What is the Origin / Etiology of Primary Hyperparathyroidism?

• The precise origin of PHPT is unknown:
  • Although exposure to low-dose therapeutic ionizing radiation and familial predisposition account for some cases:
    • Irradiation for acne:
      • Could have accounted for a 2 to 3-fold increase in the incidence of this disease at some point in time
    • 4-fold increase was noted in survivors of the atomic bomb
  • Schneider et al., in their study of 2555 patients followed for 50 years:
    • Even low doses of radiation exposure during the teenage years:
      • Was associated with a slight risk of developing PHPT
    • In this study a dose response was documented in people receiving external-beam radiotherapy for benign diseases before their 16th birthday
    • The latency period for the development of PHPT after radiation exposure:
      • Is longer than that for the development of thyroid tumors:
        • With most cases occurring 30 to 40 years after exposure
    • Patients who have been radiated have:
      • Similar clinical manifestations and serum calcium levels when compared to patients without a history of radiation exposure:
        • However, the former tend to have higher PTH levels and a higher incidence of concomitant thyroid neoplasms
• Certain medications have been implicated in the development of hypercalcemia:
  • Lithium therapy has been known to:
    • Shift the set point for PTH secretion in parathyroid cells:
      • Thereby resulting in elevated PTH levels and mild hypercalcemia
    • Lithium stimulates the growth of abnormal parathyroid glands in vitro and also in susceptible patients in vivo
    • Unusual metabolic features associated with lithium use include:
      • Low urinary calcium excretion
      • Normal cyclic AMP excretion
      • Lack of calcic nephrolithiasis
    • The mechanism probably results from:
      • Lithium linking with the calcium sensing receptor on the parathyroid glands resulting in PTH secretion
• Elevated serum calcium levels have been associated with thiazide diuretic:
  • The overall annual age- and sex-adjusted (to 2000 U.S. whites) incidence was:
    • 7.7 (95% CI, 5.9 to 9.5) per 100,000 individuals
  • The average 24-hour plasma calcium concentrations are increased with thiazide diuretic use:
    • But the mean 24-hour PTH levels remain unchanged:
      • In subjects with normal baseline PTH levels and no evidence of hypercalciuria
  • Thiazides diuretics have several metabolic effects that may contribute to increased calcium levels:
    • A decrease in urine calcium excretion is the most likely cause:
      • But in some cases diuretic use has been associates with a metabolic alkalosis:
        • That could also increase the total serum calcium levels through a pH-dependent increase in protein-bound calcium
    • Although plasma 1,25 (OH) vitamin D levels are unchanged:
      • Increased intestinal calcium absorption in response to thiazide diurectic use:
        • Has been noted and could also contribute to an increase in serum calcium
    • One last possible explanation for the elevated serum calcium levels associated with thiazide diuretic use is:
      • Hemoconcentration associated with dieresis
• Numerous genetic abnormalities have been identified in the development of PHPT, including:
  • Anomalies in tumor suppressor genes and proto-oncogenes
    • Specific DNA mutations in a parathyroid cell:
    • May confer a proliferative advantage over normal neighboring cells:
      • Thus allowing for clonal growth:
        • Large populations of these altered cells containing the same mutation within hyper functioning parathyroid tissue:
          • Suggest that such glands are a result of:
            • Clonal expansion
• The majority of PHPT cases are:
  • Sporadic
  • Nonetheless, PHPT also occurs within the spectrum of a number of inherited disorders such as:
    • Multiple endocrine neoplasia syndromes (MEN):
      • MEN type 1 (Wermer Syndrome)
      • MEN type 2A (Sipple Syndrome)
    • Isolated familial HPT
    • Familial HPT with jaw-tumor syndrome
  • All of these are inherited in an:
    • Autosomal dominant fashion

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