body fluids & electrolytes pt. 2

key components of bone

calcium (Ca²⁺), phosphorus (as phosphate, PO₄^3-), & magnesium (Mg²⁺). calcium is most abundant

bone structure

organic matrix (~30%): gives bone resiliency. inorganic mineral salt (~70%): embedded in the organic matrix, made of hydroxyapatite crystal (calcium & phosphate). 

calcium (Ca²⁺)

bone & teeth formation, nerve & brain function (signal conduction), neuromuscular excitability, muscle contraction, cofactors for blood coagulation & many enzymes. most abundant electrolyte. 99% in bone/teeth, 1% in blood/soft tissue. normal range: 8.6-10 mg/dL (total)

calcium is present in plasma in 3 forms:

1. protein bound (mainly albumin)

2. complexed (anions = phosphate or citrate)

3. ionized or “free” (iCa²⁺), RR: 4.4-5.3 mg/dL, ~47%, the only one that’s physiologically active & is closely regulated (by PTH)

total calcium

affected by serum albumin level (b/c binding): low albumin → low even w/ normal iCa²⁺, high albumin → high even w/ normal iCa²⁺. not affected by acute changes in acid-base balance

ionized calcium

active form. affected by acute changes in acid-base balance b/c pH alters binding to proteins. acidic pH → high b/c H⁺ competes w/ Ca²⁺ for binding sites, less Ca²⁺ bound to proteins. alkaline pH → low b/c less H⁺ competing, more Ca²⁺ is bound to proteins. not affected by changes in albumin

calcium homeostasis

the body’s calcium is in a state of constant flux b/t blood, GI tract, kidney, & bone. maintained by an endocrine system involving 3 hormones & 3 organs

3 major hormones that maintain calcium homeostasis

parathyroid hormone (PTH, most important), vitamin D (important), calcitonin (not as important)

3 organ systems that maintain calcium homeostasis

1. GI tract: vit D inc absorption of dietary Ca²⁺

2. bone: PTH & vit D inc bone resorption (breakdown), releasing Ca²⁺ into blood

3. kidney: PTH inc reabsorption of Ca²⁺ from ultrafiltrate, vit D inc reabsorption of both

parathyroid hormone (PTH)

secreted from parathyroid glands. active portion is where the N-terminal segment is on the single polypeptide chain. most important regulator of plasma Ca²⁺ & phosphate levels. synthesis regulated primarily by plasma Ca²⁺ levels

how does low Ca²⁺ influence PTH secretion?

increase PTH secretion

how does high Ca²⁺ influence PTH secretion?

decrease PTH secretion (negative feedback)

how does PTH increase blood Ca²⁺?

stimulates small intestine to absorb dietary Ca²⁺ (& phosphate) indirectly thru activation of vit D. stimulates bone to inc bone resorption, releasing Ca²⁺ (& phosphate) into blood. stimulates kidney to inc renal reabsorption of Ca²⁺, & dec renal reabsorption of phosphate, activate vit D

why does the kidney decrease renal reabsorption of phosphate to increase blood Ca²⁺?

it lowers blood phosphate levels. inverse relationship between blood Ca²⁺ & phosphate levels

vitamin D (calcitriol)

steroid hormone. cofactor for normal response to PTH, critical for maintaining adequate Ca²⁺ & phosphate levels for proper mineralization of bone. important in neuromuscular/immune systems. from diet & synthesis (needs light). raises blood Ca²⁺

how does vitamin D raise blood Ca²⁺?

acts on small intestine directly to inc Ca²⁺ & phosphate absorption, bone (in concert w/ PTH) to release Ca²⁺ & phosphate from bone, kidney to assist PTH reabsorbing Ca²⁺ & phosphate, thyroid gland to inhibit release of calcitonin

vitamin D synthesis

humans can make it w/ sufficient sun exposure. involves skin, liver, kidneys. UV light transforms 7DC to vit D in skin. vit D hydroxylated to 25-OH vit D (calcifediol) in liver. serum 25-OH can monitor stored vit D. vit D hydroxylated to active form 1,25-(OH)₂ vit D (calcitriol). when blood Ca low, PTH released & stimulates kidneys to inc vit D formation

calcitonin

produced in medulla of thyroid glands. reduces serum Ca²⁺ by affecting bone (blocking bone resorption) & kidney (inhibits renal reabsorption of Ca²⁺ & P). levels do not greatly influence serum Ca²⁺. mainly used to Dx medullary thyroid cancer (very high levels in serum).

how is calcitonin production regulated?

by plasma Ca²⁺ levels. high when Ca²⁺ is high, low when Ca²⁺ is low. ‹

hypocalcemia

total [Ca²⁺] & iCa²⁺ low. critical (panic): total [Ca²⁺] < 6mg/dL. mild to life-threatening. arrhythmias & cardiac arrest. neuromuscular irritability (major): neurologic excitability, tetany. impaired intellectual functioning, psychoses, convulsions if severe. osteoporosis & pathologic fractures if chronic

hypercalcemia

total [Ca²⁺] & iCa²⁺ high. critical (panic): total [Ca²⁺] > 15mg/dL. often asymptomatic. arrhythmias & cardiac arrest. neuromuscular irritability (major): weakness, lethargy. groans (confusion, depression), bone (demineralization/fracture from high resorption), moans (constipation → abdominal pain, N/V), & kidney stones

primary cause of hypocalcemia

problems w/ parathyroid gland: low serum PTH, primarily hypoparathyroidism (thyroidectomy, autoimmune destruction, mutations, etc). low serum PTH → low Ca²⁺& vit D, high P

secondary causes of hypocalcemia

problems independent of parathyroid gland: high serum PTH (secondary hyperparathyroidism). pseudohypoparathyroidism, severe vit D deficiency, chronic kidney dz/failure (most common)

hypocalcemia due to pseudohypoparathyroidism

hereditary lack of response to PTH. low Ca²⁺ & vit D, high P → high serum PTH.

hypocalcemia due to severe vitamin D deficiency

renders PTH ineffective. low vit D → low Ca²⁺ & low P → high serum PTH.

hypocalcemia due to chronic kidney disease (failure)

most common. low vit D activation, high Ca²⁺ renal loss, low P renal excretion. low vit D & Ca²⁺ → high serum PTH. GFR low. high BUN, Cr, urine Ca²⁺. soft tissue calcification (Ca²⁺-P precipitate), Ca²⁺ kidney stones

primary cause of hypercalcemia

problem w/ parathyroid gland: high serum PTH. primary (parathyroid adenoma/hyperplasia, most common) or tertiary hyperparathyroidism. high serum PTH → high Ca²⁺, vit D, urine Ca, urine P, low serum P. kidney Ca²⁺ stone

secondary cause of hypercalcemia

problem independent of parathyroid gland: low serum PTH. malignancy & vitamin D intoxication

hypercalcemia due to malignancy

rapidly progressive. direct invasion of bone, secretion of PTH related peptide (PTHrP) by various tumors (MM). high serum PTHrP → high Ca²⁺, low P, serum PTH, vit D. PTHrP has PTH-like activity, but can be high b/c production not regulated by blood Ca²⁺

hypercalcemia due to vitamin D intoxication

high vit D → high Ca²⁺, P, low serum PTH. Ca²⁺-P precipitated in soft tissues. kidney Ca²⁺ stone

soft tissue calcification

tissue becomes hardened by deposition of calcium salts, which normally occurs in bone/teeth. from abnormal serum Ca or P levels in trophic tissues. conditions a/w these: chronic kidney failure, hyperparathyroidism, selected neoplasms, hypervitaminosis D

tests for calcium disorders

Ca²⁺ & PTH levels. Ca²⁺ (total or i): establish Ca D/O. iCa²⁺: best screening test for Ca D/O. avoid oxalate, citrate, or EDTA (anticoagulant) due to chelating effect (falsely low). albumin, vit D, PTHrP, urea/creatine, alkaline phosphatase, phosphorus & magnesium

PTH measurement

use to determine cause of Ca D/O. specimen type: serum or plasma (green). immunoassay, best method uses Abs that detect both active amino end & intact PTH

low PTH in hypocalcemia

indicative of primary hypoparathyroidism

high PTH in hypocalcemia

indicative of secondary hyperparathyroidism (pseudo-hypoparathyroidism, vit D deficiency, or renal failure)

high PTH in hypercalcemia

indicative of primary hyperparathyroidism

low PTH in hypercalcemia

indicative of secondary hypoparathyroidism (malignancy or vit D intoxication)

albumin test for Ca D/Os

to distinguish true hypo-/hypercalcemia

vitamin D test for Ca D/O

to evaluate hypo-/hypercalcemia & renal failure. serum or plasma (EDTA). method: LC-MS/MS or immunoassay

PTHrP test for Ca D/O

to evaluate hypercalcemia a/w malignancy. method: immunoassay

urea/creatine test for Ca D/O

to assess renal function

alkaline phosphatase test for Ca D/O

to detect high bone turn-over

phosphate

79% in bone, 20% in ICF, <1% in plasma. exists in 3 forms: free form (80%) is active form. bone formation, energy, DNA/RNA synthesis, coenzymes, Hgb function, structure, buffering. plasma concentration controlled by 2 hormones: vit D & PTH

how does vit D affect plasma [PO₄]?

increases it by increasing its GI absorption & bone resorption.

how does PTH affect plasma [PO₄]?

decreases it by increasing renal phosphate excretion (while increasing reabsorption of Ca²⁺). plasma [PO₄] tends to be inversely proportional to [Ca²⁺] (PTH action in kidney & tendency to precipitate)

hypophosphatemia

less common but more damaging. 30% mortality w/ severe (PO₄ < 1mg/dL). affects neuromuscular, muscular, immune system, bone, & CNS.

causes of hypophosphatemia

low GI intake: vit D deficiency (rickets), oral phsophate binders (Ca- antacids), malabsorption (celiac). high renal loss: primary hyperparathyroidism, Fanconi’s (renal tube D/O). high cellular uptake: redistribution w/ insulin or glucose therapy, re-feeding after starvation. multiple causes: chronic alcoholism

hyperphosphatemia

typically asymptomatic. soft tissue calcification: Ca-phosphate precipitation, result in hypocalcemia & high PTH (secondary hyperparahyroidism). tetany: tonic spasm of muscles, from hypocalcemia b/c of calcification

causes of hyperphosphatemia

vitamin D intoxication. low renal excretion (high retention): renal insufficiency/renal failure (common in dialysis), hypoparathyroidism or pseduohypoparathyroidism. cellular release: diseases w/ high cell turnover (ALL). artifactual: hemolysis (phosphate is main intracellular anion)

tests for phosphate disorders

phosphate: serum/plasma (heparin), avoid hemolysis, separate serum/plasma from cells ASAP, urine, spectrophotometry method. Ca²⁺, urea/creatine (kidney function), Mg²⁺, PTH, vit D

magnesium

exists in 3 forms in plasma: free ionized (55%) is active form. major cofactor/activator for many enzymes. required for neuromuscular function, controlling heart rhythm. regulates ATPase ion pumps. component of bone. required for synthesis & secretion of PTH

how is magnesium regulated?

renal control (main). Ca²⁺ & P: hypercalcemia & hypophosphatemia dec renal Mg²⁺ reabsorption, promotes urinary loss. PTH: inc renal Mg²⁺ reabsorption in deficiency states, prevents urinary loss (major). GI absorption in small intestine, PTH enhances

hypomagnesemia

more common. common in critically ill patients, poor prognosis. caused by low intake (malnutrition, seen in alcoholics), redistribution of extracellular Mg to intracellular, high renal loss (primarily drugs, many include diuretics).

signs & symptoms of hypomagnesemia

like those seen in hypocalcemia (largely due to the role Mg plays in neuromuscular function). neuromuscular: tetany (Ca²⁺ normal). cardiovascular: cardiac arrhythmia. muscle: weakness. bone: osteoporosis 

hypermagnesemia

depression of neuromuscular system: respiratory paralysis. cardiac arrest when > 10meg/L. caused by low excretion (renal failure, most common), high intake of Mg²⁺ (medications like excess antacid or laxative intake)

tests for magnesium disorders

Mg²⁺: serum/heparin plasma, fasting preferred, avoid hemolysis (oxalate, citrate, ETDA), separate ASAP, urine. Ca²⁺, urea/creatine

metabolic bone diseases

abnormal bone mineralization caused by mineral or vitamin deficiencies (Ca²⁺, PO₄, or vit D) that result in abnormal bone mass or structure. disorders a/w vit D deficiency. disorders related to bone Ca loss. paget

disorders associated with vitamin D deficiency

low Ca & PO₄ → high PTH. rickets (children): deformed bones. osteomalacia (adults): soft bones

disorders related to bone Ca loss

normal Ca & PO₄. osteoporosis

paget

may have genetic component. imbalance bone remodeling → abnormally large, dense, weak bones

osteoporosis 

normal Ca & PO₄. causes: hereditary tendency (white, asian women), lifestyle (lack of exercise, poor diet, lack of sun), medications (steroids, etc), diseases (Cushing’s, hyperthyroidism, etc). treated with Ca & vit D supplements, drugs to inhibit bone resorption