Abstract

Introduction

Altitude-related hypoxia affects erythropoiesis and iron metabolism; however, pediatric data regarding age-related hematologic adaptation remain limited. The aim of this study was to evaluate altitude-associated hematologic changes and age-related differences in children living at high altitude and sea level.

Materials and Methods

This retrospective study compared hematologic and iron-related parameters in children aged 5–14 years living at high altitude (Ağrı, 1640 m) and sea level (İstanbul, 40 m). Children with vitamin B12 deficiency, low ferritin levels, or elevated inflammatory markers were excluded. Age-stratified analyses were performed in three groups: 5–8 years, 9–11 years, and 12–14 years.

Results

A total of 1000 children were initially screened. After applying exclusion criteria, 482 children (240 from İstanbul and 242 from Ağrı) were included in the final analysis. Children living at high altitude demonstrated significantly higher hemoglobin and red blood cell (RBC) values, whereas total iron-binding capacity (TIBC) and mean corpuscular hemoglobin concentration (MCHC) were lower compared with children living at sea level. Hemoglobin differences became less pronounced with increasing age, while elevated RBC levels persisted across most age groups.

Conclusion

Altitude is associated with age-dependent hematologic adaptation in children. Persistent RBC elevation and alterations in iron-related parameters suggest ongoing adaptation to chronic hypoxic exposure during childhood. These findings indicate that environmental altitude should be considered when interpreting hematological parameters in pediatric populations.

Introduction

Hematological parameters in children are influenced by a variety of physiological and environmental factors, including age, nutritional status, socioeconomic conditions, and geographic characteristics (1). Among these factors, altitude has been recognized as one of the most important environmental determinants affecting hematological profiles (2). Reduced atmospheric pressure and lower oxygen availability at higher altitudes lead to chronic hypoxic exposure, which triggers a series of physiological adaptations aimed at maintaining adequate tissue oxygenation (3).

One of the most prominent physiological responses to high altitude is the stimulation of erythropoiesis. Hypoxia stimulates the production of erythropoietin, which subsequently increases red blood cell production and Hb concentration. As a result, individuals living at high altitude typically exhibit higher Hb levels, erythrocyte counts, and hematological indices compared with populations residing at sea level (4). These adaptive hematological changes have been widely documented in adult populations as well as in children living in mountainous regions.

Previous studies conducted in high-altitude regions such as the Andes and other mountainous areas have reported significant differences in Hb levels and erythrocyte indices between populations living at high altitude and those living at lower elevations (5, 6). These findings highlight the importance of considering geographic altitude when interpreting hematological values, particularly in pediatric populations where physiological reference ranges may vary according to environmental conditions.

However, the interpretation of hematological parameters in children is often complicated by nutritional deficiencies, which remain highly prevalent worldwide. Iron deficiency and vitamin B12 deficiency are among the most common nutritional disorders in childhood and can significantly affect Hb levels and erythrocyte indices (7). Therefore, when evaluating the potential effects of altitude on hematological parameters, it is essential to control for nutritional factors that may act as confounding variables.

Despite the well-established effects of altitude on erythropoiesis, data regarding altitude-related variations in erythrocyte and iron-related hematological parameters among children remain limited. Moreover, many previous studies did not adequately account for nutritional deficiencies that may influence hematological findings. This limitation makes it difficult to determine whether observed hematological differences are attributable to altitude-related physiological adaptation or underlying nutritional disorders.

Therefore, the present study aimed to compare erythrocyte and iron-related hematological parameters among children aged 5–14 years living at different altitudes by analyzing populations from Ağrı, a high-altitude region in eastern Türkiye, and Istanbul, a city located at sea level. To minimize potential confounding effects, children with vitamin B12 deficiency and low ferritin levels were excluded from the analysis. This study aimed to evaluate the independent effect of altitude on erythrocyte parameters in a pediatric population.

Materials and Methods

Study design and Population

This retrospective study included pediatric patients aged 5–14 years from two regions of Türkiye with different altitudes: Istanbul, located at sea level (approximately 40 m), and Ağrı, a high-altitude city located at approximately 1640 m above sea level. Patient data were obtained retrospectively from hospital electronic medical record systems.

Initially, a total of 500 pediatric patients from each center were screened, resulting in a total of approximately 1000 children included in the preliminary dataset.

Inclusion and Exclusion Criteria

To minimize potential confounding effects of nutritional deficiencies and acute infections on hematological parameters, several exclusion criteria were applied. Patients with vitamin B12 levels below 200 pg/mL and ferritin levels below 20 ng/mL were excluded to minimize the potential confounding effect of nutritional anemia. In addition, patients with elevated C-reactive protein (CRP) levels suggesting acute infection or inflammation were excluded from the analysis. After applying these exclusion criteria, the remaining patients constituted the final study population.

Age Group Stratification

To evaluate potential age-related differences, patients were categorized into three age groups: 5–8 years, 9–11 years, and 12–14 years. Hematological parameters were analyzed separately within these age groups to allow a more detailed comparison between the two geographical regions.

Laboratory Measurements

Laboratory parameters were obtained from the hospital laboratory information systems. Complete blood count (CBC) parameters related to erythrocyte indices were analyzed. These included RBC, Hb, mean corpuscular volume (MCV), MCHC, red cell distribution width (RDW), and red cell distribution width–standard deviation (RDW-SD). In addition, iron metabolism parameters including serum iron, ferritin, and TIBC were recorded for all included patients.

Statistical Analysis

Statistical analyses were performed using Jamovi statistical software. The distribution of continuous variables was evaluated using the Shapiro–Wilk normality test. Continuous variables were presented as mean ± standard deviation for normally distributed data or median (interquartile range) for non-normally distributed data.

Comparisons between the two study groups (Istanbul and Ağrı) were performed using the independent samples t-test for normally distributed variables and the Mann–Whitney U test for variables that did not follow a normal distribution. A p value of <005 was considered statistically significant.

Results

A total of 1000 pediatric patients were screened, including 500 children from Istanbul and 500 from Ağrı. Patients with vitamin B12 levels below 200 pg/mL, ferritin levels below 20 ng/mL, or elevated CRP levels indicating possible infection were excluded. After applying these criteria, 482 children were included in the final analysis (240 from Istanbul and 242 from Ağrı) (Table 1).

In the overall analysis, children living at high altitude demonstrated higher erythrocyte-related parameters. Red blood cell (RBC) counts and Hb levels were higher in children from Ağrı compared with those from Istanbul. In contrast, TIBC and MCHC were lower in the high-altitude group. The decrease in TIBC was consistent across age groups and both sexes (Table 2).

Ferritin levels were slightly higher in children living at sea level, although the clinical relevance of this difference is uncertain (Table 2).

Age-stratified analyses demonstrated that the altitude-related increase in Hb became less pronounced with increasing age. In the 5–8-year age group, RBC and Hb values were significantly higher in children living at high altitude. In this age group, MCV was also significantly higher in the high-altitude population, and this difference was observed in both girls and boys as well as in the overall analysis (Table 3).

In the 9–11-year age group, sex-related differences were observed. While Hb levels did not differ significantly between regions among girls, boys living at high altitude demonstrated significantly higher Hb and RBC values compared with those living at sea level (Table 4).

In the 12–14-year age group, the altitude-related increase in Hb was no longer observed. RBC differences were also less prominent in this age group. However, the decrease in TIBC and MCHC values remained evident (Table 5).

Detailed comparisons of hematological parameters according to age group and sex are presented in Tables 1, 2, 3, 4, 5.

Discussion

The present study demonstrated that hematologic adaptation to altitude during childhood may follow an age-dependent pattern extending beyond hemoglobin elevation alone. Reduced oxygen pressure at higher altitudes stimulates erythropoietin production and increases erythropoiesis, resulting in elevated Hb and RBC levels as part of physiological adaptation to hypoxia. Previous studies have demonstrated that Hb concentration increases with altitude, reflecting an adaptive response aimed at improving oxygen transport capacity (3, 8, 9).

In the present study, children living at high altitude demonstrated significantly higher hemoglobin and RBC values compared with those residing at sea level. These findings are consistent with previous studies reporting increased hemoglobin concentrations and erythrocyte counts in populations exposed to chronic hypoxia. High-altitude adaptation involves several physiological mechanisms that enhance oxygen delivery, including stimulation of erythropoiesis and increased red blood cell production. An important observation of this study was the age-related pattern in hemoglobin differences between the two populations. Age-stratified analyses showed that the difference in hemoglobin levels was more pronounced in younger children but became less evident in older age groups. This pattern may reflect developmental changes in physiological adaptation to chronic hypoxic exposure during childhood. In contrast, RBC counts remained relatively higher in most age groups among children living at high altitude, suggesting that erythrocyte production continues to contribute to altitude adaptation throughout childhood (10-12).

Another major finding of the present study was the consistently lower TIBC observed in children living at high altitude. This difference was present across nearly all age groups and both sexes. Iron metabolism plays a crucial role in altitude adaptation because hypoxia-induced erythropoiesis increases systemic iron demand and alters iron transport dynamics. Changes in iron-related parameters in high-altitude populations have been described in several studies investigating hypoxia-related hematological adaptation (9, 12).

Additionally, MCHC values were generally lower in children living at high altitude in the present study (13). Alterations in erythrocyte indices have been reported in populations exposed to chronic hypoxia and may reflect adaptive changes in erythrocyte structure and Hb distribution within red blood cells (11, 14).

Overall, the findings of this study indicate that altitude influences several hematological parameters in children. While both Hb and RBC levels are elevated in children living at high altitude, the age-related reduction in Hb differences suggests that the impact of altitude on Hb concentration may diminish during adolescence. In contrast, the persistence of higher RBC levels and the consistent differences observed in TIBC and MCHC support the presence of ongoing hematological adaptation to altitude during childhood (10, 12, 15).

Study Limitations

Several limitations of this study should be acknowledged. First, this study was conducted retrospectively using data obtained from hospital records, which may limit the ability to control for potential confounding factors. Second, although children with iron deficiency, vitamin B12 deficiency, and inflammatory markers were excluded, other nutritional or socioeconomic variables that may influence hematological parameters could not be fully evaluated. Third, the study population consisted of children from two specific geographic regions, and therefore the findings may not be fully generalizable to other populations living at different altitudes. Finally, additional physiological markers related to hypoxia, such as erythropoietin levels or oxygen saturation, were not available in the dataset. Additionally, the duration of residence at high altitude and possible population genetic differences were not evaluated, which may influence hematological adaptation.

Conclusion

In conclusion, this study demonstrated that altitude is associated with significant differences in hematological parameters among children. Hb and RBC values were generally higher in children living at high altitude, although the difference in Hb levels decreased with increasing age. In contrast, RBC elevation persisted across most age groups. Additionally, consistent differences were observed in TIBC and MCHC levels. These findings suggest that altitude-related hematological adaptation occurs during childhood and may vary according to age. Further prospective studies investigating iron metabolism and erythropoietic responses in children living at different altitudes are warranted.

These findings have important clinical implications. Interpretation of hematological parameters in children may need to consider environmental altitude, particularly in regions where populations live at substantially different elevations. Reference values derived from sea-level populations may not accurately reflect physiological hematological ranges in children residing at higher altitudes. Therefore, altitude-specific reference ranges may improve the clinical interpretation of hematological findings in pediatric populations living in high-altitude regions.