1: Calcium Metabolism Flashcards
4 functions of calcium in the body
muscle contraction
action potential
coagulation cascade
pancreatic enzyme release and activation
calcium normal range
2.2 - 2.6 mmol/L
3 forms of serum calcium
normal albumin range
free (ionised) = 50%
- biologically active
protein-bound = 40%
- to albumin
- albumin normal range = 35 - 50 g/L
complexed = 10%
- citrate/phopshate
effect of abnormal albumin levels on serum calcium -> corrected calcium formula
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
calcium homeostasis pathway
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
2 key hormones in in calcium homeostasis
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.
Vitamin D synthesis
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)
Relationship with sarcoidosis
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).
3 roles of activated 1,25(OH)2 Vitamin D
other effects
what is vit D deficiency associated with
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)
Role vit D in bone
ALP
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
ALP is raised (bone causes) = 3
post-fracture
abnormal PTH secretion
Children when growing
Bone is a reservoir of (3)
calcium
phosphate
magnesium (important in PTH synthesis as deficiency in magnesium -> hypocalcaemia)
Role of the skeleton
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
overview of metabolic bone diseases (5)
Vitmain D deficiency = which conditions, pathophysiology
impaired absorption of BOTH calcium and phosphate across intestinal wall
defective bone mineralisation
osteomalacia (adults), rickets (children)
Risk factors for vitamin D deficiency (4)
Lack of sunlight
Dark skin (less sunlight can reach cells that produce vitamin D)
Dietary changes
Gut malabsorption (e.g. coeliac disease)
Clinical features of vitmain D deficiency: osteomalacia vs rickets
Osteomalacia: most common cause
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
Other causes of osteomalacia aka vit D deficiency (4)
mx for one of them
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
osteoporosis definition
what is it accelerated by
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
osteoporosis presentation
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
Causes of osteoporosis
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
osteoporosis diagnosis
vs osteopenia
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
Lifestyle tx of osteoporosis
weight-bearing exercise
stop smoking
reduce alcohol consumption
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)
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
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
What is the most common cause of Hypercalcaemia?
pathophysiology
Primary hyperparathyroidism
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)
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
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
CaSR: familial hypocalciuric/benign hypercalcaemia
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
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)
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
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)
Causes of hypocalcaemia
Ix for hypocalcaemia
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
How do we interpet hypocalcaemia
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
Other metabolic bone disorders
Biochemistry table in Metabolic Bone Disease
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)
Assessment and Ix for hypercalcaemia
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
