9% female) and of iron-deficient erythropoiesis, 31.9% (12.4% male; 50.6% female). The rate of LF deferrals was 26.9% (16.7% male; 36.6% female). The proportion of LF donors decreased with increasing predonation hemoglobin and rose with increasing RBC donations in the prior 24 months. Seasonality in LF deferrals and the RBC contribution from teen donors was observed. Ferritin testing of teen donors identified individuals with LF who might benefit from risk mitigation. LF is more common in teenage female than male donors and those with RBC donations in the prior 24 months. An appreciable number of new/lapsed donors presented with LF, however. These data may be useful in guiding future risk mitigation efforts.

Frequent source plasma donors are not at risk of iron depletion: the Ferritin Levels in Plasma Donor (FLIPD) study.

Whole blood and red blood cell (RBC) donors are at risk of iron deficiency. Since Source plasma (SP) donors have RBCs returned during apheresis, risk of iron depletion appears low. However, SP donors can donate frequently and assessment of frequent donor iron status is needed. A total of 1254 SP donors were enrolled in four frequency groups determined by donations in the prior 12 months: no donations and 1 to 24, 25 to 69, and 70 or more donations. Ferritin was determined for each donor. Donors with ferritin levels of less than 12 ng/mL were classified as having absent iron stores (AIS). Compared to new donors, ferritin for females was higher in each successive frequency group. For 70 or more donations, ferritin was 13 ng/mL higher than in new donors (p = 0.02). For males, 1 to 24 donations had the highest ferritin levels. Compared to new donors, highest-frequency donors had lower ferritin levels, 114 ng/mL versus 100 ng/mL (p = 0.14). Age for females and males increased with each successive frequency group. Age adjustment resulted in smaller ferritin differences for females and larger differences for males in the high-frequency groups; AIS for females was highest in new donors (7%) and lowest in the highest-frequency group (1%). In aggregate, AIS occurred in less than 1% of all male donors. Male new and highest-frequency donors had 1% AIS with none in the other groups. Few SP donors have iron depletion and it is not higher in frequent donors. Frequent SP donation does not adversely impact iron stores. Thus, monitoring donor iron status or iron supplementation is not necessary.

Phenotypic heterogeneity in seven Italian cases of aceruloplasminemia

IntroductionAceruloplasminemia is an ultra-rare hereditary disorder characterized by iron-restricted microcytic anemia and tissue iron overload associated with diabetes, retinal and progressive neurological degeneration. We describe genotypes and phenotypes at diagnosis, and disease evolution of seven Italian patients. MethodsAnagraphical, biochemical, genetic, clinical and instrumental data were collected at diagnosis and during a long-term follow-up. Mutations, ferroxidase activity and Western Blot analysis of ceruloplasmin were performed according to standard protocols. ResultsThree mutations were already described (p.Phe217Ser, deletions of exon 11 and 12), p.Ile991Thr is a very rare variant, p.Cys338Ser and IVS6+1G > A were novel mutations. In silico analyses suggested they were highly likely or likely to be damaging. At diagnosis, 100% had microcytosis, 86% had mild-moderate anemia, low serum iron and high serum ferritin. Four (57%) had type 1 diabetes or glucose intolerance, 3/7 had neurological manifestations, and only one had early diabetic retinopathy. All but one underwent iron chelation therapy requiring temporary discontinuation because of anemia worsening. At the end of follow-up, three patients aggravated and 2 developed neurological symptoms; only two patients were free of neurological manifestations and showed mild or absent brain iron. ConclusionAceruloplasminemia phenotypes ranged from classical characterized by progressive neurologic derangement to milder in which signs of systemic iron overload prevailed over brain iron accumulation. Within this large heterogeneity, microcytosis with or without anemia, low serum iron and high serum ferritin were the early hallmarks of the disease. Therapeutic approaches other than iron chelation should be explored to reduce morbidity and improve life expectancy.

Serum ferritin as an indicator of iron status: what do we need to know?

Determination of iron status in pregnancy and in young children is essential for both clinical and public health practice. Clinical diagnosis of iron deficiency (ID) through sampling of bone marrow to identify the absence of body iron stores is impractical in most cases. Serum ferritin (SF) concentrations are the most commonly deployed indicator for determining ID, and low SF concentrations reflect a state of iron depletion. However, there is considerable variation in SF cutoffs recommended by different expert groups to diagnose ID. Moreover, the cutoffs used in different clinical laboratories are heterogeneous. There are few studies of diagnostic test accuracy to establish the sensitivity and specificity of SF compared with key gold standards (such as absent bone marrow iron stores, increased intestinal iron absorption, and hemoglobin response to SF) among noninflamed, outpatient populations. The limited data available suggest the commonly recommended SF cutoff of <15 μg/L is a specific but not sensitive cutoff, although evidence is limited. Data from women during pregnancy or from young children are especially uncommon. Most data are from studies conducted >30 y ago, do not reflect ethnic or geographic diversity, and were performed in an era for which laboratory methods no longer reflect present practice. Future studies to define the appropriate SF cutoffs are urgently needed and would also provide an opportunity to compare this indicator with other established and emerging iron indexes. In addition, future work would benefit from a focus on elucidating cutoffs and indexes relevant to iron adequacy.