Full Length ArticleUnexpected widespread hypophosphatemia and bone disease associated with elemental formula use in infants and children
Introduction
Hypophosphatemia is uncommon in childhood and can occur either with or without depletion of whole-body phosphate [P] stores [1]. In the acute setting, or upon refeeding after prolonged depletion, phosphate may shift from extracellular to intracellular compartments resulting in transient hypophosphatemia without phosphate depletion. In the more chronic setting, long-term phosphate depletion may occur after prolonged inadequate intake, malabsorption, or excessive urinary losses due to renal tubular disease. As phosphate is abundant in Western diets, inadequate phosphate supply is rarely encountered in the United States [US] and Canada, and observed in very specific situations, such as the breastfed premature infant (owing to the low P content of breast milk). Decreased intestinal absorption of phosphate may occur with generalized malabsorption, vitamin D deficiency or due to the use of phosphate binding agents. One such example has been often reported in individuals abusing antacids, whereby resultant bound phosphate is less available for intestinal absorption [2]. Alternatively, abnormal renal losses of phosphate may occur in the setting of hyperparathyroidism, excess fibroblast growth factor 23 [FGF23], or primary disorders of the renal tubule [1]. Generally, hypophosphatemia encountered in childhood is accompanied by characteristic historic and/or clinical features that suggest the most likely etiology.
The composition of nutritional formulas designed for infants and children follows nationally- and globally-established guidelines to maximize safety and nutritional adequacy across a variety of intakes [3]. When formula is used as the sole source of nutrition, intake is determined by energy requirements and micronutrient intake varies accordingly. Despite this variability in intake, micronutrient intake from formula is usually adequate to meet requirements for most nutrients until intakes fall far below expected for age. As such, micronutrient deficiencies in children consuming infant and pediatric formulas across a wide range of intakes are rare. Furthermore, when low formula volumes are consumed due to low energy requirements, intake of all micronutrients is reduced, resulting in potential deficiencies of multiple micronutrients. Thus isolated micronutrient deficiency in a formula-fed population is not commonly encountered.
In this manuscript, we describe a series of children who had unexpected and unexplained hypophosphatemia, and who had in common the consumption of single brand of amino-acid based nutritional formula.
Section snippets
Patients and methods
This was a retrospective chart review conducted in 17 centres in North America and Ireland between 2014 and 2016. Patients were referred to the various authors because of unexplained mechanism of marked hypophosphatemia in infants and young children, sometimes accompanied by significant bone disease. This case series was compiled when, it became evident that several common clinical and biochemical features suggested a limitation in dietary phosphate intake or its intestinal absorption. After
Case vignette 1
An 18 month-old boy had a history of esophageal atresia/tracheo-esophageal fistula repair and necrotizing enterocolitis. He was orally fed, receiving diuretics and glucocorticoids, and was relatively immobile. After 1 year of Neocate® feeding, he demonstrated irritability associated with knee and skeletal manipulation. A radiographic skeletal survey showed numerous fractures including those of the femur, fibulae, ulna, metatarsals, a metacarpal, and 3 ribs. Upon identification of a low blood P
Discussion
We describe a cohort of infants and children with previously unrecognized hypophosphatemia accompanied in most cases by significant bone disease. All had in common the use of amino-acid based infant or pediatric formulas. The formulas were prepared by a single manufacturer (Nutricia: Neocate Infant®, Neocate Junior®, and Neocate Advance®), although the possibility that hypophosphatemia may occur with other amino-acid based formulas cannot be excluded. Review of records from several patients in
Conclusion
Clinicians should be aware of the potential for significant hypophosphatemia and bone disease in children receiving amino-acid based formula products (especially Neocate®), and particularly those with medically complex conditions receiving formula as their sole source of nutrition. The children in this series were managed with supplemental phosphate or alternative formula products, implicating reduced bioavailability of phosphorus in the formula for certain individuals. Patient-related
Funding source
Dr. Gordon was funded in part by NIH/NIDDK grant T32DK065522. No other funding was secured for this study.
Disclosures
Thomas O. Carpenter and Linda Casey have performed consulting services for Nutricia, North America. The other authors have indicated they have no financial relationships relevant to this article to disclose.
Conflict of interest
Ruth Faircloth, MD: The views expressed are those of the authors and do not reflect the official policy or position of the US Army, Department of Defense nor the US Government. The other authors have no potential conflicts of interest to disclose.
Acknowledgements
We thank Dr. Renee Mobley for her assistance with preparation of the graphic material and Drs. Mobley and Melinda Sharkey for informative and instructive discussion.
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Cited by (43)
Current Practices, Challenges, and Recommendations in Enteral Nutrition After Necrotizing Enterocolitis
2023, Clinics in PerinatologyHypophosphatemia: A Practical Guide to Evaluation and Management
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2022, Saudi Journal of Biological SciencesPhosphorus bioaccessibility measured in four amino acid–based formulas using in-vitro batch digestion translates well into phosphorus bioavailability in mice
2021, NutritionCitation Excerpt :Our mice rendered hypophosphatemic and hypophosphaturic on low phosphorus diet mirrored similar metabolic changes as observed in a small number of children with chronic diseases with complex GI conditions under nutrition management with powdered infant and junior Neocate in addition to diverse medical and drug interventions, that is, suppressed iPTH and iFGF23 and increased 1,25-D along with hypophosphatemia and hypophosphaturia [13]. Furthermore, consistent with the finding in complex patients that substitution by human milk, alternate formula, or phosphate supplementation along with Neocate was able to reverse the hypophosphatemia [13]; our mice normalized blood and urine phosphorus rapidly, when fed a control diet. Blood phosphorus in mice was higher following 2 wk of nutrition with the control diet, albeit non-significantly, when compared with control diet + PPI.
Different elemental infant formulas show equivalent phosphorus and calcium bioavailability in healthy volunteers
2021, Nutrition ResearchCitation Excerpt :Additionally, it has been shown that infants aged 0 to 8 months diagnosed with CMA who received an elemental formula for 16 weeks had blood (trace) mineral concentrations (calcium, phosphorus, chloride, sodium, potassium, magnesium, and ferritin) within the age-specific reference ranges [13,14]. Despite this, recent retrospective chart reviews [15-20] have reported cases of hypophosphatemia associated with elemental formula use in infants and children with complex medical conditions and extensive medical histories. Hypophosphatemia may be caused by three main mechanisms: (1) decreased intake and intestinal absorption of phosphorus e.g., due to low dietary intake, malnutrition, prematurity, diarrhea, vomiting, gastrointestinal symptoms, intestinal mucosal hypoplasia, short gut, postpyloric feeding, and total parenteral nutrition, low plasma levels of vitamin D, phosphate absorption-inhibitors such as phosphate binders, and acid-suppressive medication), (2) increased urinary loss (e.g., due to lack of renal conservation, metabolic acidosis or (diuretic) drug use, secondary hyperparathyroidism, chronic kidney disease or kidney diseases such as Fanconi syndrome), or (3) internal redistribution of phosphate from serum to cells (e.g., due to recovery from malnutrition, refeeding syndrome, recovery from diabetic ketoacidosis, respiratory alkalosis, rapid cell proliferation/uptake (e.g., hungry bone syndrome, acute leukemia, Burkitt lymphoma), and hormonal and other agents (e.g., insulin, glucagon, epinephrine, dopamine, beta-2 agonists, steroids, xanthine derivatives) [21,22].
Bone Health in Childhood Chronic Disease
2020, Endocrinology and Metabolism Clinics of North America
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Authors LC and TOC contributed equally to this work.