PhD student, University of Alberta
Understanding how infants and children absorb and retain dietary calcium for appropriate growth
Calcium is essential in the body, partly because it forms the foundation of bone structure. Bone growth occurs rapidly in infancy and continues throughout childhood, with bone mass peaking in early adulthood and then declining throughout the rest of life. It is, therefore, crucial to build strong bones during childhood. As a pediatric dietitian, I have experience caring for infants and children who are at risk of poor bone health due to factors that may include prematurity, gut disease, and kidney disease. Unfortunately, we do not fully understand the normal physiology of calcium homeostasis in children and therefore have failed to advance health care outcomes for this vulnerable population.
The intestines, kidneys, and bones maintain calcium homeostasis. Calcium enters the body through the intestines and is retained by the kidneys. Unfortunately, how the body absorbs and holds on to enough calcium to maintain a positive calcium balance required for appropriate growth is not clearly understood. We have detailed the current state of knowledge in this field in a recent review. Our major research aim is to understand this phenomenon. The first objective is to understand the molecular details of calcium absorption across the small intestine early in life. To date, using molecular biology and electrophysiology in a mouse model, we have identified novel absorption pathways that exist in the distal small intestine only during infancy. Our second objective will be to determine the mechanisms mediating the drastic alterations noted in our first objective. We hypothesize that bioactive compounds present in breast milk facilitate expression of the novel pathways observed. Our third objective is to determine post natal alterations in calcium reabsorption in the kidney.
Overall, results of this research plan will advance our knowledge of physiology that is critical to appropriate postnatal development. Understanding how dietary calcium is absorbed from the intestine of infants and children will inform adequate calcium intake throughout growth in healthy and ill populations. The results of this research will have further wide-ranging impact including optimizing delivery of calcium in infant formulas and the dairy industry. This research will also provide potential drug targets for diseases caused by disrupted calcium balance and thus lay the foundation for future measures to improve the health and care of infants and children.
Abstract: Calcium is an important ion in cell signaling, hormone regulation, and bone health. Its regulation is complex and intimately connected to that of phosphate homeostasis. Both ions are maintained at appropriate levels to maintain the extracellular to intracellular gradients, allow for mineralization of bone, and to prevent extra skeletal and urinary calcification. The homeostasis involves the target organs intestine, parathyroid glands, kidney, and bone. Multiple hormones converge to regulate the extracellular calcium level: parathyroid hormone, vitamin D (principally 25(OH)D or 1,25(OH)2D), fibroblast growth factor 23, and α-klotho. Fine regulation of calcium homeostasis occurs in the thick ascending limb and collecting tubule segments via actions of the calcium sensing receptor and several channels/transporters. The kidney participates in homeostatic loops with bone, intestine, and parathyroid glands. Initially in the course of progressive kidney disease, the homeostatic response maintains serum levels of calcium and phosphorus in the desired range, and maintains neutral balance. However, once the kidneys are no longer able to appropriately respond to hormones and excrete calcium and phosphate, positive balance ensues leading to adverse cardiac and skeletal abnormalities. © 2016 American Physiological Society. Compr Physiol 6:1781-1800, 2016.
Pub.: 27 Oct '16, Pinned: 23 Aug '17
Abstract: A female infant was admitted to hospital due to failure to thrive. She presented hypercalcemia (4.09 mmol/L, normal range: 2.2-2.65 mmol/L), high 25-hydroxyvitamin D (283 nmol/L, normal range: 75-250 nmol/L), 1,25-dihydroxyvitamin D in the upper normal range, and low parathyroid hormone. Vitamin D intoxication was suspected. The patient had received routine rickets prophylaxis.Williams-Beuren syndrome was genetically excluded. Sequencing of CYP24A1 showed 2 mutations: c.443T>C and c.1186C>T.The patient's clinical status improved after intravenous rehydration, cessation of supplementation, and on a low-calcium diet. 25-Hydroxyvitamin D concentrations normalized within days, while 1,25-dihydroxyvitamin D remained in the upper normal range. We also investigated our patient's bone health.The patient was hospitalized initially on suspicion of vitamin D intoxication but proved to be a case of compound heterozygosity. Data on the long-term clinical and biochemical evolution of patients with idiopathic infantile hypercalcemia are sparse. Our follow-up showed seasonal variations of vitamin D and calcium parameters, with no influence on kidney function or bone health for the investigated period.
Pub.: 01 Nov '16, Pinned: 23 Aug '17
Abstract: Maintaining plasma calcium levels within a narrow range is of vital importance for many physiological functions. Therefore, calcium transport processes in the intestine, bone and kidney are tightly regulated to respectively fine-tune the rate of absorption, storage and excretion. The TRPV5 and TRPV6 calcium channels are viewed as the gatekeepers of epithelial calcium transport. Several calciotropic hormones control the channels at the level of transcription, membrane expression, and function. Recent technological advances have provided the first near-atomic resolution structural models of several TRPV channels, allowing insight into their architecture. While this field is still in its infancy, it has increased our understanding of molecular channel regulation and holds great promise for future structure-function studies of these ion channels. This review will summarize the mechanisms that control the systemic calcium balance, as well as extrapolate structural views to the molecular functioning of TRPV5/6 channels in epithelial calcium transport.
Pub.: 30 Nov '16, Pinned: 23 Aug '17
Abstract: Significant alterations in maternal calcium (Ca2+) and magnesium (Mg2+) balance occur during lactation. Ca2+ is the primary divalent cation mobilized into breast milk by demineralization of the skeleton and alterations in intestinal and renal Ca2+ transport. Mg2+ is also concentrated in breast milk, but the underlying mechanisms are not well understood. To determine the molecular alterations in Ca2+ and Mg2+ transport in the intestine and kidney during lactation, 3 groups of female mice consisting of either non-pregnant controls, lactating mice, or mice undergoing involution were examined. The fractional excretion of Ca2+, but not Mg2+, rose significantly during lactation. Renal 1-alpha hydroxylase and 24-OHase mRNA levels increased markedly as did plasma 1,25 dihydroxyvitamin D levels. This was accompanied by significant increases in intestinal expression of Trpv6 and S100g in lactating mice. However, no alterations in the expression of cation permeable claudins (-2, -12 or -15) were found in the intestine. In kidney, increased expression of Trpv5 and Calb1 was observed during lactation, while no changes in claudins involved in Ca2+ and Mg2+ transport (-2, -14, -16 or -19) were found. Consistent with the mRNA expression, both Calbindin-D28K and TRPV5 protein expression increased. Colonic Trpm6 expression increased during lactation, while renal Trpm6 remained unaltered. In conclusion, proteins involved in transcellular Ca2+ and Mg2+ transport pathways increase during lactation, while expression of paracellular transport proteins remained unchanged. Increased fractional Ca2+ excretion can be explained by vitamin D-dependent intestinal hyperabsorption and bone demineralization, despite enhanced transcellular Ca2+ uptake by the kidney.
Pub.: 26 May '17, Pinned: 23 Aug '17
Abstract: Adequate intake of calcium and phosphorus in the appropriate ratio of 1-2:1 (Ca:P), in addition to magnesium and vitamin D, is vital for bone health and development of an infant. In this feasibility study, the ratio of Ca:P in conjunction with vitamin D and other essential elements (Cu, Fe, K, Mg, Na, and Zn) in a range of commercial infant food products in the UK is investigated. The elemental analysis was carried out using inductively coupled plasma optical emission spectrometry, and vitamin D levels were determined using an enzyme-linked immunosorbent assay. The quantitative data were further evaluated, based on a standardized menu, to measure the total daily intake of an infant aged 7-12 months against the Reference Nutrient Intake. The results from the study show that the Ca:P ratio of the infant's total dietary intake was within the recommended range at 1.49:1. However, the level of intake for each of the nutrients analyzed, with the exception of sodium, was found to be above the Reference Nutrient Intake, which warrants further investigation in relation to both micronutrient interactions and in situations where the intake of fortified infant formula milk is comprised. Finally, as the study is the first to include consumption of infant snack products, the level of total calorie intake was also calculated in order to assess the total daily estimated energy intake; the results indicate that energy intakes exceed recommendations by 42%, which may have implications for obesity.
Pub.: 10 Sep '16, Pinned: 23 Aug '17
Abstract: Calcium is an essential ion in all organisms and participates in a variety of structural and functional roles. Calcium (re)absorption occurs in epithelia, including the intestine, kidney, mammary glands, placenta, and gills of fish. Its transport is regulated by a complex array of processes that are mediated by hormonal, developmental, and physiological factors involving the gastrointestinal tract, bone, kidney, and the parathyroids. Here we review the calcium transport mechanisms-paracellular, which is energy independent, and transcellular, which is energy dependent-primarily focusing on the intestine. We provide a new perspective on the facilitated diffusion and vesicular transport models to account for the emerging concepts on transcellular calcium transport. Finally, we discuss how 1,25(OH)2D3 and parathyroid hormone regulate calcium transport.
Pub.: 05 Jul '08, Pinned: 23 Aug '17
Abstract: Calcium is a vital mineral for the developing newborn infant. This review discusses perinatal and neonatal calcium metabolism, with an emphasis on enteral calcium absorption and the nutritional factors affecting calcium bioavailability including the three major endocrine hormones involved in calcium metabolism: parathyroid hormone, vitamin D, and calcitonin. The placenta transports calcium to the fetus throughout pregnancy, with the largest amount of fetal calcium accumulation occurring in the third trimester. At birth, the newborn transitions to intestinal absorption to meet the body's calcium needs. Most calcium is absorbed by paracellular passive diffusion in the small intestine. Calcium intestinal absorption is affected by the type and amount of calcium ingested. It is also affected by the amount of intestinal calcium that is bound to dietary fats and proteins. One major consequence of decreased calcium absorption is metabolic bone disease in which there is a failure of complete mineralization of the bone osteoid.
Pub.: 13 Jul '06, Pinned: 23 Aug '17