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Calcium metabolism Flashcards

1
Q

does ionised calcium levels change

A

Plasma calcium NEVER changes especially ionised calcium
if Low calcium: body will slowly sacrifice bone to help increase calcium in the blood stream to maintain plasma calcium in a fixed place.

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2
Q
  • What happens to nerves If calcium:
    o GOES DOWN
    o GOES UP

and why does this happen

A

GOES DOWN- the nerves become excitable: nerves and muscles become irritable: GREATER Na influx and so increased membrane excitability

*Tetany: wrists start to flex and cannot relax
*Tapping the cheek causes jerk.
*If this progresses, then can develop epileptic fit
enables greater Na influx and so increased membrane excitability

GOES UP- the nerves become too stable and nerve muscle transport stops working.
BLOCKS Na influx so less membrane excitability

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3
Q

stores of calcium and their proportions

A
  • Bone – 99%
  • Serum – 1%
  • Free, ionised, biologically active – 50%
  • Bound to albumin – 40%
  • Complexed with citrate/phosphate – 10%
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4
Q

three forms of serum calcium

A

Free (‘ionised’) – 50% , biologically active- this needs to be kept at a fixed level

Protein-bound – 40%, inactive + mostly bound to albumin

Complexed – 10% , can also be bound to citrate/ PO4

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5
Q
  • Total serum calcium normal range
A

2.2-2.6mmol/L

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6
Q

define corrected calcium

A

correcting for albumin which can vary depending on illness (sepsis/liver failure)

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7
Q

equation for corrected calcium

A

Total Serum Calcium + 0.02 (40 - serum albumin in g/L)

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8
Q

what happens to calcium if there is low albumin

A

The bound calcium is low, but the free calcium will be normal

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9
Q

if the corrected calcium is in normal range but overall calcium is not what does this mean

A

Thus, as the corrected calcium is within the normal range, it tells you that the problem is the albumin and not the calcium

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10
Q

explain Calcium Homeostasis- response to low calcium

A

Hypocalcaemia is detected by the parathyroid gland

Parathyroid gland then releases PTH

PTH increases blood calcium levels from THREE sources

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11
Q

3 sources to release more calcium when low

A

o Bone
 Activates osteoclasts- break down bone and release calcium in circulation

o Gut (absorption)
Increases gut intestinal calcium absorption 
 1alpha-hydroxylase is found in the kidney is activated by PTH which activates the vitamin D which increases gut absorbtion of Ca

o Kidney
 1alpha-hydroxylase is found in the kidney
 1alpha-hydroxylase is inactive but is activated by PTH
 This will increase the gut absorption by activating vitamin D
 Kidneys will also reabsorb calcium in the renal tubule due to PTH

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12
Q

2 Key Hormones involved in Calcium Homeostasis and what types of hormones are they

A
  • PTH- (peptide hormone
  • Vitamin D (steroid hormone)- originates from cholestrol
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13
Q

vitamin D3 and D2 names and which is animal and plant derived

A

o Vitamin D3 (cholecalciferol)= animal product - this is what you get in the diet; so if you have dietary deficiency this would be low –> low 25 hydroxy vitamin D3
o Vitamin D2 (ergocalciferol)= plant product

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14
Q

3 roles of PTH

A
  • Bone and renal calcium resorption
  • Stimulates 1alpha-hydroxylase in kidneys to form active vitamin D
  • Also stimulates renal PO4 wasting – lose PO4 in the urine (phosphaturic): Phosphate Trashing Hormone
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15
Q

Vitamin D synthesis

A
  • UV converts 7-dehydrocholesterol to cholecalciferol (Vitamin D3) in the skin
  • 100% of Vitamin D3 is then converted to 25-hydroxycholecalciferol by first pass metabolism in the liver by 25alpha-hydroxylase. this is INACTIVE vitamin D and is measured in blood tests
  • 25-hydroxycholecalciferol is converted to 1,25-dihydroxycholecalciferol- ACTIVE FORM- by 1alpha-hydroxylase in the kidney

(active form = CALCITRIOL)

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16
Q

which is the rate limiting step in vitamin D synthesis

A

25-hydroxycholecalciferol is converted to 1,25-dihydroxycholecalciferol- ACTIVE FORM- by 1alpha-hydroxylase in the kidney

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17
Q

where is 1 alpha hydroxylase found and effects of this

A

kidneys
lungs - ectopic activation by macrophages in sarcoidosis = activation of vitamin D

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18
Q

which is the type of vitamin D taken for supplements

A

: calcitriol- is active vitamin D- never take this as supplement, should be given cholecalciferol

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19
Q

role of activated vitamin D

A
  • Increases Intestinal calcium absorption
  • Increases Intestinal PO4 absorption
  • Critical for bone formation
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20
Q

marker for bone formation

A

ALP

Wherever osteoblasts try and lay down bone, some Alkaline Phosphatase (ALP) is leaked out.

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21
Q

how does vitamin D and PTH affect phosphate absorption?

A

vitamin D- increased intestinal absorption of phosphate from gut
PTH- increased loss of phosphate via kidneys

so note when PTH is increased then you get some absorption from gut and some loss from kidneys

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22
Q
A

Osteoporosis

  • Osteomalacia
  • Paget’s disease
  • Parathyroid bone disease-
  • Renal osteodystrophy
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23
Q

vitamin D deficiency in children and adults

A

o Childhood- rickets: Ends plates of bones cannot grow properly
o Adulthood- osteomalacia: Bones have weakened

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24
Q

biochemistry of osteomalacia:

A

Biochemistry: LOW Ca, LOW PO4, RAISED ALP

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25
Q

clinical features of rickets and osteomalacia:

A

osteomalacia: increased risk of fractures + pseudofractures (LOOSER’S ZONES FRACTURES)+ Bone and muscle pain

Rickets: Bowing of legs + Myopathy- get weak muscles

LOOSER- FAKING IT - PSEUDO fracture- osteomalacia

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26
Q

causes of osteomalacia (6)

A

vitamin D deficiency due to:

  • renal failure: cannot activate vitamin D
  • liver failure
  • malabsorption - gut disease
  • Anti-convulsant: induve liver enzyme break down of vitamin D (esp in rickets in children when used to to prevent fits)
  • lack of sunlight
  • dark skin
  • reduced dietary intake
  • chapathi- induces enzyme that chelates calcium from gut
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27
Q

what happens to calcium levels in pregnancy

A

normal
baby uses more calcium from mother to grow but placenta produces PTHr peptide which releases more calcium.
rate of consumption of calcium = production so normal serum calcium levels in mother

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28
Q

secondary hyperparathyrodism: what drives it + biochemical levels and examples

A

CALCIUM IS ALWAYS LOW
low calcium drives secondary hyperparathyrodism i.e. due to vitamin D deficiency

low Calcium, low phosphate, high ALP and high PTH

seen in osteomalacia with pseudofractures

29
Q

osteoporosis + biochemical + clinical features + diagnosis

A

bone loss with reduced bone mineral density with NORMAL calcium
normal Ca, Normal P04, normal ALP

first clinical feature- fracture

Dexa scan- diagnosis

30
Q

T score and Z score

A

to determine osteoporosis

T score – SD from mean of young healthy population (useful to determine fracture risk)

Z score – SD from mean of age-matched control (useful to identify accelerated bone loss in younger patients)

31
Q

T score of osteoporosis and osteopaenia

A
  • Osteoporosis= T-score < -2.5
  • Osteopenia= T score between -1 & -2.5
32
Q

where are fractures common in osteoporosis

A

Typical fracture= neck of femur (NOF), vertebral (get shortened height), wrist (Colle’s)

33
Q

causes of osteoporosis

A
  • Age-related decline in bone mass
  • Failure to attain peak bone mass- childhood illness
  • Early menopause (lack of oestrogen)

Lifestyle: sedentary, alcohol, smoking, low BMI/ nutritional

Endocrine: hyperprolactinaemia, thyrotoxicosis, Cushing’s
 Hyperthyroidism = high rate of bone turnover = bone loss

Drugs: steroids
Others e.g. genetic, prolonged intercurrent illness

34
Q

treatment for osteoporosis

A
  • Lifestyle
    o Weight-bearing exercise
    o Stop smoking
    o Reduce alcohol
  • Drugs
    o Vitamin D with/without calcium
    o Bisphosphonates (e.g. alendronate)- reduce bone resorption
    o Teriparatide (PTH derivative) – anabolic
    o Strontium – anabolic + anti-resorptive
    o Oestrogens- HRT
    o SERMs e.g. raloxifene
     Oestrogen receptor modulator- helps to reduce breast cancer
35
Q

differences between osteomalacia and osteoporosis

A

osteomalacia:
- due to vitamin D deficiency
- reduced calcification of bone: abnormal calcium: osteoid(protein) ratio
- low Ca, low PO4, high ALP, high PTH
- psuedofractures

osteoporosis

  • normal ageing response
  • normal bone but reduced bone mineral density
  • ratio of calcium: osteoid (protein) is normal
  • normal Ca, PO4, ALP
  • pathological fractures
36
Q

Hypercalcaemia Symptoms

A

osmotic diuresis: - Polyuria/ polydipsia
constipation
abdominal pains and cramps
depression
if really high >3 can get confusion

BONES- PTH bone disease – get osteomalacia, osteoporosis and fractures

STONES- renal calculi

MOANS (abdominal)- constipation, pancreatitis  due to hypercalcaemia

GROANS (psychic)- confusion if very high >3, depression

37
Q

Hormonal response to Hypercalcaemia

A
  • PTH release SHOULD be SUPPRESSED:
    o Losing more calcium
    o Not having activated Vitamin D
    o Not having gut absorption of calcium

A normal PTH in someone with hypercalcaemia should be 0pmol/L

38
Q

Causes of Hypercalcaemia

A

Raised/inappropriately normal PTH:
- MOST COMMON: primary hyperparathyroidism: tumour of PTH glands

Familial hypocalciuric hypercalcaemia- VERY RARE

Suppressed PTH: PTH is 0:
o Malignancy - VERY COMMON
o Sarcoidosis- activation of 1 alpha hydroxylase in lung = inappropriate vitamin D activation
o Thyrotoxicosis – this causes increased bone turnover and so slightly raised calcium

Rare causes of suppressed PTH (0):
o Vitamin D excess e.g. sunbeds

o Milk alkali syndrome - in kids when lots of alkali sweets are eaten

  • Hypoadrenalism- renal calcium transport
  • Thiazide diuretics- renal calcium transport: Reduces calcium excretion in the urine
39
Q

which cause of hypercalcaemia has good prognosis

A

hypercalcaemia with normal/raised PTH = Parathyroid tumour = curable = good prognosis

hypercalcaemia with suppressed PTH = malignancy/sarcoidosis = poor prognosis

40
Q
  • Commonest cause of hypercalcaemia
A

Primary Hyperparathyroidism;
- Parathyroid adenoma, hyperplasia or carcinoma

Hyperplasia is associated with MEN 1

41
Q
  • Signs and symptoms of Primary Hyperparathyroidism
  • biochemicals of primary hyperparathyroidism:
A

high serum calcium, high/NORMAL PTH, low serum PO4
high urinary calcium

signs of hypercalcaemia:

  • osmotic diuresis: polyuria, polydipsia,
  • abdominal pain and cramps

BONES- PTH bone disease – get osteomalacia, osteoporosis and fractures

STONES- renal calculi

MOANS (abdominal)- constipation, pancreatitis  due to hypercalcaemia

GROANS (psychic)- confusion if very high >3, depression

42
Q

pathophysiology of familial hypocalcuric hypercalcaemia
+ degree of increased calcium levels + treatment

A

Calcium Sensing Receptor (CaSR) gene is not working
cannot sense calcium, no negative feedback. so stimulates Parathyroid gland to produce more PTH to release more calcium

mild hypercalcaemia: Higher ‘set point’ for PTH release which leads to mild hypercalcaemia. R shift of curve- check image on document

PTH causes increased renal calcium absorption, thereby reducing urine calcium (thus, DO NOT get kidney stones from hypercalcaemia)

treatment: leave them alone, parathyroid gland should not be removed

43
Q

where is PTH related peptide found normally and abnormally

A

normally present in foetus from placenta. PTHrP is NOT PRESENT in NORMAL adults

abnormally: - Humoral hypercalcemia of malignancy e.g. small cell lung carcinoma

44
Q

how is PTH related peptide a prognostic factor

A

very bad prognostic feature to have of cancer
because it causes metastases to spread

45
Q

3 types of hypercalcaemia in malignancy

A
  • Humoral hypercalcemia of malignancy e.g. small cell lung carcinoma: cancer cells secrete PTHr peptide
  • Bone metastases e.g. breast cancer: Cause local bone osteolysis by activating osteoclasts
  • Haematological malignancy e.g. myeloma- produces cytokines
46
Q

Causes of non-PTH driven Hypercalcaemia

A
  • Sarcoidosis- due to non-renal 1alpha hydroxylation
  • Thyrotoxicosis- thyroxine leads to increased bone resorption

Rare causes:

  • Hypoadrenalism- renal calcium transport
  • Thiazide diuretics- renal calcium transport: Reduces calcium excretion in the urine
  • Excess Vitamin D- e.g. sunbeds
47
Q

Hypercalcaemia Treatment: acute management

A

o PLENTY 0.9% saline + + +
 Give 1L over 1 hour in a young, fit person
 If older, give 500ml over 1 hour

o Bisphosphonates- e.g. alendronate if primary cause is CANCER + good for bone pain, otherwise avoid

  • Treat underlying cause e.g. resection of parathyroid adenoma
48
Q

Hypocalcaemia Signs

A

Neuro-muscular excitability

  • Carpal spasm in the wrist- Trousseau’s sign
  • Hyperreflexia
  • Chvostek’s sign (face twiches when touch)
  • Laryngeal spasm (stridor)
  • Convulsions – with sudden falls in calcium: WANT TO PREVENT THIS
  • Prolonged QT interval on ECG
  • Choked disk (eye)
49
Q

Hypocalcaemia- Treatment

A
  • Calcium + Vitamin D
  • Usually activated 1alpha vitamin D to help rapidly improve by activating calcium absorption
50
Q

causes of hypocalcameia + examples

A

If PTH is low:
absence of parathyroid glands:
i.g. DiGeorge syndrome: absence of parathyroid glands so early presentation of hypocalcaemia

if PTH is raised- secondary hyperparathyroidism
** can progress to tertiary hyperparathyroidism:

non PTH driven i.e. they are working fine so raised PTH
severe vitamin D deficiency i.e. Rickett’s, pseudohypoparathyroidism

51
Q

biochemicals in non PTH driven hypocalcaemia

A

secondary hyperparathyroidism: due to vitamin D deficiency so parathyroid glands work very hard.
 So the PTH levels will be VERY HIGH and calcium will be low

52
Q

how do you treat non PTH driven hypocalcaemia

A

Vitamin D replacement

53
Q

what type of hyperparathyroidism can CKD Lead to and how

A

CKD can lead to tertiary hyperparathyroidism

years of vitamin D deficiency and secondary hyperparathyroidism = parathyroid glands are huge/working hard
when you get a renal transplant, can produce 1alpha hydroxylase so calcium levels return to normal.
But large parathyroid glands are overreactive so CANNOT stop producing PTH
This leads to primary hyperparathyroidism

tertiary is secondary hyperparathyroidism that becomes AUTONOMOUS

54
Q

which to types of hyperparathyroidism have same biochemicals

A

primary + tertiary hyperparathyroidism have the same biochemistry (VERY LOW calcium)

55
Q

what is pseydohyperparathyroidism +.biochemicals + 1 main distinctive clinical feature

A

o RARE
gene for PTH receptor is missing
PTH does not work and the kidneys do NOT see the PTH

high PTH and low calcium

those with pseudohypoarathyroidism have a short 4th metacarpal

56
Q

Paget’s Disease: clinical features

A

Focal PAIN
warmth
deformity
fracture
spinal cord compression,
malignancy
cardiac failure

Get bone growth though so can affect hearing and vision due to nerve compression

57
Q

which bones does pagets disease affect

A

Pelvis, femur, skull and tibia

58
Q

biochemicals of pagets disease

A

Elevated alkaline phosphatase (ALP) – VERY HIGH
Calcium + PO4 = NORMAL

59
Q

diagnosis and treatment of pagets disease

A

diagnosis : Nuclear medicine scan/ XR

Treatment: Bisphosphonates (for pain

60
Q

complication of primary hyperparathyrodism

A

o Osteitis fibrosa cystica
lots of cysts in the bone due to long standing bone loss

61
Q

what is Renal osteodystrophy

A

Due to secondary hyperparathyroidism + retention of aluminium from dialysis fluid

 Have renal failure (no 1 hydroxylase in the kidney) and so secondary hyperparathyroidism
 This leads to loss of bone and end up with bone disease

62
Q

summarise the biochemistry of
osteoporosis
osteomalacia
pagets
parathyroid bone disease
renal bone disease

A

Osteoporosis:
normal Ca, PO4, ALP
normal PTH
normal Vitamin D

Osteomalacia:
Reduced Vitamin D,
Low/normal Ca
low/normal PO4
high PTH- secondary hyperparathyroidism
high ALP

Pagets:
High ALP
normal Ca
Normal PO4
normal PTH
normal vitamin D

Parathyroid bone disease:
High/NORMAL PTH
high Ca
Low PO4
normal vitamin D
high/normal ALP

Renal bone disease:
normal vitamin D although low 1alpha hydroxylase
low/normal Ca
high PO4- retention as not excreted by kidneys
High/normal ALP
high PTH- secondary hyperparathyroidism

63
Q

TABLE FROM KARIM MEERAN’S LECTURE ON METABOLIC BONE DISEASE - IGNORE PATH GUIDE

A

**in renal bone disease, vitamin D levels are normal but it’s just ot functional**

64
Q

Pseudohypoparathyroidism

A
  • Caused by resistance to PTH
  • Results in low calcium, high phosphate, high PTH
  • Features include hypocalcaemia, round face and short metacarpals/metatarsals
65
Q

Why is phosphate high in chornic kidney disease causing secondary hyperparathyoirdism?

A

**even tho PTH is high, phosphate is acc high**

**this is because the primary problem is kidney disease - lack of ability to excrete phosphate so it builds up** - independent of PTH

66
Q

difference between primary and tertiary hyperparathyrodism

A
67
Q

what happens to PTH levels in squamous cell cancers producing PTHrP

A

PTH level is low.

68
Q

What effect does dietary vitamin D deficiency have on the axis?

A

Low cholecalciferol (Viytamin D3) - this is what comes from the diet

This leads to low 25,hydroxy vitamin D3

This leads to secondary hyperparathyroidism

This leads to more 25 hydroxy vitamin D3 being converted to 1,25 hydrovitamin D3

Hence: 1) low 25 hydrox, 2) high 1,25 hydroxy and 3) high PTH

chemical pathology (22 decks)

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