Hypercalcemia, Severe

Thirsty
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Diagnosis and reasoning

This elderly gentleman has presented with thirst and polyuria. Examination reveals postural hypotension, indicating significant dehydration and volume loss. Uncontrolled diabetes mellitus is by far the commonest cause of these symptoms. The other important conditions which should be kept in mind are diabetes insipidus (either central or nephrogenic) and hypercalcemia. A fasting blood glucose is a suitable first-line investigation. In this patient, the normal result excludes diabetes mellitus. The next step should be estimation of serum electrolyte levels (including calcium and phosphate). This reveals the presence of severe hypercalcemia (also termed a "hypercalcemic crisis"), yielding the cause of his symptoms. Note that hypercalcemia itself is merely a manifestation of underlying disease - his evaluation should not stop here. The commonest causes of hypercalcemia in this age group are primary hyperparathyroidism and hypercalcemia of malignancy. Note that primary hyperparathyroidism typically causes mild hypercalcemia, while malignancies often cause a more severe elevation. Note also the high ESR, normocytic normochromic anemia with rouleaux formation, grossly elevated globulin fraction, borderline renal impairment and normal alkaline phosphatase levels. These findings are highly suggestive of multiple myeloma - he should urgently undergo serum protein and urine electrophoresis to find a M-component, as well as a skeletal survey and bone marrow biopsy. Severe hypercalcemia is a medical emergency. He needs urgent rehydration and volume expansion with IV fluids, as well as treatment with a bisphosphonate such as pamidronate. While melphalan is key in the chemotherapy of multiple myeloma, it should not be commenced before the diagnosis is established. Insulin is not indicated in this patient.


Discussion

Hypercalcemia is defined as a serum calcium level over 10.5 mg/dl (2.5 mmol/l). It is a common association of malignancy, occurring in up to 20% to 30% of patients at some stage. There are four mechanisms via which malignancies may cause hypercalcemia: - local osteolysis by tumor cells. - systemic secretion of parathyroid hormone related protein (PTHrP), resulting in increased bone resorption and renal retention of calcium. - systemic secretion of the active form of vitamin D (calcitriol), causing increased intestinal calcium absorption. - ectopic secretion of authentic parathyroid hormone (PTH). Depending on the degree of elevation, hypercalcemia may be subdivided into mild hypercalcemia (10.5 - 11.9 mg/dl), moderate hypercalcemia (12 - 13.9 mg/dl), and severe hypercalcemia (over 14 mg/dl). However, certain points should be kept in mind when estimating serum calcium levels: - In normal individuals, approximately half of the serum calcium is bound to proteins such as albumin. The remainder is present as ionized ("free") calcium - this is the fraction which exerts biological effects. - Total calcium levels are altered by fluctuations in serum albumin. However, ionized calcium levels remain unaltered. - The reference ranges for hypercalcemia are based on the assumption that albumin levels are normal. However, in patients with malignancies, albumin levels are frequently abnormal. - It is possible to estimate what the level of calcium would be if albumin were normal ("corrected calcium") via the equation "corrected calcium = [total calcium in mg/dl + 0.8 * (4.0 - serum albumin in g/dl)]" - However, this equation does not cover all eventualities - for example, certain patients with myeloma may secrete calcium-binding immunoglobulins, resulting in an elevated total calcium level. Thus, it is better to directly estimate the level of ionized calcium, if facilities are available. The clinical manifestations of hypercalcemia are multisystemic and include gastrointestinal symptoms such as anorexia, nausea and constipation; neuropsychiatric symptoms such as impaired concentration, confusion, or coma; and renal symptoms such as polydipsia and polyuria. Note that the degree of symptomaticity depends not only upon the severity of hypercalcemia, but also on the rate of ascent of the serum calcium level, as well as the age and general condition of the patient. Thus, an elderly patient with acute mild hypercalcemia might be comatose, while a young patient with chronic severe hypercalcemia may only show minimal symptoms. In general, acute or symptomatic hypercalcemia mandates intervention, as does severe hypercalcemia, regardless of symptomaticity. These patients are dehydrated and volume depleted due to osmotic diuresis. Hypovolemia results in a diminished glomerular filtration rate (GFR), reducing renal clearance of calcium. Thus, aggressive rehydration with intravenous (IV) saline is a key component of the initial therapy. This will restore the intravascular volume, replenish the extracellular fluid, and promote saline diuresis. Note that up to 3,000 to 6,000 ml of fluids may be required in the first 24 hours. Following volume resuscitation, loop diuretics may be judiciously used to increase renal calcium excretion (by inhibiting calcium reabsorption in the loop of Henle). Another key intervention is therapy with bisphosphonates (which interfere with osteoclast mediated bone resorption). Unfortunately, bisphosphonates require 2 to 4 days to exert their maximum effect. They should be administered intravenously, as oral absorption is poor. Given the delayed onset of action of bisphosphonates, some authorities encourage the use of calcitonin (which increases renal calcium excretion and also blocks osteoclast maturation). Calcitonin acts within 12 to 24 hours, but rapidly decreases in efficacy afterwards, such that its effect is minimal after 48 hours of therapy (possibly due to receptor down-regulation). Other drugs which may be used include plicamycin and gallium nitrate (which are antineoplastic agents with calcium-lowering abilities), while denosumab (a monoclonal antibody used in the treatment of osteoporosis and bone metastases) is undergoing clinical trials for efficacy. Glucocorticoid therapy inhibits intestinal absorption of calcium and may be considered in selected patients, such as those with steroid-responsive tumors such as lymphomas and myeloma, or those whose hypercalcemia is secondary to increased vitamin D secretion by tumor cells. Dialysis may be considered in patients unresponsive to other measures. Dialysis should also be considered if acute or chronic renal failure is present (as aggressive rehydration cannot be performed in these patients, and bisphosphonates can only be used with caution, if at all). Important general measures include discontinuation of medications that may exacerbate the hypercalcemia (i.e. thiazide diuretics and calcium or vitamin D supplements) and elimination of calcium from enteral and parenteral feeding solutions. Note also that the underlying malignancy should be treated simultaneously. Overall, hypercalcemia in a patient with malignancy signifies a poor prognosis. Approximately 50% of such patients die within 1 month and 75% within 3 months, even with treatment.


Take home messages

  1. The commonest causes of thirst and polyuria in the elderly are diabetes mellitus, diabetes insipidus and hypercalcemia.
  2. The commonest causes of hypercalcemia in the elderly are primary hyperparathyroidism and malignancies.
  3. Serum levels of ionized calcium are better for detection and quantification of hypercalcemia.
  4. Acute or symptomatic hypercalcemia mandates intervention, as does severe hypercalcemia, regardless of symptomaticity.
  5. Key elements of the management include aggressive rehydration with saline, bisphosponates and/or calcitonin, and supportive measures.

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  2. Current Opinion in Endocrinology & Diabetes : Mechanisms and treatment of hypercalcemia of malignancy (2011)
  3. Endocrine-Related Cancer : Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone (2005)
  4. Expert Opinion on Pharmacotherapy : Treatment of malignant hypercalcaemia (2002)
  5. Journal of Bone and Mineral Research : Differential Diagnosis of Hypercalcemia (1991)
  6. NEJM: Hypercalcemia Associated with Cancer (2005)
  7. NEJM: Multiple Myeloma (2011)
  8. The American Journal of Medicine : Hypercalcemia of Malignancy (1997)