Hypercalcaemia

Question 1

What is calcium affected by?

Answer 1

Albumin if albumin is low total measured calcium will be low, however there is less bound- The ionized physiologically active calcium remains normal!- this is what is on blood gas

PH, If there are more hydrogen ions they bind to albumin and displace the calcium and vice versa
PH down (Acidosis): ionized calcium increases
PH goes up: ionized calcium decreases
E.g tingling in hyperventilation (Respiratory alkalosis)

Other factors such as proteins in myeloma, cirrhosis, individual variation affect binding therefore be cautious in interpreting

Question 2

What should you do if you are in doubt over a high calcium?

Answer 2

If in doubt over high Ca2+, take blood samples uncuffed (remove tourniquet after needle in vein, but before blood sample), and with patient fasted

Question 3

What is the definition of high calcium?

Answer 3

Condition which is characterised by a increased serum calcium concentration of 2.6mmol/L or higher on two occasions

Following an adjustment for serum albumin []

Mild is 2.6-3.00mmol/
Moderate is 3.01-3.40
Severe >3.40

Question 4

What makes up 90% of hypercalcaemia causes?

Answer 4

Hyperparathyroidism and malignancy

Question 5

Which type of hyperparathyroidism does NOT cause hypercalcaemia?

Answer 5

Secondary

Question 6

List the causes of hypercalcaemia

Answer 6

Excessive PTH secretion: primary hyperparathyroidism, tertiary hyperparathyroidism, ectopic

Malignant disease

Excessive action of vit D (iatrogenic/self administered, granulomatosis, lymphoma)

Excessive calcium intake: Milk-alkali syndrome

Endocrine diseases (mild hypercalcaemia)

Drugs

Other: aki, immbobility, dehydration, familial hypocalciuric hypercalcemia, HIV, bone

Question 7

Why does malignancy cause hyperparathyroidism

Answer 7

• 80% are due to secretion of PTH related hormone and other circulating factors by the tumor (paraneoplastic)
  
  • 20% due to bone mets causing osteolysis and release of skeletal calcium e.g myeloma and breast cancer
  • Overproduction of 1,25 vitamin D (e.g in lymphoma)
  • PTH driven (in ectopic or parathyroid carcinoma)

Question 8

What is milk alkali syndrome?

Answer 8

due to taking too much calcium -high blood calcium, renal impairment, metabolic alkalosis (too much calcium and absorbable alkali)

e.g due to Caused by taking too much calcium (eg as supplements for osteoporosis) + absorbable alkali (e.g antacids drugs)
Calcium co-prescribed with antacids or calcium and vitamin D preparations so called calcium alkali syndrome

Question 9

When should malignant disease be suspected?

Answer 9

If rapid onset, severe, and/or symptoms

Question 10

What endocrine diseases cause mild hypercalcaemia

Answer 10

• Thyroxicosis- high bone turn over and alkaelaemia due to hyperventilation
• Addison’s disease
○ Increased calcium from bone and hydration
• Phaeochromatoma
○ This can cause hypercalcaemia due to the production of parathyroid hormone-related peptide (PTHrP) and co-existing primary hyperparathyroidism in MEN type 2A syndrome
• Acromegaly
• Vasoactive intestinal polypeptide hormone-producing tumour (VIPoma, a type of islet cell tumour)
○ When hypercalcaemia is present, it can be severe and the mechanism is unclear. Clinical features include large-volume diarrhoea and hypokalaemia

It may be associated with rare inherited endocrinopathies including multiple endocrine neoplasia (MEN) type 1 and type 2A syndromes, hyperparathyroidism jaw tumour syndrome, and familial isolated hyperparathyroidism

Question 11

What drugs cause hypercalcaemia

Answer 11

• Thiazide diuretics: Usually mild and caused by reduced calcium excretion- Usually returns after discontinuation
• Vitamin D analogues, oral intake, application of potent analogues
• Lithium administration : Directly stimulates PTH and increase renal calcium absorption- typically reverses on withdrawal- decreases sensitivity of the calcium-sensing receptor to calcium, and it may also unmask pre-existing primary hyperparathyroidism
• Vitamin A: Excessive amounts for weeks- months
Other manifestations of vitamin A toxicity include dermatitis, alopecia, and hepatic dysfunction.
•Calcium
• Antacids
• Theophylline toxicity

Question 12

What is familial hypocalciuric hypercalcaemia?

Answer 12

It is a defect in the calcium sensing receptor autosomal dominant- which increases the threshold calcium concentration which these are activated at
Mild lifelong asymptotic hypercalaemia, hypophosphatasemia, reduced renal calcium, normal or elevated PTH

Question 13

What granumotaous disease cause hypercalcaemia

Answer 13

sarcoidosis, histoplasmosis, TB, leprosy, candidiasis, coccidiomycosis, berylliosis, eosinophilic granuloma, and silicone-induced granuloma - 10% causes due to extra renal conversion of 25OD to 1,25 OHD

Question 14

What cause a suppressed/low PTH

Answer 14

Malignancy
Granulomatous disease
Drugs: calcium, and/or vit D, antacids, thiazides, lithium, theophylline
Rhabdomyolysis
Rarely: adrenal insufficiecny, thyrotoxicosis, phaeo

Question 15

What cause a high or normal PTH

Answer 15

Primary hyperparathyroidism
Tertiary hyperparathyroidism
Familial hypocalciuric hypercalcaemia

Question 16

What are the symptoms of hypercalcaemia

Answer 16

Bones PAIN
Stones KIDNEY AND GALLBLADDER
Groans CONSTIPATION AND MUSCLE WEAKNESS
Thrones POLYURIA
Psychiatric overtones DEPRESSION/CONFUSION

Question 17

What is the ECG features of hypercalcaemia

Answer 17

Shortening of QT interval - lessexcitable
Osborn wave- J wave - the j point where the QRS complex joins the ST segment. It represents the approximate end of depolarization and the beginning of repolarization as determined by the surface ECG. There is an overlap of around 10ms.
Cardiac arrthymias
Bradycardia

Question 18

How should you investigate hypercalcaemia?

Answer 18

History: ask about clinical features, systems review, medical conditions, Fx, any drugs

Examination: hydration + GCS/cognition, look for cause

ECG/CXR

Bloods: corrected calcium, phosphate, PTH, vitamin D, ALP, Mg, albumin, UE
Serum ACE for sarcoid

Question 19

What specialist tests can you do?

Answer 19

Specialist tests: 24hr urinary calcium excretion, DEXA scan: osteoporosis, parathyroid MIBI scan and US parathyroid (if surgical candidate)

Question 20

What would PTH, ALP and phosphate look like in primary or tertiary hyperparathyroidism

Answer 20

Normal/raised PTH
normal/raised ALP
Low phosphate

Question 21

What would PTH, ALP, phosphate look like in bone mets

Answer 21

Low PTH
Raised ALP
Raised phosphate

Question 22

What would PTH, ALP, phosphate look like in myeloma, vit D overdose, or granulmatous

Answer 22

Low PTH
Normal ALP
Raised phosphate

Question 23

How do you manage hypercalcaemia

Answer 23

DICUSS WITH SENIOR
Diagnose and treat the underlying cause:
If calcium >3.0mmol/L unless value is stable and asymptomatic, in patients with malignancy treat >3 even if minimal symptoms
AE with cardiac monitoring
1. Correct dehydration if they are dehydrated give IV saline 0.9% 4-6L in 24hrs
a. Hypercalcaemia causes dehydration- monitor for fluid overload
2. Bisphosphonates (zoledronate or pamidronate as per local guidelines)- must be well hydrated first
○ Prevent bone reabsorption by inhibiting osteoclast activity
○ Typically take 2-3 days to work - max effect is 7 days
○ IV Pamidronate 30mg (in 300ml over 3hours)
or IV Zoledronic Acid 4mg (in 100ml over 15mins) shown to be more potent, and agent of choice for malignant associated hypercalcemia.

Question 24

What is some further management of hypercalcamia

Answer 24

○ Stop contributing drugs
○ Chemotherapy for malignancy
○ Calcitonin, denosumab, calcimimetics or parathyroidectomy
○ Prednisolone in lymphoma, granulomatous, or Vit D
○ Salmon calcitonin acts similar to bisphosphonates with a quicker onset of action about 48hrs
○ Loop diuretics may be used but evidence is scant- should be used carefully as worsen electrolyte abnormalities. These inhibit calcium reabsorption therefore it is lost
May use dialysis in patients who have anuria (AKI or CKD) or where fluid overload is an issue