17 - calcium - physiology and clinical aspects

name some dietary sources of calcium

milk cheese and dairy

green leafy veg

soya beans

tofu

nuts

bread - fortified

fish where you can eat the bones e.g. sardines and pilchards

40% of calcium is bound in plasma, which plasma protein is it bound to?

albumin

15% of calcium is non-ionised or..

complexed to citrate or PO4 etc

how is the rest of calcium found

free - biologically important (45%)

what is the normal range of serum calcium

2.20-2.60 mmol/L

how is free calcium calculated

increased albumin DECREASES free calcium

decreased albumin INCREASES free calcium

- adjust Ca2+ by 0.1mmol/l for each 5g/L reduction in albumin from 40g/l

acidosis increases ionised calcium which predisposes to what?

predisposing to hypercalcaemia

a patient has a calcium of 2.55 mmol/L

- albumin = 30g/L

- what is the corrected calcium

adjust calcium by 0.1 for each 5g/L from 40g

- 40 - 30 = 10

- 10/5 = 2

- 0.1 x 2 = 0.2

calcium =)

= 2.55 + 0.2

= 2.75

decreased albumin = increased calcium

what cells respond directly to changes in Ca2+ concentrations

chief cells

alterations in ECF Ca2+ levels are transmitted into which cells via which receptors

parathyroid cells via calcium sensing receptors

what hormone is released in response to a fall in calcium

PTH

increased calcium causes PTH to what

decrease

why is PTH important for calcium

promotes calcium reabsorption from renal tubules and bone

what does PTH do for vitamin D

mediates conversion of vitamin D from inactive form to active form in kidneys

where is vitamin D inactivated

liver

what is calcium vital for

structural - Essential for bone and tooth formation

signal transduction - acts as second messenger in many cell signalling pathways

neuromuscular - required for neurotransmitter release and muscle contraction

biochemical - cofactor for many enzymes e.g. clotting factors in coagulation cascade

cellular - cell division

overall effect of PTH on plasma Ca2+ and phosphate concentrations

increase plasma Ca2+ and decrease plasma phosphate (PO43− ) concentrations.

effects of PTH on bone

Stimulates osteoclasts to resorb bone, releasing Ca2+ and phosphate into the blood

Describe effects of PTH on renal formation of 1a, 25 - dihydroxycholecalciferol (calcitriol)

PTH upregulates the enzyme 1α-hydroxylase in the kidneys, which converts 25-hydroxyvitamin D into the active form, 1α, 25-dihydroxycholecalciferol (calcitriol)

effects of PTH on kidneys

• Increases Ca2+ reabsorption in the distal convoluted tubule. 

• Decreases phosphate reabsorption in the proximal tubule (promoting phosphaturia). This prevent the Ca2+ from forming insoluble salts with phosphate, keeping it in its active, ionized form. 

what investigations are used to detect abnormalities of calcium control especially hypercalcaemia

serum adjusted calcium levels

PTH levels

phosphate, magnesium and creatinine

Vitamin D

Imaging

what imaging is done

ultrasound

sestamibi

4D-CT

when checking PTH levels what are you looking for?

to distinguish between PTH-mediated (primary hyperparathyroidism) and non-PTH mediated causes (e.g. malignancy)

most common causes of hypercalcaemia

primary hyperparathyroidism (usually a benign adenoma)

malignancy (cancers secreting PTHrP or bone metastases)

vitamin D toxicity

thiazide diuretics

hypercalcaemia clinical features

bones, stones, groans and psychic moans

e.g.

osteoporosis

nephrolithiasis (kidney stones)

polydipsia

polyuria

constipation

nausea & vomiting

anorexia

decreased concentration

shortening of the QT interval

what does a calcium level of <0.3mmol/l tell you

often asymptomatic and does usually require urgent correction

what does a calcium range of 3-3.5mmol/l tell you

may be well tolerated if it has risen slowly but may be symptomatic and prompt, treatment usually indicated

what does a calcium level >3.5mmol/l tell you

requires urgent correction due to risk of dysrhythmia and coma

examination of hypercalcaemia

lymph nodes

concerns about malignancy (breast, lung etc)

investigations for hypercalcaemia

U&Es

Ca

PO4

Alkaline Phosphate

Myeloma screen

Serum ACE

PTH

-consider ECG

hypercalcaemia process

recheck calcium & albumin, ensure corrected calcium calculated

check PTH

if PTH normal or increased → primary hyperparathyroidism or familial hypocalciuric hypercalcaemia (rare) or tertiary hyperparathyroidism (renal failure)

if PTH low → malignancy, drug causes

Mr blogs, 75 yo

changed bowel habits and weight loss

calcium 2.76, corrected calcium 2.86

hilar mass on CXR

heavy smoker, chronic cough

repeated corrected calcium 2.81

-what is the most likely diagnosis

hypercalcaemia of malignancy

mrs jones, 54 yo

routine bloods shows adjusted calcium of 3.05mmol/l

asymptomatic

serum calcium 2.95mmol/l 3 years ago while inpatient for cholycystectomy

-what is the likely diagnosis?

primary hyperparathyroidism

what is the main primary hyperparathyroidism

parathyroid adenoma

investigations for primary hyperparathyroidism

Ca, PTH

U&Es: check renal function

abdominal imaging: renal caliculi

DEXA: osteoporosis

urinary calcium/creatinine ratio

24hr urinary calcium (if elevated likely to recommend surgery)

vitamin D

indications for primary hyperparathyroidism surgery:

serum calcium > 0.25mmol/l above the upper limit of normal (2.85 in Aberdeen)

skeletal: osteoporosis on DEXA or vertebral fracture

renal: eGFR <60 or presence of kidney stones or hypercalciuria

Age: <50 years

medical management of primary hyperparathyroidism

fluid intake

vitamin D replacement

cinacalcet

function of cinacalcet

acts as a calcimetic i.e. mimics the effect of calcium on the calcium sensing receptor on chief cells, leads to fall in PTH levels and subsequently calcium levels

familial hypocalciuric hypercalcaemia

autosomal dominant disorder of the calcium sensing receptor

low levels of urinary calcium

benign, no therapy indicated

+ve family history

PTH may be normal or slightly elevated

no evidence of abnormal parathyroid tissue on ultrasound or isotope scan

multiple endocrine neoplasia type 1

3 P’s

• primary hyperparathyroidism

• pancreatic

• pituitary

multi-gland involvement

high recurrence risk

MENIN mutation (Chr 11)

multiple endocrine neoplasia type 2A

• medulla thyroid cancer

• phaeochromocytoma (secreting too much adrenaline/noradrenaline from adrenal glands)

• primary hyperparathyroidism

RET mutation

1st line management of hypercalcaemia

rehydration

• 0.9% saline 4-6 litres over 24hrs

• monitor for fluid overload

• consider dialysis if severe renal failure

1st line management of hypercalcaemia after rehydration

IV biphosphates

• zolendronic acid 4mg over 15 mins

• give more slowly and consider dose reduction if renal impairment

• calcium will reach nadir at 2-4 days

2nd line management of hypercalcaemia

glucocorticoids

calcitonin

calcimimetics

parathyroidectomy

when would you use glucocorticoids in hypercalcaemia

in lymphoma, other granulomatous disease or 25OHD poisoning

when would you use calcitonin in hypercalcaemia

if poor response to biphosphates

when would you use calcimimetics in hypercalcaemia

in primary hyperparathyroidism, parathyroid carcinoma or renal failure

when would you do parathyroidectomy in hypercalcaemia

acute presentation of primary hyperparathyroidism, if severe hypercalcaemia and poor response to other measures

mr arthur 74 yo

brought to GP by wife appeared confused and has been constipated

under treatment for multiple myeoloma

adjusted calcium is 3.75

what should you do?

admit

groups at risk of vitamin D deficiency

children

pregnant women

black people

those inside a lot e.g. residential homes

people who have lots of their skin covered for religious reasons e.g. hijabis

what is acute hypocalcaemia defined as

serum calcium <2.20

clinical features of hypocalcaemia

neuromuscular irritability (tetany)

prolonged QT interval

papilloedema

parasthesia - tingling in fingers or around mouth

signs of hypocalcaemia

Chvostek’s sign (facial twitching)

Trousseau’s sign (carpal spasm with BP cuff). 

causes of hypocalcaemia

hypoparathyroidism

vitamin D deficiency

magnesium deficiency

total thyroidectomy

selective parathyroidectomy

radiation induced

autoimmune

what are you looking for in examination of hypocalcaemia

neck scars

investigations for hypocalcaemia

ECG

serum calcium

albumin

phopshate

PTH

U&Es

Vitamin D

Magnesium

if confirmed hypocalcaemia (adjusted for albumin) and PTH is low or normal:

check magnesium

if low → magnesium deficiency

if normal → hypoparathyroidism or calcium sensing receptor defect (rare)

if confirmed hypocalcaemia (adjusted for albumin) and PTH is high

check urea and creatinine

if urea and creatinine high → renal failure

if normal → check vitamin D

if low → vitamin D deficency

if normal → pseudohypoparathyroidism or calcium deficiency (rare)

total calcium, ionised calcium, phosphate, PTH levels in:

vitamin D deficiency

hypoparathyroidism

Vitamin D deficiency: low, low, low, high

hypoparathyroidism: low, low, high, low

hypoparathyroidism may result from

agenesis (e.g. DiGeorge syndrome)

destruction (neck surgery, autoimmune disease)

infiltration (e.g. haemochromatosis or wilson’s disease)

reduced secretion of PTH (neonatal hypocalcaemia, hypomagnesaemia)

resistance to PTH

what is DiGeorge syndrome

22q11 deletion resulting in learning difficulties, speech & hearing problems, heart problems

pseudohypoparathyroidisim

presents in childhood

kidney and bone unresponsiveness to PTH

characterised by hypocalcaemia, hyperphosphatemia and elevated PTH concentration

albright’s hereditary osteodystrophy

obesity

short

shortening of metacarpal bones that can occur in some patients with pseudohypoparathyroidisim

(AHO alone without abnormalities of calcium or parathyroid hormone is pseudo-pseudohypoparathyroidism)

treatment of mild hypocalcaemia

asymptomatic

serum calcium >1.9mmol/l

oral calcium tablets

if post thyroidectomy repeat calcium 24 hours later

start vitamin D if deficient

stop any precipitating drug and replace Mg2+ if low

treatment of severe hypocalcaemia

symptomatic or serum calcium <1.9mmol/l

medical emergency

IV calcium gluconate 10-20ml 10%

initial bolus repeated until patient asymptomtic and/or calcium levels significantly increased

calcium gluconate infusion can follow (100ml of 10% calcium gluconate in 1L 0.9% saline)

aim to achieve normal calcaemia

treat underlying cause

mrs smith 62 yo

presents to GP complaining of vague symptoms

adjusted calcium 1.95mmol/l

she is on biphosphonate for osteoporosis

dietary intake of calcium reasonable

investigations show low Ca, low PO4, PTH awaited

what is her treatment?

vitamin D replacement

what type of vitamin D should be prescribed for patients with severe renal impairment?

alfacalcidol or calcitriol (hydroxylated derivatives - active form)

maintenance dose and loading dose of vitamin D

maintenance: 400-1000 international units

loading: 3200 units daily

20,000 units weekly for 12 weeks