|Year : 2022 | Volume
| Issue : 2 | Page : 95-100
Lower serum ferritin levels and higher inattentiveness in attention deficit hyperactivity disorder in a case–control study
Bhogaraju Anand1, Chemarthi Venkata Sireesha2
1 Professor of Psychiatry, Malla Reddy Institute of Medical Sciences, Hyderabad, Telangana, India
2 Postgraguate Year 2, Internal Medicine, Lincoln Medical Center, Bronx, New York
|Date of Submission||19-Jan-2022|
|Date of Acceptance||15-Mar-2022|
|Date of Web Publication||17-May-2022|
Dr. Bhogaraju Anand
Malla Reddy Institute of Medical Sciences, Suraram, Hyderabad - 500 055, Telangana
Source of Support: None, Conflict of Interest: None
Introduction: Attention deficit hyperactivity disorder (ADHD) has hyperactivity, impulsivity, and inattentiveness. Brain iron stores influence dopamine synthesis and behavior. Serum ferritin is a marker for iron stores. Few studies are there on serum ferritin levels in ADHD, and the results showed either way as low or equal to controls. Contradictory results were observed in two published Indian studies, hence the need for the study.
Aims and Objectives: The objectives of this study were to compare serum ferritin and hematological indexes between children with ADHD and normal controls and also to compare ADHD subscales in two of ADHD groups divided on a cutoff serum value of below 15 ng/ml (World Health Organization criteria).
Materials and Methods: Children with ADHD without comorbidities were compared with controls at a child and adolescent psychiatry unit, Hyderabad, India, after ethics committee approval. The assessments included Conners' Parent Rating Scale (CPRS)-Revised (S), serum ferritin, and hematological indexes.
Results: Two-three children with ADHD and 38 normal children as controls participated. The mean (standard deviation [SD]) of serum ferritin levels in the ADHD group 28.26 (16.46) and controls 23.06 (18.88) was not statistically significant. Significantly higher mean values (14.60) on cognitive/inattention subscale was noticed In below (15 ng/ml) serum ferritin level group compared to the mean (11.50) in above (15 ng/ml) serum ferritin group. Negative nonsignificant correlation (r = −0.366) between cognitive-inattention subscale of ADHD and serum ferritin levels was noticed.
Conclusions: Iron-deficiency state showed higher inattentiveness on CPRS subscale than noniron-deficiency state. There is a weak negative correlation between serum ferritin and inattentiveness.
Keywords: Attention deficit hyperactivity disorder, Conners' Parent Rating Scale, inattention, serum ferritin
|How to cite this article:|
Anand B, Sireesha CV. Lower serum ferritin levels and higher inattentiveness in attention deficit hyperactivity disorder in a case–control study. Arch Ment Health 2022;23:95-100
|How to cite this URL:|
Anand B, Sireesha CV. Lower serum ferritin levels and higher inattentiveness in attention deficit hyperactivity disorder in a case–control study. Arch Ment Health [serial online] 2022 [cited 2023 May 28];23:95-100. Available from: https://www.amhonline.org/text.asp?2022/23/2/95/345401
| Introduction|| |
Attention deficit hyperactivity disorder (ADHD) is a clinical syndrome defined in both the Diagnostic and Statistical Manual of Mental Disorders 5th-Edition (DSM-5) and International Classification of Diseases-10 by the presence of high levels of hyperactive, impulsive, and inattentive behaviors beginning during early childhood and persistent over time, pervasive across situations. Systematic review and meta-analysis of 175 studies estimated the pooled prevalence of ADHD for children was 7.2% and in adults as 5% s. These children have poor school performance and difficulties with social skills.
Several theories have been proposed explaining the pathophysiology of ADHD, and the dopamine deficit theory is a well-accepted one. Association between ADHD and dopamine receptor D4 gene and dopamine transporter gene was shown in molecular genetic studies., Dopamine synthesis is dependent on iron as a cofactor for tyrosine hydroxylase enzyme, which converts tyrosine to L-dopa, which in turn decarboxylated to dopamine. Dopamine transporter density and activity are reduced in iron deficiency, consequently, increased extracellular dopamine, and reduced dopamine receptors in the striatum., Hence, brain iron stores may influence dopamine synthesis and further affect behavioral features in ADHD. Iron deficiency and nutritional certain micronutrient deficiencies have been increasingly implicated as possible risk factors for ADHD.,,
Studies on the brain iron levels using magnetic resonance imaging (MRI) in ADHD children have shown that the brain iron levels were significantly decreased., In a systematic review, it was suggested that the brain iron concentrations, in the thalamus, are lower in children with ADHD compared with healthy controls. There is some evidence, suggesting that brain iron rather than systemic iron levels may be more associated with the pathophysiology of ADHD in children. However, larger, longitudinal, MRI studies need to examine correlations of iron deficiency in specific brain regions and symptoms of ADHD.
Serum ferritin is an intracellular protein, and its concentration is a good marker of iron stores in the body tissues. However, whether the serum ferritin is a good indicator of iron stores in the brain is debatable. The World Health Organization (WHO) strongly recommends that it can be used to diagnose iron deficiency in otherwise apparently healthy individuals. Ferritin testing is usually performed along with hemoglobin (Hb) testing to assess the prevalence of iron-deficiency anemia. In children (5–<20 years), <15 ng/ml in apparently healthy individuals is indicative of iron-deficiency state. Ferritin is measured using radiometric, nonradiometric, and agglutination assays. One method does not appear to be superior to another and all methods are acceptable if the WHO international reference standard is used to calibrate the assay.
Studies comparing serum ferritin in children with ADHD and normal controls showed contrasting results.
Some reported no statistically significant differences with controls on serum ferritin levels.,,, Islam et al. in an Indian study showed a lack of significant association between serum ferritin levels and ADHD symptom severity. Neuropsychological test scores in ADHD were not related to ferritin, but lower ferritin levels had higher Conners' Parent Rating Scale (CPRS) hyperactivity scores.
Studies showed significantly lower ferritin values in ADHD than controls.,, Juneja et al. in their study from India reported serum ferritin levels to be significantly lower in children with ADHD (6.04 ± 3.85 ng/mL) and significant negative correlation between serum ferritin levels and oppositional subscore on Conners' Rating Scale. Wang et al. in a meta-analysis (a subset of 10 studies), found serum ferritin levels were lower in ADHD cases than controls. Also there was no correlation between serum iron levels and ADHD. Their analysis noted a significant statistical heterogeneity across studies. Tseng et al. in their meta-analysis of 17 studies reported that children diagnosed with ADHD have lower serum ferritin levels compared to those without ADHD.
Limitations pointed from studies
The number of studies was small, with small datasets and lack of long-term follow-up studies. Iron deficiency in children is the most prevalent in India and its role in contributing to ADHD symptoms needs study. Juneja et al. and Islam et al. are the only two published studies in the Indian context.
Justification to carry out the present study
Meta-analysis noticed that there were some studies showing no statistical difference on serum ferritin levels in ADHD and controls while some others did. The WHO gave the guidelines regarding iron-deficiency state as serum ferritin levels below 15 with other blood indexes, but there are few studies considering this aspect. Association between serum ferritin levels and ADHD rating scales and its subscales needs to be examined. With a dearth of Indian studies, more data need to be generated and contribute to the literature. Hence, the present study has been undertaken.
Aims and objectives
The primary objective is to compare serum ferritin and hematological blood indexes between children with ADHD and normal controls. The secondary objectives are to compare ADHD subscales in two of ADHD groups divided on a cutoff serum value of below 15 ng/ml (WHO criteria) and to study the association between serum ferritin levels with ADHD rating scale subscales.
| Materials and Methods|| |
A case control study was done at Niloufer hospital for women and children, child and adolescent Psychiatry unit, Hyderabad, India. Cases included children diagnosed as having ADHD and controls were children attending a school. Parents were formally interviewed in the control group for behavior problems in their children and included only when they did not have them. Institutional ethics committee approval was obtained before the start of the study. The children between the ages of 7–18 years diagnosed with ADHD according to DSM-5 criteria and no comorbidity were recruited into the study after written assent from parents was taken. Children on iron supplementation and suffering from major illnesses and chronic diseases were excluded from the study.
Conners' Parent Rating Scale-Revised (S)
This scale by Conners, is a 27-item rating scale used to obtain the parent's observations about the child's behavior in ADHD and its most common comorbid problems in children and adolescents aged 6–18 years. Questions are on a Likert 4-point scale (from “never” to “very often”), and it takes under 10 min to complete. The items on the measures are face valid and like the diagnostic criteria for ADHD in the DSM-IV. It has three subscales (oppositional, cognitive problems/inattention, and hyperactivity) and an ADHD index.
Two milliliters of EDTA-anticoagulated venous blood was collected and Hb%, packed cell volume (PCV), mean corpuscle volume (MCV), mean corpuscular Hb (MCH), MCH concentration (MCHC), red cell distribution width (RDW) were measured in the pathology laboratory of the hospital by automated method using Sysmex XP-100 cell counter.
Two milliliters of blood was collected in clot activator and it was centrifuged and the serum was separated and serum ferritin was measured by electrochemiluminescence immunoassay method using Beckman Coulter machine.
Descriptive statistics mean, standard deviation (SD), median, and bar diagrams were used. Student's t-test was used to compare the groups. To measure the degree of association, Pearson's product-moment correlation was used. P ≤ 0.05 was considered for the level of significance. Scatterplots with the best fitting line and 95% confidence intervals were projected.
| Results|| |
Thirty ADHD children were screened, but after obtaining parent's consent, only 23 formed ADHD group. Control group consisted of 38 children (matched for age) from a school were included after parental consent. There were 20 males and 3 females in the ADHD group and 35 males and 3 females in the control group. For serum ferritin levels, only 22 cases in the ADHD group were included as one blood sample was ineligible.
[Table 1] depicts the comparison between the ADHD and control groups on variables age and hematological parameters Hb%, PCV, MCV, MCH, MCHC, RDW, and serum ferritin. There are no statistically different means between the groups.
|Table 1: Differences between attention deficit hyperactivity disorder and control groups|
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[Table 2] depicts the comparison between serum ferritin levels at or below and above 15 ng/ml.
|Table 2: Comparison below and above cutoff value of serum ferritin with hematological values|
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There is a statistically significant difference in serum ferritin levels which is explainable. There are no differences in the hematological values.
[Table 3] depicts that the scales of ADHD have been compared in two groups of serum ferritin levels at or below and above 15 ng/ml. There are statistically significant higher values on cognitive/inattention scale with the ADHD group mean value in the group with lower serum ferritin values.
|Table 3: Comparison below and above cutoff value of serum ferritin with Conners' Parent Rating Scale symptoms|
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[Table 4] depicts the correlation between scales of ADHD and serum ferritin levels, and it can be seen that only the cognitive subscale of Conners' scale is near the significance level with r = −0.366 suggesting a negative correlation.
|Table 4: Pearson's product-moment correlations between serum ferritin and subscale of Conners' Parent Rating Scale (n=22)|
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[Graph 1] depicts scatterplot with best fitting line and 95% confidence levels between the serum ferritin values and ADHD subscale of cognition/inattention. It can be seen that half of the value is within the confidence limits only and half as outliers.
| Discussion|| |
In our study, we found that mean (SD) of serum ferritin levels in the ADHD group 28.26 (16.46) is higher than the control group 23.06 (18.88) but not statistically significant. Our findings were similar to a studies by Millichap et al., Menegassi et al. Donfrancesco et al. where no significant differences were found on serum ferritin levels in ADHD and control groups. Furthermore, they did not find differences between subtypes of ADHD on serum ferritin values. Romanos, in a large population of 2805 children aged 10 years, reported that ferritin was not associated with ADHD symptoms even after adjusted analysis.
Oner et al. showed that in 52 ADHD children, neuropsychological test scores didn't correlate with serum ferritin levels. However, lower ferritin levels had higher CPRS hyperactivity scores.
Islam et al. in Indian study did not find any significant correlation between severity of ADHD and hematological indicators of iron deficiency. Median instead on mean was chosen by the authors to project summary measures as there was wide dispersion of values.
Studies showing significantly lower ferritin values in attention deficit hyperactivity disorder group than controls
Konofal et al. reported that serum ferritin levels (mean ± SD) were significantly lower in 58 ADHD children 23 ± 13 ng/mL than in the 27 controls 44 ± 22 ng/mL. Furthermore, low serum ferritin levels correlated with higher ADHD symptoms on CPRS. Konofal et al. reported significantly lower ferritin levels (mean=25) in 10 ADHD subjects than in 10 controls (mean= 46). Cortese et al.'s study showed that significantly lower serum ferritin in 18 ADHD children was 32.4 (13.4) than in 18 healthy controls who scored 51.6 (16.4). Juneja et al. in their study from India reported serum ferritin levels to be significantly lower in children with ADHD (6.04 ± 3.85 ng/mL), but Hb% was not in iron-deficient anemia range. A significant negative correlation was also reported between serum ferritin levels and oppositional subscore on Conners' Rating Scale. In their sample, there were children with oppositional defiant disorder which contributed to higher scores on this subscale of CPRS. Wang et al. in their meta-analysis found serum ferritin levels were lower in ADHD cases than controls. Also there was no correlation between serum iron levels and ADHD. Their analysis showed significant statistical heterogeneity across studies. Tseng et al. in their meta-analysis of 17 studies reported that children diagnosed with ADHD have lower serum ferritin levels compared to those without ADHD.
Cutoff values for serum ferritin
Lahat et al. compared two groups of 67 ADHD with serum ferritin below 20 (ng/ml) with 46 ADHD above 20 (ng/ml) and found no statistical difference on mean CPRS scores. Abou-Khadra et al. divided ADHD groups into two groups with a serum ferritin value of 30 ng/ml and found no difference in the scores on subscales of CPRS in 25 and 16 subjects and lack of correlation with serum ferritin levels.
The division of two groups based on a cutoff as value of 30 for serum ferritin appears arbitrary and not according to the WHO which gave the value below 15 as iron-deficient group.
Doom et al. divided groups based on ferritin <12 μg/L and found higher ADHD symptoms and low intelligence quotient (IQ).
Fuglestad et al. took standard criteria in their study that defined iron deficiency as two or more abnormal indexes: transferrin saturation (TS)\12%, serum ferritin (SF)\12 lg/L, and MCV\74 fL. Iron-deficiency anemia was defined as iron deficiency with Hb\11.0 g/dL. They found that those with iron deficiency at follow-up displayed more hyperactivity in children 9–46 months of age.
Role of ferritin and the cutoff values have been recently published in the WHO documents in 2007 and 2020.Ferritin can be considered a good indicator of iron stores and used as a measure of iron deficiency in healthy subjects. They advised measurement of ferritin along with Hb levels for diagnosis of iron-deficiency anemia or iron overload in prevalence studies. Ferritin values in children between 5 and 18 years are now established as <15 in apparently healthy individuals are indicative of iron deficiency. Keeping into view the cutoff value given by the WHO, many studies in meta-analysis, showing low ferritin values are still in normal range and cannot be considered an iron-deficiency state. The lower end of a range is on a dimension and should be taken as a normal iron-deficiency state. In our study, a negative correlation of-0.308 between serum ferritn and cognition/Inattenton subscale of CPRS was not significant. At least 50% of of the values were outliers as depicted on the scatter plot with the best fit line. This significant value can be considered an iron-deficiency state associated with cognitive changes.
Do different estimation methods of serum ferritin contribute to variability across studies?
Ferritin is measured by radiometric, nonradiometric, and agglutination assays that are all acceptable, and there is no difference as per the WHO statement. This was reiterated in another meta-analytic study in 2018.
Iron deficiency and cognitive functions
Iron deficiency and iron-deficiency anemia are prevalent conditions worldwide. In Indian National Fertility and Health Survey on a sample of 112714 children (collected from the 2015 to 2016), the prevalence of iron-deficiency anemia in children aged 1–4 years was 36.5%. 5 to 9 years (15.6%) and among 10–18 years (21.3%).
Studies done on iron-deficiency anemia and neuropsychiatric symptoms showed deficits in scholastic performance especially in mathematics, and verbal learning. Attention, mental balance, and IQ scores were lower in iron-deficient school-going girls than non iron deficient group. Iron deficiency has a negative impact on cognition, behavior, and motor skills. Some studies showed an association between anemia and impaired concentration, intellectual status, memory, and learning skills and low Mini-Mental State Examination score associated with low Hb. Iron deficiency and iron-deficiency anemia exacerbate cognitive problems.
With such a highly prevalent iron-deficient anemia in India combined with lower cognitive functioning, the cognitive symptoms in ADHD cannot be ascribed solely to ADHD condition. In our study, it can be seen that the mean serum ferritin levels in the control group were lower than the ADHD group, and when a cutoff value of <15 ng/ml was taken, cognition/inattention scores on CPRS were significantly higher than above cutoff group. In the serum ferritin lower than cutoff value (15 ng/ml) group, Hb% was in normal range suggesting it's only iron-deficiency state.
From our results, we suggest that iron may play a significant role in the cognitive/inattention disturbances which is also noticed in ADHD where the ferritin levels were below a cutoff point. We observe a wide range of serum ferritin values in controls. Even with larger samples in previous studies also noticed this, hence. Only one study studied the effects of iron supplementation on ADHD children by Konofal et al. There was a progressive significant decrease in the ADHD rating scale after 12 weeks on iron but no significant improvement on CPRS and Teacher Rating Scale.
The effect of iron supplementation on ADHD children also has to be studied on a larger scale and comes to conclusions which might have a beneficial effect to the children suffering from ADHD.
There is a significant negative correlation between serum ferritin and cognitive subscale in the serum ferritin group below 15 ng/ml. Although the sample size is 6, the SD around the mean values is low, hence used in comparison with the control group
| Conclusion|| |
The results in our studies support the view that iron-deficiency state and inattention are associated despite ADHD. There was a negative correlation between lower serum ferritin levels and cognitive/inattention subscale of CPRS but not significant.
Cognitive inattentiveness subscale of CPRS may not be adequate to capture varied cognitive deficits and neuropsychological scales would be of greater importance
Limitations of the study
One of the limitations in our study is potential confounding effect of food iron intake on peripheral iron status, however, there are only a few studies which provided such information.
Financial support and sponsorship
Our work received funding grant number STS 2014-00266 from the Indian Council of Medical Research
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]