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Hypercalcaemia

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An albumin adjusted serum calcium of over 2.6 mmol/L (UK). More than 90% of cases are due to malignancy or primary hyperparathyroidism

Initial Hypercalcaemia: Total serum calcium > 10.5 mg/dL (2.6 mmol/L).
ABC. Oral hydration (3-4 L/day) alone for euvolaemic patients with Ca²⁺ < 3.0 mmol/L (12.0 mg/dL) If moderate to severe hypercalcaemic and dry then 4-6 L N-Saline IV per 24 hrs Caution with more than 2-3 L/day fluids in those at risk of heart failure Look for and treat cause. Check Ca²⁺ and P/ALP/PTH/CXR/ESR/PPE. Once hydrated if Calcium still elevated consider either IV Zoledronate 4 mg in 100 ml NaCl 0.9% over 15 minutes or IV Pamidronate 60-90 mg over 2 hrs (over 4-5 hrs if Renal failure) into a large vein takes 2-3 days to work [Pamidronate dose Ca < 3.00 mmol/L 15-30 mg, 3-3.5 30-60 mg, 3.5-4.0 60-90 mg and Ca > 4 then 90 mg] Steroids may be useful in Sarcoidosis Prednisolone 40-60 mg OD but take specialist advice. Consider PPI.

Initial Hypercalcaemia: Total serum calcium > 10.5 mg/dL (2.6 mmol/L).

ABC. Oral hydration (3-4 L/day) alone for euvolaemic patients with Ca²⁺ < 3.0 mmol/L (12.0 mg/dL)
If moderate to severe hypercalcaemic and dry then 4-6 L N-Saline IV per 24 hrs
Caution with more than 2-3 L/day fluids in those at risk of heart failure
Look for and treat cause. Check Ca²⁺ and P/ALP/PTH/CXR/ESR/PPE.
Once hydrated if Calcium still elevated consider either
IV Zoledronate 4 mg in 100 ml NaCl 0.9% over 15 minutes or IV Pamidronate 60-90 mg over 2 hrs (over 4-5 hrs if Renal failure) into a large vein takes 2-3 days to work [Pamidronate dose Ca < 3.00 mmol/L 15-30 mg, 3-3.5 30-60 mg, 3.5-4.0 60-90 mg and Ca > 4 then 90 mg]
Steroids may be useful in Sarcoidosis Prednisolone 40-60 mg OD but take specialist advice. Consider PPI.

About/Conversion

Hypercalcaemia is a corrected Calcium > 2.50 mmol/l or 10.9 mg/dl
Total calcium (bound and free) is measured typically
10.5 mg/dl = 2.6 umol/L is mild
12 mg/dl = 3.0 umol/L is moderate
14 mg/dl = 3.5 umol/L is severe

Aetiology

It is the free ionised form of Calcium - Ca²⁺ which is biologically active but this is too difficult to measure and only Total Calcium is measured routinely.
The unionised Calcium is carried bound to albumin, citrate and phosphate - a low albumin gives a falsely low [Ca] and vice-versa and correction is needed.
The amount of free calcium also depends on acid/base balance - Acidosis decreases the number of protein binding sites and so increases the amount of ionised calcium
Alkalosis results in more protein binding sites and so lowers ionized calcium so much so that signs of hypoglycaemia may develop with for example a respiratory alkalosis and a normal measured total calcium.
The body contains 1-2 kg calcium almost all of which is in bone. The body uses this store to supplement the blood level of calcium when there is any hypocalcaemia by the action of parathormone

Causes

Cause	Clinical Features	Investigations	Management
Primary Hyperparathyroidism	Often asymptomatic; can present with bone pain, fractures, nephrolithiasis, polyuria, constipation, and mental disturbances ("stones, bones, abdominal groans, and psychiatric overtones").	Elevated serum calcium, elevated or inappropriately normal PTH levels, low serum phosphate, 24-hour urinary calcium excretion.	Surgical removal of the overactive parathyroid gland(s), hydration, bisphosphonates for bone protection, monitoring in mild cases.
Malignancy-Associated Hypercalcemia	Symptoms of advanced malignancy, such as weight loss, fatigue, bone pain, polyuria, dehydration, and confusion; may be related to PTHrP-secreting tumours or osteolytic metastases.	Elevated serum calcium, suppressed PTH, elevated PTHrP in cases of humoral hypercalcemia of malignancy, imaging studies to identify primary tumour or metastases.	Intravenous fluids, bisphosphonates, denosumab, treatment of the underlying malignancy, corticosteroids in certain cases.
Vitamin D Toxicity	Hypercalcemia with symptoms like nausea, vomiting, polyuria, dehydration, and confusion, usually related to excessive vitamin D or calcium intake.	Elevated serum calcium, elevated 25-hydroxyvitamin D levels, suppressed PTH, normal or elevated serum phosphate.	Discontinue vitamin D and calcium supplements, hydration, corticosteroids, and bisphosphonates in severe cases.
Sarcoidosis and Other Granulomatous Diseases	Fatigue, weight loss, polyuria, hypercalcemia-related symptoms; may also present with symptoms of the underlying disease such as respiratory issues in sarcoidosis.	Elevated serum calcium, elevated 1,25-dihydroxyvitamin D levels, suppressed PTH, imaging and biopsy for granulomas.	Corticosteroids to reduce granuloma formation, hydration, and bisphosphonates in severe cases.
Thiazide Diuretics	Thiazide-induced hypercalcemia typically presents with mild, asymptomatic hypercalcemia; may exacerbate underlying hyperparathyroidism.	Elevated serum calcium, suppressed PTH, history of thiazide use, exclusion of other causes.	Discontinuation of thiazide diuretics, monitoring serum calcium levels, and treatment of any underlying conditions.
Familial Hypocalciuric Hypercalcemia (FHH)	Mild hypercalcemia, often asymptomatic, with a family history of hypercalcemia; typically presents in childhood or early adulthood.	Elevated serum calcium, low urinary calcium excretion, genetic testing for mutations in the CASR gene, normal or mildly elevated PTH.	No treatment required, as this condition is usually benign; genetic counseling may be offered.
Immobilization	Hypercalcemia typically occurs in patients with prolonged immobilization, especially those with high bone turnover (e.g., Paget's disease, adolescents).	Elevated serum calcium, normal or suppressed PTH, history of prolonged immobilization, elevated bone turnover markers.	Increased mobility if possible, bisphosphonates to reduce bone resorption, hydration.
Hyperthyroidism	Symptoms of hyperthyroidism such as weight loss, tachycardia, heat intolerance, along with mild hypercalcemia.	Elevated serum calcium, suppressed PTH, elevated thyroid hormones (T3, T4), suppressed TSH.	Treatment of hyperthyroidism (e.g., antithyroid drugs, radioactive iodine), hydration, bisphosphonates if hypercalcemia is severe.

Lung cancer a cause of hypercalcaemia

Algorithm

Clinical: "Bones, Moans, Groans, Stones"

Bone pain: metastases, myeloma and fractures
Groans (Abdo pain): Constipation, nausea and vomiting, Pancreatitis (also associated with low calcium), Peptic ulcer disease
Moans: Confusion, depression, delirium even psychosis and coma
Stones: Urinary stones, Polyuria and/or polydipsia
Hypotonia, hyporeflexia, Weakness, Tongue fasciculation
Long-standing hypercalcaemia may cause band keratopathy
Hypertension, calcium deposition in tissues

Investigations

FBC: anaemia with myeloma, cancer, renal disease
U&E: dehydration, renal failure (myeloma). Raised serum Calcium
↑ ESR: myeloma, malignancy
ECG: a short QT interval
CXR: Squamous cell carcinoma, BHL and fibrosis of sarcoid
24 hr Urinary calcium: usually ↑ in Hypercalcaemia except for milk-alkali syndrome, thiazide diuretic and FHH with low urinary calcium.
[PTH] in the setting of a raised [Ca²⁺] is low
Serum Phosphate: Low in malignancy and primary hyperparathyroidism but high in other causes
↑ or normal PTH = Primary hyperparathyroidism
Isotope bone scan
PTHrp in malignancy, Myeloma screen (BJP and PPE and Skeletal survey)
Vitamin D and its active metabolites.
Serum angiotensin converting enzyme (ACE) if sarcoid suspected.

Lab markers that suggest malignancy as cause

↓ Albumin
↓ Chloride
↑ pH Alkalosis
↓ K⁺
↑ PO4
↑ ALP
↓ PTH

Management

Assess the degree of hydration using clinical findings and laboratory results. The primary focus is on rehydration as patients have calcium-induced polyuria.
Calcium levels below 3.5 mmol/L (14 mg/dl) can usually be managed by ensuring oral plus if needed IV hydration. Depends on clinical assessment and ability to maintain own hydration so those who are obtunded need IV fluids.
Well patients can be managed through ambulatory services. Stop thiazides and vitamin D compounds. Causes are usually Malignancy or primary hyperparathyroidism
If levels = 3.5 mmol/L and dry then rehydrate with oral fluids + 0.9% Saline. Patients may need up to 4 to 6 Litres of 0.9% saline over 24 hours and careful fluid balance management is needed. Caution in elderly and heart disease. It may require HDU admission.
Furosemide: Useful once hydrated or overhydrated. Furosemide will also help clear calcium. Give loop diuretic, e.g. Furosemide 40-80 mg orally or IV twice daily, if urine output slow to increase.
Bisphosphonate once hydrated Pamidronate 60-90 mg IV in 500 ml 0.9% saline over 4 hrs. [Pamidronate dose Ca²⁺ < 3.00 mmol/L 15-30 mg, 3-3.5 30-60 mg, 3.5-4.0 60-90 mg and Ca > 4 then 90 mg]. Alternatives are Zoledronic acid 4 mg IV in 100 ml NaCl 0.9% over 15 minutes.
Occasionally Prednisolone 40-60 mg OD may be given if myeloma, sarcoidosis or Vitamin D excess or lymphoma (after rheumatology/oncology discussion) usually with PPI.
Calcitonin is occasionally used in malignancy-related hypercalcaemia as 100-400 units every 8 hours SC or IM
Dialysis may be considered with low-calcium dialysate calcium fails to respond to saline, Furosemide and bisphosphonate but ensure euvolaemic

Considering Malignancy Causes

PTH < 1.6 pmol/l suspect non parathyroid cause. Malignancy needs to be considered.
Symptom guided malignancy work up CXR, Breast exam, PSA, Myeloma screen
Further referral to NICE 2ww cancer guidance

References

Hypercalcaemia Guideline for Primary Care