REB 7. Calcium Homeostasis Flashcards
What is the source of calcium?
It cannot be produced in the body - must be acquired through diet
What is Hydroxylapatite made up of? What is an example of a use of it?
- made up of calcium and phosphorus
- makes up bone and teeth
What is the most abundant mineral in the human body?
calcium
If there is a deficit in calcium ions what happens?
hyperexcitability of cells
If there is an excess in calcium ions what happens?
increases in contractility
What are the main functions of calcium?
[1] Muscle Contraction + Nerve Excitability
[2] Neurotransmitter + Hormonal Release
[3] Enzyme Function
[4] Blood Coagulation
[5] Structural Support for Healthy Bone and Teeth
[6] Membrane Integrity + Permeability
The regulation of calcium depends on 3 factors which are?
[1] Balance of Intake, Absorption + Excretion
- dietary calcium
- vitamin D
[2] Normal Functioning of…
- Intestine
- Parathyroid Glands
- Kidneys
[3] Hormones
- Parathyroid Hormones (parathyroid gland)
- Calcitonin (thyroid gland)
What are the 2 separate mechanisms of intestinal calcium absorption? What is the difference between the two and where can it be found?
[1] Passive Absorption
- throughout entire small intestine
[2] Active Transport
- localized in small intestine
- dependent on vitamin D metabolite
What is the mechanism/steps by which intestinal absorption occurs?
main goal: absorb calcium from intestinal lumen into blood stream
Steps:
[1] Ca2+ enters from intestinal lumen across apical brush border mediated by CaT1 channel
[2] Ca2+ is transported across the enterocyte by the calcium binding protein, Calbindin
[3] Ca2+ exits across the basolateral membrane - mediated by the Ca2+-ATPase (PMCA1)
What are the factors affecting calcium metabolism?
[1] Dietary Calcium Intake + Urinary Loss
[2] Plasma Hormones + Vitamins
- parathyroid hormone
- calcitonin
- vitamin D (active metabolite)
[3] End-Organ Function
- intestinal tract
- kidneys
- liver
- parathyroid glands
[4] Plasma Concentration
- plasma/albumin concentration
- acid/base changes
What is the function of parathyroid hormone?
[1] increases calcium blood level (Ca2+)
[2] acts on bone, kidney and intestine
[3] increases Ca2+ (and Mg2+) reabsorption from kidney
[4] increases Ca2+, HPO4- and Mg2+ uptake from GI tract into blood
[5] increases activity of osteoclasts (bone resorption)
[6] promote formation of active vitamin D (increases activity of 1-alpha-hydroxylase in kidneys)
What inhibits the parathyroid hormone (PTH) in a negative feedback loop?
increased plasma free ionised Ca2+
What is PTHrP?
Parathyroid Hormone-Related Protein (PRHrP)
Where is PTHrP synthesized?
- it is synthesized by many fetal and adult tissues
- e.g. cartilage, bone, smooth, cardiac and skeletal muscle, skin, breast, intestines, parathyroid glands, pancreatic islets, pituitary, placenta and central nervous system
What is the difference between PTH and PTHrP?
- they are both structurally related
- they bind to the same receptor
- PTHrP binds to several other receptors
- PTHrP has a broader spectrum of effects than PTH
What are some of the other effects that PTHrP may have that PTH doesn’t?
- mammary gland development and lactation
- placental transfer of calcium
- early development (bone mineralization, cartilage differentiation)
- smooth muscle functioning - thus, acting as a vasodilating hormone
If PTHrP is secreted by a breast tumour or lung cancer what may happen?
- uncontrolled secretion leads to hypercalcemia
- stimulates calcium resorption from bone
- suppresses calcium loss in urine
- unlike PTH, PTHrP does NOT stimulate vitamin D
- unlike PTH, PTHrP does NOT incrrease intestinal calcium absorption
What are the 2 types of PTH receptors? (just name them)
[1] Type I PTH Receptor
- binds to PTH + PTHrP
- GPCR (hormone binds activating 2nd messenger - adenylate cyclase)
- 7-transmembrane segments
[2] Type 2 PTH Receptor
- binds to PTH + low affinity for PTHrP
- mRNA expressed in only a few tissues
Where is the Type I PTH Receptor abundant in (where is it most abundant in)?
- bone (chondrocytes at growth plates)
- kidney
- other tissues at lower levels
What is the main function of Calcitonin?
opposes the effects of PTH
What stimulates the secretion of Calcitonin?
- secreted from the thyroid (parafollicular cells)
- stimulated by raised plasma ionized Ca2+
What is the mechanism of action of Calcitonin?
- binds to calcitonin receptor (GPCR) on osteoclasts inhibiting their activity
- stimulates osteoblasts
- lower plasma calcium concentration by inhibiting Ca2+ resorption from bone
What are the 2 types of cells/locations that code the calcitonin gene? How do they differ?
[1] C-Cells of Thyroid Gland (Parafollicular Cells)
- codes for preprocalcitonin (calcitonin precursor)
- inhibits bone resorption
- N-terminal peptide
- C-terminal peptide
- mRNA contains 4/6 exons!!
[2] CNS
- codes for calcitonin-gene related peptide (CGRP)
- potent vasodilator
- N-terminal peptide
- C-terminal peptide (CTP-2)
- mRNA contains 5/6 exons!!1
What is the function of C-cells of the thyroid gland?
codes for preprocalcitonin which inhibits bone resorption
What is the function of CNS of the thyroid gland?
codes for calcionin-gene related peptide which is a potent vasodilator
What is a source of Ergocalcigerol (D2)?
vegetables
What is a source of Cholecalciferol (D3)?
meat
What is the endogenous form of vitamin D (that is created on skin)?
7-dehydrocholesterol synthesis
What is the name for the active form of vitamin D?
1,25 Dihydroxycholecalciferol (1,25-diOH-D3)
aka Calcitrol
What is the process of changing 7-dehydrocholesterol into 1,25 Dihydroxycholecalciferol (1,25-diOH-D3)?
[1] presence of UV light
[2] hydroxylation in the liver
[3] hydroxylation in the kidney
[4] active form is now made!
What hormone helps convert 25-OH D3 to 1,25-OH D3?
Parathyroid Hormone
What stimulates the release of PTH to convert 25-OH D3 to 1,25-OH D3?
[1] low plasma PO4 3-
[2] low plasma Ca2+
What inhibits the release of PTH to convert 25-OH D3 to 1,25-OH D3?
excess 1,25-diOH-D3
What are the functions of calcitrol/active vitamin D?
To maintain adequate serum levels of Ca2+ by:
- increasing Ca2+ uptake in intestine
- minimizing Ca2+ loss by kidney by increasing resorption in kidney tubule
- stimulating resorption (demineralization) of bone when blood Ca2+ is low
- resorption is enhanced by PTH
How is calcium excreted?
- excreted via urine and faeces
- normal daily urinary excretion in adults
- < 250 mg for women
- < 300 mg for men
- dermal loss < 50mg/d unless excessive perspiration
What is the normal daily urinary excretion in adults (males and women)?
Males – < 300 mg for men
Females – < 250 mg for women
What are some factors that increase calcium excretion?
[1] Increased Plasma Ca2+ [2] Deprivation of Phosphate [3] Excess of Vitamin D [4] Increased Urinary Excretion of Sodium [5] Immobilization [6] Corticosteroid Administration [7] Increased Dietary Ca2+ [8] Metabolic Acidosis [9] Hyperthyroidism
What are some factors that decrease calcium excretion?
[1] Decreased Plasma Ca2+ [2] Decreased Glomerular Filtration Rate [3] Parathyroid Hormone [4] Decreased Dietary Ca2+ [5] Increased Dietary Phosphate [6] Increased Ca2+ Utilization (growth, pregnancy, lactation)
What form of calcium is biologically active?
free-ionized calcium
What are the 3 different types of cells that regulate bone turnover?
[1] Osteoclasts
- “bone-resorbing cells”
- destruction of old worn out bone
- necessary for repair and remodelling
[2] Osteoblasts
- “bone forming cells”
- secrete osteoid (unmineralised collagen)
- influence activity of osteoclasts
[3] Osteocytes
- “embedded osteoclasts”
- involved in sensing internal bone environment
What is hyperparathyroidism?
- increased bone resorption
What is osteomalacia/rickets? What is the difference between them?
both are a disorder of vitamin D deficiency leading to net bone demineralization
Osteomalacia: (adults)
- demineralization of pre-existing bones
- increased susceptibility to fractures
Rickets: (children)
- continued formation of collagen bone matrix, but incomplete mineralization leads to SOFT, PLIABLE BONES
What is the diagnosis of osteomalacia/rickets?
- Xrays of affected bones
- serum calcium
- serum alkaline phosphatase
- serum phosphorus
What is the treatment of osteomalacia/rickets?
Cholecalciferol - Vitamin D
What is Osteoporosis a disease of?
disorder of reduced bone matrix
- not a primary disorder of Ca2+ metabolism
- resembles osteomalacia, but plasma Ca2+ and phosphate are normal
What is the diagnosis of osteoporosis?
- fractures with little trauma
- bone mineral density testing (DEXA scan)
What is the treatment of osteoporosis?
- Calcitrol (active form of Vitamin D)
- Bisphosphonates (e.g. Fosamax or Boniva)
- Calcitonin
- Hormone Replacement Therapy (HRT)
What is Paget’s Disease?
it is a progressive bone disorder with unclear aetiology
- genetic or viral exposure
- characterized by mixed lytic + sclerotic bone changes
- areas of bone resorption (increased osteoclastic activity)
- abnormal new growth leading to pain (deformity and fracture)
- can progress to bone cancer
What is the diagnosis of Paget’s Disease?
- X-rays + other imaging tests (MRI + CT scans)
- elevated serum alkaline phosphotase
What is the management of Paget’s Disease?
goal: relieve bone pain and prevent the progression of the disease
- calcitonin + bisphosphonates
(long term use of bisphosphonates can lead to osteomalacia due to impairment of new bone formation - thus given cyclically)
What are the clinical features of hypercalcaemia on CNS, renal, bones, abdominal and cardiac?
CNS:
- malaise, weakness and vomiting….
- psychiatric disturbances, confusion…
Renal:
- polyuria, polydipsia
- renal stones and nephrocalcinosis
Bones:
- bone pain
Abdominal:
- constipation
- duodenal ulceration
Cardiac:
- dysarrhythmias
What are the clinical features of hypocalcaemia on CNS, bones and neuromuscular?
Neuromuscular:
- numbness and tingling of extremities
- muscle cramps/spasms (positive Chvostek and Trousseau’s sign)
- proximal myopathy (waddling gait)
Bone:
- bone pain
- bone fractures
CNS:
- psychiatric disturbances
- memory loss/confusion
- convulsions (newborn and infancy)
- cataracts
What is Trousseau’s sign?
Induction of carpopedal spasm by inflation of a sphygmomanometer above SBP for 3 minutes
response: carpopedal spasm characterized by…
- adduction of thumb
- flexion of MCP joints
- extension of IP joints
- flexion of wrist
What is Chvostek’s sign?
Contraction of the facial muscles by tapping on facial nerve just anterior to ear
response: twitching of lip to spasm of all facial muscles
