1: Calcium Metabolism Flashcards

1
Q

4 functions of calcium in the body

A

muscle contraction

action potential

coagulation cascade

pancreatic enzyme release and activation

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2
Q

calcium normal range

A

2.2 - 2.6 mmol/L

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3
Q

3 forms of serum calcium

normal albumin range

A

free (ionised) = 50%

  • biologically active

protein-bound = 40%

  • to albumin
  • albumin normal range = 35 - 50 g/L

complexed = 10%

  • citrate/phopshate
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4
Q

effect of abnormal albumin levels on serum calcium -> corrected calcium formula

A

corrected calcium = serum calcium + (0.02 x (40 - serum albumin in g/L))

in low albumin states, the bound calcium is low but free calcium will be normal

blood gas machines can measure ionised/free calcium

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5
Q

calcium homeostasis pathway

A

hypocalcaemia detected by parathyroid gland

gland releases PTH

PTH:

  • increased 1,25 OH Vit D -> increased intestinal Ca absorption: RATE LIMITING STEP
  • increased renal Ca resorption
  • increased bone Ca resorption

rise in plasma Ca

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6
Q

2 key hormones in in calcium homeostasis

A

PTH: 84 aa protein, only from parathyroid gland

  • liberates Ca from bone
  • Stimulates 1a-hydroxylase activity -> production of calcitriol (1,25-dihydroxycholcalciferol)
  • stimulates renal phosphate excretion in urine PHOSPHATE TRASHING HORMONE

Vit D: steroid hormone, derived from cholesterol

  • in 2 forms (both active, straight to liver if taken by mouth)
  • D2 (ergocalciferol) = from plants (extra double bond)
  • D3 (cholecalciferol) = produced when 7-dehydrocholesterol -> cholecalciferol. This reaction takes place when UV light hits skin. Vit D synthesised in skin.
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7
Q

Vitamin D synthesis

A

UV light on skin = 7-dehydrocholesterol -> cholecalciferol (vit D3)

25-hydroxylase in liver = cholecalciferol (vit D3) -> 25-hydroxycholecalciferol (inactive, stored THIS IS WHAT IS MEASURED)

1a hydroxylase (activated by PTH) in kidneys = 25-hydroxycholecalciferol -> 1,25-dihydroxycholecalciferol (calcitriol)

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8
Q

Relationship with sarcoidosis

A

1a-hydroxylase can be expressed in lung cells of sarcoid tissue, hence why some patients with sarcoidosis present with features of hypercalcaemia. However, this is seasonal (patients tend to develop hypercalcaemia in summer months due to increased sun exposure (-> more vitamin D activation).

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9
Q

3 roles of activated 1,25(OH)2 Vitamin D

other effects

what is vit D deficiency associated with

A

Increased intestinal Ca2+ absorption

Increased intestinal phosphate absorption

Critical for bone formation

Other effects:

  • vit D receptor controls many genes (e.g. cell proliferation, immune system)
  • associations between vit D deficiency and cancer, autoimmune disease, metabolic disease etc.

Vit D deficiency associated with poverty and poor diet. Cancer and metabolic disease prevalent amongst pooror popualtions (perhaps associative rather than causative)

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10
Q

Role vit D in bone

ALP

A

activates osteoclasts

  • liberate Ca from bone -> holes in bone

osteoblasts activated to patch up these holes

  • ALP by-product of osteoblast activity and riseds when bone resportion is stimulated by vitamin D or PTH = states amount of BONE TURNOVER
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11
Q

ALP is raised (bone causes) = 3

A

post-fracture

abnormal PTH secretion

Children when growing

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12
Q

Bone is a reservoir of (3)

A

calcium

phosphate

magnesium (important in PTH synthesis as deficiency in magnesium -> hypocalcaemia)

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13
Q

Role of the skeleton

A

Structural framework

Strong, yet relatively light weight

Mobile

Protects vital organs

Capable of orderly growth and remodelling

Metabolic role in calcium homeostasis

Main reservoir of calcium, phosphate and magnesium

NB: bold is endocrine view non-bold is orthopaedic view

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14
Q

overview of metabolic bone diseases (5)

A
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15
Q

Vitmain D deficiency = which conditions, pathophysiology

A

impaired absorption of BOTH calcium and phosphate across intestinal wall

defective bone mineralisation

osteomalacia (adults), rickets (children)

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16
Q

Risk factors for vitamin D deficiency (4)

A

Lack of sunlight

Dark skin (less sunlight can reach cells that produce vitamin D)

Dietary changes

Gut malabsorption (e.g. coeliac disease)

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17
Q

Clinical features of vitmain D deficiency: osteomalacia vs rickets

A
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18
Q

Osteomalacia: most common cause

A

SECONDARY HYPERPARATHYROIDISM -> vit D deficiency

low calcium, high PTH, high ALP = as a result of vit D deficiency

leads to osteoclast activtion to liberate calcium form the bone

whilst this normalises plasma calcium levels, it leads to weak and demineralised bone

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19
Q

Other causes of osteomalacia aka vit D deficiency (4)

mx for one of them

A

Renal failure

  • lack of 1a-hydroxylase -> unable to activate vit D
  • Mx: calcitriol analogues (e.g. alphacalcidiol)
  • this drug is pre-activated and does not require kidney action

Anticonvulsants (carbamazepine): induce vit D breakdown

  • newer drugs do not
  • children started on these drugs are at an increased risk of developing rickets

Lack of sunlight

Chappatis (phytic acid)

  • phytic acid chelates vit D in the gut and reduces absorption
20
Q

osteoporosis definition

what is it accelerated by

A

normal wear and tear old age condition, occur more often as people live longer

reduction in bone density, normal mineralisation and normal biochemistry

bone mass gradually decreases after the age of around 20 years

accelerated by:

  • low testosterone
  • oestrogen
  • Cushing’s syndrome
  • Hyperthyroidism
21
Q

osteoporosis presentation

A

cause of pathological fracture

  • neck of femur (NOF)
  • vertebral
  • wrist (Colle’s)
  • hip

ASYMPTOMATIC BEFORE FRACTURE (fractive is first symptom)

  • by this point it is too late
22
Q

Causes of osteoporosis

A

Age-related decline in bone mass (failure to attain peak bone mass -> fracture earlier on)

Normally from disuse of bones

Endocrine:

  • Hyperthyroidisim + Cushing’s syndrome = increased catabolism
  • Acromegaly = testosterone deficiency -> osteoporosis
  • Early menopause

More rapid bone loss during adulthood, due to:

  • sedentary lifestyle
  • alcohol, smoking
  • low BMI
  • hyperprolactinaemia
  • thyrotoxicosis
  • Cushing’s syndrome
  • steroids (young and male)
  • prolonged recurrent illness
  • CKD
23
Q

osteoporosis diagnosis

vs osteopenia

A

DEXA scan

  • often hip or lumbar spine
  • T-score: number of standard deviations from the mean of a young healthy population (useful to determine fracture risk)
  • Z-score: number of standard deviations from the age-matched control (useful to identify accelerated bone loss in younger patients)

Osteoporosis = T-score < -2.5 (more than 2.5 standard deviations below the mean)

Osteopenia = T-score between -1 and -2.5

24
Q

Lifestyle tx of osteoporosis

A

weight-bearing exercise

stop smoking

reduce alcohol consumption

25
drug txs for osteoporosis
**Vit D/calcium** **Bisphosphonates** (e.g. _alendronate,pamidronate_ = decreases bone resorption) * have **nitrogen** in them * bisphosphonates encourage osteoblasts to incorporate calcium bisophosphonate into bone * **osteoclasts cannot breakdown the nitrogen-phosphate bone** * patient has almost undegradable bone * too much -\> **brittle bones** (over 5 years, large fracture risk reduction) * Side effects: nausea and gastric irritation * use **_FRAX tool_** to see if bisphosphonates are needed * **_CONTAINDICATED in CKD_** Teriparatide (PTH derivative) = stimulates bone formation (anabolic - increases osteoblast activity) * activates osteoblasts more than osteoclasts Strontium (anabolic and anti-resorptive) = side effects * laid down as bone; may not be good as normal bone HRT (oestrogens) = if early menopause (but increases breast cancer risk) SERM (e.g. raloxifene) = behave like oestrogen on bone, but not on the breast * bone agonist * breast antagonist (e.g. raloxifen) * not good at treating hot flushes **Denosumab** (monoclonal antibody)
26
symptoms of hypercalcaemia
polyuria/polydipsia (it is an osmotic diuretic) constipation neurological: confusion, seizures, coma * these sx usually occur when Ca \>3.0 mmol/L (very high) **these sx oveerlap with sx of hyperparahthyroidism**
27
interpreting hypercalcaemia
is this a genuine result? repeat if in doubt * you cannot measure PTH from first sample * requires a different tube * we take two bloods = one for Ca, one for PTH what is the PTH? should be low when the Ca is high
28
What is the most common cause of Hypercalcaemia? pathophysiology
Primary hyperparathyroidism ## Footnote PTH activates osteoclasts -\> calcium and phosphate release into blood PTH activates pump in nephron -\> enhanced Ca absorption, inhibition of phosphate reabsorption (high Ca, low phosphate)
29
causes of primary hyperparathyroidism
_Parathyroid adenoma_ (COMMONEST CAUSE of hypercalcaemia in primary hyperparathyroidism) Parathyroid hyperplasia (genetic cause where all 4 glands grow) = MEN1associated * **MEN1** = rare condition. common in Wesr London Parathyroid carcinoma (very rare) more common in **women**
30
features of primary hyperpatahytoridism (biochemical and clinical)
High Ca, inappropriately non-suppressed PTH (high/normal), low phosphate hypercalciuria results from hypercalcaemia = this can cause kidney stones Clnical features: * bones * stones (renal calculi) * abdominal moans (constipation, pancreatitis) * psychic groans
31
CaSR: familial hypocalciuric/benign hypercalcaemia
32
Hypercalcaemia in malignancy (3) aka HIGH CALCIUM WITH A SUPPRESSED PTH
Multiple myeloma * normal ALP = as only increase in osteoclast acitvity. Remember ALP is raised when osteoblast activity increases * low Hb = anaemia * high creatinine = renal impairment * high phosphate = increase osteoclasts
33
Other causes of non-PTH driven hypercalcaemia
Sarcoidosis (due to non-renal 1a-hydroxylase expression) Thyrotoxicosis (thyroxine increases bone resorption and turnover) Hypoadrenalism (renal Ca2+ transport) Thiazide diuretics (renal Ca2+ transport) Excess vitamin D (e.g. sun beds)
34
Hypercalcaemia tx
Acute = **FLUIDS, FLUIDS, FLUIDS** (normal saline) * these patients are dehydrated = if they are rehydrated, they will excrete lots of calcium * 0.9% sodium chloride 1L infusion over 4 hours * 0.9% Saline 4L/24 hours **Bisphosphonates (e.g. alendronate, pamidronate) if the cause is cancer** = it will stop the cancer from eating the bone _Treat the underlying cause_ * haem malignancies (lymphoma, multiple myeloma) = **corticosteroids** (inhibits 1a-hydroxylase) after fluids instead of bisphosphonates * tertiary hyperparathyroidism = **parathyroidectomy.** Side effects = hypocalcaemia, hoarse/loss voice from recurrent laryngeal nerve damage
35
Features of hypocalcaemia
Neuro-muscular excitablity * Trousseau’s Sign (carpopedal spasm with BP cuff) * Chvostek’s Sign (tapping of face -\> twitching) * Increased reflexes * Stridor (spasm of the larynx) * Arrhythmia = prolonged QT interval -\> fatal arrhythmia like ventricular tachycardia (e.g. torsades de pointes)
36
Causes of hypocalcaemia
37
Ix for hypocalcaemia
38
Tx of hypocalcaemia
acute: * mild = oral calcium supplementation * severe (spasms/ECG changes) = IV calcium gluconate LT: * Treat cause * Encourage good dietary calcium and Vitamin D intake * Calcium and Vitamin D supplementation * Alphacalciferol if CKD 'activiated form' * Magnesium supplements if concurrent hypomagnesaemia
39
How do we interpet hypocalcaemia
40
Paget's disease definition presentation (clinical and biochemical) Ix Tx
_focal disorder of bone remodeling_ **focal pain,** warmth, deformity, many fractures, SC nerve compression, malignancy, **cardiac failure** pelvis, femur, skull, tibia **Elevated ALP** (only abnormal test = both bone formation and turnover increased, but at the same rate) Ix: **nuclear med scan** (pt given IV radio-labelled bisphosphate) * osteoblasts use this bisphosphonate to make bone = we can see where they are working * we see 'hot' areas = this suggests pathology (may also see hot nodules in metasases) Tx: **bisphosphonates**
41
Other metabolic bone disorders
42
Biochemistry table in Metabolic Bone Disease
43
secondary and TERTIARY hyperparathyroidism CKD definitive tx side effects of tx
definitive tx = parathyroidectomy side effects = hypocalcaemia (commonest), hoarse/loss voice from recurrent laryngeal nerve damage (common)
44
Assessment and Ix for hypercalcaemia
45
pseudo vs pseudopseudohypoparathyrodiism
pseudo = bone problems, low calcium, high PTH in absence of kidney disease (as that would make you think of secondary hyperparathyroidism) pseudo pseudo = an inherited condition that causes short stature, round face, and short hand bones