Elsevier

Bone

Volume 97, April 2017, Pages 287-292
Bone

Full Length Article
Unexpected widespread hypophosphatemia and bone disease associated with elemental formula use in infants and children

https://doi.org/10.1016/j.bone.2017.02.003Get rights and content

Highlights

  • Hypophosphatemia due to elemental formula feeding has not previously been described.

  • Elemental formula-induced hypophosphatemia may have severe skeletal consequences.

  • Correction of prolonged hypophosphatemia in this setting must be done under close observation to avoid severe hypocalcemia.

Abstract

Objective

Hypophosphatemia occurs with inadequate dietary intake, malabsorption, increased renal excretion, or shifts between intracellular and extracellular compartments. We noticed the common finding of amino-acid based elemental formula [EF] use in an unexpected number of cases of idiopathic hypophosphatemia occurring in infants and children evaluated for skeletal disease. We aimed to fully characterize the clinical profiles in these cases.

Methods

A retrospective chart review of children with unexplained hypophosphatemia was performed as cases accumulated from various centres in North America and Ireland. Data were analyzed to explore any relationships between feeding and biochemical or clinical features, effects of treatment, and to identify a potential mechanism.

Results

Fifty-one children were identified at 17 institutions with EF-associated hypophosphatemia. Most children had complex illnesses and had been solely fed Neocate® formula products for variable periods of time prior to presentation. Feeding methods varied. Hypophosphatemia was detected during evaluation of fractures or rickets. Increased alkaline phosphatase activity and appropriate renal conservation of phosphate were documented in nearly all cases. Skeletal radiographs demonstrated fractures, undermineralization, or rickets in 94% of the cases. Although the skeletal disease had often been attributed to underlying disease, most all improved with addition of supplemental phosphate or change to a different formula product.

Conclusion

The observed biochemical profiles indicated a deficient dietary supply or severe malabsorption of phosphate, despite adequate formula composition. When transition to an alternate formula was possible, biochemical status improved shortly after introduction to the alternate formula, with eventual improvement of skeletal abnormalities. These observations strongly implicate that bioavailability of formula phosphorus may be impaired in certain clinical settings. The widespread nature of the findings lead us to strongly recommend careful monitoring of mineral metabolism in children fed EF. Transition to alternative formula use or implementation of phosphate supplementation should be performed cautiously with as severe hypocalcemia may develop.

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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Authors LC and TOC contributed equally to this work.

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