Comment on “Serum Hepcidin and Soluble Transferrin Receptor in the Assessment of Iron Metabolism in Children on a Vegetarian Diet”
Comment on BSerum Hepcidin and Soluble Transferrin Receptor in the Assessment of Iron Metabolism in Children on a Vegetarian Diet^
Piotr Rzymski 0 1
Tomas Ganz 0 1
0 Departments of Medicine and Pathology, David Geffen School of Medicine, University of California , Los Angeles , USA
1 Department of Environmental Medicine, Poznan University of Medical Sciences , Poznań , Poland
2 Piotr Rzymski
We read with great interest the paper by Ambroszkiewicz
et al. [
] entitled BSerum hepcidin and soluble transferrin
receptor in the assessment of iron metabolism in children on a
vegetarian diet^ that was published in the journal of
Biological Trace Element Research (DOI: https://doi.org/10.
1007/s12011-017-1003-5). It presents the results of an
observational study of markers of iron status in children
aged 4.5–9.0 years on lacto-ovo-vegetarian (n = 43) or
omnivorous diet (n = 46). The research compared biochemical
parameters (serum concentration of ferritin, transferrin, soluble
transferrin receptor, hepcidin, iron, hemoglobin, and
Creactive protein) and erythrocyte parameters, as well as
estimated energy and nutrient intakes, between the two groups.
The vegetarian children had a two-fold decrease in serum
hepcidin level accompanied by decreased ferritin level and
slight but statistically significant increase in concentration of
soluble transferrin receptor (sTfR), but no differences in
concentration of hemoglobin, mean corpuscular volume, iron, and
transferrin compared to the omnivorous group. Moreover,
vegetarian children had comparable total iron intake but
consumed more (approx. by 30%) ascorbic acid in food [
paper suggests that subclinical iron deficiency in vegetarian
children is manifested by elevated sTfR concentration and
decreased hepcidin. Here, we would like to present an
alternative view that these changes may reflect a clinically benign
form of adaptation for more efficient iron absorption and
Owing to the increasing popularity of vegetarian diets, their
clinical consequences are becoming clearer and include such
potential health benefits as decreased all-cause mortality and
decreased risks of obesity, type 2 diabetes, and coronary heart
disease . Reputable medical societies, including Academy of
Nutrition and Dietetics (USA), acknowledge that appropriately
planned vegetarian diets, including the vegan form, are suitable
for all stages of the life cycle, including pregnancy, lactation,
infancy, childhood, adolescence, and older adulthood, and even
for athletes . However, unbalanced vegetarianism can be as
harmful as an unbalanced omnivorous diet .
Most data on the health effects of vegetarian diets were
collected from adults, so the study by Ambroszkiewicz et al.
], despite its small sample size, is an important contribution
to the field. The diet of children is largely determined by their
caregivers and it is understandable that some (including
caregivers already practicing some form of vegetarianism) will
fear that restriction of meat consumption may lead to
deficiencies and adversely affect the development of their children.
This is particularly important in the case of iron as it plays a
central role in many key biological processes, including
intermediary metabolism, energy production, and oxygen delivery
to tissues . Globally, iron deficiency is recognized as a
major health problem known to be associated with serious
neurodevelopmental and cognitive deficits in low-resource
settings . However, it is still not clear to what extent these
serious problems depend on coexisting nutritional
deficiencies, alcohol and drug use during pregnancy, endemic
infections, and other confounding factors that are uncommon
among persons in high-resource settings who adopt
vegetarianism as a lifestyle choice. In this regard, it is somewhat
reassuring that even very severe isolated iron deficiency, with
anemia and severe microcytosis caused by mutations in
TMPRSS6 (matriptase 2), did not cause developmental
deficits in children diagnosed in high-resource settings [7, 8].
The study by Ambroszkiewicz et al. [
] reported no significant
difference in iron intake between the two groups. Some authors
argue that, in vegetarians, iron intake needs to be much higher (up
to 80%) to overcome the lower biological availability of iron
forms in their diet . We question this recommendation because
it does not sufficiently consider factors that enhance iron
absorption in vegetarians. Higher intake of ascorbic acid in vegetarians
supports the reduction of the trivalent iron to its more soluble and
absorbable divalent form . Moreover, iron absorption is
increased in subjects with low serum hepcidin or its surrogate, low
serum ferritin . The study by Ambroszkiewicz et al. [
observed higher intake of ascorbic acid in vegetarian children and
acknowledged that this may partially counteract the
ironsequestering effects of polyphenols and phytic acid in a
vegetarian diet . Furthermore, habitual consumption of high-phytate
foods may reduce the negative effect of phytate on non-heme iron
Ambroszkiewicz et al. [
] noted the increased
concentrations of sTfR (mean 1.33 vs 1.12 mg/L, p < 0.01) and
decreased hepcidin level (5.46 vs 11.54 ng/L; p < 0.05) in
lacto-ovo-vegetarian children. Based on these findings, the
authors suggest that the vegetarian children may suffer from
subclinical iron deficiency. Their view is supported by two
references in which similar trends in hepcidin and sTfR levels
were found in children diagnosed with iron deficiency [14,
15]. However, as yet, no reference ranges of sTfR and
hepcidin levels have been established for children.
Moreover, in Ambroszkiewicz et al. [
], the mean difference
in sTfR concentration between lacto-ovo-vegetarian and
omnivorous children was only 18% (0.21 mg/L). Although serum
ferritin was lower in lacto-ovo-vegetarians than that in
omnivores, it is notable that, in every case, it fell within the
established reference range of ≥ 12 μg/L in cases of children
aged below 5 years and ≥ 15 μg/L for children older than
5 years of age . Using the recently proposed criteria to
detect clinically significant iron deficiency in children by
decreased mean corpuscular volume of erythrocytes , only
four children in each group could be considered to have
We would like to suggest that instead of diagnosing a
potential disease condition in the lacto-ovo-vegetarian children,
the biochemical changes could be considered a form of
adaptation wherein a slight increase in sTfR and two-fold decrease
in hepcidin as observed by Ambroszkiewicz et al. [
evidence of homeostatic changes that increase iron utilization
and absorption from diets that contain less bioavailable iron.
Increased sTfR reflects higher expression of TfR in
erythrocyte precursors, allowing more efficient iron uptake even
when plasma iron concentrations are decreased. There is also
evidence that increased TfR expression helps mediate
suppression of hepcidin in the liver . By degrading duodenal
ferroportin, hepcidin is a key regulator of iron uptake from the
diet [19, 20]; therefore, its lower circulating concentrations
should enhance iron absorption from diets with restricted
bioavailable iron. Moreover, vegetarian children demonstrated a
significantly increased intake of vitamin C [
] which may
promote iron absorption. It would be very interesting to follow
up on children studied by Ambroszkiewicz et al. [
] within the
next 2–4 years to ascertain whether any of them will have
developed clinical iron deficiency.
Finally, simple measures can be taken to enhance the
availability of dietary iron in children or adults who do develop
clinical iron deficiency on vegetarian diets. The consumption
of diets containing ferritin-rich seeds (legumes, nuts, corn)
provides iron in a more bioavailable form than other
vegetables . In some countries, certain foods (e.g., cereals) are
fortified with iron and represent an acceptable dietary
supplement for many vegetarians.
In summary, there is no evidence that the adaptive changes
described by Ambroszkiewicz et al. [
] in vegetarian children
in high-resource settings indicate any adverse effects on their
well-being or development. We recognize that such children
have not been adequately studied and encourage further
research in this area.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
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1. Ambroszkiewicz J , Klemarczyk W , Mazur J , Gajewska J , Rowicka G , Strucińska M , Chełchowska M ( 2017 ) Serum hepcidin and soluble transferrin receptor in the assessment of iron metabolism in children on a vegetarian diet . Biol Trace Elem Res 180 ( 2 ): 182 - 190 .
https://doi.org/10.1007/s12011-017 -1003-5 2 . Kahleova H , Levin S , Barnard N ( 2017 ) Cardio-metabolic benefits of plant-based diets . Nutrients 9 ( 8 ). doi:https://doi.org/10.3390/ nu9080848 3. Melina V , Craig W , Levin S ( 2016 ) Position of the Academy of Nutrition and Dietetics: vegetarian diets . J Acad Nutr Diet 116 ( 12 ): 1970 - 1980 . https://doi.org/10.1016/j.jand. 2016 . 09 .025 4. Satija A , Bhupathiraju SN , Spiegelman D , Chiuve SE , Manson JE , Willett W , Rexrode KM , Rimm EB , FB H ( 2017 ) Healthful and unhealthful plant-based diets and the risk of coronary heart disease in U.S. adults . J Am Coll Cardiol 70 ( 4 ): 411 - 422 . https://doi.org/10.
1016/j.jacc. 2017 . 05 .047 5. Miller JL ( 2013 ) Iron deficiency anemia: a common and curable disease . Cold Spring Harb Perspect Med 3 ( 7 ). https://doi.org/10.
1101/cshperspect.a011866 6 . Allali S , Brousse V , Sacri AS , Chalumeau M , de Montalembert M ( 2017 ) Anemia in children: prevalence, causes, diagnostic work-up, and long-term consequences . Expert Rev Hematol 10 ( 11 ): 1023 - 1028 . https://doi.org/10.1080/17474086. 2017 .1354696 Camaschella C, Poggiali E ( 2011 ) Inherited disorders of iron metabolism . Curr Opin Pediatr 23 ( 1 ): 14 - 20 . https://doi.org/10.1097/ MOP.0b013e3283425591 Arsenault V , Mailloux C , Bonnefoy A , Lemyre E , Pastore Y ( 2016 ) Iron-refractory iron deficiency anemia may not lead to neurocognitive dysfunction: a case report . Pediatrics 138 ( 1 ): e20153608. https://doi.org/10.1542/peds.2015-3608 Food and Nutrition Board . Institute of Medicine ( 2001 ) Dietary reference intake for vitamin A, vitamin K, arsenic , boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. National Academy Press, Washington DC Teucher B, Olivares M , Cori H ( 2004 ) Enhancers of iron absorption: ascorbic acid and other organic acids . Int J Vitam Nutr Res 74 ( 6 ): 403 - 419 . https://doi.org/10.1024/ 0300 - 9831 . 74 .6.403 Collings R , Harvey LJ , Hooper L , Hurst R , Brown TJ , Ansett J , King M , Fairweather-Tait SJ ( 2013 ) The absorption of iron from whole diets: a systematic review . Am J Clin Nutr 98 ( 1 ): 65 - 81 .
https://doi.org/10.3945/ajcn.112.050609 Hurrell R , Egli I ( 2010 ) Iron bioavailability and dietary reference values . Am J Clin Nutr 91 : 1461 -1467 Armah SM , Boy E , Chen D , Candal P , Reddy MB ( 2015 ) Regular consumption of a high-phytate diet reduces the inhibitory effect of phytate on nonheme-iron absorption in women with suboptimal iron stores . J Nutr 145 ( 8 ): 1735 - 1759 . https://doi.org/10.3945/jn.
114.209957 Choi HS , Song SH , Lee JH , Kim HJ , Yang HR ( 2012 ) Serum hepcidin levels and iron parameters in children with iron deficiency .
Korean J Hematol 47 ( 4 ): 286 - 292 . https://doi.org/10.5045/kjh.
Weiler HA , Jean-Philippe S , Cohen TR , Vanstone CA , Agellon S ( 2015 ) Depleted iron stores and iron deficiency anemia associated with reduced ferritin and hepcidin and elevated soluble transferrin receptors in a multiethnic group of preschool-age children . Appl Physiol Nutr Metab 40 ( 9 ): 887 - 894 . https://doi.org/10.1139/apnm2014-0328 World Health Organization ( 2011 ) Serum ferritin concentrations for the assessment of iron status and iron deficiency in populations.
WHO , Geneva McCarthy EK , Kiely ME , Hannon G , Ahearne C , Kenny LC , Hourihane JO , Irvine AD , Murray DM ( 2017 ) Microcytosis is associated with low cognitive outcomes in healthy 2-year-olds in a high-resource setting . Br J Nutr 118 ( 05 ): 360 - 367 . https://doi.org/ 10.1017/ S0007114517001945 Keel SB , Doty R , Liu L , Nemeth E , Cherian S , Ganz T , Abkowitz JL ( 2015 ) Evidence that the expression of transferrin receptor 1 on erythroid marrow cells mediates hepcidin suppression in the liver .
Exp Hematol 43 ( 6 ): 469 - 478 . https://doi.org/10.1016/j.exphem.
2015 . 03 .001 Nemeth E, Tuttle MS , Powelson J , Vaughn MB , Donovan A , Ward DM , Ganz T , Kaplan J ( 2004 ) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization .
Science 306 ( 5704 ): 2090 - 2093 . https://doi.org/10.1126/science.
1104742 Ganz T ( 2003 ) Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation . Blood 102 ( 3 ): 783 - 788 .
https://doi.org/10.1182/blood-2003 -03-0672 Lönnerdal B ( 2009 ) Soybean ferritin: implications for iron status of vegetarians . Am J Clin Nutr 89 ( 5 ): 1680S - 1685S . https://doi.org/ 10.3945/ajcn. 2009 .26736W