Differential Diagnosis of Primary Hyperparathyroidism (PHPT)

  • Atypical presentations of PHPT include a spectrum of disturbances in calcium homeostasis, ranging from:
    • Symptomatic severe hypercalcemia (parathyroid crisis) to normocalcemic PHPT
  • Laboratory testing often can distinguish atypical presentations of PHPT from other diseases, such as:
    • Malignancy
    • Familial hypocalciuric hypercalcemia (FHH)
    • Secondary hyperparathyroidism
  • In PHPT and FHH:
    • The calcium and PTH levels:
      • Are usually simultaneously elevated
  • Nonparathyroid-mediated causes of hypercalcemia, including milk-alkali syndrome, granulomatous disease, and hypervitaminosis D:
    • Are associated with suppressed rather than elevated PTH concentrations
  • Malignancy:
    • PHPT and malignancy are the most common causes of hypercalcemia:
      • Accounting for more than 90% of the cases:
        • It is usually not difficult to differentiate between them
    • Malignancy is often evident clinically by the time it causes hypercalcemia:
      • Patients with hypercalcemia of malignancy have higher calcium concentrations and are more symptomatic from hypercalcemia than individuals with PHPT
      • However, it may be difficult to differentiate the two problems clinically when the presentation is less typical:
        • As an example, some patients with occult malignancy may present with mild hypercalcemia
        • Alternatively, patients with hyperparathyroidism can occasionally have acute onset of severe, symptomatic hypercalcemia (parathyroid crisis):
          • In these cases, measurement of intact PTH will usually distinguish the two diseases:
            • Intact PTH concentrations are generally:
              • Undetectable or very low in hypercalcemia of malignancy
              • Elevated or high-normal in PHPT
          • It is uncommon for patients with hypercalcemia of malignancy to have elevated PTH levels:
            • But this finding may occur rarely in individuals with:
              • Hypercalcemia of malignancy and concomitant PHPT or
              • In individuals with PTH-secreting tumors:
                • Which are also rare
      • Patients with parathyroid carcinomas:
        • Have severe hypercalcemia and PTH levels in the hundreds to thousands pg/mL range
  • Familial hypocalciuric hypercalcemia (FHH):
    • An autosomal dominant disorder characterized by:
      • Longstanding, mild hypercalcemia:
        • Normal or mildly elevated PTH levels
        • Low urinary calcium excretion:
          • Less than 100 mg/24 hours
    • In most cases, it is due to:
      • An inactivating mutation in the calcium-sensing receptor in the parathyroid glands and the kidneys
    • A family history of hypercalcemia:
      • Especially in young children
      • And the absence of symptoms and signs of hypercalcemia are characteristic of this disorder
    • 15% to 20% of patients with FHH:
      • May have a mildly elevated PTH concentration:
        • In these individuals, it may be difficult to distinguish asymptomatic PHPT from FHH:
          • It is important to make this distinction, however, because FHH is a benign inherited condition:
            • That typically does not require parathyroidectomy and will not be cured by it
    • The major feature that distinguishes FHH from PHPT is:
      • A low urine calcium excretion and calcium/creatinine (Ca/Cr) clearance ratio
    • In contrast, in the absence of hypovitaminosis D, most patients with PHPT have either normal or elevated urinary calcium excretion. Because the calcium-sensing receptor is a cation receptor, urinary magnesium excretion parallels calcium excretion and is therefore low in FHH, in contrast with PHPT. Measurement of urinary magnesium is not, however, recommended in the evaluation of PHPT or FHH.
  • Drugs — Two drugs deserve special consideration when evaluating a patient for hyperparathyroidism: thiazide diuretics and lithium.
  • Thiazide diuretics, including chlorthalidone, reduce urinary calcium excretion and therefore can cause mild hypercalcemia (up to 11.5 mg/dL [2.9 mmol/L). In addition, some patients with hyperparathyroidism 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 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 withdrawal suggests that the thiazide has unmasked PHPT.
  • Lithium decreases parathyroid gland sensitivity to calcium, shifting the calcium-PTH curve to the right. Lithium may also reduce urinary calcium excretion. Lithium is thought to affect calcium-PTH dynamics through an action downstream of the calcium-sensing receptor, but the exact locus is still unknown. Some patients taking lithium develop hypercalcemia and hypocalciuria, and a subset of these individuals have high serum PTH concentrations. If the lithium can be stopped without exacerbating the psychiatric condition, the hypercalcemia may resolve. Following discontinuation, the serum calcium concentration is more likely to normalize if the duration of lithium use had been relatively short (eg, less than a few years), but less likely if it had been longer (eg, more than 10 years).
  • Secondary hyperparathyroidism — Occasionally, patients with PHPT have consistently normal total and ionized calcium concentrations (normocalcemic PHPT). These patients typically come to medical attention in the setting of an evaluation for low bone mineral density (BMD). In these cases, it may be difficult to distinguish secondary hyperparathyroidism from early PHPT because the biochemical findings may be similar.
  • Secondary hyperparathyroidism occurs when the parathyroid gland appropriately responds to a reduced level of extracellular calcium. PTH concentrations rise, and calcium is mobilized by increasing intestinal absorption (via increase in calcitriol) and by increasing bone resorption. Thus, it is characterized biochemically by elevated PTH and normal or low serum calcium concentrations.
  • Secondary hyperparathyroidism may occur in patients with renal insufficiency or failure and impaired calcitriol (1,25 dihydroxyvitamin D) production, as well as in individuals with inadequate calcium intake or absorption, as can occur with vitamin D deficiency or with gastrointestinal diseases causing malabsorption. Assessment of renal function (serum creatinine), vitamin D status (25-hydroxyvitamin D [25(OH)D]), and calcium sufficiency (urinary calcium excretion) may help differentiate normocalcemic primary and secondary hyperparathyroidism. Further assessment and work-up for specific gastrointestinal disorders is generally undertaken only when the clinical suspicion is high.
  • Some patients may have more than one condition leading to increased PTH secretion. Co-existing PHPT and vitamin D deficiency is not uncommon. When this occurs, the serum calcium level in the primary hyperparathyroid patient may be reduced (into the normal range in some cases) due to vitamin D deficiency.

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