chemical pathology > Calcium metabolism > Flashcards

Calcium metabolism Flashcards

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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
clinical features of rickets and osteomalacia:
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**
26
causes of osteomalacia (6)
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
27
what happens to calcium levels in pregnancy
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
28
secondary hyperparathyrodism: what drives it + biochemical levels and examples
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
osteoporosis + biochemical + clinical features + diagnosis
bone loss with reduced bone mineral density with NORMAL calcium normal Ca, Normal P04, normal ALP first clinical feature- fracture Dexa scan- diagnosis
30
T score and Z score
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
T score of osteoporosis and osteopaenia
- Osteoporosis= T-score \< -2.5 - Osteopenia= T score between -1 & -2.5
32
where are fractures common in osteoporosis
Typical fracture= neck of femur (NOF), vertebral (get shortened height), wrist (Colle’s)
33
causes of osteoporosis
- 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
treatment for osteoporosis
- 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
differences between osteomalacia and osteoporosis
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
Hypercalcaemia Symptoms
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
Hormonal response to Hypercalcaemia
- 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
Causes of Hypercalcaemia
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
which cause of hypercalcaemia has good prognosis
hypercalcaemia with normal/raised PTH = Parathyroid tumour = curable = good prognosis hypercalcaemia with suppressed PTH = malignancy/sarcoidosis = poor prognosis
40
- Commonest cause of hypercalcaemia
Primary Hyperparathyroidism; - Parathyroid adenoma, hyperplasia or carcinoma Hyperplasia is associated with MEN 1
41
- Signs and symptoms of Primary Hyperparathyroidism - biochemicals of primary hyperparathyroidism:
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
pathophysiology of familial hypocalcuric hypercalcaemia + degree of increased calcium levels + treatment
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
where is PTH related peptide found normally and abnormally
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
how is PTH related peptide a prognostic factor
very bad prognostic feature to have of cancer because it causes metastases to spread
45
3 types of hypercalcaemia in malignancy
- 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
Causes of non-PTH driven Hypercalcaemia
- 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
Hypercalcaemia Treatment: acute management
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
Hypocalcaemia Signs
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
Hypocalcaemia- Treatment
- Calcium + Vitamin D - Usually activated 1alpha vitamin D to help rapidly improve by activating calcium absorption
50
causes of hypocalcameia + examples
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
biochemicals in non PTH driven hypocalcaemia
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
how do you treat non PTH driven hypocalcaemia
Vitamin D replacement
53
what type of hyperparathyroidism can CKD Lead to and how
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
which to types of hyperparathyroidism have same biochemicals
primary + tertiary hyperparathyroidism have the same biochemistry (VERY LOW calcium)
55
what is pseydohyperparathyroidism +.biochemicals + 1 main distinctive clinical feature
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
Paget’s Disease: clinical features
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
which bones does pagets disease affect
Pelvis, femur, skull and tibia
58
biochemicals of pagets disease
Elevated alkaline phosphatase (ALP) – VERY HIGH Calcium + PO4 = NORMAL
59
diagnosis and treatment of pagets disease
diagnosis : Nuclear medicine scan/ XR Treatment: Bisphosphonates (for pain
60
complication of primary hyperparathyrodism
o Osteitis fibrosa cystica lots of cysts in the bone due to long standing bone loss
61
what is Renal osteodystrophy
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
summarise the biochemistry of osteoporosis osteomalacia pagets parathyroid bone disease renal bone disease
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
TABLE FROM KARIM MEERAN'S LECTURE ON METABOLIC BONE DISEASE - IGNORE PATH GUIDE
\*\*in renal bone disease, vitamin D levels are normal but it's just ot functional\*\*
64
Pseudohypoparathyroidism
* Caused by resistance to PTH * Results in low calcium, high phosphate, high PTH * Features include hypocalcaemia, round face and short metacarpals/metatarsals
65
Why is phosphate high in chornic kidney disease causing secondary hyperparathyoirdism?
\*\*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
difference between primary and tertiary hyperparathyrodism
67
what happens to PTH levels in squamous cell cancers producing PTHrP
PTH level is low.
68
What effect does dietary vitamin D deficiency have on the axis?
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
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