Investigation of the role of Irisin and FABP4 in iron deficiency anemia

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Methods The study was conducted by the Department of Pediatric Hematology Oncology Faculty of Medicine,Fırat University.Our study evaluated ID in three distinct periods,including iron storage depletion,latent iron deficiency without anemia,and iron deficiency anemia.We analyzed the effects of these three periods, along with a control group, on serum and urine Ir, as well as FABP4 levels, both before and after iron treatment. Results The mean serum Ir levels in our study revealed statistically significant differences between the patient groups and the control group, with lower levels observed in the patient groups before treatment(p < 0.05).After treatment, a statistically significant increase(p 0.05). Conclusion In our study,we found that the feeling of coldness and decreased cognitive functions seen in iron deficiency may be related to serum Ir level.Today, IDA is an important public health problem and affects many systems. Iron deficiency anemia Irisin FABP4 cold intolerance Iron deficiency Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTİON Iron Deficiency Anemia Anemia, defined as a hemoglobin level two standard deviations below the mean for age, is prevalent in infants and children worldwide. Iron deficiency is the most common cause of anemia. The World Health Organisation (WHO) estimates that 293 million pre-school-age and 305 million school-age children are anemic, and more than 50% are thought to be iron deficient ( 1 ). Iron deficiency (ID) has an effect on physical development, rapid brain development and early learning capacity, especially in the infant and pre-school years ( 2 – 4 ). Iron plays a crucial role in myelin synthesis. Iron is required for myelin production from oligodendrocytes for both maturation and acquisition of function ( 5 ). ID has negative effects on brain development, myelination and development of major dopaminergic pathways. Persistent ID has lifelong effects on intelligence and learning functions. If low iron status is not corrected during developmental age, IQ scores may decrease by approximately 5–10 points ( 6 , 7 ). İrisin Irisin (Ir) was discovered in 2012 to be a muscle-associated factor involved in inducing browning of white adipose tissue (WAT). Irisin-related pathways are known to be activated by peroxisome proliferator-activated receptor (PPAR)-γ, coactivator (PGC)-1α and its release is increased by exercise. Irisin is a newly discovered peptide hormone released by proteolysis of (FNDC)5 in circulation ( 8 , 9 ). Irisin is mainly responsible for the browning of WAT and the release of uncoupling protein-1 (UCP1). UCP1 exerts its effect by increasing total energy expenditure through thermogenesis ( 10 ). Irisin levels are thought to be determinant in fat storage and metabolic dysfunction ( 11 ). FABP4 Fatty acid binding proteins (FABPs) are chaperones involved in intracellular fatty acid transport, regulate lipid responses in cells and are also linked to metabolic and inflammatory pathways. FABPs with a molecular weight of 14–15 kDa that bind reversibly with high affinity to hydrophobic ligands such as saturated and unsaturated long-chain fatty acids, eicazonoids and other fats. To date, 9 FABP types have been identified ( 12 ). FABP4 release is stimulated during adipocyte differentiation and by (PPAR)-γ receptor agonist transcription factors such as insulin, irisin, fatty acids. Currently, FABP4 has been found to have roles in maintaining glucose homeostasis and energy storage systems ( 13 ). Irisin and FABP4 play a role in metabolic control. Irisin acts in metabolic control by providing thermogenesis with heat energy. Fatty acid binding protein 4 plays a role in metabolic events such as fatty acid storage, circulation and glucose homeostasis, levels are increased in obese individuals ( 13 ). Iron deficiency anemia (IDA) patients tend to experience heightened sensitivity to cold compared to individuals with sufficient iron levels. While there are various theories regarding this phenomenon, the precise underlying cause remains unclear. The currently accepted view is that IDA results in impaired thermoregulation due to insufficiency of the thermoregulatory center, both in mice and humans. At the tissue level, ID is considered to impair the appropriate physiological response to cold because of impaired neurological control of the sympathetic nervous system ( 14 ). In addition, ID is thought to affect the ability of the endocrine system to respond to heat production and thermogenic tissues in response to cold ( 15 ). Thermogenesis capacity is impaired in ID. Brown adipose tissue (BAT) is a specialized form of adipose tissue characterized by multilocular fat droplets, high mitochondrial density, and abundant sympathetic innervation. After sympathetic stimulation in response to cold, the blood flow to BAT increases ( 16 ). Irisin browns WAT, while UCP-1 is released to release heat energy. We thought that the impaired thermogenesis capacity in ID may be due to the concomitant Ir deficiency. ID is known to cause a variety of symptoms, but the etiology of these symptoms may not be fully understood. The study's objective is to explore whether Ir and FABP4 levels might be linked to symptoms such as feeling cold, fatigue, learning difficulties, and others in individuals with ID. Material And Methods The study was conducted by the Department of Pediatric Haematology Oncology and Department of Biochemistry, Faculty of Medicine, Fırat University. In our study, ID was evaluated in 3 periods and the effects of these 3 periods on serum and urine Ir and FABP4 levels were analysed. The diagnosis of the 3 periods of ID was made according to the following laboratory values ; ( 17 ) 1. Iron storage depletion (ID) : Anemia is not seen. Iron stores depletion. Serum iron, Hb, serum iron binding capacity (SIBC), transferrin saturation (TS) are normal. Ferritin < 12 ng/mL 2. Latent Iron deficiency without anemia (LID) : There is no anemia. Iron stores are depleted. Hb is at the lower limit. Erythrocyte distribution volume and SIBC level increase. Serum iron decreases, TS < 16%, Ferritin < 12 mL. 3. Iron Deficiency Anemia (IDA) : Hypochrome microcytic anemia has developed. Hb, serum iron decreases, TS < 16%, ferritin < 12 ng/mL. In our study, a total of 60 patients from these 3 periods (n:20 patients diagnosed with ID, n:20 patients diagnosed with LID, n:20 patients diagnosed with IDA were included. From the control group with normal iron parameters, n: 20 patients were included. Oral iron treatment was started after the diagnosis of ID, LID and IDA. Patients were administered iron treatment in the form of ferrous iron (Ferro Sanol®) at a dosage of 3–6 mg/kg/day, given 2–3 times daily for a duration of 3 months. Blood and urine samples were collected from the subjects (n = 60) who received iron treatment, both just before the initiation of the treatment and 3 months afterward. Additionally, samples were collected from the control group (n = 20) once for comparison. For the diagnosis of IDA, standard diagnostic procedures were followed for all patients presenting for diagnosis and treatment. This included obtaining a complete blood count (CBC), peripheral smear, reticulocyte count, serum iron levels, SIBC, and ferritin levels, as routinely performed in clinical practice. These tests collectively help in assessing various parameters related to red blood cell production, iron levels, and iron storage, aiding in the accurate diagnosis and treatment of iron deficiency anemia. Serum and urine Ir and FABP4 levels were analysed in the patient group n:60 before and after treatment. In the control group, only serum and urine Ir and FABP4 levels were analysed at baseline. Samples were studied as described in the ma nufacturer's catalogue (Human (irisin) catalogue no: 201-12-5328, Human (FABP4) catalogue no: 201-12-2037 and manufactured at Awareness Technology, Inc Palm City, Florida, USA). At the end of the study, the samples were read at 450 nanometres with a ChroMate microplate (ChroMate 4300 Florida, USA) reader. Patients who were not included in the study; 1. Patients with chronic infection, 2. Patients who developed an allergic reaction with iron therapy or had a history of such a reaction, 3. Patients who used any iron preparation before the study, 4. Patients using vitamins, Statistical methods All data were analysed using SPSS version 22.0 (IBM, Chicago, IL, USA). Mean ± standard deviation was given for normally distributed data and median values were given for non-normally distributed variables. Wilcoxon test was used for comparison of ranks, Mann Whitney U test was used for comparison of groups of more than two, chi-square test was used for comparison of percentages, and Spearmen rank correlation tests were used for correlation tests. P < 0.05 value was considered statistically significant. Results Demographic characteristics of the patients are shown in Table.1. The anthropometric measurements of the patients before and after treatment are given in Table.2&Figure 1 . There was no statistical difference between the gender distributions in each group. Hb, haematocrit and ferritin values were found to be statistically significantly higher when compared between the groups after treatment (Table 3 , 4 &Figure 2 , 3 ). The mean serum Ir levels in our study revealed statistically significant differences between the patient groups (ID, LID, IDA) and the control group, with lower levels observed in the patient groups before treatment.(p < 0.05) (Table 5 &Figure 4 ). A statistically significant increase (p < 0.05) was found in the mean serum Ir levels in all patient groups after treatment. When urine Ir levels were analysed, an increase in urine Ir levels was found in the ID and IDA groups and a decrease in the LID group after treatment, but these changes were not statistically significant (p > 0.05) (Table 5 &Figure 4 ). Table 1 Demographic characteristics of the patients Control ID LID IDA p Age 8,76 ± 5,41 8,07 ± 6,39 8,80 ± 6,07 9,53 ± 6,12 > 0,05 Gender > 0,05 Female 11 (%55) 9 (%45) 9 (%45) 12 (%60) Male 9 (%45) 11 (%55) 11 (%55) 8 (%40) Table 2 Demographic characteristics and anthropometric values of the patients before and after treatment Age Body weight (kg) Height(cm) Weight (percentile) BMI (kg/m 2 ) Before Before After Before After Before After Before After Control 8,76 ± 5,41 28,9 ± 17,3 123,2 ± 32,8 30,9 ± 25,7 17,2 ± 2,5 ID 8,07 ± 6,39 28,6 ± 19,2 29,4 ± 18,9 a 121,4 ± 36,6 122,5 ± 35,9 a 45 ± 33,3 46,3 ± 32,6 17,1 ± 2,7 17,4 ± 2,5 a LID 8,80 ± 6,07 34,5 ± 22,0 34,6 ± 21,4 126,4 ± 36,5 127,6 ± 35,8 a 55 ± 29,2 b,c 53,8 ± 29 19,1 ± 3,6 18,9 ± 3,7 IDA 9,53 ± 6,12 32,8 ± 19,8 33,5 ± 19,3 a 129 ± 31,9 130 ± 31,3 a 41,9 ± 29,1 45,1 ± 27,2 17,7 ± 3,7 18 ± 3,4 ID; Iron depletion ,LID; Latent Iron Deficiency, IDA; Iron Deficiency Anemia; a : p < 0,05; Compared with before treatment; b : p < 0,05; Compared with control; c : p < 0,05; Comparison with ID Table 4. Comparison of ferritin, serum iron, serum iron binding capacity (SIBC), transferrin saturation values before and after treatment Ferritin (ng/dL) Serum Iron (µg/dL) SIBC (µg/dL) Transferrin Saturation Before After Before After Before After Before After Control 56,6±58,9 96,2±36,3 339,9±40,1 31±12,7 ID 8,1±2,6 b,e 24,9±15,3 a 92,1±31,2 d 88,4±25,2 367,7±34,4 b 329,7±34,6 a,e 24,9±8,4 e 26,5±7,3 LID 8,7±2,6 b 27,6±14,7 a 29,7±13 b 71,3±32,5 a 361,8±50,7 304,4±71,4 a 8,3±3,1 b,c 23,6±7,8 a IDA 4,5±3,7 b,d 46±44,8 a 23,8±11,7 b,c 76,6±33,1 a 377,3±47,4 b 288,1±54,9 a 6,6±2,7 b 26,6±8,8 a a : p < 0,05; Compared with before treatment; b : p < 0,05; Compared with control; c p < 0,05; Compared with the ID group, d p < 0,05; Compared with the LID group; e p < 0,05; Compared with the IDA group Table 5 Comparison of Ir and FABP4 levels before and after treatment Serum Urine Serum Urine Gruplar Ir Before Treatment (ng/dL) Ir After Treatment (ng/dL) Ir Before Treatment (ng/dL) Ir After Treatment (ng/dL) FABP4 Before Treatment (ng/dL) FABP4 After Treatment (ng/dL) FABP4 Before Treatment (ng/dL) FABP4 After Treatment (ng/dL) Control 45,8 ± 13,4 22,5 ± 5,2 20,4 ± 11,3 9,6 ± 3,5 ID 36,8 ± 10,5 b,d 39,3 ± 11,5 a,d 23,1 ± 4,3 25,4 ± 6,2 21 ± 12,1 21,9 ± 12,2 12,3 ± 5 13,8 ± 5,4 b LID 27 ± 10,1 b 28,7 ± 11 a,b 25,6 ± 4,3 b 24,3 ± 2,5 17,9 ± 12,7 18,6 ± 11,5 11,4 ± 5,7 12,6 ± 6,4 b IDA 25 ± 6,7 b,c 27 ± 8,3 a,c 21,3 ± 3,4 d 22,1 ± 5,1 25 ± 13,1 22,6 ± 13,7 13,7 ± 4,5 b 12,9 ± 2,2 b a : p < 0,05; Compared with before treatment; b : p < 0,05; Compared with control; c p < 0,05; Compared with the ID group; d p 0.05) (Table 5 &Figure 4 ). After treatment, an increase was found in the mean serum FABP4 levels in the ID and LID groups, whereas a decrease was found in the IDA group, but these changes were not statistically significant (p > 0.05) (Table 5 &Figure 4 ). In our study, there was no statistically significant difference between the groups in urinary FABP4 levels before and after treatment (p > 0.05). Discussion Iron deficiency anemia (IDA) is an important public health problem in developing countries. The etiology of some of the symptoms seen in ID has not been clearly elucidated. Especially within the scope of our study, we hypothesized that the sensation of coldness observed in individuals with IDA might be associated with Ir levels. This hypothesis stems from previous findings in various studies ( 18 , 19 ), which have demonstrated that Ir plays a crucial role in generating heat energy through the conversion of WAT into BAT. Irisin and FABP4 are peptide-structured hormones involved in both energy metabolism and thermoregulation processes ( 15 ). As known, iron acts as a cofactor in the enzymes required for energy metabolism, participating in thermoregulation processes. Therefore, we believe that there may be a connection between iron and these two hormones. In our study, we found that the basal serum Ir levels of ID, LID and IDA groups were statistically low compared to the control group(p < 0.05). Ir, which is known to be synthesised in almost all biological tissues, leads to heat energy production instead of ATP synthesis by increasing UCP-1 proteins ( 20 ). An increase in the amount of Ir in biological fluids may be associated with increased heat production in the body. Ir is considered a hormone that regulates energy expenditure and promotes the conversion of WAT to BAT. In this context, elevated levels of Ir in biological fluids may contribute to increased thermogenesis and heat production in the body. There are factors outside the hypothalamus that influence thermogenesis in our body, and Ir is one of these pathways. Ir increases the expression of a protein called UCP1 in white fat cells. UCP1 stimulates thermogenesis by converting energy into heat in the mitochondria of the cell. This process redirects energy towards heat production rather than the normal function of energy storage in white We observed decreased levels of Ir in cases of diminished iron, even in the absence of anemia. Furthermore, there was an elevation in serum Ir levels following iron therapy. Based on this mechanism, we posit that the diminished Ir levels may underlie the heightened sensitivity to cold in individuals with ID. As known, Ir is released from muscle tissue. In the case of ID, symptoms such as weakness and fatigue develop, and patients may move slowly and engage in less physical activity. As reported here, an increase in Ir levels was observed with iron supplementation. The likely reason for this increase is the normalization of physical activity in children, associated with a reduction in fatigue and weakness due to ID. Consequently, there may be an elevation in muscle tissue through this mechanism, leading to an increase in the levels of Ir released from the muscles. We hypothesized that the rise in Ir levels following the treatment of ID could be attributed to this mechanism. In other studies, the correlations of Ir and FABP4 serum and urine levels with anthropometric measurements were analysed. In our study, we observed no correlation between the levels of serum and urine Ir and FABP4 and gender, as well as anthropometric measurement data.Similarly, Moreno et al,( 21 ) Liuliu et al. ( 22 ) found no relationship between Ir concentrations and gender. However, Al-Delghri et al. ( 23 ) in a cohort study of 153 Saudi Arabian children found that circulating Ir levels in the blood were higher in girls than in boys. Siahanidou et al. ( 24 ) found no significant correlation between FABP4 levels and gender, body weight, height and BMI, but Ibarretxe et al. ( 25 ) found high FABP4 levels in females in a study. In our study, we also investigated urine samples to establish a potential link between Ir and ID using a simpler and non-invasive approach. However, we did not find any correlation between the levels of Irisin in serum and urine samples. On the other hand, no difference was observed in the changes in urine depending on the treatment, and the possible reason for this was thought to be that there was no correlation between the circulating level of Ir and its excretion from urine. As it is known, decreases in neurocognitive functions such as attention deficit, learning difficulties, behavioural disorders, decreased perceptual functions, retardation in motor and mental development tests are observed in ID. Studies in school children have shown that learning and various developmental tests are impaired in ID with or without anemia, but learning difficulty may improve with iron treatment ( 26 ). In our study, it was thought that the decline in cognitive functions might be related with Ir, which is known to be released from all biological tissues. FNDC5/irisin has been shown as a new therapeutic factor that can improve cognition, learning and memory function ( 27 ). FNDC5 has been found to reduce some factors that provide neuronal destruction, and it has also been found that FNDC5 administration with adenovirus increases neuroprotective factors ( 28 , 29 ) Moon et al. ( 30 ) found that Ir at pharmacological concentrations increased STAT3 levels in H 19 − 7 hippocampal neuronal cells and STAT3 levels in mice, and low levels of Ir decreased differentiation in neuronal functions in mouse embryonic stem cells. Low levels of Ir in serum have been shown to reduce the level of FNDC5, an Ir precursor in the human brain. A direct relationship has been shown in hippocampal neurogenesis. Dun et al ( 31 ) showed in another immunohistochemical study that purkinje cells in rats and mice express Ir and also FNDC5 in recent days. It is known that the hippocampus is a critical region in learning and memory formation, and is a very important structure in spatial memory formation. According to our current knowledge, the cellular and molecular mechanisms of learning and memory formation are explained by long-term potentiation (LTP) in the hippocampus ( 32 ). Since Ir and hippocampus are especially related in learning, we think that decreased Ir level in ID may be related to the decrease in cognitive functions seen in ID. In addition, the fact that these symptoms are reversible with iron supplementation suggests that they may be directly related to the increased Ir level after iron treatment. Limitation In our study, the groups consisted of 20 patients each. More studies are needed to ensure the general validity of the results. Conclusion In our study, we found that the feeling of coldness and decreased cognitive functions seen in iron deficiency may be related to serum Ir level. Today, IDA is an important public health problem and affects many systems. Additional studies are needed to clarify the pathophysiology of its effects on different systems. Declarations The study was designed in accordance with the principles of the Helsinki Declaration, and ethical approval was obtained from the ethics committee of Firat University Funding Funding was not utilized in our study The datasets have been uploaded to the journal Author Contribution Ahmet Selmanoglu, MD: [email protected] : made substantial contributions to design, acquisition of data, or analysis and interpretation of data; drafted the article and reviewed it critically for important intellectual content; gave final approval of the version to be published.Saadet Akarsu, MD: [email protected] : made substantial contributions to design, acquisition of data, or analysis and interpretation of data; drafted the article and reviewed it critically for important intellectual content; gave final approval of the version to be publishedSüleyman Aydin, : [email protected] : made substantial contributions to design, acquisition of data, or analysis and interpretation of data; drafted the article and reviewed it critically for important intellectual content; prepared figures, gave final approval of the version to be published. 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Journal of Neuroscience. 2009;29(41):12764-7; DOI: 10.1523/JNEUROSCI.3566-09.2009 Park H, Poo M-m. Neurotrophin regulation of neural circuit development and function. Nature Reviews Neuroscience. 2013;14(1):7-23; DOI: 10.1038/nrn3379 Moon H-S, Dincer F, Mantzoros CS. Pharmacological concentrations of irisin increase cell proliferation without influencing markers of neurite outgrowth and synaptogenesis in mouse H19-7 hippocampal cell lines. Metabolism. 2013;62(8):1131-6; DOI: 10.1016/j.metabol.2013.04.007 Dun SL, Lyu R-M, Chen Y-H, Chang J-K, Luo JJ, Dun NJ. Irisin-immunoreactivity in neural and non-neural cells of the rodent. Neuroscience. 2013;240:155-62; DOI: 10.1016/j.neuroscience.2013.02.050 Schmidt B, Marrone DF, Markus EJ. Disambiguating the similar: the dentate gyrus and pattern separation. Behavioural brain research. 2012;226(1):56-65; DOI: 10.1016/j.bbr.2011.08.039 Additional Declarations No competing interests reported. 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Iron deficiency is the most common cause of anemia. The World Health Organisation (WHO) estimates that 293\u0026nbsp;million pre-school-age and 305\u0026nbsp;million school-age children are anemic, and more than 50% are thought to be iron deficient (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Iron deficiency (ID) has an effect on physical development, rapid brain development and early learning capacity, especially in the infant and pre-school years (\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Iron plays a crucial role in myelin synthesis. Iron is required for myelin production from oligodendrocytes for both maturation and acquisition of function (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). ID has negative effects on brain development, myelination and development of major dopaminergic pathways. Persistent ID has lifelong effects on intelligence and learning functions. If low iron status is not corrected during developmental age, IQ scores may decrease by approximately 5\u0026ndash;10 points (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eİrisin\u003c/h3\u003e\n\u003cp\u003eIrisin (Ir) was discovered in 2012 to be a muscle-associated factor involved in inducing browning of white adipose tissue (WAT). Irisin-related pathways are known to be activated by peroxisome proliferator-activated receptor (PPAR)-γ, coactivator (PGC)-1α and its release is increased by exercise. Irisin is a newly discovered peptide hormone released by proteolysis of (FNDC)5 in circulation (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Irisin is mainly responsible for the browning of WAT and the release of uncoupling protein-1 (UCP1). UCP1 exerts its effect by increasing total energy expenditure through thermogenesis (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Irisin levels are thought to be determinant in fat storage and metabolic dysfunction (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eFABP4\u003c/h3\u003e\n\u003cp\u003eFatty acid binding proteins (FABPs) are chaperones involved in intracellular fatty acid transport, regulate lipid responses in cells and are also linked to metabolic and inflammatory pathways. FABPs with a molecular weight of 14\u0026ndash;15 kDa that bind reversibly with high affinity to hydrophobic ligands such as saturated and unsaturated long-chain fatty acids, eicazonoids and other fats. To date, 9 FABP types have been identified (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). FABP4 release is stimulated during adipocyte differentiation and by (PPAR)-γ receptor agonist transcription factors such as insulin, irisin, fatty acids. Currently, FABP4 has been found to have roles in maintaining glucose homeostasis and energy storage systems (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Irisin and FABP4 play a role in metabolic control. Irisin acts in metabolic control by providing thermogenesis with heat energy. Fatty acid binding protein 4 plays a role in metabolic events such as fatty acid storage, circulation and glucose homeostasis, levels are increased in obese individuals (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIron deficiency anemia (IDA) patients tend to experience heightened sensitivity to cold compared to individuals with sufficient iron levels. While there are various theories regarding this phenomenon, the precise underlying cause remains unclear. The currently accepted view is that IDA results in impaired thermoregulation due to insufficiency of the thermoregulatory center, both in mice and humans. At the tissue level, ID is considered to impair the appropriate physiological response to cold because of impaired neurological control of the sympathetic nervous system (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In addition, ID is thought to affect the ability of the endocrine system to respond to heat production and thermogenic tissues in response to cold (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Thermogenesis capacity is impaired in ID. Brown adipose tissue (BAT) is a specialized form of adipose tissue characterized by multilocular fat droplets, high mitochondrial density, and abundant sympathetic innervation. After sympathetic stimulation in response to cold, the blood flow to BAT increases (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Irisin browns WAT, while UCP-1 is released to release heat energy. We thought that the impaired thermogenesis capacity in ID may be due to the concomitant Ir deficiency. ID is known to cause a variety of symptoms, but the etiology of these symptoms may not be fully understood. The study's objective is to explore whether Ir and FABP4 levels might be linked to symptoms such as feeling cold, fatigue, learning difficulties, and others in individuals with ID.\u003c/p\u003e"},{"header":"Material And Methods","content":"\u003cp\u003eThe study was conducted by the Department of Pediatric Haematology Oncology and Department of Biochemistry, Faculty of Medicine, Fırat University. In our study, ID was evaluated in 3 periods and the effects of these 3 periods on serum and urine Ir and FABP4 levels were analysed. The diagnosis of the 3 periods of ID was made according to the following laboratory values ; (\u003cspan\u003e17\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e\u003cstrong\u003e1. Iron storage depletion (ID)\u003c/strong\u003e: Anemia is not seen. Iron stores depletion. Serum iron, Hb, serum iron binding capacity (SIBC), transferrin saturation (TS) are normal. Ferritin\u0026thinsp;\u0026lt;\u0026thinsp;12 ng/mL\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e\u003cstrong\u003e2. Latent Iron deficiency without anemia (LID)\u003c/strong\u003e: There is no anemia. Iron stores are depleted. Hb is at the lower limit. Erythrocyte distribution volume and SIBC level increase. Serum iron decreases, TS\u0026thinsp;\u0026lt;\u0026thinsp;16%, Ferritin\u0026thinsp;\u0026lt;\u0026thinsp;12 mL.\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e\u003cstrong\u003e3. Iron Deficiency Anemia (IDA)\u003c/strong\u003e: Hypochrome microcytic anemia has developed. Hb, serum iron decreases, TS\u0026thinsp;\u0026lt;\u0026thinsp;16%, ferritin\u0026thinsp;\u0026lt;\u0026thinsp;12 ng/mL.\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eIn our study, a total of 60 patients from these 3 periods (n:20 patients diagnosed with ID, n:20 patients diagnosed with LID, n:20 patients diagnosed with IDA were included. From the control group with normal iron parameters, n: 20 patients were included. Oral iron treatment was started after the diagnosis of ID, LID and IDA. Patients were administered iron treatment in the form of ferrous iron (Ferro Sanol\u0026reg;) at a dosage of 3\u0026ndash;6 mg/kg/day, given 2\u0026ndash;3 times daily for a duration of 3 months. Blood and urine samples were collected from the subjects (n\u0026thinsp;=\u0026thinsp;60) who received iron treatment, both just before the initiation of the treatment and 3 months afterward. Additionally, samples were collected from the control group (n\u0026thinsp;=\u0026thinsp;20) once for comparison. For the diagnosis of IDA, standard diagnostic procedures were followed for all patients presenting for diagnosis and treatment. This included obtaining a complete blood count (CBC), peripheral smear, reticulocyte count, serum iron levels, SIBC, and ferritin levels, as routinely performed in clinical practice. These tests collectively help in assessing various parameters related to red blood cell production, iron levels, and iron storage, aiding in the accurate diagnosis and treatment of iron deficiency anemia. Serum and urine Ir and FABP4 levels were analysed in the patient group n:60 before and after treatment. In the control group, only serum and urine Ir and FABP4 levels were analysed at baseline. Samples were studied as described in the ma nufacturer\u0026apos;s catalogue (Human (irisin) catalogue no: 201-12-5328, Human (FABP4) catalogue no: 201-12-2037 and manufactured at Awareness Technology, Inc Palm City, Florida, USA). At the end of the study, the samples were read at 450 nanometres with a ChroMate microplate (ChroMate 4300 Florida, USA) reader.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients who were not included in the study;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e1. Patients with chronic infection,\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e2. Patients who developed an allergic reaction with iron therapy or had a history of such a reaction,\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e3. Patients who used any iron preparation before the study,\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e4. Patients using vitamins,\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cdiv id=\"Sec6\"\u003e\n \u003ch2\u003eStatistical methods\u003c/h2\u003e\n \u003cp\u003eAll data were analysed using SPSS version 22.0 (IBM, Chicago, IL, USA). Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation was given for normally distributed data and median values were given for non-normally distributed variables. Wilcoxon test was used for comparison of ranks, Mann Whitney U test was used for comparison of groups of more than two, chi-square test was used for comparison of percentages, and Spearmen rank correlation tests were used for correlation tests. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 value was considered statistically significant.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eDemographic characteristics of the patients are shown in Table.1. The anthropometric measurements of the patients before and after treatment are given in Table.2\u0026amp;Figure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. There was no statistical difference between the gender distributions in each group. Hb, haematocrit and ferritin values were found to be statistically significantly higher when compared between the groups after treatment (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e,\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e\u0026amp;Figure \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e,\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). The mean serum Ir levels in our study revealed statistically significant differences between the patient groups (ID, LID, IDA) and the control group, with lower levels observed in the patient groups before treatment.(p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e\u0026amp;Figure \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). A statistically significant increase (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) was found in the mean serum Ir levels in all patient groups after treatment. When urine Ir levels were analysed, an increase in urine Ir levels was found in the ID and IDA groups and a decrease in the LID group after treatment, but these changes were not statistically significant (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e\u0026amp;Figure \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDemographic characteristics of the patients\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eID\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLID\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIDA\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8,76\u0026thinsp;\u0026plusmn;\u0026thinsp;5,41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8,07\u0026thinsp;\u0026plusmn;\u0026thinsp;6,39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8,80\u0026thinsp;\u0026plusmn;\u0026thinsp;6,07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9,53\u0026thinsp;\u0026plusmn;\u0026thinsp;6,12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;0,05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;0,05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (%55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (%45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (%45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (%60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (%45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (%55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (%55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (%40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDemographic characteristics and anthropometric values of the patients before and after treatment\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eBody weight (kg)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eHeight(cm)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eWeight (percentile)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBefore\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBefore\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAfter\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBefore\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAfter\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBefore\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAfter\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBefore\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAfter\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e8,76\u0026thinsp;\u0026plusmn;\u0026thinsp;5,41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28,9\u0026thinsp;\u0026plusmn;\u0026thinsp;17,3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e123,2\u0026thinsp;\u0026plusmn;\u0026thinsp;32,8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30,9\u0026thinsp;\u0026plusmn;\u0026thinsp;25,7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17,2\u0026thinsp;\u0026plusmn;\u0026thinsp;2,5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e8,07\u0026thinsp;\u0026plusmn;\u0026thinsp;6,39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28,6\u0026thinsp;\u0026plusmn;\u0026thinsp;19,2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29,4\u0026thinsp;\u0026plusmn;\u0026thinsp;18,9\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e121,4\u0026thinsp;\u0026plusmn;\u0026thinsp;36,6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e122,5\u0026thinsp;\u0026plusmn;\u0026thinsp;35,9\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45\u0026thinsp;\u0026plusmn;\u0026thinsp;33,3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46,3\u0026thinsp;\u0026plusmn;\u0026thinsp;32,6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17,1\u0026thinsp;\u0026plusmn;\u0026thinsp;2,7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17,4\u0026thinsp;\u0026plusmn;\u0026thinsp;2,5\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e8,80\u0026thinsp;\u0026plusmn;\u0026thinsp;6,07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34,5\u0026thinsp;\u0026plusmn;\u0026thinsp;22,0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34,6\u0026thinsp;\u0026plusmn;\u0026thinsp;21,4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e126,4\u0026thinsp;\u0026plusmn;\u0026thinsp;36,5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e127,6\u0026thinsp;\u0026plusmn;\u0026thinsp;35,8\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55\u0026thinsp;\u0026plusmn;\u0026thinsp;29,2\u003csup\u003eb,c\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53,8\u0026thinsp;\u0026plusmn;\u0026thinsp;29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19,1\u0026thinsp;\u0026plusmn;\u0026thinsp;3,6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18,9\u0026thinsp;\u0026plusmn;\u0026thinsp;3,7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eIDA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e9,53\u0026thinsp;\u0026plusmn;\u0026thinsp;6,12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32,8\u0026thinsp;\u0026plusmn;\u0026thinsp;19,8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33,5\u0026thinsp;\u0026plusmn;\u0026thinsp;19,3\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e129\u0026thinsp;\u0026plusmn;\u0026thinsp;31,9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e130\u0026thinsp;\u0026plusmn;\u0026thinsp;31,3\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41,9\u0026thinsp;\u0026plusmn;\u0026thinsp;29,1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45,1\u0026thinsp;\u0026plusmn;\u0026thinsp;27,2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17,7\u0026thinsp;\u0026plusmn;\u0026thinsp;3,7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u0026thinsp;\u0026plusmn;\u0026thinsp;3,4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"11\"\u003eID; Iron depletion ,LID; Latent Iron Deficiency, IDA; Iron Deficiency Anemia;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"11\"\u003e\u003csup\u003e\u003cstrong\u003ea\u003c/strong\u003e\u003c/sup\u003e: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0,05; Compared with before treatment; \u003csup\u003e\u003cstrong\u003eb\u003c/strong\u003e\u003c/sup\u003e: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0,05; Compared with control; \u003csup\u003e\u003cstrong\u003ec\u003c/strong\u003e\u003c/sup\u003e: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0,05; Comparison with ID\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/122228_c8a1650c59388082/122228_custom_files/img1710831336.png\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Comparison of ferritin, serum iron, serum iron binding capacity (SIBC), transferrin saturation values before and after treatment\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"860\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.846689895470384%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.64808362369338%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eFerritin (ng/dL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.835075493612077%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum Iron\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e(\u0026micro;g/dL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.835075493612077%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSIBC\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e(\u0026micro;g/dL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.835075493612077%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eTransferrin Saturation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.438735177865613%\"\u003e\n \u003cp\u003e\u003cstrong\u003eBefore\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.25296442687747%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAfter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.989459815546772%\"\u003e\n \u003cp\u003e\u003cstrong\u003eBefore\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.779973649538867%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAfter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.38471673254282%\"\u003e\n \u003cp\u003e\u003cstrong\u003eBefore\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.38471673254282%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAfter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.570487483530961%\"\u003e\n \u003cp\u003e\u003cstrong\u003eBefore\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.198945981554678%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAfter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.846689895470384%\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.846689895470384%\"\u003e\n \u003cp\u003e56,6\u0026plusmn;58,9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.801393728222996%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.56910569105691%\"\u003e\n \u003cp\u003e96,2\u0026plusmn;36,3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.265969802555169%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.917537746806039%\"\u003e\n \u003cp\u003e339,9\u0026plusmn;40,1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.917537746806039%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.962833914053427%\"\u003e\n \u003cp\u003e31\u0026plusmn;12,7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.872241579558652%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.846689895470384%\"\u003e\n \u003cp\u003e\u003cstrong\u003eID\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.846689895470384%\"\u003e\n \u003cp\u003e8,1\u0026plusmn;2,6\u003csup\u003eb,e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.801393728222996%\"\u003e\n \u003cp\u003e24,9\u0026plusmn;15,3\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.56910569105691%\"\u003e\n \u003cp\u003e92,1\u0026plusmn;31,2\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.265969802555169%\"\u003e\n \u003cp\u003e88,4\u0026plusmn;25,2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.917537746806039%\"\u003e\n \u003cp\u003e367,7\u0026plusmn;34,4\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.917537746806039%\"\u003e\n \u003cp\u003e329,7\u0026plusmn;34,6\u003csup\u003ea,e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.962833914053427%\"\u003e\n \u003cp\u003e24,9\u0026plusmn;8,4\u003csup\u003ee\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.872241579558652%\"\u003e\n \u003cp\u003e26,5\u0026plusmn;7,3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.846689895470384%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLID\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.846689895470384%\"\u003e\n \u003cp\u003e8,7\u0026plusmn;2,6\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.801393728222996%\"\u003e\n \u003cp\u003e27,6\u0026plusmn;14,7\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.56910569105691%\"\u003e\n \u003cp\u003e29,7\u0026plusmn;13\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.265969802555169%\"\u003e\n \u003cp\u003e71,3\u0026plusmn;32,5\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.917537746806039%\"\u003e\n \u003cp\u003e361,8\u0026plusmn;50,7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.917537746806039%\"\u003e\n \u003cp\u003e304,4\u0026plusmn;71,4\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.962833914053427%\"\u003e\n \u003cp\u003e8,3\u0026plusmn;3,1\u003csup\u003eb,c\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.872241579558652%\"\u003e\n \u003cp\u003e23,6\u0026plusmn;7,8\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.846689895470384%\"\u003e\n \u003cp\u003e\u003cstrong\u003eIDA\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.846689895470384%\"\u003e\n \u003cp\u003e4,5\u0026plusmn;3,7\u003csup\u003eb,d\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.801393728222996%\"\u003e\n \u003cp\u003e46\u0026plusmn;44,8\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.56910569105691%\"\u003e\n \u003cp\u003e23,8\u0026plusmn;11,7\u003csup\u003eb,c\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.265969802555169%\"\u003e\n \u003cp\u003e76,6\u0026plusmn;33,1\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.917537746806039%\"\u003e\n \u003cp\u003e377,3\u0026plusmn;47,4\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.917537746806039%\"\u003e\n \u003cp\u003e288,1\u0026plusmn;54,9\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.962833914053427%\"\u003e\n \u003cp\u003e6,6\u0026plusmn;2,7\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.872241579558652%\"\u003e\n \u003cp\u003e26,6\u0026plusmn;8,8\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e: \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0,05; Compared with before treatment; \u003cstrong\u003e\u003csup\u003eb\u003c/sup\u003e\u003c/strong\u003e: \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0,05; Compared with control;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003csup\u003ec\u003c/sup\u003e\u003c/em\u003e\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0,05; Compared with the ID group, \u003cem\u003e\u003csup\u003ed\u003c/sup\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0,05; Compared with the LID group; \u003cem\u003e\u003csup\u003ee\u003c/sup\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0,05; Compared with the IDA group\u003c/p\u003e\n\u003cdiv\u003e\u003cbr\u003e\u003c/div\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab5\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eComparison of Ir and FABP4 levels before and after treatment\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eSerum\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eUrine\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eSerum\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eUrine\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGruplar\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIr Before Treatment\u003c/p\u003e\n \u003cp\u003e(ng/dL)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIr After Treatment\u003c/p\u003e\n \u003cp\u003e(ng/dL)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIr Before Treatment (ng/dL)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIr After Treatment\u003c/p\u003e\n \u003cp\u003e(ng/dL)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFABP4 Before Treatment\u003c/p\u003e\n \u003cp\u003e(ng/dL)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFABP4\u003c/p\u003e\n \u003cp\u003eAfter Treatment\u003c/p\u003e\n \u003cp\u003e(ng/dL)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFABP4 Before Treatment\u003c/p\u003e\n \u003cp\u003e(ng/dL)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFABP4\u003c/p\u003e\n \u003cp\u003eAfter Treatment\u003c/p\u003e\n \u003cp\u003e(ng/dL)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e45,8\u0026thinsp;\u0026plusmn;\u0026thinsp;13,4\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e22,5\u0026thinsp;\u0026plusmn;\u0026thinsp;5,2\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e20,4\u0026thinsp;\u0026plusmn;\u0026thinsp;11,3\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e9,6\u0026thinsp;\u0026plusmn;\u0026thinsp;3,5\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36,8\u0026thinsp;\u0026plusmn;\u0026thinsp;10,5\u003csup\u003eb,d\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39,3\u0026thinsp;\u0026plusmn;\u0026thinsp;11,5\u003csup\u003ea,d\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23,1\u0026thinsp;\u0026plusmn;\u0026thinsp;4,3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25,4\u0026thinsp;\u0026plusmn;\u0026thinsp;6,2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21\u0026thinsp;\u0026plusmn;\u0026thinsp;12,1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21,9\u0026thinsp;\u0026plusmn;\u0026thinsp;12,2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12,3\u0026thinsp;\u0026plusmn;\u0026thinsp;5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13,8\u0026thinsp;\u0026plusmn;\u0026thinsp;5,4\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27\u0026thinsp;\u0026plusmn;\u0026thinsp;10,1\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28,7\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003csup\u003ea,b\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25,6\u0026thinsp;\u0026plusmn;\u0026thinsp;4,3\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24,3\u0026thinsp;\u0026plusmn;\u0026thinsp;2,5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17,9\u0026thinsp;\u0026plusmn;\u0026thinsp;12,7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18,6\u0026thinsp;\u0026plusmn;\u0026thinsp;11,5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11,4\u0026thinsp;\u0026plusmn;\u0026thinsp;5,7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12,6\u0026thinsp;\u0026plusmn;\u0026thinsp;6,4\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eIDA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25\u0026thinsp;\u0026plusmn;\u0026thinsp;6,7\u003csup\u003eb,c\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27\u0026thinsp;\u0026plusmn;\u0026thinsp;8,3\u003csup\u003ea,c\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21,3\u0026thinsp;\u0026plusmn;\u0026thinsp;3,4\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22,1\u0026thinsp;\u0026plusmn;\u0026thinsp;5,1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25\u0026thinsp;\u0026plusmn;\u0026thinsp;13,1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22,6\u0026thinsp;\u0026plusmn;\u0026thinsp;13,7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13,7\u0026thinsp;\u0026plusmn;\u0026thinsp;4,5\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12,9\u0026thinsp;\u0026plusmn;\u0026thinsp;2,2\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\"\u003e\u003csup\u003e\u003cstrong\u003ea\u003c/strong\u003e\u003c/sup\u003e: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0,05; Compared with before treatment; \u003csup\u003e\u003cstrong\u003eb\u003c/strong\u003e\u003c/sup\u003e: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0,05; Compared with control;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\"\u003e\u003csup\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0,05; Compared with the ID group; \u003csup\u003e\u003cem\u003ed\u003c/em\u003e\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0,05; Compared with the LID group\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eIn our study, there was no statistically significant difference between the groups in serum FABP4 levels of the patients before and after treatment (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e\u0026amp;Figure \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). After treatment, an increase was found in the mean serum FABP4 levels in the ID and LID groups, whereas a decrease was found in the IDA group, but these changes were not statistically significant (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e\u0026amp;Figure \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). In our study, there was no statistically significant difference between the groups in urinary FABP4 levels before and after treatment (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIron deficiency anemia (IDA) is an important public health problem in developing countries. The etiology of some of the symptoms seen in ID has not been clearly elucidated. Especially within the scope of our study, we hypothesized that the sensation of coldness observed in individuals with IDA might be associated with Ir levels. This hypothesis stems from previous findings in various studies (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), which have demonstrated that Ir plays a crucial role in generating heat energy through the conversion of WAT into BAT. Irisin and FABP4 are peptide-structured hormones involved in both energy metabolism and thermoregulation processes (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). As known, iron acts as a cofactor in the enzymes required for energy metabolism, participating in thermoregulation processes. Therefore, we believe that there may be a connection between iron and these two hormones.\u003c/p\u003e \u003cp\u003eIn our study, we found that the basal serum Ir levels of ID, LID and IDA groups were statistically low compared to the control group(p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Ir, which is known to be synthesised in almost all biological tissues, leads to heat energy production instead of ATP synthesis by increasing UCP-1 proteins (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). An increase in the amount of Ir in biological fluids may be associated with increased heat production in the body. Ir is considered a hormone that regulates energy expenditure and promotes the conversion of WAT to BAT. In this context, elevated levels of Ir in biological fluids may contribute to increased thermogenesis and heat production in the body. There are factors outside the hypothalamus that influence thermogenesis in our body, and Ir is one of these pathways. Ir increases the expression of a protein called UCP1 in white fat cells. UCP1 stimulates thermogenesis by converting energy into heat in the mitochondria of the cell. This process redirects energy towards heat production rather than the normal function of energy storage in white We observed decreased levels of Ir in cases of diminished iron, even in the absence of anemia. Furthermore, there was an elevation in serum Ir levels following iron therapy. Based on this mechanism, we posit that the diminished Ir levels may underlie the heightened sensitivity to cold in individuals with ID.\u003c/p\u003e \u003cp\u003eAs known, Ir is released from muscle tissue. In the case of ID, symptoms such as weakness and fatigue develop, and patients may move slowly and engage in less physical activity. As reported here, an increase in Ir levels was observed with iron supplementation. The likely reason for this increase is the normalization of physical activity in children, associated with a reduction in fatigue and weakness due to ID. Consequently, there may be an elevation in muscle tissue through this mechanism, leading to an increase in the levels of Ir released from the muscles. We hypothesized that the rise in Ir levels following the treatment of ID could be attributed to this mechanism.\u003c/p\u003e \u003cp\u003eIn other studies, the correlations of Ir and FABP4 serum and urine levels with anthropometric measurements were analysed. In our study, we observed no correlation between the levels of serum and urine Ir and FABP4 and gender, as well as anthropometric measurement data.Similarly, Moreno et al,(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) Liuliu et al. (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) found no relationship between Ir concentrations and gender. However, Al-Delghri et al. (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) in a cohort study of 153 Saudi Arabian children found that circulating Ir levels in the blood were higher in girls than in boys. Siahanidou et al. (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) found no significant correlation between FABP4 levels and gender, body weight, height and BMI, but Ibarretxe et al. (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) found high FABP4 levels in females in a study.\u003c/p\u003e \u003cp\u003eIn our study, we also investigated urine samples to establish a potential link between Ir and ID using a simpler and non-invasive approach. However, we did not find any correlation between the levels of Irisin in serum and urine samples. On the other hand, no difference was observed in the changes in urine depending on the treatment, and the possible reason for this was thought to be that there was no correlation between the circulating level of Ir and its excretion from urine.\u003c/p\u003e \u003cp\u003eAs it is known, decreases in neurocognitive functions such as attention deficit, learning difficulties, behavioural disorders, decreased perceptual functions, retardation in motor and mental development tests are observed in ID. Studies in school children have shown that learning and various developmental tests are impaired in ID with or without anemia, but learning difficulty may improve with iron treatment (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). In our study, it was thought that the decline in cognitive functions might be related with Ir, which is known to be released from all biological tissues. FNDC5/irisin has been shown as a new therapeutic factor that can improve cognition, learning and memory function (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). FNDC5 has been found to reduce some factors that provide neuronal destruction, and it has also been found that FNDC5 administration with adenovirus increases neuroprotective factors (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) Moon et al. (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) found that Ir at pharmacological concentrations increased STAT3 levels in H 19\u0026thinsp;\u0026minus;\u0026thinsp;7 hippocampal neuronal cells and STAT3 levels in mice, and low levels of Ir decreased differentiation in neuronal functions in mouse embryonic stem cells. Low levels of Ir in serum have been shown to reduce the level of FNDC5, an Ir precursor in the human brain. A direct relationship has been shown in hippocampal neurogenesis. Dun et al (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) showed in another immunohistochemical study that purkinje cells in rats and mice express Ir and also FNDC5 in recent days. It is known that the hippocampus is a critical region in learning and memory formation, and is a very important structure in spatial memory formation. According to our current knowledge, the cellular and molecular mechanisms of learning and memory formation are explained by long-term potentiation (LTP) in the hippocampus (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Since Ir and hippocampus are especially related in learning, we think that decreased Ir level in ID may be related to the decrease in cognitive functions seen in ID. In addition, the fact that these symptoms are reversible with iron supplementation suggests that they may be directly related to the increased Ir level after iron treatment.\u003c/p\u003e"},{"header":"Limitation","content":"\u003cp\u003eIn our study, the groups consisted of 20 patients each. More studies are needed to ensure the general validity of the results.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn our study, we found that the feeling of coldness and decreased cognitive functions seen in iron deficiency may be related to serum Ir level. Today, IDA is an important public health problem and affects many systems. Additional studies are needed to clarify the pathophysiology of its effects on different systems.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe study was designed in accordance with the principles of the Helsinki Declaration, and ethical approval was obtained from the ethics committee of Firat University\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Funding was not utilized in our study\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; The datasets have been uploaded to the journal\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAhmet Selmanoglu, MD: [email protected]: made substantial contributions to design, acquisition of data, or analysis and interpretation of data; drafted the article and reviewed it critically for important intellectual content; gave final approval of the version to be published.Saadet Akarsu, MD: [email protected]: made substantial contributions to design, acquisition of data, or analysis and interpretation of data; drafted the article and reviewed it critically for important intellectual content; gave final approval of the version to be publishedS\u0026uuml;leyman Aydin, : [email protected]: made substantial contributions to design, acquisition of data, or analysis and interpretation of data; drafted the article and reviewed it critically for important intellectual content; prepared figures, gave final approval of the version to be published.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDe Benoist B, Cogswell M, Egli I, McLean E. 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Early human development. 2010;86(4):197-201; DOI: 10.1016/j.earlhumdev.2010.02.008\u003c/li\u003e\n\u003cli\u003eIbarretxe D, Girona J, Plana N, Cabr\u0026eacute; A, Heras M, Ferr\u0026eacute; R, et al. FABP4 plasma concentrations are determined by acquired metabolic derangements rather than genetic determinants. Nutrition, Metabolism and Cardiovascular Diseases. 2015;25(9):875-80; DOI: 10.1016/j.numecd.2015.05.008\u003c/li\u003e\n\u003cli\u003eGrantham-McGregor S, Ani C. A review of studies on the effect of iron deficiency on cognitive development in children. The Journal of nutrition. 2001;131(2):649S-68S; DOI: 10.1093/jn/131.2.649S\u003c/li\u003e\n\u003cli\u003eLourenco MV, Frozza RL, de Freitas GB, Zhang H, Kincheski GC, Ribeiro FC, et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer\u0026rsquo;s models. 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Neuroscience. 2013;240:155-62; DOI: 10.1016/j.neuroscience.2013.02.050\u003c/li\u003e\n\u003cli\u003eSchmidt B, Marrone DF, Markus EJ. Disambiguating the similar: the dentate gyrus and pattern separation. Behavioural brain research. 2012;226(1):56-65; DOI: 10.1016/j.bbr.2011.08.039 \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Iron deficiency anemia, Irisin, FABP4, cold intolerance, Iron deficiency","lastPublishedDoi":"10.21203/rs.3.rs-4065551/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4065551/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eAnemia is defined as a condition in which the level of Hemoglobin is lower than the expected level based on age and gender.Irisin (Ir) was discovered in 2012 to be a muscle-associated factor.Fatty acid binding proteins (FABPs) are chaperones involved in intracellular fatty acid transport.Iron deficiency(ID) causes various symptoms, but their etiology may not be fully understood.The study's objective is to explore whether Ir and FABP4 levels might be linked to symptoms such as feeling cold, fatigue, learning difficulties, and others in individuals with ID.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe study was conducted by the Department of Pediatric Hematology Oncology Faculty of Medicine,Fırat University.Our study evaluated ID in three distinct periods,including iron storage depletion,latent iron deficiency without anemia,and iron deficiency anemia.We analyzed the effects of these three periods, along with a control group, on serum and urine Ir, as well as FABP4 levels, both before and after iron treatment.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe mean serum Ir levels in our study revealed statistically significant differences between the patient groups and the control group, with lower levels observed in the patient groups before treatment(p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).After treatment, a statistically significant increase(p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) was found in the mean serum Ir levels in all patient groups.In our study, there was no statistically significant difference between the groups in serum FABP4 levels (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIn our study,we found that the feeling of coldness and decreased cognitive functions seen in iron deficiency may be related to serum Ir level.Today, IDA is an important public health problem and affects many systems.\u003c/p\u003e","manuscriptTitle":"Investigation of the role of Irisin and FABP4 in iron deficiency anemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-19 15:22:35","doi":"10.21203/rs.3.rs-4065551/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1bf2054f-e5c0-492a-af24-cbd85de25cec","owner":[],"postedDate":"March 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-26T05:21:05+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-19 15:22:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4065551","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4065551","identity":"rs-4065551","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}