REB 7. Calcium Homeostasis Flashcards by Jennita Ariaratnam

What is the source of calcium?

It cannot be produced in the body - must be acquired through diet

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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

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What is the most abundant mineral in the human body?

calcium

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If there is a deficit in calcium ions what happens?

hyperexcitability of cells

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If there is an excess in calcium ions what happens?

increases in contractility

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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

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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)

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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

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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)

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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

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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)

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What inhibits the parathyroid hormone (PTH) in a negative feedback loop?

increased plasma free ionised Ca2+

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What is PTHrP?

Parathyroid Hormone-Related Protein (PRHrP)

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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

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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

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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

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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

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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

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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

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What is the main function of Calcitonin?

opposes the effects of PTH

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What stimulates the secretion of Calcitonin?

secreted from the thyroid (parafollicular cells)

- stimulated by raised plasma ionized Ca2+

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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