Electrolyte Imbalances: Calcium, Phosphate & Magnesium

• Hypocalcemia is a lower-than-normal calcium level, often due to vitamin D deficiency, hypoparathyroidism, or chronic renal failure.
• Hypercalcemia is an elevated level of calcium in the blood, possibly from hyperparathyroidism, malignancy, or excessive vitamin D intake.
• Hypermagnesemia is an excess of magnesium in the blood, which may be caused by renal failure or excessive magnesium intake.
• Hypomagnesemia is a deficiency of magnesium, commonly seen in alcoholism, malabsorption disorders, and renal disease.
• Hyperphosphatemia is an increased phosphate level, frequently associated with renal failure, hypoparathyroidism, or excessive vitamin D intake.
• Hypophosphatemia is a decreased phosphate level, often due to hyperparathyroidism, malnutrition, or chronic alcoholism.
• Ionized calcium is the biologically active form of calcium in the blood while non-ionized calcium refers to calcium bound to proteins or other molecules, making it physiologically inactive.
• Calcium is essential for bone structure, muscle contraction, nerve function, blood coagulation, and enzymatic activity.
• Magnesium acts as an enzyme cofactor and is important for bone structure.
• Phosphate is incorporated into bone, nucleic acids/phospholipids, phosphoproteins/ATP.
• Vitamin D regulates calcium and phosphate homeostasis by promoting intestinal absorption, bone resorption, and renal reabsorption.
• Approximately 50% of calcium in the blood is ionized and physiologically active.
• Approximately 40% of calcium is protein-bound, mostly to albumin.
• Approximately 10% of calcium is complexed with citrate or phosphate.
• Parathyroid hormone (PTH) increases calcium levels by stimulating bone break down/resorption, enhancing renal calcium reabsorption, and promoting vitamin D activation for increased intestinal calcium absorption.
• PTH decreases phosphate levels by increasing renal phosphate excretion.
• Calcitonin is secreted by the thyroid gland when calcium levels are too high, it lowers calcium levels by inhibiting bone resorption, stimulating osteoblast activity, stopping intestinal absorption and increasing kidney calcium excretion.
• Decreased calcium or magnesium, or increased phosphate leads to PTH secretion signaled.
• Increased calcium or decrease magnesium results in PTH halt.
• Increased Phosphate reduces phosphate and PTH leads to decreased phosphate.
• Magnesium kidney regulation involves thyroxine, aldosterone, and PTH.
• Magnesium is absorbed from the diet in meat and green vegetables in the upper intestine.

Abnormal Calcium, Phosphate, Magnesium, Parathyroid Hormone and Vitamin D Concentrations

• Primary hyperparathyroidism results in high calcium due to inappropriate PTH secretion.
• Secondary hyperparathyroidism results in low calcium due to renal disease, intestinal malabsorption, or vitamin D deficiency.
• Hypoparathyroidism can be caused by injury or trauma to thyroid gland resulting in hypocalcemia and hyperphosphatemia.
• Hypercalcemia can result in calcium deposits in bad places.
• Conditions like Primary hyperparathyroidism, milk alkali syndrome (antacids), PTH-secreting cancers, hyperthyroidism, Addison's disease (adrenal insufficiency), vitamin D overdose, and FHH can lead to hypercalcemia.
• Hypocalcemia can lead to tetany where muscles can't relax.
• Conditions like decreased total protein resulting in decreased protein-bound calcium causing more free circulating calcium stimulating calcitonin and decrease calcium, chronic renal failure causing loss protein and vitamin D3 activation, hypoparathyroidism, dietary insufficiency, and vitamin D deficiency can lead to hypocalcemia.
• Hyperphosphatemia can be caused by hypocalcemia, bone metastasis, hypoparathyroidism, renal failure, or vitamin D intoxication.
• Hypophosphatemia can be caused by decreased reabsorption by kidneys, hyperparathyroidism, or starvation & malabsorption.
• Chronic kidney disease presents with hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism.
• Vitamin D deficiency results in hypocalcemia and secondary hyperparathyroidism.
• Hypomagnesemia can be a symptom of alcoholism or laxative use associated with tetany.
• Hypermagnesemia can be a symptom of renal disease, dehydration, laxative use, or bone metastases that causes neuromuscular defects.

Vitamin D Synthesis and Activation

• Vitamin D is obtained through diet and skin synthesis (from cholesterol) upon UVB exposure
• It goes next to the liver to be 25-hydroxyvitamin D
• It gets activated in the kidney into 1,25-dihydroxyvitamin D, which facilitates calcium and phosphate absorption.
• Increased blood pH enhances calcium binding to proteins, reducing ionized calcium levels and releasing PTH.
• Decreased pH decreases protein binding, increasing ionized calcium and halting PTH release.
• Low plasma protein levels reduce total calcium but do not significantly affect ionized calcium.

Specimen Collection

• Serum is the preferred specimen for calcium, phosphate, and magnesium analysis.
• Use liquid heparin only, and not EDTA, oxalate, or citrate (chelate Ca2+).
• Samples exposed to air increase sample pH due to loss of CO2, which matters in ionized Ca
• Patients should fast before collection.
• Serum, heparin plasma, and 24-hour urine are used for phosphate analysis.
• Avoid hemolyzed samples (phosphate in RBCs), soap contamination, icteric, or lipemia
• Separate from RBCs as soon as possible
• Serum and lithium heparin are used for magnesium anlaysis
• Do not use oxalate or EDTA tubes.
• Separate RBCs as soon as possible, and avoid hemolysis.

Specimen Collection Errors

• Hemolysis falsely increases phosphate and magnesium levels.
• Delayed centrifugation leads to phosphate diffusion from RBCs, causing falsely high results.
• EDTA/citrate/oxalate tubes bind calcium and magnesium, leading to falsely low levels.
• Colorimetric assays are commonly used- arsenazo III or CPC for calcium, ammonium molybdate for phosphate, and calmagite for magnesium.

Total Calcium Methods

• Arsenzao - Calcium + arsenazo turns into Calcium-arsenazo complex (purple color) at acid pH.
• Orthocresolphthalein complexone - Calcium + CPC turns into a Calcium - CPC complex (purple color) at acid pH, and acid releases protein-bound calcium.

Reference Ranges

• Total calcium reference interval: 8.5-10.5 mg/dL (2.12-2.62 mmol/L)
• Critical values (total calcium) ≤ 6.4 mg/dL or ≥ 13.0 mg/dL
• Ionized calcium should be done if patient has protein or pH issues.

Ionized Calcium

• Measurement uses Ion specific electrode with gel ion exchange membrane specific for Ca2+
• 4.4-5.2 is the normal mg/dL range
• Perform this test if there is loss cardiac/neuromuscular function, massive transfusions, renal failure, neonates, critically ill patients.
• Phosphate measurement involves measuring loss of color or molybdenum blue.
• Total calcium reference range: 8.5-10.5 mg/dL and Critival Values are: ≤6.4 mg/dL or ≥13.0 mg/dL.
• Ionized calcium is measured in critically ill patients, those with acid-base imbalances, massive transfusions, renal failure, and neonates.
• Bone formation is the process of osteoblasts synthesizing collagen and minerals to build bone.
• Bone resorption is the process of osteoclasts breaking down bone to release calcium and phosphate.
• Alkaline phosphatase marks bone formation, measured by enzymatic assays.
• Osteocalcin is produced by osteoblasts and detected by immunoassay.
• Collagen propeptides indicate bone formation
• Collagen metabolites (N-terminal telopeptide, C-terminal telopeptide, pyridinoline, and deoxypyridinoline) are markers reflect bone resorption, and are measured in urine or serum.
• Bone formation markers: Alkaline phosphatase, osteocalcin, and collagen propeptides that are measured in serum.
• Bone resorption markers: N-terminal telopeptide, C-terminal telopeptide, pyridinoline, and deoxypyridinoline that are measured in 24-hour urine.
• They reflect osteoclasts activity and are used to monitor therapy.

Bone Disorders

• Osteoporosis means decreased bone density/mass due to aging, hormonal imbalance, or drug therapies.
• Diagnoses involves a bone density scan and lab tests may show increased bone resorption markers, increased ALP, and increased osteocalcin
• Osteogenesis imperfecta are genetic collagen defects (COL1A1/COL1A2) and it is aka "brittle bone disease"
• Paget disease is an excessive bone turnover, disordered pattern/structure bone made.
• Symp may include bone pain, fractures/deformity and lab results can show increased ALP, nominal calcium/phosphate, and increased uric acid (gout)
• Rickets/osteomalacia (kids/adults): deficiency of vitamin D leading to calcium and weak bones where kids have bowing/bending bones typically.
• Labs may show increased ALP, decreased calcium, increased PTH, nominal/decreased Phosphate, and decreased vit D

Joints

• A joint is a connection between two bones.
• Fibrous joints (e.g., skull sutures) allow no movement
• Cartilaginous joints (e.g., intervertebral discs) allow limited movement
• Synovial joints (e.g., knee) allow free movement
• Osteoarthritis: mechanical wear causing degenerative cartilage loss and is more common in obese, presenting with joint pain.
• Diagnosis involves radiology.
• Rheumatoid arthritis: autoimmune disease where ab attack cartilage, bone on bone rubbing= inflammation
• Labs will show increased RF and anti-CCP.
• Ankylosing spondylitis is a chronic, systemic inflammatory spinal disease presenting with slow onset (get better after morning/movement), and possible eye inflammation
• Lab tests may show HLA-B27 result (good pos predictive value caucasians)
• Gout results when monosodium uric acid crystal deposition in joints, leads to inflammation
• Symp: presents with pain, swelling, redness, big toe most common
• Labs: ↑ serum uric acid, monosodium urate= negative birefringent
• Pseudo gout has pyrophosphate that is pos birefringent