Nephrology
Question 42 of 180
You have been asked to give a teaching session to a group of medical students. The topic of the session is "Hypercalcaemia". Which of the following is the most common cause of hypercalcaemia?
Answer:
Primary hyperparathyroidism is the commonest cause of hypercalcaemia and usually presents as mild asymptomatic hypercalcaemia.Hypercalcaemia
Nephrology / Oncology & Palliative Care
Last Updated: 30th March 2023
Hypercalcaemia is defined as a serum calcium concentration of 2.6 mmol/L or higher, on two occasions, following adjustment (correction) for the serum albumin.
Classification
- Mild: 2.6 – 3.0 mmol/L
- Moderate 3.01 – 3.40 mmol/L
- Severe: > 3.40 mmol/L
Causes
There are multiple possible underlying causes of hypercalcaemia, the two most common being primary hyperparathyroidism and malignancy (which together account for 90% of cases).
- Primary hyperparathyroidism
- Commonest cause of hypercalcaemia and usually presents as mild asymptomatic hypercalcaemia
- Excessive and inappropriate secretion of parathyroid hormone (PTH) alters the regulation of serum calcium directly by increasing bone resorption and renal calcium reabsorption and indirectly by increasing intestinal calcium absorption
- A solitary parathyroid adenoma is the cause in about 85% of cases
- Less commonly, secretion is from multiglandular parathyroid hyperplasia, ectopic parathyroid adenomas, or parathyroid cancer (very rare)
- Typical lab findings:
- Serum calcium - high-normal to elevated
- PTH - high-normal to elevated
- Vitamin D - may be low
- ALP - may be raised
- Serum phosphate - low or low-normal
- Malignancy
- Second most common cause of hypercalcaemia; it is often a late finding in advanced malignancy, and the underlying disease is often known when hypercalcaemia is identified
- Malignancy-related hypercalcaemia should be suspected if there is rapid-onset hypercalcaemia, severe hypercalcaemia, and/or symptoms. Typically serum PTH levels are suppressed or undetectable
- The malignancies most commonly associated with hypercalcaemia include lung, oesophageal, head and neck, skin, cervix, breast, kidney, and bladder cancer
- In 80% the mechanism is secretion of parathyroid hormone-related protein and other circulating factors by the tumour (a paraneoplastic syndrome)
- In 20% bone metastases cause osteolysis and release of skeletal calcium, for example in breast cancer and multiple myeloma
- Other causes
- Drugs e.g. thiazide diuretics, lithium, vitamin D, vitamin A, calcium
- Granulomatous disease e.g. sarcoidosis or tuberculosis
- Late stage chronic kidney disease (tertiary hyperparathyroidism)
- Familial hypocalciuric hypercalcaemia
- Immobility in people with accelerated bone turnover e.g. Paget’s disease
- Non-parathyroid endocrine disease
- Thyrotoxicosis
- Addison’s disease
- Pheochromocytoma
- Vasoactive intestinal polypeptide hormone-producing tumour
Clinical features
Hypercalcaemia is most commonly detected on the basis of blood test results in the UK, and mild chronic hypercalcaemia is usually asymptomatic.
- Thrones and Stones (RENAL)
- Polyuria
- Polydipsia
- Dehydration
- Renal stones
- Renal impairment
- Bones (SKELETAL)
- Bone pain (worse at night and with weight-bearing)
- Skeletal deformities
- Osteoporosis
- Fragility fractures
- Groans (GASTROINTESTINAL)
- Nausea and vomiting
- Anorexia
- Weight loss
- Abdominal pain
- Constipation
- Peptic ulcer, pancreatitis
- Moans (NEUROMUSCULAR AND NEUROPSYCHIATRIC)
- Drowsiness, delirium, coma
- Fatigue, lethargy, muscle weakness, insomnia
- Impaired concentration and memory, confusion
- Depression, anxiety, irritability, psychosis
- Neurological signs (for example upper motor neurone deficits, hypotonia, hyporeflexia, and ataxia)
- CARDIOVASCULAR:
- Hypertension
- Arrhythmias
- ECG changes:
- Short QT interval (most common)
- Prolonged PR interval
- Prolonged QRS interval
- T wave flattening or inversion
- J wave at the end of the QRS complex
- Cardiac arrest (VF/pVT, PEA, asystole)
Investigations
Consider arranging additional investigations to determine the underlying cause, depending on clinical judgement, and manage appropriately:
- Full blood count — to diagnose or exclude anaemia of chronic disease or haematological malignancy.
- Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) — may be increased in malignancy or other inflammatory or granulomatous conditions.
- Estimated glomerular filtration rate (eGFR) and creatinine — to assess hydration status, for acute kidney injury (AKI) and chronic kidney disease (CKD).
- Serum and urine protein electrophoresis, including testing for urine Bence-Jones protein — to exclude myeloma.
- Liver function tests — to exclude liver metastases or chronic liver failure; alkaline phosphatase may be increased in primary hyperparathyroidism, Paget's disease with immobilisation, myeloma, or bone metastases.
- Thyroid function tests — to exclude thyrotoxicosis.
- Parathyroid hormone (PTH) — typically raised in primary (and tertiary) hyperparathyroidism, and suppressed or undetectable in malignancy-related hypercalcaemia or other non PTH-dependent causes.
- Vitamin D — if vitamin D toxicity is suspected (rare).
- Serum cortisol (morning sample at 8–9 am) — if Addison's disease is suspected.
- Early morning urine sample to measure the urinary albumin:creatinine ratio (ACR) — if CKD is suspected.
- Chest X-ray — to exclude lung cancer or metastases, lymphoma, sarcoidosis, or tuberculosis.
Management
- The management of hypercalcaemia depends on the presentation and likely underlying cause.
- It is important to avoid medications that can worsen hypercalcaemia (e.g. thiazide diuretics, calcitriol [(1,25-dihydroxyvitamin D)], calcium supplementation, antacids, lithium) and those that may worsen the symptoms of hypercalcaemia (e.g. sedatives, hypnotics, analgesics when possible).
- Severe hypercalcaemia
- Severe hypercalcaemia may present with profound lethargy or coma in the emergency department. Measurement of calcium and an ECG are required as part of the evaluation of any semiconscious patient. Markedly elevated calcium and shortened QT interval require urgent treatment and the electrolyte abnormality can be further investigated when the patient is stabilised.
- Initial treatment includes:
- Hydration with 0.9% sodium chloride to dilute calcium levels
- Loop diuretics in association with 0.9% sodium chloride infusion to increase calcium excretion
- Bisphosphonates to inhibit osteoclast activity
- Calcitonin to inhibit osteoclast activity and enhance urinary excretion of calcium
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
