Calcium Homeostasis

Question 1

Calcium Role in Body

Answer 1

1. SIGNALLING - Ca2+ important signalling molecules - exocytosis of synaptic vesicles
   
   2. BLOOD CLOTTING - essential component of clotting cascade (in young ppl Ca2+ deficiency more likely to cause tetany & respiratory failure rather than failure of blood clotting)
   3. APOPTOSIS - programmed cell death
   4. SKELETAL STRENGTH - 99% calcium in bone for strength
   5. MEMBRANE EXCITABILITY - Ca2+ decreases Na+ permeability - most critical in short term homeostasis; v. important for function of nervous system
      a. HYPOCALCAEMIA = tetany + aspiration if spreading to larynx & respiratory system (extreme cases)
      b. HYPERCALCAEMIA = depresses neuromuscular activity + trigger cardiac arrhythmias (extreme cases)

Question 2

Calcium Distribution in Body

Answer 2

• BONES = 99% (~1kg)

	○ Stored in calcified ECM - mostly in form of HYDROXYAPATITE

	○ Sooooo… PHOSPHATE HOMEOSTASIS IMP. IN DETERMINING Ca2+ BALANCE

• INTRACELLULAR = 0.9% (~24mM)

	○ Mostly stored inside mitochondria & sarcoplasmic reticulum

	○ 0.001mM in cytosol soln.

	○ Free [Ca2+]ic v. low

• ECF = 0.1% (2.2-2.6mM)

	○ Of which nearly 1/2 is bound to protein

	○ Only 0.05% of Ca2+ in body is free in soln. = physiologically active [Ca2+]ECF MAINTAINED W/I TIGHT LIMITS

Question 3

Extracellular Ca2+ Stores & How does pH affect Calcium Binding

Answer 3

Ca2+ HAS V. HIGH AFFINITY FOR PROTEINS + IN PLASMA, 40% BOUND TO PLASMA PROTEINS

* [Ca2+] IN PLASMA = ~2.4 mM
* PHYSIOLOGICALLY ACTIVE [Ca2+] AS FREE IONS = 1.2mM (~50%)
* REMAINING 10% of PLAMA Ca2+ IONS = BIND TO PLASMA ANIONS (-ve ions)

BINDING CAPACITY OF CALCIUM INCREASED UNDER ALKALOTIC CONDITIONS (H+ displace Ca2+ binding to plasma proteins)

Question 4

Control of ECF Calcium & The Role of Bone

Answer 4

• TOTAL BODY CALCIUM = DETERMINED BY INTAKE & EXCRETION
  
  • MAINTAINING ECF [Ca2+] TAKES PRECEDENCE OVER BONE STRUCTURAL DENSITY/MECHANICAL SUPPORT OF BONE○ CALCIUM FROM BONE CAN BE TAKEN FROM/ADDED TO AS REQ.

Question 5

Calcium Storage in Bone

Answer 5

CONTINUOUS TURNOVER IN BONE BY:

	○ OSTEOBLASTS = BONE BUILDING, HIGHLY ACTIVE CELLS, LAY DOWN COLLAGEN ECM, which they then CALCIFY

	○ THEN DIFFERENTIATE, FORMING OSTEOCYTES IN ESTABLISHED BONE - less active, may regulate osteoblast & osteoclast activity

	○ OSTEOCLASTS RESPONSIBLE FOR MOBILISING BONE = SECRETE H+ IONS TO DISSOLVE CALCIUM SALTS + PROVIDE PROTEOLYTIC ENZYMES TO DIGEST ECM

Question 6

Hormones Increasing Plasma Calcium lvls

Answer 6

1. PARATHYROID HORMONE (PTH)
   a. Polypeptide hormone produced by parathyroid glands
   
   2. CALCITRIOL
      a. Active form of vitamin D3; steroid hormone produced from vitamin D by the liver & kidneys

Question 7

Stimuli Increasing PTH Secretion

Answer 7

• RELEASED IN RESPONSE TO DECREASED FREE [Ca2+]plasma

Question 8

PTH Primary Actions

Answer 8

INCREASES PLASMA CALCIUM by:

1. INCREASES RESORPTION OF Ca2+ & PHOSPHATE from BONE
	a. By stimulating osteoclasts, effects seen w/I 12-24hrs
2. INHIBITS Ca2+ DEPOSITION in BONE
	a. By inhibiting osteoblasts
3. INCREASES REABSORPTION OF Ca2+ from KIDNEY TUBULES
	a. This causes reduced calcium urinary excretion
4. INCREASING RENAL EXCRETION OF PHOSPHATE
	a. Elevates free [Ca2+] by preventing it from being deposited back into bone (which req. phosphate)
5. STIMULATES KIDNEY TO SYNTHESIS CALCITRIOL
	a. Promotes calcium absorption at gut & kidney

Question 9

Calcitriol Production

Answer 9

• Aka ACTIVE VITAMIN D3
  
  • STEROID HORMONES PRODUCED IN 2 STEPS:
    1. LIVER
    2. KIDNEY

Question 10

Stimuli Increasing Calcitriol Secretion

Answer 10

• DECREASING [Ca2+]plasma
  
  • DIETARY VITAMIN D (fat soluble vitamin)
  • UV LIGHT on SKIN - ACTIVATES CHOLESTEROL DERIVATIVES to become calcitriol○ Active Vitamin D3 = formed from cholesterol derivatives by action of UV light on skin, can also be gained from diet: fatty fish (mackerel, tuna), fish liver oils, egg yolks
  • PROLACTIN IN LACTATING WOMEN

Question 11

Calcitriol Primary Actions

Answer 11

• BINDS TO NUCLEAR RECEPTORS IN TARGET TISSUES (INTESTINE, BONE, KIDNEY)

1. INCREASES ABSORPTION OF Ca2+ FROM GUT
	a. Most Ca2+ excreted in faeces, calcitriol can activate active transport system, moving Ca2+ from intestinal lumen to blood
2. FACILITATES RENAL ABSORPTION OF Ca2+
3. MOBILISED Ca2+ STORED IN BONE BY STIMULATING OSTEOCLAST ACTIVITY

COMPLEMENTS PTH ACTIONS TO INCREASE [Ca2+]plasma

Question 12

Vitamin D Deficiency

Answer 12

• CIRCULATING VITAMIN D LVLS < 20 ng/Ml

	○ INSUFFICIENCY = LACKING IN VITAMIN D + NO SYMPTOMS

* Vitamin D releases calcium from bone & increases gut and kidney absorption from calcium
* Soooo… NET EFFECT INCREASES [Ca2+]plasma + MINERALISATION OF BONE
* Essentially, if pt. calcium deficient & their vitamin D lvls are fine then they can replenish calcium from their diet
* HOWEVER, VITAMIN D DEFICIENCY = PT. HAS TO REPLENISH [Ca2+]plasma FROM OWN BODY/BONE via PTH - BONE BECOMES SOFT

	○ CHILDREN = RICKETS as constant calcium removal causes GROWING BONES TO BECOME BENT

	○ ADULT = OSTEOMALACIA as constant calcium removal increases RISK OF FRACTURES

Question 13

Risk Factors for Vitamin D Deficiency

Answer 13

• AGE > 65 = REDUCED GUT ABSORPTION, REDUCED Ca2+ MOBILITY
• ASIAN (pigmented skin less able to make vitamin D in response to UV light & chapatti flour contains phytate which binds dietary Ca2+)
• CLOTHING
• UVB SUNSCREEN
• DIET
• LACK OF SUNLIGHT

Question 14

Hormones Decreasing Plasma Calcium lvls

Answer 14

1 KEY HORMONE DECREASES [Ca2+ ]plasma:

• CALCITONIN: LITTLE EVIDENCE IT'S IMP. IN HUMANS

	○ THYROID HORMONE PRODUCED BY THYROID GLAND stimulated by increasing [Ca2+ ]plasma (binds to osteoclasts to inhibit bone resorption + increases renal excretion)

1. CORTISOL
   • INHIBITS OSTEOBLASTS, INCREASES RENAL EXRETION OF Ca2+ & PHOSPHATE, REDUCES INTESTINAL ABSORPTION OF Ca2+
   • REDUCES PLASMA [Ca]2+ = INCREASES PTH = INCREASES BONE RESORPTION
   • W/ REDUCED BONE FORMATION, CAN CAUSE OSTEOPOROSIS
2. INSULIN
   • INCREASES BONE FORMATION + ANTAGONISES CORTISOL
   • DIABETICS MAY HAVE SIG. BONE LOSS
3. OESTROGEN
   • PROMOTES BONE FORMATION via OESTROGEN RECEPTORS ON OSTEOBLASTS
   • POST-MENOPAUSAL OSTEOPOROSIS is a big problem
4. GH• CONSTANT STIMULUS FOR BONE FORMATION
5. PROLACTIN• PROMOTES CALCIUM ABSORPTION FROM GUT BY STIMULATING CALCITRIOL SYNTHESIS