Epidemiology and Etiology of Primary Hyperparathyroidism (PHPT)

• PHPT is defined as hypercalcemia or widely fluctuating levels of serum calcium levels:
  • Resulting from the inappropriate or autogenous secretion of PTH by one or more parathyroid glands:
    • In the absence of a known or recognized stimulus
• The most common cause of hypercalcemia in the outpatient setting is PHPT:
  • With approximately 100,000 new cases per year reported in the United States
• Since the advent of routine laboratory testing:
  • The prevalence of the disease has increased from 0.1% to 0.4%:
    • One to seven cases per 1000 adults
• In a study by Yeh et al., the incidence of PHPT fluctuated between:
  • 36.3 and 120.2 cases per 100,000 women-years
  • 13.4 and 35.6 in 100,000 men-years
• PHPT may present at any age:
  • With the vast majority of cases occurring in patients older than 45 years of years
• Women have consistently made up the preponderance of cases:
  • With a female-to-male ratio of:
    • 3:1 to 4:1
  • Based on a population based study from Rochester Minnesota:
    • The higher incidence of this could be secondary (hypothetically) to estrogen deficiency after menopause that reveals underlying HPT
• 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, and a 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 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 syndromes are inherited in an:
      • Autosomal dominant fashion

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