Calcium Absorption and Bioavailability

Calcium Absorption

• Requires digestion to free it from salt form
• Stomach is effective because of its low pH
• Absorption occurs through active and passive mechanisms
• Active transport is regulated by vitamin D
• Calcium enters enterocytes via TRPV6
• Calbindin transports calcium to the basolateral membrane
• Ca2+ ATPase pumps calcium into the blood
• Calcitriol enhances active transport
• Passive transport occurs between cells and is enhanced by calcitriol
• Dietary calcium absorption is 25-30% which changes if a person is taking supplements to 25-40%

Key Proteins for Calcium Absorption

• TRPV6 transports calcium through the enterocyte
• Calbindin moves calcium to the basolateral membrane
• Calcitriol enhances the absorption process

Factors Affecting Calcium Bioavailability

• Vitamin D
  • Calcitriol enhances calbindin
  • Adequate vitamin D prevents decreased calcium absorption, even with sufficient calcium intake
• Lactose
  • Found in dairy
  • Enhances bioavailability by maintaining solubility
• Proteins
  • Can increase calcium excretion while also increasing intestinal calcium transport
  • Certain amino acids such as lysine and arginine form soluble calcium complexes

Inhibitors of Calcium Bioavailability

• Phytates/Phytic acid
  • Found in whole grains, legumes, and seeds
  • Binds calcium, forming an insoluble complex that can't be absorbed
  • Commonly found in plant-based diets
• Oxalates
  • Found in spinach, rhubarb, beets, and nuts
  • Reduces bioavailability
• Excess phosphorus intake
  • Can reduce bioavailability by forming insoluble calcium phosphate precipitates (calciphylaxis)
• Excessive sodium
  • Competes for reabsorption and increases calcium excretion
• Excessive magnesium and zinc
  • Interfere with absorption and compete for intestinal transport pathways

Other Factors That Affect Absorption

• High calcium levels inhibit non-heme iron, zinc, and magnesium absorption by competing for intestinal transporters, which may cause iron deficiency anemia
• Fat-soluble vitamins and calcium are needed for vitamin K activation and excessive intake can interfere with vitamin K-dependent clotting factors
• Calcium can bind to fluoride, reducing bioavailability

Calcium Transport and Distribution

• Calcium circulates in blood in ionized, protein-bound, and complexed forms
• 40-45% is bound to albumin and acts as a reservoir
• 10% is bound to anion and remains bioavailable
• 45-50% is free and ionized, representing the active form used in:
  • Muscle contraction
  • Nerve signaling
  • Blood clotting
  • General signaling
• Low albumin levels require corrected calcium calculations to accurately reflect calcium status

Calcium Reference Ranges

• Normal range of ionized calcium is 4.6-5.2 mg/dL

Extracellular Regulation

• Normal range of total calcium is 8.5-10.5 mg/dL

Regulation of Calcium Levels

• Intestines: Site of absorption
• Kidney: Regulation through excretion and reabsorption
• Bones: Act as a reservoir
• Hormonal Control
  • PTH increases calcium levels when low
  • Promotes bone resorption to release calcium into the bloodstream
  • Reduces calcium loss in urine by increasing renal calcium reabsorption
  • Vitamin D enhances intestinal absorption
• Calcitonin lowers calcium levels
  • Secreted by the thyroid when calcium levels are too high
  • Inhibits osteoclast activity
  • Increases renal calcium excretion

Calcium Homeostasis

• Low serum calcium stimulates PTH to increase calcium levels, stimulating osteoclasts to break down bone and release calcium into the blood
• PTH activates vitamin D (calcitriol), enhancing calcium absorption in the intestine, and reduces urinary calcium loss
• Calcitonin inhibits urinary excretion of calcium
• High serum calcium inhibits PTH and stimulates calcitonin, which inhibits osteoclast activity, reduces calcium release into the bloodstream, and prompts kidneys to excrete calcium

Calcium Within Cells and Calcium Channels

• Calcium concentration inside cells is lower than outside
• Calcium channels facilitate calcium movement across the cell membrane
  • Voltage-gated channels respond to electrical signals, such as those in muscle cells
  • Ligand-gated channels respond to hormones and neurotransmitters like insulin

Calcium Pumps and Messengers

• ATPase pumps maintain low intracellular calcium levels by moving calcium out of the cytosol into storage sites, such as mitochondria
• In muscle cells, the endoplasmic reticulum (ER) and sarcoplasmic reticulum (SR) store and release calcium when needed
• Calcium triggers muscle contraction by binding to troponin and initiating the sliding filament mechanism

Functions of Calcium

• Osseous role: Bone mineralization via hydroxyapatite
  • Hydroxyapatite creates crystalline structure
  • Peak bone mass development during childhood
• Non-osseous role: Neuromuscular signaling
  • Impaired nerve impulses
  • Acts as signaling molecule in synaptic cleft
  • Can cause damage to the heart
  • Regulates troponin levels
• Contributes to blood coagulation through Factor 4 and the conversion of prothrombin to thrombin and fibrin
• Intracellular signaling via calmodulin involvement
• Regulates hormone secretion
  • Acts as a second messenger
  • Pancreatic beta-cells use calcium to release insulin
  • Impacts PTH, calcitonin, and adrenaline secretion
• Enzymatic reactions
  • Protein kinase and pancreatic lipase activity
• Calmodulin activation
  • Acts as a molecular switch
  • Smooth muscle contraction, blood vessel dilation, and gene expression

Calcium Imbalances

• Hypocalcemia:
  • May result in rickets, secondary hyperparathyroidism, calciphylaxis in renal patients and osteopenia / osteoporosis
  • Symptoms include muscle cramps, arrhythmias, hypertension, seizures, and depression
• Hypercalcemia
• Upper Limit (UL) Considerations
  • UL for adults aged 19-650 is 2500mg, and for adults 51+ is 2000mg
  • Exceeding the UL increases risk of kidney stones and calcium-alkali syndrome

Assessment of Calcium Status

• Corrected calcium is used when albumin levels are low to accurately assess calcium levels Interpreting Calcium Values:
  • Normal serum calcium: 8.5-10.5 mg/dL
  • Normal ionized calcium: 4.6-5.2 mg/dL
• Accurate assessment of active calcium
• Measurements of PTH and vitamin D (calcitriol) are helpful
• DEXA scans assess bone density

Calcium Balance

• Negative calcium balance: More calcium is lost than absorbed, results in osteoporosis and kidney disease
• Positive calcium balance: More calcium is absorbed than excreted, supporting growth and pregnancy

Phosphorus Forms and Sources

• Intracellular
• Free phosphate
• Active form
• Plays a role in energy metabolism and signaling
• Forms and Sources
  • Exists in organic and inorganic forms
  • Free ionic anion
  • Inorganic salts form calcium phosphate
  • Organic forms bind to proteins, nucleic acids, sugars, and phospholipids
• Phytic Acid
  • Phytic acid is a phosphorus form found in grains
  • Humans lack phytase, the enzyme needed to break down phytic acid in grains/legumes into phosphate
  • Relevant in plant-based diets Bioavailability:
  • Animal products is higher at 80%
  • Additives is almost 100% in processed foods
  • Phosphoric acid provides tartness and extends shelf-life
  • Plant source bioavailability is 40-50%
  • Vitamin D enhances phosphorus absorption

Digestion And Absorption Of Phosphorus

• Bound phosphate must be freed during digestion
  • Accomplished by phospholipase C (Zn-dependent) and alkaline phosphatase (Zn-dependent)
• Transporters
  • Transporters like NaPi2b facilitate absorption in the jejunum through passive diffusion
  • Active transport occurs when phosphate levels are low, utilizing NaPi2b, which is abundant in skeletal tissue
  • 1% is present in extracellular fluid (ECF) and 14% in muscles and soft tissues
• Hormonal Influences
  • PTH, stimulated by low calcium levels, causes kidneys to excrete more phosphorus and increase calcium reabsorption from bones
  • Stimulates calcitriol (the active form of vitamin D), which enhances the intestinal absorption of both calcium and phosphate
  • FGF23 is released by osteocytes and calcitonin to inhibit bone breakdown and encourage phosphate excretion
  • Calcitriol is the active form of vitamin D that enhances intestinal absorption of calcium and phosphate

Regulation Of Phosphorus

• PTH promotes phosphate excretion in the urine and increases calcium reabsorption in response to low serum calcium
• FGF23 acts on the kidneys to reduce phosphate reabsorption and suppress calcitriol production, released by osteocytes in response to high phosphate levels
• Functions
  • Bone mineralization
  • ATP/energy metabolism and requires phosphate for ATP (energy storage)
  • Acid-base balance, acting as a buffer to maintain pH Kidneys:
    • Excrete excess hydrogen ions (acidic)
  • DNA/RNA synthesis
  • Cell membranes, specifically phospholipids
  • Oxygen delivery via 23BPG released to release O2 from tissues
• Maintenance
  • The body maintains homeostasis via renal excretion and intestinal absorption

Phosphorus High Levels

• A diet high raises extracellular phosphate (ECF PO42-) levels
• High phosphate levels are detrimental
  • Cytotoxicity
  • Vascular calcification, calcium deposits and calciphylaxis, CVD
• Stimulates PTH and FGF23

Causes Of Deficiencies of Phosphorous

• Hypophosphatemia causes
  • Refeeding syndrome
• Refeeding syndrome
  • Due to rapid uptake by the cells of phosphorus, potassium, and magnesium
  • Is dangerous
  • Serum levels drop after rapid uptake of carbs
  • Reintroducing carbs slowly helps because a large increase in insulin release cellular uptake of phosphates
• Clinical Symptoms
  • Muscular system: Respiratory muscles
  • Numbness
  • Rhabdomyolysis
  • Hemolytic anemia

Toxicity From High Levels Of Phosphorous

• Often related to impaired renal function
• Rare
• Intake levels of 4g (9-70), 3g (>70), 3.5-4g (preg/lac)
• Clinical manifestations stem from secondary effects
  • Hypocalcemia
• Acidosis shifts phosphate from cells into extracellular space
• Assessment
• Limitations of serum phosphorus in detecting true status
  • Fluctuating
  • Is not sensitive or specific
  • Normal level may not indicate adequate PO42-
  • Monitor patient's diet and extracellular serum phosphorus levels (tightly regulated)
  • 2.5-4.5 mg/dL

Magnesium Regulation, Absorption, And Transport

• Regulated by the kidneys
• Absorption and Transport
  • Does not require digestion Two major absorption mechanisms
    • Active (TRPM6) is most active when:
      • Dietary Mg intake is low
      • Occurs in the distal small intestine
      • Uses TRPM6 (brush border membrane)
    • Passive magnesium is most active when
      • Between cells
      • Body allows amount absorbed based on intake
      • Body needs concentrations
      • Mg intake is high
• Modulation and Compensation
  • Magnesium decreases when intake is excessive
  • Is modulated by PO42+ and Potassium

Storage And Distribution

• Predominantly stored in bones, muscle, and soft tissues compared to extracellular fluid
• 50-55% of magnesium is free
• 20-30% is bound to protein
• 5-15% is complexed with charged anions
• Present in Bones and Muscles
  • 50-60% in skeletal (bone) Dynamic Exchange:
    • Plasma Magnesium
    • Abundant in the body
    • Only 1% in Extracellular Fluid ECF
• Muscles
  • 39-49% in skeletal muscle and soft tissue

Magnesium Levels and Functions

• Typical Serum levels is 1.7-2.3 mg/dL
• The normal rate of excretion varies between 3-5 mEq/d or 36-120 mg/d

Magnesium Functions

• Plays numerous roles in enzymatic activity, over 300 reactions
  • Ribosomes
  • Calcium potassium channels
• Responsible for and connects magnesium to
  • Bone mineralization
  • Neuromuscular function
  • ATP stabilization
  • Glycolysis, FA synthesis
  • Chronic disease prevention

Deficiency of Magnesium

• Often found in Hospital patients
• Caused by Alcoholism, GI loss, and medications
• Deficiency and impact
  • Affects PTH, calcium, and potassium levels
  • Hypocalcemia and hypokalemia PTM Secretion:
    • PTH secretion is impaired
• Impacts PTH and Kidneys
  • PTH enhances magnesium reabsorption in the kidneys
• May increase the release of magnesium from the bone
  • Required for Sufficient PTH Magnesium Deficiency:
    • Functional parathyroid state
    • Hypocalcemia

Magnesium Toxicity and Overdose

• Recognize common symptoms, for example:
  • Tetany
  • Muscle cramps
  • Arrhythmias
  • Neurological signs
• Food is Rarely the Cause,
• At-Risk and Impairment
  • Be able to identify risk in renal impairment or excessive supplement intake.
• Daily intake
  • 350 mg/day supplement (non-food)

Assessment of Magnesium

• Why is it not Reliable, for example:
  • Compensatory shifts
  • Affects less than 1% of total body stores
• Other Methods and Tests
  • Be familiar with Urinary exertion and alternative methods
  • 24/hr mg excretion and look for renal and non-renal causes
• Retention Testing
  • Retention load testing
  • A known amount is administered and measured High Retention:
    • Deficiency

Mineral Interactions

• Understand interactions between calcium, magnesium, and phosphorus

Deficiencies:

• How deficiencies affect the others
• Give example: Magnesium deficiency lowers PTH
• Affects calcium
• Application and Knowledge
• Be able to apply knowledge clinically
• Give values or symptoms
• Evaluate likely imbalances
• Effects and Considerations
  • What effects can conditions like CKD, immobilization, diuretic use, and refeeding have on mineral status