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NiinaMatikainen

Hypercalcaemia and Hyperparathyroidism

Essentials

  • The most common causes of hypercalcaemia are primary hyperparathyroidism, cancers and chronic renal failure.
  • The most important test steering the diagnostics is concentration of parathyroid hormone (PTH).
  • In primary hyperparathyroidism, the parathyroid glands produce an excess of parathyroid hormone in relation to the blood calcium concentration.
  • PTH-independent hypercalcaemia is associated with malignant tumours or other systemic diseases.

Definition and prevalence of hypercalcaemia

  • Plasma ionized calcium concentration repeatedly exceeds the value 1.3 mmol/l or plasma calcium concentration, after albumin correction, the value 2.51 mmol/l. Reference ranges and determination methods vary from laboratory to laboratory and according to the patient's age. Do not confuse these with the decision-making threshold.
  • The prevalence of primary hyperparathyroidism in postmenopausal women is > 1%. See below the prevalence of hypercalcaemia in cancer patients. Otherwise hypercalcaemia is quite rare in primary care.

Common causes of hypercalcaemia

PTH-dependent hypercalcaemia

  • Primary hyperparathyroidism (hyperplasia, adenoma or, rarely, carcinoma of the parathyroid gland)
    • Sporadic primary hyperparathyroidism (the most common)
    • Hereditary associated with e.g. MEN1 syndrome
    • Long-term adverse effect of lithium use
  • Tertiary hyperparathyroidism (patients on dialysis)
    • Patients with renal failure
  • Familial hypocalciuric hypercalcaemia

PTH-independent hypercalcaemia

  • Tumours
    • In cancer, plasma calcium concentration increases because of either lytic bone metastases or hormone-like transmitters secreted by the cancer.
    • Hypercalcaemia is detected in about 20% of patients with breast cancer, about 10-15% of patients with lung or renal cancer, 10-30% of patients with multiple myeloma, and 10% of patients with leukaemia or lymphoma.
  • Sarcoidosis, other granulomatous diseases, tuberculosis and certain types of lymphoma
  • Hyperthyroidism, cortisol deficiency, pheochromocytoma, acromegaly
    • Mild hypercalcaemia is common; it will be corrected as the underlying cause is treated.
  • Acute renal failure, recovery phase
  • Pharmaceuticals
    • Vitamin D or A overdose
    • Thiazide diuretics (promote the expression of mild hyperparathyroidism)
  • Immobilization

Symptoms of hypercalcaemia

  • The severity of the symptoms varies from asymptomatic to severe systemic symptoms. Usually asymptomatic when plasma ionized calcium concentration is < 1.4 mmol/l (plasma calcium < 2.8 mmol/l).
  • Primary hyperparathyroidism is often detected incidentally. It may also be found in patients with chronic aches, constipation or depressive symptoms, or when looking for the cause of urinary calculi or osteoporosis. Rapidly progressing symptoms and poor general condition indicate a malignant tumour.
  • Systemic symptoms
    • Fatigue, loss of appetite
  • Gastrointestinal symptoms
    • Nausea, constipation, abdominal pain, peptic ulcer, pancreatitis
  • Kidneys and fluid balance
    • Urinary and kidney calculi
    • Polyuria, polydipsia, dehydration
    • Renal insufficiency, nephrocalcinosis
  • Bones and joints
    • Arthralgia, bone aches, pain, fractures
    • Radiological changes (in hyperparathyroidism, malignancies)
  • Neuropsychiatric symptoms
    • Inability to concentrate, depression, dementia
    • Confusion, psychosis
  • Cardiovascular symptoms
    • Short QT interval and arrhythmias
    • Hypertension
  • In hypercalcemic crisis the plasma calcium concentration is usually over 3.75 mmol/l (ionized calcium > 2.0 mmol/l) and the patient has
    • acute symptoms of hypercalcaemia and worsened general condition
    • dehydration
    • oliguria and impaired renal function

Laboratory investigations

  • Plasma ionized calcium, or albumin-corrrected plasma calcium. A 10 g/l change in plasma albumin causes a 0.2 mmol/l change in the same direction in plasma calcium. Ionized calcium is more useful than calcium if there are serum protein disturbances.
  • Plasma PTH levels can be used for differential diagnosis between PTH-dependent and PTH-independent hypercalcaemia.
    • In PTH-dependent hypercalcaemia, PTH concentration is high or near the upper limit of the normal range.
    • In PTH-independent hypercalcaemia, PTH concentration is low or too low to measure.
    • Note: Secondary hyperparathyroidism caused by insufficient intake or malabsorption of dietary calcium and/or vitamin D is a common cause for increased PTH levels. In this case, plasma calcium levels are either normal or low. Secondary hyperparathyroidism is extremely common in renal failure.
  • Specific investigations to discover the cause of hypercalcaemia are selected according to the suspected aetiology. Primary hyperparathyroidism can be diagnosed if plasma ionized calcium or plasma calcium levels are increased and plasma PTH concentration is increased or close to the upper limit of the normal range. Further investigations to be considered include ALP, serum 25-OH vitamin D, 24 h urinary calcium and bone densitometry. In PTH-independent hypercalcaemia, a malignant tumour with bone metastases or sarcoidosis are usually looked for (investigations in specialized health care).

Treatment

Urgency

  • If plasma ionized calcium is < 1.6 mmol/l (plasma calcium < 3.25 mmol/l), immediate treatment is rarely indicated.The underlying cause is treated according to regular procedures.
  • If plasma ionized calcium is > 1.75 mmol/l (plasma calcium > 3.5 mmol/l), assess whether the patient requires emergency treatment and consider particularly whether severe general symptoms exist or the renal function is impaired.

Treatment of hypercalcaemic crisis

  • Discontinue calcium products and thiazide, correct dehydration (starting with 0.9% sodium chloride solution) and ensure diuresis (furosemide will increase urinary calcium excretion). Give potassium and magnesium supplements as needed. Monitor and manage actively cardiac arrhythmias.
  • Decrease plasma calcium concentrations by giving a single intravenous dose of bisphosphonate (5 mg zoledronate in 100 ml 0.9% sodium chloride solution over 15 minutes) or alternatively a single dose of denosumab (60-120 mg) subcutaneously. Denosumab is particularly suitable in severe renal failure.
  • The calcitonin dose is 5-10 IU/kg/day in 500 ml 0.9% sodium chloride solution / 6 h. It has a weak effect which lasts for a short time.
  • In severe PTH-dependent hypercalcaemia, also cinacalcet is used (consult an endocrinologist or nephrologist).
  • Glucocorticoids are useful in myeloma, sarcoidosis, vitamin D overdose and hypercalcaemia related to lymphomas, e.g. 30-100 mg of prednisone or methylprednisolone orally per day.
  • Renal insufficiency is in most cases improved by fluid therapy and when the plasma calcium concentration declines, or it may be treated by haemodialysis which reduces calcium concentration.

Primary hyperparathyroidism

  • The only curative treatment is surgery. Indications of surgical treatment:
    • plasma ionized calcium > 1.4-1.5 mmol/l (plasma calcium > 2.90 mmol/l)
    • increased plasma creatinine
    • kidney or urinary calculi
    • osteoporotic fracture or osteoporosis detected by bone densitometry
    • neuropsychiatric symptoms
    • a female patient planning pregnancy.
  • For a surgical assessment, refer the patient to an endocrinology clinic where possible localizing imaging studies are planned.
  • If surgical treatment is not indicated in primary hyperparathyroidism or surgery is not performed for some other reason, plasma ionized calcium (plasma calcium) levels should be monitored 1-2 times annually and plasma creatinine (eGFR Gfr Calculator) is measured once per year.
    • If plasma ionized calcium levels increase the need for surgery should be re-assessed.
    • Cinacalcet therapy is applicable for some symptomatic patients, when the risks of surgical treatment are high.
    • Plasma ionized calcium levels often remain unchanged year after year-particularly in elderly women. There is no need to restrict dietary calcium intake, however, unnecessary calcium supplements are not recommended. Optimal calcium intake is 800-1 000 mg daily.
    • Vitamin D supplementation 10-20 µg/day is indicated, if serum 25-OH vitamin D is < 50-75 nmol/l.
    • Treatment with bisphosphonates or denosumab is recommended if the T-score in bone density measurement is < -2.5 SD.

Other causes

    References

    • Matikainen N, Pekkarinen T, Ryhänen EM, et al. Physiology of Calcium Homeostasis: An Overview. Endocrinol Metab Clin North Am 2021;50(4):575-590. [PubMed]
    • Maier JD, Levine SN. Hypercalcemia in the Intensive Care Unit: A Review of Pathophysiology, Diagnosis, and Modern Therapy. J Intensive Care Med 2015;30(5):235-52. [PubMed]
    • Ahmad S, Kuraganti G, Steenkamp D. Hypercalcemic crisis: a clinical review. Am J Med 2015;128(3):239-45.[PubMed]