Hypercalcaemia, also spelt hypercalcemia (US), is a high calcium (Ca2+) level in the blood serum. The normal range for total calcium is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcaemia. Those with a mild increase that has developed slowly typically have no symptoms. In those with greater levels or rapid onset, symptoms may include abdominal pain, bone pain, confusion, depression, weakness, kidney stones or an abnormal heart rhythm including cardiac arrest.
Most outpatient cases are due to primary hyperparathyroidism and inpatient cases due to cancer. Other causes of hypercalcaemia include sarcoidosis, tuberculosis, Paget disease, multiple endocrine neoplasia (MEN), vitamin D toxicity, familial hypocalciuric hypercalcaemia, and certain medications, such as lithium and hydrochlorothiazide. Diagnosis should generally include either a corrected calcium or ionised calcium level and be confirmed after a week. Specific changes, such as a shortened QT interval and prolonged PR interval, may be seen on an electrocardiogram (ECG).
Treatment may include intravenous fluids, furosemide, calcitonin, intravenous bisphosphonate, in addition to treating the underlying cause. The evidence for furosemide use, however, is poor. In those with very high levels, hospitalisation may be required. Haemodialysis may be used in those who do not respond to other treatments. In those with vitamin D toxicity, steroids may be useful. Hypercalcaemia is relatively common. Primary hyperparathyroidism occurs in 1–7 per 1,000 people, and hypercalcaemia occurs in about 2.7% of those with cancer.
Signs and symptoms + Mnemonic for symptoms Stones Kidney or biliary Bones Bone pain Groans Abdominal discomfort Moans Complaints of non-specific symptoms Thrones Constipation and excessive urination volume Muscle tone Muscle weakness, decreased reflexes Psychiatric overtones Depression, anxiety, cognitive dysfunction
The neuromuscular symptoms of hypercalcaemia are caused by a negative bathmotropic effect due to the increased interaction of calcium with sodium channels. Since calcium blocks sodium channels and inhibits depolarisation of nerve and muscle fibres, increased calcium raises the threshold for depolarisation. This results in decreased deep tendon reflexes (hyporeflexia), and skeletal muscle weakness.
Other symptoms include cardiac arrhythmias (especially in those taking digoxin), fatigue, nausea, vomiting (emesis), loss of appetite, abdominal pain, and paralytic ileus. If kidney impairment occurs as a result, manifestations can include increased urination, urination at night, and increased thirst. Psychiatric manifestation can include emotional instability, confusion, delirium, psychosis, and stupor. Calcium deposits known as limbus sign may be visible in the eyes.Orient, Dr. Jane M. (2011). Amazon Sapira's Art & Science of Bedside Diagnosis (Kindle Edition) Lippincott Williams & Wilkins. Retrieved January 7, 2012.
Symptoms are more common at high calcium blood values (12.0 mg/dL or 3 mmol/L). Severe hypercalcaemia (above 15–16 mg/dL or 3.75–4 mmol/L) is considered a medical emergency: at these levels, coma and cardiac arrest can result. The high levels of calcium ions decrease the neuron membrane permeability to sodium ions, thus decreasing excitability, which leads to hypotonicity of smooth and striated muscle. This explains the fatigue, muscle weakness, low tone and sluggish reflexes in muscle groups. The sluggish nerves also explain drowsiness, confusion, hallucinations, stupor or coma. In the gut this causes constipation. Hypocalcaemia causes the opposite by the same mechanism.
Hypercalcaemic crisis A hypercalcaemic crisis is an emergency situation with a severe hypercalcaemia, generally above approximately 14 mg/dL (or 3.5 mmol/L).Hypercalcaemia in Emergency Medicine at Medscape. Author: Robin R Hemphill. Chief Editor: Erik D Schraga. Retrieved April 2011
The main symptoms of a hypercalcaemic crisis are oliguria or anuria, as well as somnolence or coma. After recognition, primary hyperparathyroidism should be proved or excluded.
In extreme cases of primary hyperparathyroidism, removal of the parathyroid gland after surgical neck exploration is the only way to avoid death. The diagnostic program should be performed within hours, in parallel with measures to lower serum calcium. Treatment of choice for acutely lowering calcium is extensive hydration and calcitonin, as well as bisphosphonates (which have effect on calcium levels after one or two days).Page 394 in:
Causes Primary hyperparathyroidism and malignancy account for about 90% of cases of hypercalcaemia.Table 20-4 in:
Causes of hypercalcaemia can be divided into those that are PTH dependent or PTH independent.
Parathyroid function Primary hyperparathyroidism Solitary parathyroid adenoma Primary parathyroid hyperplasia Parathyroid carcinomaHu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP. "Thyroid and Parathyroid Cancers" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach . 11 ed. 2008. Multiple endocrine neoplasia (MEN1 & MEN2A) Familial isolated hyperparathyroidism Lithium use Familial hypocalciuric hypercalcaemia/familial benign hypercalcaemia
Cancer Hypercalcaemia of malignancy (cancer) is due to a variety of mechanisms. The two most common are humoral hypercalcaemia of malignancy and local osteolytic hypercalcaemia due to bony metastasis. Humoral hypercalcaemia of malignancy involves the tumour releasing a hormone which increases calcium mobilisation (most commonly parathyroid hormone-related protein (PTHrP)) into the circulation. PTHrP acts similarly to parathyroid hormone in that it binds to the parathyroid hormone 1 receptors on the kidneys and bones and causes an increased tubular reabsorption of calcium and activation of osteoclast activity, respectively. Osteoclasts are a type of bone cell which cause bone resorption, releasing calcium into the bloodstream. PTHrP also acts by activating rank ligand and inhibiting osteoprotegerin which activates nuclear factor kappa B, which causes further activation of osteoclast activity. The combination of PTHrP driven osteoclast activation and calcium reabsorption by the kidneys causes hypercalcaemia associated with malignancy (humoral type).
Another mechanism in which cancer causes hypercalcaemia is via local osteolysis due to metastasis to bone. Tumor bone metastasis releases local cytokines including IL-6, IL-8, IL-11, interleukin-1 beta, TNF alpha, and macrophage inflammatory protein. These cytokines activate osteoclasts and inhibit osteoblasts (the cell type responsible for laying down new bone) via the rank ligand pathway leading to bone resorption and calcium release into the bloodstream. The massive release of calcium from bone metastasis and osteoclast activation usually overwhelms the kidney's ability to secrete calcium, thus leading to hypercalcaemia.
Hypercalcaemia of malignancy may also occur due to tumour production of vitamin D or parathyroid hormone. These causes are rare and constitute about 1% of all causes of hypercalcaemia of malignancy.
Hypercalcaemia of malignancy usually portends a poor prognosis, and the medial survival is 25–52 days of its development. It has an incidence of 30% in those with cancer, and the prevalence is estimated to be about 2-3% in the United States.
Common cancer types that are associated with hypercalcaemia of malignancy include: Solid tumour with metastasis via local osteolytic hypercalcaemia: which can be due to any tumour that metastasises to the bone. But common causes include breast cancer, lung cancer, kidney cancer, and myeloma or lymphoma of the bone Solid tumour with humoral mediation of hypercalcaemia: lung cancer (especially squamous cell tumours, a type of non-small cell lung cancer), squamous cell cancers of the head and neck, kidney cancer or other urothelial cancers, and breast cancer. Haematologic cancers: including multiple myeloma, lymphoma, leukaemia Ovarian small cell carcinoma of the hypercalcaemic type
Vitamin-D disorders Hypervitaminosis D (vitamin D intoxication) Elevated 1,25(OH)2D (see calcitriol under Vitamin D) levels (e.g., sarcoidosis and other granulomatous diseases such as tuberculosis, berylliosis, histoplasmosis, Crohn's disease, and granulomatosis with polyangiitis) Idiopathic hypercalcaemia of infancy Rebound hypercalcaemia after rhabdomyolysis
High bone-turnover Hyperthyroidism Multiple myeloma Prolonged immobilisation Paget's disease Thiazide use Vitamin A intoxication
Kidney failure Tertiary hyperparathyroidism Aluminium intoxication Milk-alkali syndrome
Other Acromegaly Adrenal insufficiency Zollinger–Ellison syndrome Williams Syndrome Excessive calcium consumption
Diagnosis Diagnosis should generally include either a calculation of corrected calcium or direct measurement of ionised calcium level and be confirmed after a week. This is because either high or low serum albumin levels does not show the true levels of ionised calcium. There is, however, controversy around the usefulness of corrected calcium as it may be no better than total calcium.
Once calcium is confirmed to be elevated, a detailed history taken from the subject, including review of medications, any vitamin supplementations, herbal preparations, and previous calcium values. Chronic elevation of calcium with absent or mild symptoms often points to primary hyperparathyroidism or familial hypocalciuric hypercalcaemia. For those who has underlying malignancy, the cancers may be sufficiently severe to show up in history and examination to point towards the diagnosis with little laboratory investigations.
If detailed history and examination does not narrow down the differential diagnoses, further laboratory investigations are performed. Intact PTH (iPTH, biologically active parathyroid hormone molecules) is measured with immunoradiometric or immunochemoluminescent assay. Elevated (or high-normal) iPTH with high urine calcium/creatinine ratio (more than 0.03) is suggestive of primary hyperparathyroidism, usually accompanied by low serum phosphate. High iPTH with low urine calcium/creatinine ratio is suggestive of familial hypocalciuric hypercalcaemia. Low iPTH should be followed up with Parathyroid hormone-related protein (PTHrP) measurements (though not available in all labs). Elevated PTHrP is suggestive of malignancy. Normal PTHrP is suggestive of multiple myeloma, vitamin A excess, milk-alkali syndrome, thyrotoxicosis, and immobilisation. Elevated Calcitriol is suggestive of lymphoma, sarcoidosis, granulomatous disorders, and excessive calcitriol intake. Elevated calcifediol is suggestive of vitamin D or excessive calcifediol intake.
The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcaemia. Moderate hypercalcaemia is a level of 2.88–3.5 mmol/L (11.5–14 mg/dL) while severe hypercalcaemia is > 3.5 mmol/L (>14 mg/dL).
ECG
Abnormal heart rhythms can also result, and ECG findings of a short QT interval suggest hypercalcaemia. Significant hypercalcaemia can cause ECG changes mimicking an acute myocardial infarction. Hypercalcaemia has also been known to cause an ECG finding mimicking hypothermia, known as an Osborn wave.
Treatments The goal of therapy is to treat the hypercalcaemia first and subsequently effort is directed to treat the underlying cause. In those with a calcium level above 13 mg/dL, calcium level that is rising rapidly or those with altered mental status, urgent treatment is required.
Fluids and diuretics Initial therapy: