Fatty Acids and Child Development Across the Globe: Comparison
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Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Vanessa N. Cardino.

Malnutrition is prevalent in low-middle-income countries (LMICs), but it is usually clinically diagnosed through abnormal anthropometric parameters characteristic of protein energy malnutrition (PEM). In doing so, other contributors or byproducts of malnutrition, notably essential fatty acid deficiency (EFAD), are overlooked. Previous research performed mainly in high-income countries (HICs) shows that deficiencies in essential fatty acids (EFAs) and their n-3 and n-6 polyunsaturated fatty acid (PUFA) byproducts (also known as highly unsaturated fatty acids or HUFAs) lead to both abnormal linear growth and impaired cognitive development. These adverse developmental outcomes remain an important public health issue in LMICs. To identify EFAD before severe malnutrition develops, clinicians should perform blood fatty acid panels to measure levels of fatty acids associated with EFAD, notably Mead acid and HUFAs.

  • fatty acids
  • linoleic acid (LA)
  • alpha-linolenic acid (ALA)
  • highly unsaturated fatty acids
  • children
  • Mead acid
  • essential fatty acid deficiency (EFAD)
  • malnutrition
  • growth
  • cognition

1. Introduction

In 2021, 45.4 million children under 5 years old suffered from wasting, and 149.2 million children under 5 years old were stunted globally [1]. Although the global prevalence of malnutrition-related growth failures has decreased overall in the past two decades, it is concentrated within a small number of low-middle-income countries (LMICs) [2]. In 2020, 94% of stunted children and 97% of wasting children either lived in Asia or Africa [2]. This is especially alarming when considering that many of the LMICs within these continents are unlikely to achieve at least one of the three 2030 Sustainable Development Goals regarding child malnutrition [2].
Childhood malnutrition, as it occurs during a period of rapid growth, can lead to abnormal physical and cognitive development, which can ultimately lead to increased morbidity and mortality in both childhood and adulthood [3]. Specifically, undernutrition during childhood can result in a low weight-for-age z-score (WAZ), a standardized measure of underweight, a low height-for-age z-score (HAZ), a standardized measure of stunting that is largely correlated with cognitive deficits, and a low weight-for-height z-score (WHZ), a standardized measure of recent, life-threatening weight loss referred to as wasting [1,3][1][3]. Undernutrition and micronutrient-related malnutrition can also lead to poor cognitive skills, such as verbal and spatial ability, reading and scholastic ability, and neuropsychologic performance [4]. Considering the prevalence of childhood malnutrition and its adverse outcomes, there is an urgent need to focus malnutrition prevention and remediation efforts on child populations in LMICs.
Childhood malnutrition can develop due to environmental, behavioral, municipal, and biological factors [5,6,7][5][6][7]. The identification of community childhood malnutrition in LMICs, however, is largely dependent on the physical manifestation of malnutrition, which is synonymous with protein energy malnutrition (PEM) [8]. Thus, malnutrition is often assessed using three categories of anthropometric measurements: those which assess body mass (such as weight), those which assess linear growth (such as height), and those which assess body composition (such as skinfold thickness, mid-upper arm circumference, and the relative proportions of subcutaneous fat and muscle) [9]. This is problematic because the sole use of anthropometric measurements to diagnose malnutrition can undermine the complexity of the condition. The anthropometric diagnosis of PEM does not allow clinicians to measure less apparent symptoms characteristic of malnourished individuals, such as impaired cognitive development. Additionally, PEM takes time to develop and, therefore, diagnose, meaning that the affected individuals were likely dealing with malnutrition for months or even years [10]. Finally, the focus on protein deficiency may prevent clinicians and healthcare workers from identifying other nutritional deficiencies, which may lead to PEM and more severe symptoms.
One such nutritional deficiency is essential fatty acid deficiency or EFAD. EFAD is a deficiency in the essential fatty acids (EFAs) linoleic acid (LA, 18:2n-6) and α-linolenic acid (ALA, 18:3n-3). It is prevalent in both LMICs and high-income countries (HICs), likely a consequence of the Westernization of diets globally which results in higher saturated fatty acid (SFA) intake and lower polyunsaturated fatty acid (PUFA) intake [11,12,13][11][12][13]. Since the human body cannot synthesize EFAs, humans must obtain them through the diet via food sources such as nut and vegetable oils [14]. Desaturase enzymes, such as delta-5-desaturase (D5D) and delta-6-desaturase (D6D), are two enzymes that modify the conversion of LA and ALA into their downstream omega-6 (n-6) and omega-3 (n-3) PUFA products [15,16][15][16]. As the body becomes deficient in n-3 ALA and n-6 LA (the fatty acids (FAs) which have the highest affinity for desaturases), it stops synthesizing n-3 and n-6 byproducts such as arachidonic acid (ARA, 20:4n-6 or triene) and begins converting the precursor omega-9 (n-9) FA oleic acid into Mead acid (tetraene, 20:3n-9) [17]. The tetraene:triene (T:T) ratio is the gold standard for diagnosing EFAD, as a value greater than 0.02 signifies deficiency, while values greater than 0.2 represent severe deficiency [18,19][18][19]. Mead acid levels > 0.21% of total FA may also be used as a clinical cut-point for severe EFAD diagnosis, as increases in Mead acid are associated with low EFA intake in populations which did not meet the criteria for EFAD [17,18][17][18].
T:T ratio and Mead acid levels correspond with physical symptoms of severe EFAD such as weight loss, skin changes, and visual and cognitive impairment as well as change in organ function [20,21,22][20][21][22]. The similarity between these adverse outcomes caused by EFAD and those caused by PEM demonstrates that the presence of EFAD and PEM in an individual may compound to produce more severe functional disruptions [9,23][9][23]. EFAD exacerbates the effects of PEM, and PEM may induce more severe EFAD because it disrupts the digestion and absorption of free fatty acids [9,23][9][23]. Thus, clinicians should consider assessing both EFAD and PEM in potentially malnourished individuals.

2. Comparison of PUFA Levels between Global Child Populations

Studies that reported FA levels in child populations 16 years of age and under demonstrate that FA levels, specifically EFA levels, vary greatly. When comparing EFA levels, child whole-blood LA levels range from a low of 8.83% total FA in Pakistan [31][24] to a high of 36.8% in Uganda [32[25][26],33], and child whole-blood ALA levels range from 0.17% in Pakistan [31][24] and 0.54% in the United Kingdom [34][27]. HUFA levels also demonstrated variability. ARA levels were highest among South Korean children (15.3%) [35][28] and lowest among Cambodian children (3.6%) [36][29]. Moreover, EPA levels varied from 0.1% in Cambodia [36][29] to 0.84% in Inuit children living in Canada [37][30], and DHA levels varied from 0.8% in Cambodian children [36][29] to 8.3% in South Korean children [35][28]. Child populations had amounts of DGLA as low as 0.56% in Uganda [32,33][25][26] and as high as 19.1 ng/uL in Gambia [38][31], and DTA levels as high as 3.05% in Pakistan [31][24] and as low as 0.018% in Uganda [32,33][25][26]. DPAn-6 levels ranged from 0.01% (in Uganda) [32,33][25][26] to 3.32 ng/uL (in Gambia) [38][31], while DPAn-3 levels ranged from 0.067% (in Uganda) [32,33][25][26] to 11.9 ng/uL (in Gambia) [38][31]. Mead acid, which was the most understudied fatty acid, ranged from 0.07% in Burkina Faso [39][32] to 0.37% in Pakistan [31][24]. Although these FA levels were measured from a variety of FA pools which may reflect long- or short-term dietary intake, including whole blood, red blood cells, plasma, and serum [40,41[33][34][35],42], research shows that the relative percentages of fatty acids are comparable regardless of sample type [43][36]. A closer examination comparing LMIC child populations to HIC child populations may explain these wide ranges. In general, child populations in LMICs did not necessarily have lower levels of EFAs and their HUFA metabolites. The observations do not fully support prior evidence which shows that gross national income is significantly correlated to higher ARA and DHA intake [55][37] and that LMIC populations are at an increased risk of underconsumption of important dietary FAs [56,57][38][39]. For instance, Tanzanian infants and children had DGLA and DPA n-6 levels higher than those in European and Colombian children [34,45,49,51[27][40][41][42][43][44],53,54], and South African and Ghanian children had higher levels of ARA than children from the United Kingdom, Norway, and Colombia [34,45,46,47,52,58][27][40][45][46][47][48]. In fact, southern Ghanian children had higher DHA levels than many of the HIC child populations observed [34,45,47,49,51][27][40][41][42][46]. Consequently, LMIC child populations had the highest level of a number of fatty acids. LA levels were the highest among Ugandan children aged 6–10 years (mean (SD): 36.8 (0.35)% total FA) [32[25][26],33], DGLA and DPAn-6 levels were highest among 3–9-month-old Gambian children (DGLA: 19.1 (6.49) ng/uL; DPAn-6: 3.32 (1.24) ng/uL)) [53][43], and DTA levels were highest among 0–5-year-old Pakistani children (median (IQR): 3.05 (2.13–3.85)% total FA) [31][24]. Lastly, DPAn-3 levels were highest among Gambian children aged 3–9 months (mean (SD): 11.9 (3.82) ng/uL) [38][31]. The discrepancy between ourthe findings and previous results is likely because these earlier studies measured FA intake solely using food fatty acid composition and consumption data. By not measuring blood fatty acid levels, these studies relied on more subjective measures of FA intake and thus may not have accurately measured PUFA intake. Considering these data, LMIC child populations tend to have higher levels of n-6 HUFAs, and HIC child populations tend to have higher levels of n-3 HUFAs. Since a higher proportion of n-3 HUFAs is linked to better health outcomes [28][49], children in LMICs may be at a greater health disadvantage during a critical developmental period. Mead acid levels cannot be compared by country income status because it was only measured in LMICs, but 0–5-year-old Pakistani children had the highest concentration of Mead acid (median (IQR): 0.37 (0.14–1.32)% total FA) [31][24]. As Mead acid is synthesized in both the absence of LA and ALA, which serve as the precursors for n-6 and n-3 HUFAs, respectively, children in LMICs may have lower levels of both n-6 and n-3 HUFAs which are both necessary in sufficient amounts during childhood [17,28,29,30][17][49][50][51]. Collectively, this evidence demonstrates that LMICs may be at a higher risk of unhealthful HUFA balance and lower HUFA levels overall, but it is difficult to compare the potential for EFAD across countries since Mead acid is not commonly measured or reported in studies performed in HICs. FA levels among child populations differ greatly within country income categories. For instance, Ugandan children aged 6–10 years have higher LA levels (mean (SD): 36.8 (0.35)% total FA) but lower DGLA (0.56 (0.20)%), DPAn-6 (0.014 (0.001)%, ALA (0.26 (0.10)%), and DPAn-3 levels (0.067 (0.003)%) [32,33][25][26] compared to other LMIC child populations within sub-Saharan Africa and Asia. Colombian children 5–12 years old, however, had LA levels (30.3 (3.10)%) [45][40] comparable to those of the Ugandan children. Additionally, 2–6-year-old southern Ghanian children had mean EPA levels of 0.80% (SD: 0.35) [47][46], which approach those of well-nourished Inuit children (0.84 (0.16)%) [37][30], whose diet consists primarily of cold-water fish, and healthy European children [49][41]. In Burkina Faso, which shares a border with Ghana, children’s whole-blood EPA levels (median (IQR): 0.13 (0.10, 0.18)%) [39][32] trended lower than those in southern Ghana [47][46]. Based on this evidence, it is important to compare LMIC child populations with one another rather than grouping them all together. HIC child populations also exhibit variability in FA levels. The mean DHA level of children 7–9 years old from the United Kingdom was 1.9% (SD: 0.53) [34][27], which was relatively low compared to LMIC child populations, notably Nepalese children from 0 to 12 months old (mean: 4.9%, SD not reported) [50][52]. Many other HIC child populations, however, had higher DHA levels than those seen in the United Kingdom, notably Inuit Canadian children aged 11–53 months (mean (SD): 2.67 (1.52)%) [37][30], Dutch children aged 7–8 years (2.8 (0.7)%) [51][42], Norwegian children aged 1 year (6.00 (1.00)%) [58][48], and South Korean children aged 4–6 years (8.3 (1.3)%) [35][28]. Although ALA levels were generally higher among HIC populations compared to LMIC populations, Colombian children aged 5–12 years (0.49 (0.15)%) [45][40] and children from the United Kingdom aged 7–9 years (0.54 (0.25)%) [34][27] had mean ALA levels which trended higher than those of other HIC child populations. 1-year-old Norwegian children (12 (2)%) [58][48] and 11–53-month Canadian Inuit children (10.11 (0.37)%) [37][30] had the highest ARA levels of the HIC populations, but they were still comparable to most LMIC child population ARA levels. LA and EPA levels were relatively comparable across HIC populations, but LA levels were noticeably higher among 7–8-year-old Dutch children (23.2 (2.3)%) [51][42] and 5–12-year-old Colombian children (30.3 (3.10)%) [45][40], and EPA levels were noticeably higher among 11–53-month-old Canadian Inuit children (0.84 (0.61)%) [37][30] compared to other HIC populations. The same is true for DPAn-3, which was also noticeably higher among Inuit children (1.54 (0.69)%) [37][30]. Overall, HIC child populations demonstrated fewer variations in FA levels than LMIC child populations. Other factors besides country income status may contribute more substantially to differences in FA levels across child populations. Comparison of various child populations by age shows that older children, i.e., children 6–16 years old, demonstrate higher levels of LA and ALA, but younger children, i.e., 0–6 years old, demonstrate higher levels of DGLA, DPAn-6, EPA, DPAn-3, DHA, and Mead acid. Thus, the age of children in the population of interest may influence their FA levels. Additionally, dietary intake largely influences FA levels. For instance, food frequency questionnaires from a study conducted in northern and southern Ghana demonstrated that the latter population consumed more fish compared to their counterpart due to their proximity to the Gulf of Guinea, which was confirmed by higher n-3 and lower n-6 whole-blood FA levels [46,47,59][45][46][53]. Dietary intake can also influence FA levels indirectly by altering the activity of the desaturase enzymes involved in the conversion of LA and ALA into their downstream PUFA byproducts, i.e., delta-5-desaturase (D5D) and delta-6-desaturase (D6D). Six-week EPA fish oil supplementation increased D5D activity by 25% and decreased D6D activity by 17% (p < 0.0001) [15]. FA intake also influences the expression of D5D and D6D by altering fatty acid desaturase (FADS) genotypes [60][54]. A study conducted among Greenlandic Inuit showed that the population experienced gradual changes in FADS1 and FADS2 expression over generations due to high n-3 PUFA consumption, which led to increased D5D activity [61][55]. Besides influencing the level of PUFAs in the blood, FADS expression may have implications for chronic disease, as increased FADS2 expression is linked to adverse health outcomes such as obesity, type 2 diabetes, and high triglyceride scores [60,62][54][56]. Factors such as dietary intake and genotypes should be considered over country income status as important determinants of population FA levels and resulting morbidities. Overall, there is variability in the FA profiles of children globally. It is difficult to generalize and say that HIC child populations have more sufficient FA levels overall compared to those from LMICs. There is a trend, however, that LMICs have higher n-6 HUFA levels than HICs, while HICs have higher n-3 HUFA levels than LMICs, which may give children in HICs a health advantage. More researchers should consider measuring Mead acid levels in HICs populations to aid in comparison with levels of LMICs and determine if they have a similar prevalence of EFAD. Nevertheless, country income status may not be the best predictor of FA levels. Better determinants of FA levels include age, dietary intake, and genetics. To confirm these findings, more studies assessing the relationship between food consumption and FA levels in child populations of various age ranges are needed. Other studies should also be carried out to examine the effect of intake of certain fatty acids on epigenetics, notably the expression of FADS genotypes and resulting desaturase activity.

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