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
Parathyroid Adenoma

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