What is the most prevalent cation in the body (1-1.3 Kg) that makes up 99% skeletal and 1% extracellular fluid and soft tissue?
What are the serum fractions of calcium?
- 1. 50% free, aka ionized calcium (iCa, bioactive form)
- 2. 10% complexed (bicarb, lactate, citrate, phosphate)
- 3. 40% ion bonded to protein (primarily albumin)
What is the total calcium reference range?
8.5 – 10.4 mg/dL
What is the ionized (free) calcium reference range?
What factors influence ionized calcium levels to vary?
- - pH—lower pH means more hydrogen ions that push calcium off of proteins, increasing highelr levels of free ionized calcium
- - albumin or total protein does not affect levels of ionized calcium
What are the functions of calcium?
- - skeletal mineralization
- - blood coagulation
- - neural transmission
- - enzyme activity
- - muscle tone
- - skeletal/cardiac muscle excitability
How much Phosphorous/Phosphate is in the body and what/where is the percentage distributed?
- - 700 – 800 g in the body
- - 85% skeletal, 15% extracellular fluid / intracellular.
What form of phosphate is being measured when the sample is from the blood?
What is the reference range for phosphate?
What is the total approximation of magnesium in the body?
What is the percent distribution of magnesium in the body?
- -55% skeletal
- -45% intracellular
- -1% extracellular
What is the major role of magnesium?
a cofactor that controls potassium levels.
What can happen if levels of magnesium are low?
Hypokalemia can occur due to hypomagnesemia and will require replacement of both potassium and magnesium.
What is magnesiums relationship with calcium in regards to neuromuscular synapses?
Magnesium competes with calcium for reuptake in neuromuscular synapses. Decreased magnesium allows for increased rate of calcium reuptake, and thus increased excitability.
What do Ca, Mg, and PO4 concentrations depend on.
- -net balance of bone deposition
- -bone resorption
- -intestinal absorption of ions
- -renal excretion of ions
Ca and PO4 are hormonally controlled by which products?
- -parathyroid hormone (PTH)
- -vitamin D
How does ionized calcium affect the control of calcium levels?
- -control of calcium levels is based on iCal
- -The body supplies adequate ionized calcium at the cost of bone mineralization.
- -Adequate Ca in the diet is key in preventing the development of osteoporosis.
What is the avg daily intake of calcium?
What percent of the daily intake of calcium is absorbed? How much is secreted back into the intestine?
What is the recommended daily intake of calcium?
-1000 mg/day to 1200 mg (women >50; men >70; pregnant women or breastfeeding.
Where is calcium absorbed and what may inhibit its absorption?
- -Calcium is absorbed in small fractions in the small intestine
- -Calcium absorption is dependent on age; decreases with old age
- -phytic acid (cereal/grains) and oxalate inhibit calcium absorption
What can cause an increase in calcium absorption rates?
- -growth hormone
- -pregnancy and lactation
How much calcium do we excrete on avg?
From deficits over time, where would a source of calcium come from if not supplemented?
mineralized bone calcium
What is the bone mineral of greatest dietary concern?
Calcium. Phosphate and Magnesium are normally in adequate amounts.
The body responds to low iCa levels through the actions of which two products?
-Parathyroid hormone and Vitamin D
What are the functions of PTH?
- -stimulates osteoclasts to resorb bone
- -promotes renal Ca reabsorption/inhibits renal PO4 reabsorption
- -causes kidneys to produce 1,25-(OH)2 Vitamin D
What are the functions of Vitamin D?
- -Stimulating osteoclasts to resorb bone
- -promotes renal PO4 reabsorption (opposing PTH)
- -Increases absorption of dietary Ca
- -Directly inhibits PTH synthesis/release, as well as its own synthesis
Where are parathyroid cells created, stored and ultimately released by?
Chief cells in the parathyroid glands.
Where are the parathyroid glands located?
On the posterior surface of the thyroid gland.
How many amino acids make up PTH and what larger protein is it derived from??
- a. 84
- b. Pre-pro-PTH (115 aa) —> Pro-PTH —> PTH
What is the relationship between Parathyroid and calcium?
- a. Parathyroid glands have calcium receptors that monitor ionized calcium levels.
- b. As ionized calcium drops, PTH synthesis increases, and vise versa.
What is the plasma half-life of PTH? What is the reason for this half-life?
- a. 5 minutes or less
- b. PTH is quickly metabolized by the liver and kidneys.
What cell is activated by PTH directed bone resorption using an intermediate signaling step through osteoblasts?
What is an osteoclast?
A type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone (bone resorption).
What is an osteoblast?
Mononucleate cells that are responsible for bone formation; specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.
What is the cascade that leads to osteoclast activation?
- -Decreased ionized calcium
- -increased PTH
- -RANKL (RANK ligand secreted by osteoblasts)
- -RANK (receptor on osteoclast that binds with RANKL)
- -Osteoclast differentiation/activation (from RANK/RANKL binding)
What is RANK and what is its function?
- -RANK (NF-kB) transcription factor that translocates from the cytosol to the nucleus upon activation.
- -promotes osteoclast formation and activity, and suppresses osteoclast apoptosis.
What is bone resorption?
The breakdown of bone, usually by osteoclasts
What is released into the extracellular fluid during the resorption of bone matrix by osteoclasts?
Calcium and PO4
Where do obtain Vitamin D from?
Either diet or when provitamin D3 is exposed to UV/sunlight.
What is cholecalciferol?
What is ergosterol?
Which vitamin D occurs naturally in fungi and some plants?
Which form of vitamin D is available in supplements?
Both Vitamin D2 and D3
Which version of Vitamin D is the analyte of choice for Vitamin D assays?
Where does hydroxylation of vitamin D3 to 25(OH) occur?
What metabolite of vitamin D is active and which is inactive?
- -25(OH) is inactive
- -1,25 (OH) is active
Which metabolite of Vitamin D is the preferred analyte of measurement and why?
25(OH) is the preferred choice due to its long half. Does not hormonally signal.
What is the function of 1-alpha hydroxylase and where is it found?
1-alpha hydroxylase is found in the kidneys and catalyzes the conversion of 25(OH) Vit D to 1,25(OH)2 Vit D which is the bioactive shorter lived version.
What two factors stimulate th production of 1,25(OH)2-Vit D?
PTH and low PO4.
What factors inhibit the synthesis of bioactive Vit D?
- -high ionized calcium
Where are alternative sites of 1-alpha hydroxylase expression?
- -granulomatous tissue (replacement tissue at wound sites)
Which disease is characteristic of small nodules of granulomatous tissue distributed in various organs and cells that produce 1,25(OH)2VitD? What happens if this condition goes untreated?
- a. Sarcoidosis
- b. The production of a,25(OH)2 is unregulated and will lead to hypercalcemia from constant stimulus.
What is the reference range for Vitamin D?
What is the insufficiency range for Vitamin D? Deficiency range? Most severe conditions range?
- a. 20-29 ng/mL
- b. <20 ng/mL
- c. <10 ng/mL
What are indicators of Vitamin D toxicity?
requires heavy supplementation to become toxic in the tens of thousands to millions of IUs
What is the major stimulus that regulates calcium absorption from the intestines?
What is the purpose for Vitamin D inducing the creation of intestinal-calcium binding-proteins?
to transport calcium across enterocytes.
How does Vitamin D affect osteoclasts?
- -Helps drive differentiation of osteoclast precursors (from moncyte/macrophage lineage) to mature, osteoclasts.
- -also induces osteoblast signaling/cytokines.
What analyte opposes the decrease in phosphate reabsorption caused by PTH?
What 32 amino acid peptide is synthesized and secreted by C-cells (parafollicular cells) of the thyroid gland?
What affect does calcitonin have on PTH, Vitamin D, iCa and PO4?
- Calcitonin can have hormonal effects:
- -inhibits PTH/VitD
- -increases bone deposition by blockin osteoclast activity
- -lowers plasma iCa and PO4 (reducing intestinal absorption and blocking renal absorption)
What are the symptoms of hypercalcemia?
- -neuromuscular effects
- -diminished mental capacity
What is the primary cause of hypercalcemia?
- Hyperparathyroidism with malignant neoplasms
- -account for 90%
What is the prevalence of hyperparathyroidism and what group is the most common to have it?
- - 1 in 1,000
- - women are 3xs more common to have it (especially post-menopausal)
What is the most likely cause of hyperparathyroidism?
adenoma (benign tumor of gland) of a single parathyroid gland, multiple gland dysfunction, or carcinoma
What are the rare cases of primary hyperparathyroidism involving men?
- -multiple endocrine neoplasia
- -gene mutations leading to parathyroid tumors
How is PTH used to determine adenomas in surgery?
- PTH has a short half life so it can be used to determine surgical effectiveness to get a baseline on a 0-20 minute sample.
- If PTH does not drop as expected, it may mean part of the tumor remains.
What is the most common cause of hypercalcemia if the parathyroid glands are normal?
What is PTHrP (Parathyroid Hormone Related Protein) and what is its function?
- -Protein expressed by tumors in the bone or ectopic from bone.
- -a hormone controlling bone resorption for tooth eruption and development/function of mammary glands
How is PTHrP related to PTH and what disease state is it connected with?
- -PTHrP is structurally similar to PTH due to the N-terminus thus duplicating its hormonal effects causing hypercalcemia when expressed in tumors
- -responsible for 50-66% of all breast cancer and some lung.
What are the symptoms of hypocalcemia?
- -tetany/muscle seizures
What is calciums affect on action potentials?
- Calcium limits depolarization of nerves which will limit action potential overall.
- During hypocalcemia, repolarization is delayed and action potentials are elongated.
What are the causes of hypocalcemia?
- –Hypoparathyroid (Destruction in surgery/DiGeorge syndrome/autoimmune
- –Vitamin D deficiencies (less absorption from diet, e.g.)
- –Secondary Hyperparathyroidism
- –Pseudohyperparathyroidism: genetic problem with cell signaling downstream of PTH receptor, very rare
Why would the skeleton and kidney's resist PTH when there is increased production of PTH due to Hypocalcemia?
- due to inability to produce a,25(OH)2VitD via
- -chronic renal failure
- -severe Vitamin D deficiencies (e.g. osteomalacia/rickets, malabsorption disorders)
- -PTH demineralizes bone but can't induce phosphate excretion in kidneys. High levels of calcium and phosphate together result in extraskeletal precipitation (further lowering of calcium) of calcium. (dangerous on cardiovascular system)
What factors serve to keep parathyroid glands producing more PTH in a vicious cycle?
- -diminished 1,25(OH)2VitD