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Endocrinology > 4.4 Food intake and calcium > Flashcards

4.4 Food intake and calcium Flashcards

1
Q

Name 7 roles of calcium

A
  1. major structural component of skeleton
  2. second messenger of hormone signalling (ie GPCR) –> release from endoplasmic reticulum
  3. membrane excitability (action potential)
  4. muscle contraction
  5. hormone secretion (2nd messenger –> exocytosis of granules)
  6. cofactor in blood clotting (assis in cross-linking of fibrin)
  7. cofactor in enzyme –> regulation of enzyme activities (induction of conformational changes or co-factor)
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2
Q

Calcium distribution
- total body calcium –> separated into 3
- one of them (how much) is separated into 2 –> then 1 is separated into 2 again

A
  1. skeleton (99%)
  2. intracellular (ie in ER) (1%)
  3. extracellular (0.1%) = 2.5 mmol/L OR 10 mg/dL (in plasma)
    a) ionized Ca2+ (45%) around 5 mg/dL
    b) bound Ca2+
    - to plasma proteins (45%)
    - anions (ie bicarbonate phosphate, lactate…)
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3
Q
  • Ca2+ in which 2 places are tightly regulated?
  • which Ca2+ is readily available, hence is the most important?
A
  • extracellular and intracellular
  • the non-complexed Ca2+ (ionized calcium in plasma/extracellular fluid –> 5 mg/dL
    *controlled by vit D and PTH
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4
Q
  • when was rickets in children described? how is it described as? what causes it?
  • 3 remedies?
  • theory behind it?
  • lead to the discovery of what?
A

17th century –> softening, deformation and bending of bones –> calcium and vit D deficiency
- fish liver oil, sun exposure and UV irradiation of certain foods –> these treatments were given even before understanding mechanism of disease
- vit D promotes absorption of calcium from the gut –> vit D present in fish liver oil + inactive vit D precursors can be activated by UV
- to parathyroid hormone and calcitonin

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5
Q

parathyroid glands
- how many? weight?
- NOT regulated by what?
- which cells produce PTH?
- PTH released in response to what?
- role of PTH?

A
  • 4 glands –> 40 mg each, located adjacent to thyroid
    *about 15% of people have a 5th gland
  • NOT regulated by pituitary-hypothalamus axis
  • Chief cells produce PTH
  • released in response to low levels of ionized Ca2+ in ECF
  • increases Calcium in ECF!
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6
Q

parathyroid hormone
- what type of hormone? how many aa?
- half-life?
- how is it synthesized?
- stored where? with ____a______
- what does ____a______ do? –> possible role?

A
  • peptide hormone: highly conserved: 84 aa in length
  • short half-life (2-4min)
  • synthesized as pre-prohormone
  • than stored in granules that contain mature PTH and proteases cathepsin B and H (+ carboxy terminus fragments)
  • cathepsin cleaves a portion of PTH to yield carboxy terminus fragment –> possible role = modulation of PTH signalling, bc the fragment doesn’t activate the PTHR signalling
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7
Q
  • how does calcium regulate PTH secretion? what receptor?
  • low vs high calcium levels?
A
  • Calcium sensing receptor (CaR) –> GPCR located on cell membrane of chief cells detect extracellular Ca2+ (as primary ligand) –> NOT intracellular Ca2+ (2° messenger)
    HIGH CALCIUM: Ca2++ binds to receptor –> receptor activation leads to inhibition of PTH secretion
    LOW CALCIUM: Ca2++ NOT bound to receptor –> NO inhibition –> PTH is secreted –> leads to increased [Ca2+] in ECF
  • exact mechanism of how CaR signal inhibits PTH synthesis and secretion is not well defined
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8
Q
  • what are the effects of high vs low ECF Ca concentrations on chief cells?
A

HIGH [Ca]: decreased cAMP and increased IP3 & [intracellular Ca2+]
LOW [Ca]: increased cAMP and decreased IP3 & [intracellular Ca2+]

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9
Q

what is PTH’s receptor?
- isoforms?
- which pathway?

A

PTHR –> 2 isoforms: PTHR1 and PTHR2
- GPCR –> adenyl cyclase/cAMP/PKA + PLC/IP3/DAG/PKC

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10
Q
  • on what 3 target organs does PTH functions to regulated calcium levels? explain (4)
A
  • bone, kidney and gut
    1. PTH increases bone resorption of bone by stimulating osteoclasts –> promotes release of calcium and phosphate into circulation
    2. PTH increase renal Ca2+ reabsorption
    3. PTH also makes kidney activate vit D –> increase in 1,25-dihydroxy-vitamin D3
    4. vit D acts on gut to increase GI calcium absorption
  • all 4 actions –> increase serum Ca2+ (in circulation)
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11
Q

composition of bone
- mineral content (3)
- cells (4)
- organic matrix (4)

A

MINERAL CONTENT:
- 99% of total Ca2+
- 90% of total PO4^-3
- 50% of total Mg^2+
CELLS:
- osteoprogenitor cells (differentiate into osteoclast and osteoblasts)
- osteoblasts
- osteoclasts
- osteocytes (mature osteoblasts ish)
ORGANIX MATRIX:
- collagen (90-95%)
- proteoglycans
- glycoproteins
- lipids

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12
Q

composition of bone:
- important proteins (2) + explain

A

OSTEOCALCIN (osteoblasts)
- 1-2% of bone protein
- 1 mg of osteocalcin binds to 17 mg of hydroxyapatite (organic calcium)
- serum level is indicator of bone growth
OSTEONECTIN (fibroblasts)
- binds to collagen and hydroxiapatite
- may serve as nucleator for calcium deposition in bone

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13
Q

explain osteoblast differentiation
- 3 steps ish

A
  1. mesenchymal stem cells (fibroblast-like cells located in bone marrow) –> 2. become osteoprogenitor cells (attached to bone surface, proliferating) –> 3. become osteoblasts
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14
Q

explain bone formation
- 3 steps

A
  1. osteoblasts secrete collagen and other proteins to form a matrix (osteoid)
  2. mineralization (deposition of calcium) in 2 stages:
    a) primary mineralization (60-70%) in 6-12h
    b) secondary mineralization in 1-2 months for full ossification
  3. entombed osteoblasts (surrounded by matrix and completely deposited with calcium) differentiate into osteocytes. form a network of metabolically active cells
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15
Q

how are osteocytes connected together?
- what does osteoblast organization looks like?

A
  • by gap junctions!
  • checkerboard ish where the lines are osteocytes and the spaces are filed with mineralized bone
  • checkerboard surrounded by osteoblasts + central blood vessel on one side
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16
Q
  • bone growth/remodeling requires precise balance btw (2)
  • turnover of calcium in bone is ___% per year in infants and ___% per year in adults
  • 3 factors regulate balance
A
  • btw bone resorption (osteoclasts dissolve bone) and bone resynthesis (osteoblasts lay down new bone)
  • 100% in infants (bc lots of bone growth), 18% in adults (full turnover every 5 years ish)
    1. PTH
    2. mechanical factors (exercise stimulates bone strengthening)
    3. paracrine factors (like IGF-2 produced by osteoblasts) may act on neighbouring osteoblasts and osteoclasts
17
Q
  • osteoclasts are derived from what?
  • how do osteoclasts dissolve bone/induce bone resorption?
  • then what happens to calcium?
A
  • derived from monocytes (bone marrow: gives rise to macrophages)
    1. osteoclasts attach to bone via integrins (protein on extracellular matrix) and form a tight seal
    2. proton pumps in osteoclasts (H+ dependant ATPases) move from endosomes to cell membrane where they pump out H+
    3. more H+ pumped out = acidic pH –> around 4.0 in ECF –> dissolves hydroxyapatite + acid proteases break down collagen
  • Calcium (and degradation products) is transcytosed (movement from 1 cell to another) –> and released into interstitial fluid
18
Q
  • what is an index of bone resorption activity/indicator of bone health?
  • are osteoclasts involved in acute regulation of calcium homeostasis?
A
  • pyridinoline (collagen breakdown product) in urine!
  • NO! osteoclasts are slow working cells, slow response
19
Q

explain bone remodling and its hormonal control ish
- loop! 5 steps + repeat

A
  1. vit D and PTH tell osteoblasts on bone surface to secrete osteoclast activating factors (OAFs)
  2. OAFs help osteoclast differentiation and mvt in bone –> leads to osteoclasts on bone surface resorbing bone (dissolve calcium form protein + destroys osteocytes) = lots of debris
  3. macrophages phagocytose debris + provides stimulus for osteoblasts
  4. osteoblasts appear at resorption site –> deposit calcium and secrete extracellular matrix proteins
  5. osteoblasts fill cavity with osteoid –> osteoid is mineralized and becomes quiescent bone surface
  6. repeat
20
Q

disease of the bone:
- osteopatrosis vs osteoporosis vs osteomalacia

A

OSTEOPETROSIS: (marble bone)
- increase in bone density due to defective osteoclasts –> more than normal calcium deposition = increase calcification –> bones become more brittle and are prone to fracture
OSTEOPOROSIS:
- los of bone density due to excess osteoclast function
- frequent fractures bc thinner and weaker bones (areas with trabecular bone: distal forearm, vertebral body, hip)
OSTEOMALACIA:
- loss of bone density due to excess osteoclast function –> less diffused, more patches of weaker bones
- soft bones with deformities + increased risk of fractures

21
Q
  • what happens to bone mass as we age?
  • men or women are more affected?
A
  • bone mass decreases!
  • women are more prone to decrease bone density –> especially after menopause
22
Q
  • estrogen upregulates/downregulates osteoblast/osteoclast activity?
  • how? (2)
  • menopause (OR what?) leads to estrogen level increase/decrease –> leads to osteoclast/osteoblast activity increase/decrease? –> leads to what?
A
  • estrogen downregulates osteoclast activity!
    1. inhibition of cytokines that stimulate development of osteoclasts (IL-1, IL-6, TNF) –> decrease osteoclast
    2. stimulation of cytokine TGFb that causes apoptosis of osteoclasts –> decrease osteoclast
  • menopause (OR removal of ovaries) leads to estrogen level decrease –> leads to osteoclast activity increase –> leads to weakening of bones
23
Q
  • what is hyperparathyroidism?
  • occurs in __-___% of population –> more common in men or women?
  • characterized by (2)
  • symptoms (3)
  • treatment?
A
  • increased PTH hormone
  • 0.1-0.3% of population –> more common in women (1:500) than in men (1:2000)
  • primary hyperparathyroidism is characterized by (1) increased parathyroid cell proliferation and (2) PTH secretion which is independent of calcium levels –> leads to increase calcium resorption from bone
  • osteoporosis (abnormal bone mineralization) + kidney stones (bc increased Ca2+ not excreted efficiently through kidney) + excessive urination (bc kidney is trying to get rid of calcium)
  • surgery: removal of enlarged parathyroid gland –> remove 1 or 2 out of the 4
24
Q

Hypoparathyroidism:
- may originate from 7
- major clinical symptom? explain
- treatment?

A
  1. failure of chief cells to secrete PTH
  2. altered responsiveness to PTH
  3. vit D deficiency or resistance to vit D
  4. surgery (removing thyroid gland)
  5. familial causes
  6. autoimmune disorders
  7. idiopathic causes (unknown)
    - increased neuromuscular excitability (tetany) –> reduction in extracellular calcium increases permeability for Na –> increases membrane/nerve excitability –> reduces amount of excitation needed –> spasms or tremors or seizures
    - calcium + vit D
25
Q

MILK FEVER
- what?
- occurs when?
- symptoms?
- causes (3)
- treatment?

A
  • hypocalcemia in fresh cows
  • occurs 48-72h after parturition
  • initial stages of muscle tremors and nervousness (bc increase excitability of muscles) –> followed by muscle weakness (paresis) and recumbency (cannot stay standing)
    1. blood calcium levels <7.5 mg/dL
    2. loss of calcium through colostrum (milk production)
    3. parathyroid dysfunction
  • 500 mL of 23% calcium gluconate –> IV –> quickly increase blood calcium –> 1 shot, cows can get up within 15 minutes
26
Q
  • which cells produce calcitonin?
  • role of calcitonin?
  • physiologically important in humans?
A
  • parafollicular cells or c-cells
  • reduces serum Ca2+ –> only known hormone that reduces ECF calcium
  • may NOT be physiologically important in human
  • overproduction of calcitonin (tumors of parafollicular cells) –> no phenotypic consequences
  • thyroidectomy (should decrease thryoid hormone, PTH and calcitonin) –> only low calcium due to low PTH (no symptoms related to decreased calcitonin)
27
Q

vitamin D
- ___-soluble family of compounds
- deficiency leads to _______ –> causes what? (2)
- formed where by what reaction?
- deficiency common where? –> solution?

A
  • fat-soluble family of compounds
  • leads to rickets –> bone deformations/defects + loss of calcium and phosphate from the bones
  • formed in skin by photochemical reaction
  • used to be common in northern climates bc low sunshine –> now policy: vit D commonly added to milk and butter
28
Q

how is active vit D formed? 5 steps

A
  1. sunshine/UV light can convert 7-dehydrocholesterol (present in skin) into cholecalciferol (inactive vit D3)
  2. can also take vit D2 and D3 from diet
  3. vit D2/D3 is converted to 25-hydroxyvitamin D2/D3 in LIVER
  4. in kidney, 25(OH)D2/D3 can be converted to 1,25-dihydroxyvitamin D2/D3 (calcitriol) = active form (acts as a hormone) –> acts on intestine to increase calcium absorption
  5. in kidney, 25(OH)D2/D3 can ALSO be converted to 24-25-dihydroxyvitamin D2/D3 –> uncertain role
29
Q
  • vit D is a _______ that regulates calcium uptake
  • vit D2 is a pharmaceutical product made how? –> used in food fortification such as (2)
A
  • HORMONE!
  • made by irradiating ergosterol (present in some plants)
  • used in food fortification such as margarine and milk
30
Q
  • what are the 2 main circulating derivatives of vit D? (made where?)
  • vit D binding protein present in serum binds which metabolite to a greater extent than which other metabolite?
  • all physiological effects appear to be due to which metabolite?
A
  • 25-OH-cholecalciferol (made in liver: 3-30ng/mL) and calcitriol (made in kidney: 20-60 pg/mL)
  • binds 25-OH-cholecalciferol and to a lesser extent calcitriol
  • due to calcitriol (1,25-OH2-D3/D2)
31
Q
  • what receptor does vit D bind to? what type of receptor
  • what effect does it have (5)
A
  • vitamin D receptor –> nuclear receptor –> dimerizes with RXR + acts as transcription factor in nucleus!
    1. increase osteoblast activity (mineralization)
    2. increases osteoclast activity
    3. increase intestinal calcium/PO4^3- absorption
    4. increases renal vit D degradation (catabolism)
    5. decreases parathyroid hormone synthesis
32
Q

what nutrients (increase or decrease) activate/inhibit activation of vitamin D in which organ? (4)

A
  • 25(OH)D3 –> 1,25(OH2) D3 hormone in kidney!
    ACTIVATE:
  • decrease Calcium
  • increase PTH
  • decrease PO4
    INHIBIT:
  • increase 1,25(OH2)D3
33
Q
  • homeostasis of blood calcium levels = ____ mg/100 mL
  • what happens if blood calcium level decreases?
  • vs increases?
A

10 mg/100 mL
DECREASES:
- increase PTH –> stimulates Ca2+ release from bones + Ca2+ uptake in kidneys + activation of vit D3 in kidneys –> active vit D3 increases Ca2+ uptake in intestines –> blood Ca2+ levels rise to set point –> homeostasis
INCREASES:
- thyroid gland releases calcitonin –> stimulates Ca2+ deposition in bones + reduces Ca2+ uptake in kidneys –> blood calcium level declines to set point –> homeostasis
*calcitonin basically inhibits PTH actions –> but not super sure it happens in humans

34
Q
  • what 3 cause cause vit D deficiency?
  • vit D deficiency causes what? –> results in what for children vs adults?
  • treatment?
A
  • inadequate sunlight + inadequate nutrition + malabsorption (up to 50-60% of elderly, especially if institutionalized)
  • causes abnormal mineralization of bone and cartilage –> rickets in children vs osteomalacia in adults
  • Tx: vit D supplements
35
Q
  • what can cause vit D toxicity? (2)
  • what (3) influences level required to be toxic?
  • symptoms (5) + may lead to what? (2)
  • treatment?
A
  • overdose therapeutically or accidentally (ie take weekly pills daily…)
  • difference in storage, catabolism and absorption among individuals
    1. weakness
    2. lethargy
    3. headaches
    4. nausea
    5. polyureia due to hypercalcemia and hypercalciuria
  • may lead to ectopic calcification –> calcium deposition outside of bones (kidneys, blood vessels, heart, lungs, skin) with chronic overuse
  • may lead to kidney stones
  • reduced calcium or vit D intake

Endocrinology (14 decks)

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