Relation of Iron and Zinc Deficiencies to the Occurrence of Febrile Convulsions.

CONTEXT: Febrile convulsion is one of the most important types of convulsions in children. Iron and zinc are important trace elements that affect some enzymes in central nervous system, and their deficiencies could disturb the inhibitory mechanisms in the brain, thus producing convulsions. AIM: To evaluate the relation between iron deficiency, zinc deficiency, and febrile convulsions. SETTINGS AND
DESIGN: A cross-sectional study was carried out. SUBJECTS AND METHODS: The study included 100 children of the pediatric hospital in Assiut University, Assiut, Egypt; 50 children with febrile convulsions as the study group and 50 febrile children without convulsions as the control group. STATISTICAL ANALYSIS: The Statistical Package for the Social Sciences (SPSS) software, version 20, was used for statistical analysis.
RESULTS: The mean value of hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration iron, and ferritin were significantly lower in cases than that in the control group. Significantly, zinc level was lower in 68% of cases and 36% of control children. Moreover, the mean value of zinc was significantly lower in cases than that in the control group.
CONCLUSION: Lower levels of iron and zinc seem to be predisposing factors for developing febrile convulsions.

Introduction

Febrile convulsion (FC) is defined as the convulsion occurring in the children in the age group of 6–60 months with a temperature of 38°C or more.[1] FC, according to the definition of the American Academy of Pediatrics, occur with fever with diseases in the absence of central nervous system (CNS) infection, metabolic disorders, and history of febrile seizures.[2]

FCs occur because the brain is not capable enough to withstand against the elevation of body temperature, which occur because of the effect of enzymes, ion channels, and receptors. Studies have shown that trace elements such as iron, zinc, magnesium, selenium, and copper are important in developing these convulsions.[3]

Iron is a trace element required mainly for hemoglobin synthesis and also for many reactions in brain such as myelin formation, brain energy, some neurotransmitters, and enzyme metabolism such as monoamine oxidase.[4] Neurological symptoms such as poor attention, learning deficits, weak memory, delayed motor development, and behavioral disturbances are well known to occur in iron deficiency.[4]

Alteration of brain synaptic neurotransmitters, increase of glutamate excitatory neurotransmitters, decrease of gamma-aminobutyric acid (GABA) inhibitory neurotransmitters, decrease of monoamines, and hypoxemia that occur due to iron deficiency may be responsible for the induction of convulsions.[5]

Zinc is a trace element that is important for growth, development, and normal brain function and is the principal component of different enzymes such as deoxyribonucleic acid and ribonucleic acid polymerases.[6] In brain, it regulates the activity of glutamic acid and the rate-limiting enzyme in the synthesis of GABA and facilitates the inhibitory effect of calcium on N-methyl-d-aspartate receptors and these effects prevent the stimulation of neuronal discharge.[3] Decreased zinc level lowers GABA synthesis because it increases the activity of pyridoxine needed for the synthesis of GABA, which would induce convulsions.[7]

According to the importance of FCs, in this study, we assess the relation between iron deficiency, zinc deficiency, and FCs.

Subjects and Methods

This cross-sectional study was conducted on 100 infants and children of the pediatric hospital in Assiut University, Assiut, Egypt. Subjects were divided into two groups with 50 subjects with high-grade fever with FCs as the study group and 50 subjects having a high-grade fever without convulsions as the control group.

The excluded subjects were patients below 6 months or above 5 years, patients having CNS infection or disease, children on regular iron therapy or zinc therapy, and patients with epilepsy or family history of epilepsy. Written informed consent was obtained from the parents of the children to participate in the study.

A blood sample (5mL) was collected by venipuncture from each patient: 2mL blood into Ethylenediaminetetraacetic acid tube for complete blood count (CBC) and 3mL blood for the separation of serum for measuring serum iron, serum ferritin, serum total iron binding capacity (TIBC), and serum zinc.

CBC was carried out on Celtac F analyzer (Nima Pouyesh Teb (NPT CO.), Iran). Serum iron, serum ferritin and serum TIBC were measured on Cobas C311 analyzer (Roche Diagnostics, Hoffmann-La Roche Ltd, Switzerland). Serum zinc was measured colorimetrically using kits, with 2-(5-bromo-2-pyridylazo)-5-(N-propyl-N-sulphopropylamino)phenol as the reagent.

Statistical Analysis

The collected data were analyzed using the Statistical Package for the Social Sciences (SPSS) software, version 20 (IBM Corporation, New York, United States). Chi-square test and independent t-test were used to calculate the association between different groups. P < 0.05 was considered as statistically significant.

Results

The age of the study group ranged from 0.7 to 4.3 years with mean age of 2.17 ± 1.11 years. Male patients in this group were 27/50 (54.0%).

The age of the control group ranged from 0.7 to 4.6 years with mean age of 2.27 ± 1.11 years. Male patients in this group were 35/50 (70.0%). The differences between the two groups were statistically not significant (P < 0.05).

The temperature at the time of examination in the study group ranged from 37.6° to 39.2°C. The mean temperature was 38.59 ± 0.42°C, whereas the temperature at the time of examination in the control group ranged from 37.8°C to 39.2°C with the mean temperature of 38.65 ± 0.36°C. The number of convulsion(s) measured in the study group was one convulsion in 43/50 (86.0%) of cases and two convulsions in 7/50 (14.0%) of cases, whereas 3/50 cases gave a history of previous attacks of FC (one attack for each case) several months ago. No convulsion at the recent febrile illness or a history of any previous attacks of FCs was reported in the control group. The differences between the two groups were statistically not significant.

Regarding the mean values of blood count parameters (red blood cells [RBCs], hemoglobin (HB), hematocrite (HTC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) the study group showed statistically significant lower mean values compared to the control group. While regarding the red blood cell distribution width (RDW), the mean value of the study group was statistically lower than that of the control group but not significant. The iron study markers showed that the mean serum iron and ferritin level of the study group was statistically significantly lower than that of the control group but the mean serum TIBC of the study group was higher compared to that of the controls but not statistically significant [Table 1].

Table 1

Blood parameters and iron study markers between study and control groups

Blood parameters	Study (n = 50), mean ± SD	Control (n = 50), mean ± SD	P value
RBCs	4.42 ± 0.75	4.76 ± 0.67	0.013*
HB	10.20 ± 1.42	12.22 ± 1.29	0.000**
HTC	32.30 ± 4.26	37.37 ± 3.89	0.000**
MCV	72.83 ± 7.71	82.29 ± 6.48	0.000**
MCH	23.60 ± 3.15	26.34 ± 3.15	0.000**
MCHC	31.39 ± 2.10	32.25 ± 1.98	0.031*
RDW	14.11 ± 2.18	14.44 ± 2.47	0.499
S. iron	39.68 ± 18.00	78.21 ± 42.95	0.000**
S. ferritin	65.61 ± 86.87	160.37 ± 105.76	0.000**
TIBC	283.62 ± 97.99	260.04 ± 81.65	0.237

SD = standard deviation, HB = hemoglobin, HTC = hematocrite, MCV = Mean corpuscular volume, MCH = mean corpuscular hemoglobin and MCHC = mean corpuscular hemoglobin concentration

*P < 0.05, statistically significant, **P < 0.0001, high statistically significant

Regarding serum zinc level, the mean value was significantly lower in the study group than that in the control group. A significant statistical difference was observed in the levels of serum zinc between the two groups [Table 2].

Table 2

Comparison of serum zinc level between study and control groups

Zinc level	Study group (50 patients)	Control group (50 patients)	P value
Mean ± SD	61.01 ± 8.4	70.14 ± 12.3	0.000**
Low (<63 µg/dL)	34 (68%)	18 (36%)
Normal (>63 µg/dL)	16 (32%)	32 (64%)	0.001*

SD = standard deviation

*P < 0.05, statistically significant, **P < 0.0001, high statistically significant

Discussion

The results of this study showed a significantly lower level of RBC, HB, HTC, MCV, MCH, MCHC, serum iron, and serum ferritin among the cases with FC in comparison to that in the controls.

The RDW was also lower among the cases than that in the controls, also the TIBC was higher among the cases than that in the control, but both differences failed to attain statistical significance.

There is a controversy regarding the role of iron status in the occurrence of FCs.[8] A case–control study with 50 cases and 50 controls, with age range of 6–60 months, reported a significantly lower level of HB, serum iron, and serum ferritin among the cases than that in the controls, which suggested that iron-deficient anemia was more frequent in children with FCs; this is in agreement with our results.

Fallah et al.,[8] in 2014, in a case–control study with 30 cases and 30 controls, reported the same result, that is, a significantly lower level of HB, HTC, MCV, MCH, and serum ferritin among the cases than that in the controls,[9] other studies such as the ones conducted by Aziz et al.,[10] in 2017, and Gowda and Samuel,[11] in 2018, reported similar results.

Iron deficiency may play an important role in convulsion production through decrease of GABA inhibitory neurotransmitter, change in neuron metabolism, and impairment in oxygenation and energy metabolism of the brain.[12] Ferritin, which is an acute-phase reactant, is increased during any febrile illness; in this study, fever was equally present in the two studied groups. Therefore, high statistically significant difference between serum ferritin levels in the two groups (P < 0.000) cannot be attributed to fever alone.[13]

On the contrary, Kamalammal and Balaji,[14] in 2016, observed that the HB, MCH, MCHC, and serum ferritin levels did not show any significant differences between the two groups, and only serum iron level was less in the case group than that in the control group. Also Sharif et al.,[15] in 2016, reported that only low serum iron level was associated with FCs, with a lack of significant difference in HB and with significantly higher TIBC level among the cases than that in the controls, these results differ from our results. Bidabadi and Mashouf,[16] in 2009, reported a significantly higher level of RBC, serum iron, and serum ferritin, and a significantly lower level of TIBC among the cases with FC than that in the controls, which suggest a protective effect of iron deficiency against the development of FC, these results are in contrast with our result. Possible explanations for these discrepancies are differences in nutritional habits, geographic area, sample sizes, control group, and differences in the diagnostic criteria of iron-deficient anemia between their and our study.

In our study, the mean serum zinc level was significantly lower in the patients group than that in the control group, and 68% of patients had low level of serum zinc, whereas 18% of controls had low level with a significant difference, which was in agreement with many other studies. Srinivasas and Manjunath,[17] in 2014, studied children with febrile seizures and reported that they have lower serum zinc level than the normal range. Similarly, in another study conducted by Modarresi et al.,[18] in 2011, with a comparison of serum zinc levels in the three groups of children (with febrile seizures, with fever, and healthy children), showed that the zinc level among the patients with febrile seizures was significantly lower than that of the other two groups. Pannerselvam et al.,[19] in 2015, and Rehman et al.,[3] in 2018, showed similar results.

Brain has a large amount of zinc, especially in hippocampus region. A total of 5%–15% of zinc is collected as vesicle zinc in glutamatergic synapses. Zinc acts as a neurotransmitter and improves the communicating and locomotive function and maturation of neurological system. Zinc deficiency decreases the hippocampal zinc and leads to release of convulsions.[3]

On the contrary, in 2012, Çelik et al.[20] reported that no significant difference was observed between serum zinc level in 25 children with FCs and healthy 25 children as the control group. Similar results were found in the studies conducted by Kafadar et al.[21] and Cho et al.[22] This difference seen in comparison with our result may be due to their small sample size and the difference in the control group.

Conclusion

In this study, we conclude that iron and zinc deficiency are reinforcing factors for developing FCs and they should be excluded. Iron and zinc supplementation can be helpful in the treatment or prevention of FCs in children.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.