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UG Biochemistry > 11. Calcium Regulation > Flashcards

11. Calcium Regulation Flashcards

1
Q

Where is calcium found in the body?

A

Calcium found in functionally distinct pools in body;

  1. Bony skeleton: 99%
  2. Intracellular pool: ~1%
  3. Extracellular pool: ~0.1%
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2
Q

Describe calcium uptake

A

Only in = dietary calcium;

  • dietary habits
  • supplements

Intestinal absorption;

  • absorbed across int epith cell’s brush border membrane
  • TRPV6 channel proposed: k/o didn’t change uptake
  • TRPM7 linked: k/o = strongly reduced Ca in serum/bones (prob for bulk intest uptake)

After cell uptake Ca bound to calbindin (vit D dependent Ca binding protein);

  • transfers to cells ER
  • transports to basal membrane on opposite side of cell (doesn’t enter cytosol/ICF)

Ca pumps (PMCA1) actively TP Ca into body;

  • occurs primarily in duodenum when Ca intake low
  • passive paracellular TP in jejunum + ileum when Ca intake high (independent of vit D level)

Active absorption from gut regulated by calcitriol in blood;
- increases rate of absorption

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3
Q

Why does Ca need to be regulated?

A

Excitable cells, e.g. neurons, v sensitive to changes in Ca+ conc;

Hypercalcemia = progressive depression of nervous system

Hypocalcemia = progressive excitation of nervous system

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4
Q

Where is phosphate found in the body?

A
  1. Bones: 85%
  2. ICF: 15%
  3. ECF: <1%
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5
Q

What role do the bones play in calcium homeostasis?

A

Bones serve as large reservoirs;

  • release Ca when ECF conc decreases
  • store excess Ca
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6
Q

Describe serum Ca

A

Ref range: 2.2-2.6mmol/L
Required for normal neuromuscular function

Only ~50% exists as free ions - rest mostly bound to albumin (bio-inactive)
- physiological functions depend on ionised Ca not the total Ca (inc bound)

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7
Q

List the circulating calcium fractions in the serum

A

50% ionised (free) - biologically active
40% protein-bound, non-diffusable - biologically inactive + not excreted
10% complexed with phosphate, bicarbonate + citrate

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8
Q

Describe Dr Sydney Ringers experiments on calcium

A

Experiments on calcium + frog heart contraction 1883

Recorded frog heart contractions when perfused with blood mixture;

  • substituted blood for saline: amplitude of contractions declined
  • when calcium chloride was added to the solution the contractions recovered to almost normal amplitude
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9
Q

Describe the findings in early publications on calcium ion concentration by McClean + Hastings 1934

A

“frog’s heart sensitive to changes in conc of Ca2+ but not to changes in conc of Ca2+ in non-ionised form”

Showed ionised/free Ca2+ correlated with heart contraction;
- protein/citrate-bound Ca2+ had no effect

Developed first assay for ionised/free Ca2+

Showed in blood this was closely regulated (humans: 1.18mmol/L)

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10
Q

What are the components of separated whole blood?

A

Plasma;
- if anticoagulant present: contains fibrinogen

Serum;
- no anticoagulant present

Clot;
- formed encapsulating cells

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11
Q

How is blood correctly collected + stored for calcium testing?

A

Preferred specimen for total Ca2+ = free flowing venous sample;

  • serum
  • lithium heparin-plasma

Avoid anti-coagulants, e.g. EDTA/oxalate, as bind Ca2+ tightly + interfere with measurement

Loss of CO2 increases pH = samples need to be collected anaerobically

Serum from sealed evacuated tubes can be used if clotting + centrifugation are done quickly (<30min) at room temperature

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12
Q

Describe the lab methods for Ca2+ measurement

A

Colorimetric;

  • Ca2+ released from protein carrier by acidification if sample before dye-binding reaction
  • ortho-cresophthaleine complexone (CPC) or arseno III dye forms complex with Ca2+
  • CPC method uses 8-hydroxyquinoline to prevent Mg2+ interference

AAS (atomic absorption spectroscopy) is reference method for total Ca2+ but rarely used clinically

Commercial analysers use ISEs to measure free Ca2+;

  • use membranes with molecules that selectively + reversibly bind Ca2+ ions
  • as Ca2+ binds membranes, electric potential develops proportional to ionised Ca2+ conc
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13
Q

When measuring Ca2+ why and how do we adjust for albumin?

A

Ca2+ = metabolically active

40-50% of measured total Ca bound to albumin (inactive);
- serum albumin must be considered when assesing Ca2+

Labs use formula to adjust measured Ca2+ relative to albumin levels;
- “adjusted Ca” = approximation of metabolically active Ca2+

Adjusted calcium = measured calcium + 0.02 (40 - albumin conc)

Errors are greatest at extremes of albumin concentration + when there is a suspicion/evidence of acidosis/alkalosis

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14
Q

How does the reference range for calcium vary?

A

Total Ca2+ varies with age;
- higher in adolescence when bone growth most active

Ionised Ca2+ changes from day 1-3 of life then stabilises at relatively high levels with gradual decline through adolescence

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15
Q

Describe calcium balance + its consequences

A

Calcium balance: intake = output

Negative balance: output>intake = osteoporosis
Positive balance: intake>output = occurs during growth

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16
Q

Why is calcium considered essential?

A

We can’t synthesis it, must acquire through diet

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17
Q

Which organ systems are involved in calcium metabolism?

A

Skeleton
GI tract
Kidneys

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18
Q

Define calciotrophic hormone

A

Any hormone with a major role in bone growth + remodelling

19
Q

List the main calciotrophic hormones

A

Parathyroid hormone (PTH)
Vitamin D (1, 25 dihydroxycholecalciferol)
Calcitonin (CT)
Parathyroid hormone related protein (PTHrP)

20
Q

Describe the general pathway of calcium in the body beginning at ingestion

A

Ca2+ ingested

PTH promotes active vit D formation in kidney;

  • vit D promotes absorption in small intestine
  • unabsorbed Ca2+ is lost in faeces

Ca2+ lost in the urine at kidney;
- PTH promotes Ca2+ reabsorption from urine

Ca2+ removed from blood by osteoblasts in bone;

  • PTH promotes Ca2+ release into blood by osteoclasts
  • calcitonin inhibits Ca2+ release into blood by osteoclasts
21
Q

Discuss PTH + its role in calcium homeostasis

A

Parathyroid hormone;

  • peptide hormone
  • manufactured in parathyroid glands behind thyroid

Normally tight feedback loop b/n PTH release + serum Ca2+;

  • PTH release stimulated by fall in Ca2+ = acts to restore Ca2+
  • preserve serum Ca2+ through actions on bone + kidney

Example of negative feedback control

22
Q

How many parathyroid glands are there + what are the consequences of thyroid surgery?

A

4 parathyroid glands

Difficult to locate during thyroid surgery;
- total/subtotal thyroidectomy usually = parathyroid removal

Loss of 2 = usually no major physiologic impact
Loss of 3 = transient hypoparathyroidism
Any remaining parathyroid tissue: hypertrophy

23
Q

How is PTH biosynthesis + secretion regulated by Ca2+?

A

Secretion determined chiefly by serum ionised calcium concentration through negative feedback inhibiting PTH gene transcription

Parathyroid cell CaSR (G-protein couple receptor) on surface bind extracell Ca

  • high conc Ca initiates phospholipase C pathway via Gq G-protein
  • hydrolyses PIP2 > liberates intracell messengers IP3 + DAG

IP3 + DAG (diacylglycerol) result in release of extracell Ca from intracell stores into cytoplasmic space

High extracell Ca -> increase in cyto Ca in parathyroid cells;
- inhibits fusion of vesicles containing granules of preformed PTH with cell membrane = inhibits release of PTH

24
Q

What are the 4 main actions of PTH during low serum Ca2+ (ie when it is actively secreted)?

A
  1. BONE: INCREASED OSTEOCLAST ACTIVITY = MORE BONE RESORPTION/ REDUCED OSTEOBLAST ACTIVITY = LESS BONE DEPOSITION
    - stimulates Ca2+ release;
    - initial osteocyte mobilisation of Ca2+ from bone > ECF
    - continued slow release of bone Ca2+ + phosphate from osteoblast breakdown of bone matrix
    - also reduces osteoblast activity
  2. KIDNEY: LESS URINARY CALCIUM EXCRETION = CONSERVATION OF Ca
    - increases rate of Ca2+ reabsorption from renal tubules
    - less excreted in urine
  3. KIDNEY: MORE URINARY PHOSPHATE EXCRETION = PREVENTS HYDROXYAPATITE FORMATION = LESS BONE DEPOSITION
    - increases urinary phosphate excretion
    - lowers plasma phosphate
    - reduces tendency for Ca2+ + phosphate to react (ppts)
  4. KIDNEY
    - upregulates transcription of 1-alpha hydroxylase for vit D activation in kidney
    - increases rate of vit D conversion to active form calcitriol (1, 25-dihydroxycholecalciferol)
25
Q

Describe vitamin D + its role in calcium homeostasis

A

Vit D;

  • fat soluble vitamin = can be stored
  • found in food (vit D2)

Sources;

  • eggs, fort cereals, oily fish, liver (10% from diet)
  • made in skin under influence of UVB rays in sunlight (vit D3)

Function in Ca homeostasis;

  • promotes Ca2+ absorption in GI tract + deposition in bone
  • downregulates transcription of PTH gene (neg feedback)
26
Q

Describe influence of pH on location of Ca absorption

A

Absorption of Ca: duodenum > jejunum > ileum

Absorption is better at low pH;
- stomach pH2 = highest absorption at beginning of duodenum

27
Q

Describe vit D synthesis + metabolism in tissues

A

Skin: 7-dehydrocholesterol -UV-> vitamin D3

Liver: vitamin D3 -25-hydroxylase-> 25(OH)vit D [hepatic 25-hydroxylation]

Kidney: 25(OH)vit D -1alpha-hydroxylase-> 1,25 dihydroxy vit D (active metabolite) [renal alpha1 hydroxylation]

28
Q

Describe vitamin D activation + its importance in disease

A

Reqs;

  • 25 hydroxylase (liver)
  • 1alpha-hydroxylase (kidney)

Conversion of 25-hydroxy cholecalciferol > 1,25 dihydroxycholecalciferol;

  • occurs in prox renal tubules
  • most active form of vit D
  • Ca ion itself slightly prevents conversion

Conversion in prox tubule requires PTH from parathyroid;
- PTH promotes conversion if Ca conc <9mg/100mL

At higher conc Ca = PTH suppressed;
- 25-hydroxy vitD in prox tubule converted to 24, 25-dihydroxy vitD (almost no vit D effect)

Patients with CKD fail to activate vitamin D = bone disease

29
Q

List the actions of vit D in calcium homeostasis

A

Increase rate of Ca2+ uptake in gut;
- replaces Ca2+ lost in urine

Stimulates phosphate absorption in gut

Stimulates Ca2+ + phosphate reabsorption in kidney

In very high levels of activated Vit D;
- increases osteoclastic bone resorption + release of Ca2+ + phosphate to ECF

30
Q

What 2 factors stimulate Vit D formation?

A
  1. PTH (in response to low Ca2+)

2. low plasma phosphate

31
Q

Describe the mechanisms of action of vitamin D

A

Vitamin D binds the VD receptor (VDR) + translocates to the nucleus to upregulate transcription of the vit D-response gene

Vit D inhibits transcription of PTH gene + stimulates transcription of the Ca2+ transporter in the intestinal brush border epithelium

Binding of active vit D to VDR in the intestine affects transcription of genes inc calbindin + may also permit Ca2+ entry through channels in brush border

  • calbindin proposed to ferry Ca2+ through cell
  • exit step through basolateral membrane may involve a Ca2+ pump and/or Na/Ca exchange
32
Q

Describe vitamin D deficiency + associated disorders

A

Cause: inadequate intake + absence of sunlight

Lesser degrees of vit D deficiency common;

  • 1 in 7 adults
  • esp in winter
  • contributes to osteoporosis

Most prominant clinical effect = osteomalacia;
- defective mineralisation of bone matrix (rare)

Vit D deficiency in children = rickets (rare)

Deficiency of renal 1alpha-hydroxylase = vit D-resistant rickets;

  • sex linked gene on x-cr
  • renal tubular defect of phosphate resorption
  • teeth may be hypoplastic + eruption affected
33
Q

Describe the role of calcitonin in Ca homeostasis

A

Source: released from parafollicular C cells in thyroid gland

Secretion: during hypercalcemia, may protect against abn rises

Bone: reduces rate of Ca2+ release to ECF (lowers plasma Ca2+)

Normal physiology: minimal if any role in control of Ca2+

34
Q

Discuss the feedback loops in calcium homeostasis

A

HIGH CA + VIT D INTAKE;
Rising blood Ca2+ = PTH suppression;
- decreased bone resorption
- increased urinary loss
- decreased 1,25dihydroxyD production = decreased GI absorption
- returns to + remains normal blood Ca2+ = good quality bones formed

LOW CA + VIT D INTAKE;
Falling blood Ca2+ = PTH stimulation;
- increased bone resorption
- decreased urinary loss
- increased 1,25dihydroxyD production (if not deficient) = increased GI absorption
- returns to + remains normal blood Ca2+

Vit D deficient = no Ca intake = bones become increasingly poor quality + liable to fracture in order to maintain plasma Ca

35
Q

List the causes of hypocalcemia

A

Parathyroid glands don’t work;
- congenital, autoimmune, surgical damage

Parathyroid glands work but PTH receptor signalling doesn’t;
- pseudohypoparathyroidism - genetic defect of G-protein Gsalpha (for activating phospholipase C pathway)

Renal failure;
- failure to excrete phosphate = precipitates Ca+

Severe vit D deficiency;
- no GI absorb of Ca

OD of Ca controlling drugs

Hypomagnesemia;
- e.g. chronic diarrhea, diuretic therapy, alcoholism

Hypercalciuric hypocalcemia;
- genetically overactive calcium sensor

36
Q

Describe the S+Ss of hypocalcemia + how it is managed

A 
>1.8mmol/L = symptoms probably mild
<1.8mmol/L = likely to be increases neuromuscular excitability, tingling in hands + feet, risk of arrhythmias + seizures (PHONE WARD)

Check if result incorrect;

  • artefact?
  • check potassium
  • look at remainder of bone profile

Oral/IV calcium + correct underlying cause
If Mg2+ not done, suggest as addition

37
Q

What is the link between calcium + magnesium and how does this affect treatment?

A

Mg2+ required for normal function of both parathyroid glands + PTH

Impossible to restore normal calcium balance if Mg2+ persistently low

May need to give IV mg2+ first

38
Q

Describe the causes of hypercalcemia

A

Overactive parathyroid gland

PTH-like substance released by tumour

Direct invasion of bone by tumour;
- overwhelms normal regulatory mechanisms

Benign hypocalciuric hypercalcemia;
- genetically defective calcium sensor

Severe vit D excess

Other causes rare

39
Q

Describe S+Ss based on calcium levels in hypercalcemia

A
  1. 6-3mmol/L;
    - likely mild symptoms

3-3.5mmol/L;

  • likely nausea, weak, complaining of aches + pains
  • non-specific symptoms: hyperCa may not be suspected = contact ward

> 3.5mmol/L;
- pt very unwell + risk of death = PHONE WARD ASAP

40
Q

What further tests are performed for hypercalcemia once blood shows elevated Ca?

A

PTH immunoassay;
- to distinguish b/n 2 main causes: hyperparathyroidism + malignancy

In hypercalcemia PTH should be fully suppressible
- if still detectable likely diagnosis = hyperparathyroidism

41
Q

How is hypercalcemia managed?

A

In emergency;
- fluids + bisphosphates to promote urinary Ca excretion + stabilise bone

Hyperparathyroidism;

  • surgical removal
  • can maintain serum Ca with vit D alone but reqs careful monitoring
42
Q

What is familial benign hypocalciuric hypercalcemia?

A

Inherited condition that can cause hypercalcemia

Most cases associated with loss of function mutations in CaSR gene expressed in parathyroid + renal tissue;

  • decreased receptor sensitivity to calcium = reduced receptor stimulation at normal blood levels
  • doesn’t inhibit PTH until higher levels of Ca in blood

Response curve of PTH shifts to the right

43
Q

Describe PTH related protein (PTHrp) + its impact on Ca homeostasis

A

PTHrp;

  • protein of PTH family
  • regulates fetal bone development/EMT in mammary gland formation

Secreted by some tumours (breast, some lung inc squamous cell lung carcinoma;

  • same N-terminal end as PTH = binds same receptor, PTHR1
  • mostly same effects, except on vit D conversion = no increase in Ca gut absorption
  • responsible for most humoural malignant hypercalcemia (increased plasma Ca2+) - early sign PNP syndrome

PTHrp also not subject to same feedback regulation as PTH

44
Q

Describe typical requests, handling + testing of serum calcium measurements in the lab

A

Usually requested as part of bone profile with phosphate + ALP

Serum sample, no special requirements - but beware of EDTA contamination

Must also know serum albumin to interpret;

  • most analysers do automatically + give “corrected” result
  • corrects to what patients Ca would be if albumin was 40g/dL = same ref range used for all

UG Biochemistry (14 decks)

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