Calcium Homeostasis and Hormonal Regulation
Most prevalent metabolic bone disease in adults:
Osteoporosis
Familial Hypocalciuric Hypercalcemia:
-Benign condition -Germline mutation of CSR -Stable, mild hypercalcemia from birth -Hypocalciuria
Vitamin D:
-A hormone, not actually a vitamin -Shares striking similarities in origin with steroid hormones: it is a metabolic product of cholesterol synthetic pathway -Synthesis begins in skin, where 7- dehydrocholesterol is transformed to vitamin D3 by action of ultraviolet light. -Can also be obtained from dietary sources: fortified milk, multivitamins, cod liver oil
Medications That Affect Calcium Metabolism:
-Antiresorptive agents -Medications that stimulate bone resorption -Lithium -Thiazide diuretics -Recombinant human parathyroid hormone
Functions of Parathyroid Hormone (PTH):
* All functions raise blood calcium & are mediated via a specific PTH receptor. •Stimulates bone resorption release of calcium into blood •Acts on kidney to increase fractional reabsorption of renal tubular calcium & drive production of active metabolite •Promotes intestinal absorption of calcium
Osteoporosis
*Most prevalent metabolic bone disease in adults *Affects estimated 20-25 million Americans, with 4:1 female:male predominance
Signs and symptoms of hypercalcemia:
-CNS:lethargy, decreased alertness, depression, confusion, forgetfulness, coma -GI:anorexia, constipation, nausea & vomiting -Renal:impairs kidney's ability to concentrate urine, leading to dehydration, increased risk of kidney stones -Skeletal:increased bone resorption, increased bone demineralization & risk of fracture -Cardiovascular:causes or exacerbates hypertension
Treatment of osteoporosis:
-Directed at primary consequence of disease: fracture -Modification of preventable risk factors, such as smoking & alcohol consumption -Evaluation of fall risk -Consideration of walkers, hand rails, night lights, hip pads -Adequate dietary calcium & vitamin D -Prevention for those with family history: minimize bone loss, increase bone density, & prevent fracture -Medication
Role of Kidneys in Calcium Metabolism:
-Diseased kidney impairs calcium metabolism. -PHPT, calcium kidney stones
GI Physiology and Calcium Metabolism:
-Factors required for calcium absorption •Normal intestinal function (short bowel syndrome & genetic or physiologic defects may have negative effect) •Adequate dietary calcium intake •Normal vitamin D availability & metabolism
Endocrine Causes of Hypocalcemia:
-Hypoparathyroidism as a result of: •Neck surgery •Autoimmune destruction of parathyroid tissue •Mutations in PTH gene •Abnormal deposition of copper/aluminum in parathyroids •Magnesium deficiency -Pseudohypoparathyroidism (lack of responsiveness to PTH) -Hypovitaminosis D -Tertiary hyperparathyroidism
Organ System Causes of Hypocalcemia:
-Intestinal disorders resulting in inadequate calcium or vitamin D absorption •Short bowel syndrome, dumping syndrome, celiac sprue •Threaten hypocalcemia, increased PTH secretion -Renal insufficiency/failure •As a result of hyperphosphatemia & defective metabolism of vitamin D -Genetic defects resulting in impaired ability to recover filtered calcium from tubular fluid
Organ System Causes of Hypercalcemia:
-Milk-alkali syndrome (Burnett's syndrome) -Renal failure
Signs and symptoms of hypocalcemia:
-Neuromuscular: tetany in hands, feet, legs, back; numbness & tingling in face, hands, & feet -CNS:irritability, seizures, personality changes, impaired intellectual functioning -Cardiovascular:QT prolongation, electromechanical dissociation
Causes of hypercalcemia:
-PHPT—most common -Secondary and tertiary hyperparathyroidism -CSR (calcium sensing receptor) abnormalities -Other endocrine disorders -Cancer-mediated hypercalcemia -Granulomatous diseases -Medications -Renal disease, others -Hyperthyroidism -Addison's disease, Addisonian crisis
Medications That Can Cause Hypercalcemia:
-Thiazide diuretics •Used to treat hypertension •Causes retention of glomerularly filtered calcium -Lithium •Used to treat bipolar affective disorder •Appears to shift "set point" at calcium- sensing receptor -Vitamin A •Believed to activate osteoclasts & enhance bone resorption, elevating blood calcium; PTH & 1,25(OH)2D are suppressed
Causes of hypocalcemia:
-Parathyroid glands, when functioning properly, will not only correct falling blood calcium but also prevent it by increasing PTH secretion. -Compensatory rise in PTH secretion is known as secondary hyperparathyroidism.
Endocrine Causes of Hypercalcemia:
-Primary hyperparathyroidism -Hypervitaminosis D -Cancers (PTHrP), tumors
Parathyroid Hormone (PTH):
-Secreted from 4 parathyroid glands near thyroid -Parathyroid glands have calcium-sensing receptors that respond to calcium levels by increasing or decreasing PTH secretion.
Adult human body contains _________ of calcium
1000 g
Diagnosis of Osteoporosis:
Based on clinical characteristics and/or a DEXA scan
Vitamin A:
Believed to activate osteoclasts & enhance bone resorption, elevating blood calcium; PTH & 1,25(OH)2D are suppressed
Hypercalcemia:
Blood calcium levels above expected normal range •Binding of calcium to other substances must be taken into account when considering total calcium levels.
Cancers (PTHrP), tumors:
Cause release of hormones or hormone-like substances
Rickets and Osteomalacia:
Caused by abnormal bone mineralization & vitamin D deficiency
Hypervitaminosis D:
Caused by excessive intake of vitamin D or aberrant production of 1,25(OH)2D
Bone turnover (remodeling):
Coupled process of simultaneous bone formation & breakdown occurring throughout life
What is the most common cause of hypercalcemia in outpatient setting?
PHPT = primary hyperparathyroidism
What is the only source of calcium?
The diet
What is the only "out" of calcium?
Urine output
Trabecular bone:
axial skeleton (vertebrae); has many cross-hair type connections (trabeculae), providing strength & elasticity
When resorption exceeds formation, bone mass _____________ and causes an increased risk of fracture.
decreases
Fragility fracture:
fracture occurring at an inappropriate degree of trauma
Tissues Vitamin D affects:
gut, bone, parathyroids
Patient with _____ serum albumin would be expected to have _____ total calcium & ___________ ionized calcium.
low low normal
Bone formation is mediated by:
osteoblasts
Bone breakdown (resorption) is mediated by:
osteoclasts
Cortical bone:
primary type in long bones (femur); strong, rigid
Tissues involved in synthesis of Vitamin D:
skin, liver, kidneys
Milk-alkali syndrome (Burnett's syndrome):
•From ingestion of large amounts of calcium together with an absorbable alkali •PTH level is low
-Primary hyperparathyroidism
•Most common cause of hypercalcemia in outpatient setting •Physiologic defect in parathyroid glands Results from adenoma(s) or hyperplasia of parathyroid glands
Osteomalacia:
•Occurs in bone in adults (after closure of epiphyseal plates) •No bony deformities
Rickets:
•Occurs in growing bone (in children) •Bony deformities from bending of long bones due to gravity
Features that distinguish secondary hyperparathyroidism from primary:
•Parathyroids are functioning properly; increased PTH is appropriate mechanism. •Treatment involves identifying & correcting process threatening hypocalcemia, not removal of parathyroid(s).
Renal failure as a cause hypercalcemia:
•Renal excretion of both calcium & phosphate is severely impaired. •Production of active form of vitamin D is limited. •PTH secretion is stimulated
Calcium Homeostasis:
•Serum calcium maintains at a constant level •Cellular & tissue effects of calcium depend on blood calcium maintenance within a specific range •Adult human body contains 1,000 g of calcium -99% as hydroxyapatite salt -1% in extra-cellular fluids -Diet is only source of calcium-Urine is only significant "way out"
Hypocalcemia:
•State of blood calcium levels below expected range •Best measured by ionized calcium
Lithium:
•Used to treat bipolar affective disorder •Appears to shift "set point" at calcium- sensing receptor
Thiazide diuretics:
•Used to treat hypertension •Causes retention of glomerularly filtered calcium