Differential Diagnosis of Hypercalcemia

Primary hyperparathyroidism
Malignancy:
- Hematologic (multiple myeloma)
- Solid tumors (PTHrP)
Endocrine diseases:
- Hyperthyroidism:
  - Mild hypercalcemia occurs in up to 15% to 20% of thyrotoxic patients:
    - Due to a thyroid hormone mediated:
      - Increase in bone resorption:
        It typically resolves following correction of hyperthyroidism
- Addisonian crisis:
  - Hypercalcemia occurs in occasional patients with Addisonian crisis:
    - Multiple factors appear to contribute to the hypercalcemia including:
      - Increased bone resorption
      - Volume contraction and increased proximal tubular calcium reabsorption
      - Hemoconcentration
      - Perhaps increased binding of calcium to serum proteins
  - Cortisol administration reverses the hypercalcemia within several days
  - Hypercalcemia has also been reported in patients with secondary adrenal insufficiency due to lymphocytic hypophysitis:
    - The increased release of calcium from bone occurs:
      - Despite appropriate suppression of PTH and calcitriol release:
        And appears to be mediated, at least in part, by:
        Thyroid hormone via a process normally inhibited by glucocorticoids
- Acromegaly
- Pheochromocytoma:
  - Hypercalcemia is a rare complication of pheochromocytoma
  - It can be due to:
    - Concurrent hyperparathyroidism (in MEN type IIa) or
    - To the pheochromocytoma itself:
      - Appears to be due to:
        Tumoral production of PTH-related protein
      - Serum PTH-related protein concentrations in these patients can be reduced by alpha-adrenergic blockers:
        Suggesting a mediating role for alpha-stimulation

Vipoma
Milk alkali syndrome:
- In the absence of renal failure:
  - Hypercalcemia can be induced by a:
    - High intake of milk or more commonly, calcium carbonate:
      - Leading to the Milk-Alkali-Syndrome:
        Hypercalcemia
        Metabolic alkalosis
        Renal insufficiency
  - The metabolic alkalosis augments the hypercalcemia:
    - By directly stimulating calcium reabsorption in the distal tubule:
      - Thereby diminishing calcium excretion
  - A calcium-induced decline in renal function:
    - Due to renal vasoconstriction and, with chronic hypercalcemia:
      - Leads to structural injury:
        This can also contribute to the inability to excrete the excess calcium
  - Renal function usually returns to baseline after cessation of milk or calcium carbonate intake:
    - But irreversible injury can occur in patients who have prolonged hypercalcemia
  - Milk-alkali syndrome accounted for:
    - 8.8% of hypercalcemia cases between 1998 and 2003
Granulomatous diseases:
- Sarcoidosis
- Tuberculosis
- Berylliosis
- Histoplasmosis
- Wegeners Granulomatosis
  - Mechanism:
    - Increased calcitriol:
      - Activation of extra-renal 1-alpha-hydroxylase
Medications:
- Thiazide diuretics:
  - Thiazide diuretics reduce urinary calcium excretion:
    - And therefore can cause mild hypercalcemia (up to 11.5 mg/dL [2.9mmol/L]):
  - In addition, some patients with PHPT may be prescribed thiazides:
    - Which may elevate the serum calcium further and thereby unmask the hyperparathyroidism:
      - Following discontinuation of the drug:
        These individuals remain hypercalcemic:
        Although perhaps less so, and are found to have surgically proven hyperparathyroidism:
        Thus, if a patient taking a thiazide diuretic is found to be hypercalcemic, the drug should be withdrawn, if possible, and calcium and PTH assessed three months later:
        Persistent hypercalcemia (with elevated or high-normal PTH) after drug is withdrawal suggests that the thiazide has unmasked primary hyperparathyroidism

Lithium:
- Patients receiving chronic lithium therapy often develop mild hypercalcemia:
  - Most likely due to increased secretion of PTH:
    - Due to an increase in the set point at which calcium suppresses PTH release
    - The hypercalcemia usually, but not always:
      - Subsides when the lithium is stopped
        Lithium can also unmask previously unrecognized mild primary hyperparathyroidism (PHPT)
- Conversely, lithium can also raise serum PTH concentrations without raising serum calcium concentrations
Teriparatide
Abaloparatide
Theophylline toxicity
Vitamin A poisoning:
- Hypervitaminosis A:
  - In which there is prolonged ingestion of more than 50,000 International Units per day or the administration of retinoic acid to patients with certain tumors (as either cis-retinoic acid or all-trans retinoic acid):
    - Retinoic acid causes a dose-dependent increase in bone resorption:
      - Resulting in an overall incidence of hypercalcemia of approximately:
        30%
    - All-trans retinoic acid:
      - Inhibits cell growth in part by downregulation of interleukin-6 receptors:
        The subsequent rise in serum interleukin-6 concentrations:
        May be responsible for increased bone resorption and hypercalcemia
Vitamin D poisoning

Increased calcium intake:
- A high calcium intake alone is rarely a cause of hypercalcemia:
  - Because the initial elevation in serum calcium concentration:
    - Inhibits both the release of parathyroid hormone (PTH) and in turn the synthesis of calcitriol:
      - In patients who also have reduced urinary excretion, however:
        Increased intake can cause hypercalcemia:
        This combination of high calcium intake and low urine calcium excretion occurs in two clinical situations:
        Chronic kidney disease
        The milk-alkali syndrome
Chronic kidney disease:
- Renal failure alone, although associated with decreased calcium excretion:
  - Does not lead to hypercalcemia because of the:
    - Calcium-lowering effects of concurrent hyperphosphatemia and decreased calcitriol synthesis:
      - However, hypercalcemia is not unusual in patients who are given:
        Calcium carbonate or calcium acetate to bind dietary phosphate:
        Particularly if they have adynamic bone disease or are also treated with calcitriol (or another form of vitamin D):
        In an attempt to reverse both hypocalcemia and secondary hyperparathyroidism
Benign hypocalcuric hypercalcemia
Paget’s disease of the bone:
- With immobilization
Immobilization
Administration of estrogens or anti-estrogens (Tamoxifen):
- In patients with breast cancer or bone metastases
Rhabdomyolysis:
- With acute renal failure:
  - Hypercalcemia has been described during the diuretic phase of acute renal failure, most often in patients with rhabdomyolysis:
    - Hypercalcemia in this setting is primarily due to:
      - The mobilization of calcium that had been deposited in the injured muscle
    - Correction of hyperphosphatemia (induced by the rise in glomerular filtration rate), mild secondary hyperparathyroidism induced by the renal failure, and an unexplained increase in serum calcitriol concentrations:
      - All appear to contribute to the hypercalcemia