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Block 4 > Endocrine Control Of Calcium & Phosphate Homeostasis > Flashcards

Endocrine Control Of Calcium & Phosphate Homeostasis Flashcards

1
Q

What tissues regulate calcium and phosphate homeostasis? How?

A
  1. PT glands: detect Ca/PO4 levels + make PTH
  2. Kidney: site of regulated Ca/PO4 reabsorption + site of vitamin D activation
  3. Gut: site of Ca/PO4 uptake
  4. Thyroid: site of calcitonin synthesis + detects serum Ca levels
  5. Bone: body store of Ca/PO4 + makes fibroblast growth factor 23 (FGF-23)
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2
Q

What are the 6 roles of calcium (Ca)?

A
  1. Bone and teeth formation (growth/remodelling)
  2. Muscle contraction
  3. Nerve function
  4. Enzyme co-factor
  5. IC 2nd messenger
  6. Stabilisation of membrane potentials
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3
Q

What is the distribution of calcium (Ca) in the body?

A

Most is in the skeleton, some is IC and a tiny amount is EC. EC in the plasma, it can either be ionised or mostly, bound. 10% is bound to anions (e.g. bicarb or phosphate) whilst 45% is bound to plasma proteins (e.g. albumin + globulins). Adjusted calcium level calculation adjusts for the amount of albumin.

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4
Q

What is the UK dietary requirements for calcium (Ca)? What is the total body calcium (Ca)?

A
  1. 700mg in an adult increasing in older adults, teenagers and lactating/post-menopausal women
  2. Total body Ca = 1-2kg
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5
Q

What is the step-by-step process of calcium (Ca) homeostasis when there is low calcium (Ca)?

A
  1. Low Ca is sensed by the parathyroids which increase PTH
  2. PTH stimulates bone resorption and kidney reabsorption of Ca
  3. PTH stimulates 1α-OHase enzyme in the kidneys which converts 25(OH)D (calcidiol/inactive vit D) to 1,25(OH)2D (calcitriol/active vit D)
  4. Vit D increases bone resorption, kidney reabsorption and gut absorption of Ca
  5. Vit D and Ca -vely feedbacks to the PT glands
  6. Increased Ca in blood stimulates thyroid gland to release calcitonin which inhibit bone resorption and kidney reabsorption of Ca
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6
Q

What are the parathyroid (PT) glands? What do they do?

A

4 glands on the posterior surface of the thyroid gland but that have independent blood supply. The tissue is responsible for sensing the circulating [Ca] and chief cells synthesise and secrete PTH.

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7
Q

What is parathyroid hormone (PTH)? How does it have its affect?

A

Peptide hormone (T1/2 of mins) that acts via a GPCR called PTHR1 which is bound and activated by PTH but also, PTHrP. Enough PTH is stored for 60-90 minutes release and then more must be synthesized. Sustained release requires gene expression (hrs-dys), proliferative activity of PT cells (dys-wks/>) where eventually gland size increases.

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8
Q

What is the extracellular (EC) calcium-sensing receptor (CaSR)? What does it do?

A

A 7 transmembrane glycosylated protein that interacts with G proteins:

  1. Low Ca = decreased CaSR signalling, increased cAMP and production/secretion of PTH
  2. Normal Ca = basal PTH secretion
  3. High Ca = Ca + CaSR activates PLC suppressing PTH secretion and gene expression AND activates G-protein signalling inhibiting AC, decreasing cAMP and suppressing PTH production
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9
Q

What is parathyroid hormone related peptide (PTHrP)? What does it do?

A

A hormone that mimics PTH elevating plasma Ca
(not vit D) via PTHR1 binding. It has a paracrine and autocrine action. It is used for regulation of endochondral bone formation/mineralisation and Ca regulation in foetus and lactation. Its made by many tissues (esp. malignant tissues) so its levels are not raised in hyperparathyroidism and other non-malignant hypercalaemias but in malignant hypercalaemias.

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10
Q

What is the purpose of constant bone remodelling?

A
  1. Repairs damage (microfractures)
  2. Buffers Ca/PO4 as resportion increases blood concentration whereas formation deposits them so decreases blood concentration
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11
Q

What is bone remodelling? What controls it?

A

When bone resorption is followed by bone formation in a constant cycle - under hormonal control

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12
Q

How is calcium (Ca) absorbed in the GI tract?

A

All intake comes from the intestine esp. the duodenum and upper jejunum and it is facilitated by vitamin D by 3 methods:-

Low serum Ca:

  1. TRPV6 channels bring Ca into epithelial cells where it binds CaBP and leaves via active uptake and extrusion using NCX/PMCA
  2. TRPV6 channels bring Ca into epithelial cells where it binds CaBP in a vesicle and the complex undergoes endocytosis and exocytosis

High serum Ca:
3. Paracellular transport bound to CaBP

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13
Q

How does vitamin D (vit D) facilitate calcium (Ca) absorption in the GI tract?

A

Upregulates:

  1. Luminal Ca channels (TRPV6)
  2. Calcium binding protein (CaBP)
  3. Basolateral Ca2+ efflux transporters: CaNa exchanger (NCX) and CaATPase (PMCA)
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14
Q

Where is calcitonin (CT) synthesized?

A

In the neuroendocrine parafollicular (C) cells of the thyroid gland

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15
Q

What are the actions of calcitonin (CT)?

A

Released when high serum Ca acts on CaSR and acts via GPCRs on:
1. Primarily bone: inhibits bone resorption by preventing osteoclast action
2. Kidney: decreases reabsorption of Ca/PO4
= decrease [Ca/PO4] into blood

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16
Q

What are the 3 roles of the kidney?

A
  1. Most Ca is reabsorbed from filtrate passively in PT and TALH or actively (regulated by PTH, vit D or CT) in DT and CD
  2. Phosphate reabsorption from filtrate - stimulated by vit D but inhibited by PTH, FGF23 and CT
  3. Makes 1,25(OH)2D/calcitriol/active vit D
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17
Q

How is calcium (Ca) reabsorbed actively in the kidneys?

A

PTH and vit D upregulate luminal Ca channels (TRPV5) and basolateral Ca2+ efflux transporters (NCX/PMCA) in the DT

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18
Q

What is the difference between CaNa exchanger (NCX) and CaATPase (PMCA)?

A

NCX: low Ca affinity but high capacity for Ca transport
PMCA: high Ca affinity but low capacity for Ca transport

19
Q

What is vitamin D/calcitriol (1,25(OH)2D)?

A

A steroid hormone (T1/2 = hrs) that has cell membrane and IC transport proteins and binds to a nuclear receptor. It has endocrine and local paracrine/autocrine actions.

20
Q

What are the functions of vitamin D/calcitriol (1,25(OH)2D)?

A
  1. Facilitates Ca uptake from gut
  2. Facilitates Ca/PO4 reabsorption in kidneys
  3. Cartilage production and bone mineralisation
  4. Osteoblast and osteoclast differentiation
  5. Increases bone remodelling by promoting bone resorption
  6. Regulates immune system in infection and inflammation
21
Q

How is vitamin D synthesized?

A
  1. 90% comes from sun as D3 (colecalciferol) and 10% from food as D2/D3
  2. Calcidiol (25(OH)D)/inactive vit D is measured as an indication if vit D status
  3. 1α-OHase converts it to active vit D/calcitriol (1,25(OH)2D)
  4. In non-renal tissues, this has a paracrine/autocrine function and regulates IS (independent of serum vit D)
  5. In kidneys, it has an endocrine effect on bone calcium (dependent on serum vit D)
  6. 24-hydroxylase inactivates vit D and its excreted in urine
22
Q

What does the balance of phosphate (PO4) levels depend on?

A
  1. Diet and uptake from gut where absorption is 70-90% efficient (unlike 20% for Ca)
  2. IC:EC movement
  3. Active reabsorption at PT in kidneys and urinary excretion
  4. 84% is ionised (unlike 45% for Ca)
23
Q

What is the difference between phosphate (PO4) and calcium (Ca) levels throughout the day?

A

Ca levels are tightly regulated whereas phosphate levels vary through the day

24
Q

What are the 3 functions of phosphate (PO4)?

A
  1. IC metabolism e.g. ATP synthesis
  2. Phosphorylation e.g. enzyme activation (kinases ass whereas phosphatases remove)
  3. Phospholipids in membranes
25
Q

What is the step-by-step homeostatic process that occurs when phosphate levels are low?

A
  1. Low PO4 stimulates 1α-OHase in kidneys to convert 25(OH)D/calcidiol/inactive vit D to 1,25(OH)2D/calcitriol/vit D
    which increases PO4 reabsorption
  2. 1,25(OH)2D increases PO4 release from bone and gut PO4 absorption
  3. 1,25(OH)2D will then increase KLOTHO + FGF23 when there is enough phosphate (also happens with high PO4) which:
    - Inhibits PTH secretion which inhibits vit D activation
    - Inhibits 1α-OHase and vit D activation
    - Stimulates 24-OHase to decrease vit D signalling
    - Inhibits PO4 reabsorption
  4. PO4 levels also feedback
26
Q

What is fibroblast growth factor (FGF-23)?

A

A phosphaturic hormone predominantly made by osteocytes and osteoblasts signalling via cell surface receptor and KLOTHO (obligate receptor partner) that increases PO4 in urine and decreases PO4 in blood - defects associated with phosphate wasting disease

27
Q

How does fibroblast growth factor (FGF-23) counteract the actions of vitamin D induced phosphate (PO4) changes?

A

Prevents vit D mediated hyperphosphataemia by:

  1. Inhibiting type II Na-PO4 co-transporters (NaPi-2a and 2c in PT) decreasing PO4 reabsorption in the kidneys
  2. Inhibits 1α-OHase preventing vit D activation
  3. Stimulates 24-hydrolase inactivating vit D
  4. Inhibits PTH which further inhibits vit D activation (as usually PTH stimulates this)
28
Q

How is phosphate reabsorbed in the kidneys?

A

By Na-dependent PO4 transporters (NPT2a + NPT2c) in PT - PTH and FGF23 inhibit these transporters preventing PO4 reabsorption so its lost in the urine

29
Q

How is phosphate absorbed in the intestine?

A

By NPT2b transporter - increased by 1,25(OH)2D/calcitriol/vit D and low dietary PO4 but inhibited by high dietary PO4

30
Q

What can go wrong with these pathways?

A
  1. Altered absorption due to disease, removal of part of GI tract or strange diets
  2. Vit D deficiency due to decrease sunlight or diet
  3. Kidney disease so 1α-OHase not efficient so there is altered Ca/PO4 reabsorption
  4. Hyper/hypo-parathyroidism
  5. Bone due to remodelling or mineralisation issue

= hyper/hypocalcaemia = poor bones

31
Q

What are the signs and symptoms of hypercalcaemia?

A 
Polyuria/dipsia
Tiredness, confusion, depression and headaches
N+V, constipation + anorexia
Muscle weakness
Abdo pain
Shortened QT interval (in severe cases)

Long standing = loss of bone, kidney stones and ectopic calcification (bones, stones and moans)

32
Q

What are the common causes of hypercalcaemia?

A
  1. Primary hyperparathyroidism: increased PTH secretion due to benign tumour which cause bone loss over time
  2. Malignancy: breast, lung or multiple myeloma cause bone loss or PTHrP production
  3. Granulomatous conditions, drugs, vit D excess, genetic causes and perhaps CKD4/5
33
Q

How do you manage hypercalcaemia?

A

Restore normal Ca, treat any emergency symptoms and find underlying cause, if >3.4mmol/l (severe) give:

  • Fluids (Saline)
  • Loop diuretic (Furosemide)
  • CT
  • Bisphosphonates
  • Oral phosphate
  • Long term: PT gland surgery
34
Q

What are the signs and symptoms of hypocalcaemia?

A

Paraesthesia esp. fingers, toes and around mouth
Tetany (due to peripheral nerve fibres discharging and contracting muscles spontaneously)
Carpopedal spasm (wrist flexion and fingers drawn together)
Muscle cramps
Seizures
Prolonged QT interval

Long-term: rickets/osteomalacia and 2ndary hyperparathyroidism

35
Q

What are the causes of hypocalcaemia?

A
  1. Hypoparathyroidism (low PTH)

2. Ca deficiency: low dietary intake or vit D deficiency

36
Q

How can you treat hypoparathyroidism?

A

Lifelong vit D analogues, high Ca diet and Ca supplementation along with recombinant human PTH

37
Q

What is secondary hyperparathyroidism?

A

Where low serum Ca stimulates PTH production and secretion that is usually associated with kidney where:

  • Kidneys cant respond to PTH
  • Cant make active vit D
  • Cant increase absorption of Ca from gut or kidney
  • Cant increase PO4 excretion
  • Ca can only come from bone
  • Renal bone mineral disease

So plasma Ca decreases, plasma PO4 increases so gland enlarges and produces unregulated PTH amounts so serum Ca begins to rise eventually causing tertiary hyperparathyroidism

38
Q

How do you treat secondary hyperparathyroidism?

A

Increase Ca levels
Calcimimetics
Surgery

39
Q

How do you manage hypocalcaemia?

A

Acute (neuromuscular symptoms) = IV Ca gluconate

Chronic: oral Ca and vit D (form will depend on where defect is)

40
Q

What are normal vitamin D levels?

A

> 50nmol/L

41
Q

Who is most likely to be affected by vitamin D deficiency?

A

Most common nutritional deficiency worldwide but affects Asian and Black ethnic groups as well as females more

42
Q

What are the causes of vitamin D deficiency?

A
  1. Lack of sunlight exposure due to: staying indoors, pollution, UV and skin cancer, SPFs (>8 stops vit D synthesis), ethnic variations in skin colour and clothing e.g. fully covered up
  2. Dietary contribution
  3. Liver disease
  4. Kidney disease
43
Q

What are the treatment options for vitamin D deficiency?

A
  1. Safe sun exposure
  2. Colecalciferol (D3)
  3. Increase dietary contribution via ergocalciferol (D2)
  4. D2 an D3 both require activation so give 1,25(OH)2D/calcitriol/active vitamin D or analogues in renal patients ONLY as its very hypercalcaemic

Block 4 (33 decks)

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