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1 Advanced Nutrition Mineral Nutrition * Calcium MargiAnne Isaia, MD MPH MINERAL NUTRITION Calcium – the most abundant mineral in the human body Macro mineral – needed in amounts > 100 mg/day Nutritionally essential mineral - essentiality confirmed by biochemical mechanisms Criteria for essentiality: - is present in tissues of different animals at similar concentrations - withdrawal produces similar physiological or structural abnormalities regardless of species - presence reverses or prevents abnormalities - abnormalities are related to or a consequence of specific biochemical changes that can be reversed by the essential element MINERAL NUTRITION Biologic roles of Calcium Structural/mechanical: bone, teeth 99% of the total body Ca The skeleton – obvious structural role - important reservoir to maintain plasma Ca concentration The bone Ca pool in adults turns every 8-12 years - turnover does not occur in the teeth Remodeling of the bone continues throughout life Bone formation and bone resorption are balanced processes Bone formation exceeds resorption during growth If bone resorption exceeds bone formation – osteoporosis Osteoblasts: receptors for PTH, 1,25(OH)2 Vitamin D, estrogen, Pg E2 Osteoclasts: receptors for Calcitonin (CT) and variety of cytokynes Bone resorption – enhanced by PTH and inhibited by CT MINERAL NUTRITION The Bone Minerals Distribution (%) Tissue Calcium Phosphate Magnesium Skeleton 99 85 55 Soft tissue 1 15 45 ECF* < 0.2 < 0.1 <1 Total (g)** 1000 600 25 ECF* extra cellular fluid Total (g)** for an 70 kg male MINERAL NUTRITION Plasma levels are physiologically controlled Physiochemical states (% of total) State Calcium Phosphate Magnesium Free (ionized) 50 55 55 Protein-bound 40 10 30 Complexed 10 35 15 Serum (total) * 9-10.5 mg/dl or 2.25-2.75 mmol/L 3.0-4.5 mg/dl or 0.97-1.45 mm0l/L 1.3-2.1 mEq/L or 0.65-1.05mmol/L Serum (total)* Adult levels MINERAL NUTRITION Biologic roles of Calcium Catalytic: co-factor, co-enzyme for - proteases - blood clotting enzymes These functions are not significantly affected by changes in extracellular Ca2+ concentration Signal transmitter: ionized Ca – the most common in all of biology Binding to a large number of cell protein with activation of their unique function MINERAL NUTRITION Examples of cell proteins binding or activated by Ca Protein Function Calmodulin Troponin C Calretinin, retinin Calneurin B Protein kinase C Phospholipase A2 Caldesmon Parvalbumin Calbindin Calsequestrin Modulator/regulator of several protein kinases Modulator of muscle contraction Activator of Guanyl cyclase Phosphatase Widely distributed protein kinase Synthesis of arachidonic acid Regulator of muscle contraction Calcium storage Calcium storage Calcium storage MINERAL NUTRITION Extracellular and Intracellular Function Extracellular fluid Calcium - Forms: free ionized - approx 50% protein bound, mostly to albumin, some to globulin complexed to phosphate, citrate, etc - Functions: source of calcium to skeleton and cells blood clotting intercellular adhesion Intracellular Calcium - Function: 2nd messenger, activates kinases to phosphorylate proteins; involved in: - muscle contraction - neurotransmitter release - Glycogen metabolism - enzyme activation - hormone release - vision - cellular differentiation MINERAL NUTRITION Ca = important extracellular “first” messenger Key intracellular second messenger Ionized Ca – the most common signal transduction element in cells, because of its ability to bind to proteins reversibly To effect a regulatory change, an internal or external stimulus (physical, electrical or chemical) causes a change in Ca 2+ at a specific site in the cell, by: - releasing a store of Ca 2+ from within - causing Ca 2+ to enter the cell from outside. Accumulation of Ca 2+ in the cytosol - followed by Phosphate precipitation and cell death (Phosphate=vital in energy transfer) The plasma membrane is important in maintaining Ca homeostasis Calmodulin = intracellular Ca 2+ receptor protein that increases the total capacity of Ca/Mg-ATP-ase pump Ca 2+ flux across the plasma membrane: influx pathways: - potential-operated (voltage-dependent) channels - receptors-operated channels - Na+ channels (NCX) efflux pathways: Na+/Ca 2+ exchange pathway maintained by Na pumps PLASMA MEMBRANE AND CALCIUM HOMEOSTASIS MINERAL NUTRITION Ca Mechanism of Action Stimulus g Receptor g Response Receptors: G-protein-coupled receptors tyrosine kinases receptors Phospholipase C activated PIP2 g Phosphatidyl Inositol 4,5 –biPhosphate IP3 + Inositol triphosphate DAG Diacylglycerol IP3 binds to R in ER or sarcoplasmic reticulum it follows liberation of Ca 2+ from stores hCa 2+ in cytosol g binds to Calmodulin g activates Kinases DAG activates Protein kinase C which stimulates activity of Ca pump Ca receptor protein pathways are universal in excitable and non-excitable cells. Excitable cells(skeletal muscles, neurons) contain voltage-dependent Ca 2+ channels. Entering Ca 2+ activates Ryanodine Receptors to release Ca 2+ from internal stores. MINERAL NUTRITION Mechanism of Action Increased Ca 2+ in cytosol binds to Calmodulin Calmodulin activates Kinases MINERAL NUTRITION Calcium Homeostasis Blood Calcium levels are constant: physiologically maintained within a narrow range by: - a system of controlling factors - feed back mechanisms Serum Calcium does not reflect nutritional status Extracellular Calcium levels are detected by surface Ca 2+- sensing receptors (CaRs) - CaRs are members of the super-family of G-protein-coupled receptors - found in parathyroid, clear cells of thyroid, kidney, intestine, lung, brain, skin, bone marrow, osteoblasts etc - The CaR permits Ca 2+ to act as an extracellular 1st messenger MINERAL NUTRITION Calcium Homeostasis When blood Calcium levels fall: h Parathyroid hormone (PTH), and h formation of 1,25-(OH)2 vitamin D It results in: h Calcium absorption h renal tubular reabsorption of Calcium h bone resorption When blood Calcium levels increase: i PTH i formation of 1,25-(OH)2 vitamin D h Calcitonin (hormone produced in thyroid, it lowers blood Ca) It results in: i Ca absorption i renal reabsorption of Calcium i bone resorption The three tissues supporting Ca serum levels: gut, kidney and bone operate independently of one another. Altered responsiveness of any of these can increase bone fragility CALCIUM HOMEOSTASIS CALCIUM HOMEOSTASIS PTH/1,25(OH)2 D axis: PTH stimulates Calcitriol synthesis h renal 1 a 25 HO-ase activity MINERAL NUTRITION Calcium Homeostasis Aging-suppressor gene Klotho involved in the renal control of Calcium, Phosphate and Vitamin D metabolism Klotho - suppresses Phosphate re-absorption in renal proximal tubule by directly binding to FGF receptors - regulates Ca re-absorption in the distal convoluted tubule by stabilizing TRPV5 Ca channel in plasma membrane - decreases Calcitriol level by inhibiting renal 1- a 25-hydroxylase activity CALCIUM HOMEOSTASIS FGF 23/Klotho axis FGF 23 + Klotho actions: - synergistic with PTH (reduce tubular Phosphate reabsorption) - antagonic with PTH (inhibit Calcitriol synthesis) MINERAL NUTRITION Calcium absorption From intestinal lumen, two distinct mechanisms of absorption - their relative magnitude is determined by the amount of free Calcium available for absorption Transcellular: active, saturable, only in duodenum, when Ca intake is low Ca - enters the cell through voltage-insensitive (TRP) channels - is pumped out of the cell via PMCA, primarily - the rate limiting step is transport across the epithelial cell; - greatly enhanced by carrier protein Calbindin (Calbindin synthesis is totally dependent on Vitamin D) Paracellular: diffusional, nonsaturable, in jejunum & ileum, and lesser extent in colon, when dietary Ca is moderate or high - transfer is linear function of Ca content of the chym MINERAL NUTRITION Calcium absorption Factors affecting absorption: background diet (nutrient-nutrient interaction), Calcium intake (chemical form, solubility, pH), vitamin D status, Ca nutritional status, serum Phosphorus level, mucosal mass, intestinal transit time, health status, stage of life, drug interactions, other Increased absorption: vitamin D adequacy, dietary enhancers, increased mucosal mass, Ca deficiency, pregnancy, post-weaning status, mucosal permeability, some minerals adequacy (Mg, K, Cu, B, Mn) Decreased absorption: vitamin D deficiency, decreased mucosal mass, elderly (increased intestinal resistance to active vitamin D with age), menopause, estrogen deficiency , decreased stomach acid, rapid intestinal time, dietary inhibitors: oxalate, phytate MINERAL NUTRITION Food Sources and Bioavailability Potential Calcium sources vary in gross Ca content and bioavailability Bioavailability -fraction of an ingested component that enters the blood circulation and that can be used for physiological functions or storage. -depends on absorption, distribution, metabolism, and excretion Fractional Ca absorption from various dairy products is similar: approx. 30%. Adjuvant added to food matrices substantially alter bioavailability Some plant constituents form indigestible salts with Ca giCa absorption Oxalic Acid – the most potent inhibitor of Ca absorption (high concentration in spinach, rhubarb) Phytic Acid – modest inhibitor of Ca absorption ( the storage form of Phosphorus in seeds) Fermentation, as occurs during bread making, reduces Phytic Acid (Phytase present in yeast) results in increased Ca absorption Only concentrated sources of phytate (wheat bran ingested as extruded cereal or dried beans) substantially reduce Ca absorption MINERAL NUTRITION Food Sources and Bioavailability Plant rich in Ca Brassica genus: - broccoli, kale, bok choy, cabbage, Mustard and Turnip greens - Ca bioavailability is as good as that from milk Brassica: an anomaly in the plant kingdom oxalate not accumulated as a medium to detoxify excess Ca to protect against cell death Ca fortified food sources: fruit juices, fruit drinks, tofu, cereals Calcium content of 8 fl oz of milk (240 ml) compared to other food sources of Calcium 8 fl oz of mill = 1 cup yogurt = 1 ½ oz Cheddar cheese = 1 ½ cups cooked kale = 2 ¼ cups cooked broccoli = 8 cups of cooked spinach Mineral Nutrition Comparing food sources of absorbable Calcium FOOD serving size (g) estimate CA content (mg) percentage absorption (%) Ca per serving (mg) Milk Beans, pinto Beans, red Beans, white Bok Choy Broccoli Cheddar cheese Chinese mustard greens Juice, Ca-fortified Kale Soymilk, Ca-fortified Spinach 240 86 172 110 85 71 42 85 240 85 240 85 300 44.7 40.5 113 79 35 303 212 300 61 300 115 32.2 26.7 24.4 21.8 53.8 61.3 32.1 40.2 32.1 49.3 23.7 5.1 96.3 11.9 9.9 24.7 42.5 21.5 97.2 85.3 96.2 30.1 71.1 5.9 MINERAL NUTRITION Nutrient Impact on Intestinal Ca Absorption and Renal Ca Excretion Vitamin D - most critical factor - necessary for the active transport of Ca across the intestinal mucosa Protein - protein is a major bulk constituent of bone must be regularly supplied by the diet (low protein diets- elevated PTH; protein intake associated with higher BMD) - protein and Ca balance - studies using purified protein: 1 mg rise in urinary Ca excretion for each 1 g of ingested protein Sulfur containing AA - acid load- increase Ca excretion Phosphorus in protein-rich foods has a hypocalciuric effect - studies using whole food protein (meat, dairy): no rise in urine Ca - Kerstetter et al. 1998: high protein intake increases Ca absorption MINERAL NUTRITION Nutrient Impact on Intestinal Ca Absorption and Renal Ca Excretion Phosphorus - Bone mineral is predominantly Calcium Phosphate and adequate dietary phosphate (Pi) is essential for bone Effect of dietary Pi (Soda, additives, preservatives) - iurinary Ca losses -iCa absorption Children who drink Soda instead of milk get depleted in Calcium Ca supplements containing Phosphorus (Tricalcium Phosphate, Dicalcium Phosphate) have a diminishing effects on Ca absorption compared to supplements without Phosphate Caffeine - short-term increase in urinary Calcium (diuretic effect?) - daily consumption of caffeine equivalent to 2-3 cups of coffee accelerated bone loss from the spine and total body in postmenopausal women who consumed < 744 mg Ca/day maybe small decrease in Ca absorption or confounding factor: inverse association between milk intake and caffeine intake MINERAL NUTRITION Nutrient Impact on Intestinal Ca Absorption and Renal Ca Excretion Sodium - major determinant of urinary Ca is urinary Sodium urinary Sodium reflects mainly dietary Sodium excessive Sodium (NaCl) increases urinary Ca excretion Sodium and Calcium share some of the same transport systems in the proximal tubule: - each 1000 mmol (2.3 g) increase of Sodium excreted pulls out 0.6-1.0 mmol (20-40 mg) Ca Herbal seasoning instead substantial use of salt reduces calciuria Potassium - for each 100 mg of Potassium ingested, 15 mg Ca is conserved Calcium status is negatively impacted by an acid residue ALKALINE RESIDUE from Mg & K RICH INTAKE INHIBITS BONE RESORPTION MINERAL NUTRITION Calcium Nutrition Calcium not a typical nutrient - critical biochemical roles - inexhaustible reserve - amount absorbed and retained depends on physiological state Calcium requirements for bone health throughout life = not uniform - changes in skeletal growth - age-related changes in absorption and excretion RCT: increased Ca intake results in: increased Ca balance and increased bone gain during growth, reduced bone loss in later years, reduced fracture incidence Ca requirements based on maximal Calcium retention - DRI: Adequate Intake (AI) 9-13 years & 14-18 years: 1300 mg Adult: 1000 mg Elderly: 1200 mg MINERAL NUTRITION Infancy The rate of Ca deposition in relation to body size higher than at any other period during life Childhood and adolescence Rate of growth slows between 2 and 8 years Between 9 and 17 years, approx 45% of the adult skeleton is acquired, the rate is not uniform Maximal growth: girls 12-14 years boys 14-16 years Regulators of the pubertal growth spurt and skeletal maturation: - Insulin-like Growth Factor–1 - sex steroid hormones Peak bone mass = end of the phase of bone consolidation = the maximum amount of bone accumulated Girls, women, 90% of total body mineral content by age 16.9 99% of total body mineral content by age 22 years ADOLESCENCE The main determinant of bone density in adolescent girl is Ca intake. Other lifestyle choices that affect peak bone mass: - physical activity - intake of other nutrients that affect Ca balance - anorexia - substance abuse Beyond the timing of peak bone mass, lifestyle choices can affect the rate of bone loss, but the window of opportunity to build bone has passed. MINERAL NUTRITION - total body bone mass- relatively constant over the reproductive years Age-related bone loss - varies with the individual - most rapid during the first 3 years after menopause in women The average adult loses bone at a rate of approx 1% year Causes: declining Ca intakes, decreased efficiency of Ca conservation, declining physical activity, decreased level of gonadal hormones, decreased circulating levels of 1.25 (OH)2 D, increased intestinal resistance to 1.25 (OH)2D Results: - decreases in Ca absorption - increases in urinary Ca Ca intake required to prevent bone loss are sufficient to protect against the risk of HTN ( 500-600 mg/day) MINERAL NUTRITION Pregnancy During the third trimester 200mg/day of Ca – required for fetal growth The mother’s Ca absorption increases beginning the second trimester - to meet fetal demands - to store Ca for the lactation period Lactation Ca transfer to breast milk varies with changes in volume Breast milk concentration is relatively constant (280±26 mg/L) - independent of the Ca content of the mother’s diet Daily Calcium transfer from maternal serum to breast milk : at 3 months following parturition 168 mg/d at 6 months following parturition 280 mg/d Increased Ca absorption at the end of pregnancy gradually disappears after childbirth and during lactation period Some renal conservation occurs, but maternal skeleton is depleted at a rate of 1% per month This loss - not prevented with Ca and Vitamin D supplementation A post lactation anabolic phase allows recovery of bone density to pre lactation levels. MINERAL NUTRITION Adequacy of Calcium intake Assessing a person’s usual Ca intake – many errors - food frequency questionnaire - diet recalls - diet records - duplicate plate analysis Hidden Calcium taken in as food additives, water, fortified foods, components of pharmaceutics Upper tolerable limit, UI = 2500 mg/day Adequate Intake (AI) for Calcium Males (mg/day) Females (mg/day) 0-6 months 210 210 Infants 7-12 months 270 270 Children 1-3 years 500 500 Children 4-8 years 800 800 Children 9-13 years 1,300 1,300 Adolescents 14-18 years 1,300 1,300 Adults 19-50 years 1,000 1,000 Adults 51 years and older 1,200 1,200 Pregnancy 18 years and younger - 1,300 Pregnancy 19 years and older - 1,000 Breastfeeding 18 years and younger - 1,300 Breastfeeding 19 years and older - 1,000 Life Stage Age Infants MINERAL NUTRITION MINERAL NUTRITION Assessment of Calcium status Total body bone mineral estimation - dual energy X-ray absorptiometry (DEXA) Interpretation of the results: reserve = low - nutritional causes - other: lack of adequate PA, weight loss gonadal hormone deficiency, medical diseases & their treatments Serum Ca – total - ionized Low serum Ca – usually, means some abnormalities of PTH - rarely, because of dietary Calcium deficiency MINERAL NUTRITION Calcium toxicity Elevation of blood Calcium level = Hypercalcemia Reasons: - overconsumption of Calcium - elevation of urine Calcium excretion to the point that either the kidneys calcify or renal stones develop Hyper Ca : lax muscle tone, constipation, polyuria, nausea, confusion, coma, death Never occurs from ingestion of natural food sources Results with ingestion of large quantities of Calcium as supplements taken with absorbable alkali: h urinary pH predisposes to Ca deposits in the kidneys Milk alkali syndrome - in the treatment of Peptic Ulcers with large quantities of milk, CaCO3 and NaHCO3 CALCIUM TOXICITY - NERVE CELL MINERAL NUTRITION Calcium toxicity High Ca intakes contribute to kidney stone formation in susceptible persons. Ca oxalate – the most common form of kidney stones in the US Studies: high oxalate intake and reduced fluid consumption appear to be more of a risk factor in the formation of kidney stones than Ca in most individuals Urinary oxalate excretion - more important risk factor for stones that urinary Ca excretion In general, the stone problem is helped by increasing Ca intake a high-Ca diet: binds oxalate of dietary origin in the gut and prevents its absorption, thereby reducing urinary oxalate load References: 5 ICVN, Loma Linda USA, 2008 Modern Nutrition in Health and Disease, Shils, 10th edition www.pcrm.org www. Pubmed.org QUESTIONS? QUESTIONS? QUESTIONS? QUESTIONS? QUESTIONS? QUESTIONS? QUESTIONS? QUESTIONS? QUESTIONS? QUESTIONS? QUESTIONS?