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Essentials of Diagnosis

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  • Hypercalcemia is usually manifested as a chronic but mildly elevated serum calcium level, although more severe forms that present as hypercalcemic emergencies do exist.
  • The symptoms associated with sustained hypercalcemia are relatively nonspecific, but the constellation of symptoms often suggests the diagnosis.
  • A combination of neuropsychiatric complaints such as depression, anxiety, cognitive dysfunction, headache, fatigue and even organic brain syndrome, renal complaints including polyuria, polydipsia, nephrogenic diabetes insipidus, nephrolithiasis, nocturia, and renal insufficiency, and gastrointestinal complaints such as constipation, peptic ulcer disease, or a diagnosis of acute pancreatitis would strongly suggest the diagnosis.
  • Most patients with hypercalcemia are diagnosed based on data derived from laboratory screening tests.
  • The signs and symptoms associated with the underlying disease causing hypercalcemia may dominate the clinical picture.

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General Considerations

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Calcium in serum exists ionized, bound to organic anions such as phosphate and citrate, and bound to proteins (mainly albumin). Of these, ionized calcium is the physiologically important form. The most common abnormality that distorts the relationship between serum calcium and ionized calcium is hypoalbuminemia. The total serum calcium is lower or higher by 0.8 mg/dL (0.2 mmol/L) for every 1.0 g/dL that the serum albumin is higher or lower, respectively, than 4 g/dL. Thus, patients may have a normal serum ionized calcium but low total calcium if they have hypoalbuminemia due to nephrotic syndrome. Conversely, a patient can have high total calcium, with normal ionized calcium and increased total protein and/or albumin, as in states of severe dehydration.

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Hypercalcemia is one of the most common metabolic disorders in malignant diseases and develops in 3–30% of such patients. Hypercalcemia of malignancy is the most common cause of hypercalcemia followed by primary hyperparathyroidism in hospital populations. The most common cause in normal populations is primary hyperparathyroidism followed by transient hypercalcemia.

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Pathogenesis

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Hypercalcemia can result from increased bone resorption, decreased renal excretion, or increased gastrointestinal absorption. However, bone resorption and intestinal hyperabsorption of calcium are the predominant causes of hypercalcemia. Reduced renal excretion is a permissive factor in all cases of hypercalcemia as in the absence of renal conservation of calcium, any rise in serum calcium would result in the excretion of any excess in the urine and hypercalciuria but not hypercalcemia would ensue.

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Typically, the mechanism underlying hypercalcemia is complex and multifactorial. In primary hyperparathyroidism, all three components come into play. High parathyroid hormone (PTH) levels induce bone resorption, increase renal tubular reabsorption, and secondarily increase gastrointestinal calcium absorption as PTH stimulates production of the most active form of vitamin D, calcitriol.

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PTH is the master hormone regulating overall calcium metabolism. It is an 84-amino acid hormone that in response to a fall in serum calcium levels raises calcium levels by accelerating osteoclastic bone resorption and increasing renal tubular resorption of calcium. It also increases calcitriol, which indirectly raises serum calcium levels. ...

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