Review of approaching hypercalcaemia with a clinical application of physiology and general management

1. How to Approach
Hypercalcaemia?
Adeel Rafi Ahmed
MB BCh BAO MRCPI MRCP(UK) PGDip (ClinEd)
Holder of European Certificate in Nephrology and European Speciality Exam in Nephrology
Renal and Internal Medicine Registrar
Adjunct Clinical Lecturer UCC
University Hospital Waterford, Ireland

2. Case Study
• 71 Female presented with acute confusion
• Nausea and vomiting
• Abdominal pain
• Frequent urination
• PMHx
• IHD and hypertension
• Meds: Aspirin, hydrochlorothiazide, metoprolol, calcium supplements
and atorvastatin
O/E BP 100/60 HR 120 SPO2 97%RA RR 26 Dry Mucosa JVP<4cmH20

3. Labs
•
Reference
Hb 12
PLT 160
MCV 81
WCC 7
neutrophils 6
Na 146
K 5.1
Ca+2 3.64mmol/L 2.2-2.6mmol/L
Creatinine 200
Urea 20
CRP 7
ESR 10
Albumin 25
Ionised calcium (VBG) 1.95
TSH 2 0-4

4. 3 Key spectrums of presentation
1- Asymptomatic patient with incidental finding, may be hypertensive
as calcium causes vasoconstriction.
2- non emergency patients under investigation for symptoms such as
fatigue, weakness constipations, myalgia, depression, renal stones
‘Stones, bones, abdominal groans and psychiatric overtones’
3- Emergency presentation with altered mental status

5. Lets Recall Calcium homeostasis/regulation
• 5 key active sites of action
• Parathyroid gland
• Bones
• GI tract
• Kidneys
• Liver
• 3 Key Hormones
• PTH +- calcitonin
• 1,25(OH)2D3 ( 1,25-activated vitamin D AKA calcitriol)
• FGF 23 ( paramount in phosphate homeostasis)

6. Principles of Calcium Physiology
• Ionised calcium (active form) is a cofactor for coagulation factors, hormone
response coupling, electrical stimulus response coupling ( muscle
contraction and neurotransmitter release)
• 99% in bone. 0.99% intracellular fluid. 0.1% extracellular fluid (this is what
is measured). Of the 0.1%  50% is ionised 40%albumin bound 10% other
anion bound.
• Acidaemia ( pH<7.35) and low albumin causes increase in ionised calcium (
less bound to albumin). Alkalaemia (pH>7.45) and high albumin causes
decrease in ionised calcium ( more bound to albumin)
• Calcium is a neuromuscular ‘sedative’ decreases excitability. Low ionised
calcium gets the body ‘excited’ tetany , seizure.
Blaine J, Chonchol M, Levi M. Renal control of calcium, phosphate, and magnesium homeostasis. Clinical journal
of the American Society of Nephrology : CJASN 2015;10:1257-72.

7. Calcium Distribution
Ionised calcium. 2007. at
https://acutecaretesting.org/en/artic
les/ionized-calcium.)

8. Calcium Homeostasis
• Decrease in plasma ionised calcium detected by calcium sensing
receptors(CaSR) located in the parathyroid gland CaSR activity reduced
This increases PTH release.
• PTH stimulates
1. Bone resorptionincreases plasma calcium
2. the kidneys increases absorption from DISTAL tubule  increases calcium
3. Production of 1,25 vitamin D( calcitriol) in kidneys proximal tubule calcitriol goes
to the gut and increases absorption of calcium.
• Calcitriol (1,25 vitaD) stimulated by hypocalcaemia, hypophosphataemia
1. produced in kidney.
2. Increases absorption in the gut of calcium
3. Supports pth in bone and kidney resorption of calcium
4. 25 vitamin D is converted to active 1,25 vitamin D in the kidney.

10. Calcium and the kidneys
• 99% of filtered calcium is absorbed in the kidneys. 1% is excreted.
• 70% reabsorbed in proximal tubule via passive paracellular pathway following sodium
and water
• 20% reabsorbed in ascending loop of henle: Primarily passively via paracellular pathway
following sodium. CaSR is also present here and in hypercalcaemia prevents Ca+2
reabsorption
• Clinical Point: loop diuretics inhibit sodium absorption in ascending limb of loop of henle which
in turn inhibits calcium absorption thus used in hypercalcaemia.
• 10% absorbed in distal convoluted tubule: Active transcellular reabsorption via TRPV5
channel.
• Thiazide diuretics cause urinary calcium resorption thus decrease its excretion.
• PTH with support of calcitriol primarily works here by increasing calcium resorption in
hypocalcaemia]
• Clinical point: Volume contraction ( hypovolaemia) causes increased sodium and water
resorption in proximal tubule which also causes increased calcium resorption ( i.e
worsening hypercalcaemia). Volume expansion caused decreased sodium and water
resorption in proximal tubule thus decreased calcium reabsorption and increased urinary
calcium excretion.
Blaine J, Chonchol M, Levi M. Renal control of calcium, phosphate, and magnesium homeostasis. Clinical

11. What is the differential Diagnosis of
hypercalcaemia?
• PTH mediated or PTH independent?
1. PTH mediated
a) Primary Hyperparathyroidism
b) Tertiary hyperparathyroidism
c) Familial hypocalciuric hypercalcaemia
2. PTH independent
a) Malignancy
I. PTHrp related (most common): Soilid tumours, breast, squamous cell renal bladder
ovarian
II. Osteolysis due to mets or local mass: Multiple myeloma, breast and sometimes
lymphoma
III. 1,25 activated vitamin D ectopic secretion: Lymphoma primarily
Scott DC Stern ASC, Diane Altikorn. Symptoms to Diagnosis: An Evidence-Based Guide. fourth ed: McGraw Hill

12. Differentials continued
PTH independent continued
a) Granulomatosis Disease related : ectopic 1,25 vitamin D production
aggravated by vitamin D ingestion or sun exposure
I. Sarcoidosis : 20% of sarcoid patients
II. TB
III. Granulomatous with polyangiitis
b) Drugs
a) Thiazides: up to 8% of patients taking thiazides. A high proportion of patients may
have underlying primary hyperparathyroidism (¬40%)
b) Lithium: 15% of patients, increases PTH secretion and calcium resorption in the kidney
c) Milk Alkali syndrome: calcium based antacids+ calcium supplement => alkalosis, AKI,
hypercalciuria
d) Vitamin D and A toxicity/overdose

13. Differentials continued
• C) Endocrinopathies
I. Thyrotoxicosis: 10% of patients due to increased bone turnover
II. Adrenal insifficieny
III. Acromegaly: associated with hyperparathyroidism and overproduction of
1.25vitamin D.
IV. Pheochromocytoma
I. D) Others
I. Immobilisation: generally children and young adults 6/52 post event but can happen
months later. Increased bone resorption

14. Pearls
• 80% of outpatient hypercalcaemia cases are due to primary
hyperparathyroidism
• 80% of hospitalised patients hypercalcaemia is due to malignancy
• Hyperparathroidism is seen in MEN 1 and MEN2a

15. Diagnostic Approach
1. Correct hypercalcaemia for albumin + check ionised calcium
I. For every 5 below 40g/L add 0.1mmol/L to calcium. For eg serum calcium is
2.6mmol/L and albumin is 35g/L. corrected calcium will be 2.7mmol/L
2. Check PTH
1. High : likely HPTH
2. Normal high: likely hpth, check vitamin D and urinary calcium
3. Low: consider malignancy check PTHrP ( not commonly available),
SPEP,SFLC, CXR, CRP, ESR
1. If hx not consistent can endocrinopathies cause it? Check TFT
2. Can granulomatous disease be a cause? CXR, 1,25vitamin D

16. Diagnostic Approach 2
• Corrected calcium
• Stop any predisposing drug, thiazide lithium hormonal treatment.
• PTH and Vitamin D levels
• Mg and K
• SPEP/SFLC
• PTHrP if available
• TFT
• CRP ESR LDH
• CXR +- skeletal survey if myeloma or osteolytic lesion suspected
• +- CT TAP +- bone marrow biopsy if malignancy highly suspected
• ECG

17. Severity
• <3 mild
• 3-3.5 moderate
• >3.5 Severe

19. ECG changes

20. General Management Options
• Volume Expansion
• 0.9% saline aiming for a positive balance +2L however assess for CCF hx.
• Consider Loop diuretics once patients is adequately volume expanded. Don’t use in dry patient
• IV bisphosphonates primarily in malignancy related
• Zoledronic acid 4-8mg: longer acting than pamidronate. Hypocalcaemic effects start at around
24hrs and last upto 6 weeks.
• Pamidronate : 60-90mg
• Use under supervision of senior physician if egfr <30
• Steroids: Prednisolone effective in 1,25vitaD driven such as sarcoid and lymphoma and
other granulomatous diseases
• Calcitonin S/C 4IU-8IU/Kg BD upto QDS Tachyphylaxis.
• Cinacalcet: in HPTH related ( primary and tertiary)
• Denosumab: 60mg s/c malignancy and HPTH
• Resistant Hypercalcaemia or in ESRD: intermittent haemodialysis with low calcium bath
• Treat the primary cause for eg in parathyroid adenoma surgical resection if surgically fit.

21. Case summary
• The PTH levels were 3000 ( <150pg/ml) pg/ml
• Neck ultrasound and sestaMIBI scan suggested parathyroid adenoma
• After initial management with volume expansion bisphosphonates and cinacalcet patient was
referred for parathyroidectomy
• Generally hyperparathyroidism is coincidently found in 85% of cases and is asymptomatic
• This patient presented most likely with severe hypercalcaemia due to conjunct usage of calcium
supplements and thiazide diuretics
• Association with MEN 1 (3Ps parathyroid, pancreas, pituitary)and MEN2a( medullary thyroid
carcionoma, pheochromocytoma, HPTH)
• Parathyroidectomy is treatment of choice particularly recommended in symptomatic OR
asymptomatic with Calcium> 2.9mmol/L, osteoporosis, CrClearence< 60ml/min, Age<50, unable
to medically follow up.
• Complications of surgery: hypoparathyrodism ( usually transient), recurrently laryngeal nerve
injury and Hungry bone syndrome severe hypocalcaemia post parathyroidectomy with
preexisting bone disease.
Tao Le TEB, Peter V. Chin-Hong, Cindy J. Lai. First Aid for the Internal Medicine Boards. fourth edition ed:

22. Thank You