Indications for parathyroidectomy are indisputable in patients with primary HPT who exhibit clear and classic symptoms or marked hypercalcemia. The value of parathyroidectomy in asymptomatic patients with mild to moderate hypercalcemia has, however, been debated. Studies of the natural history of untreated primary HPT document that rapid increases in the serum calcium level, progression of symptoms or complications, or both is uncommon in patients with borderline hypercalcemia. Less clear is our knowledge about the long-term consequences of somewhat more marked hypercalcemia because no study has yet presented adequate follow-up of such patients for a prolonged period of time. It appears as if many patients with moderately elevated serum calcium levels (<3.0 mmol/L) have symptoms and silent complications of HPT if they are carefully studied. Although rapid progression of hypercalcemia is unusual, serum calcium levels, nevertheless, tend to increase progressively over years of observation in some patients.

This advancing hypercalcemia may be obscured by declining levels of active vitamin D, resulting from dietary deficiency, lack of sun exposure, and impairments of renal function. Because these factors lower serum calcium levels, progression of HPT may not be detected.7-55'56 The impact of such relative vitamin D deficiency may be difficult to determine and may simultaneously be part of the pathogenesis of primary HPT in elderly people.

The natural course of primary HPT is causally related to the genetic and functional abnormalities within the diseased parathyroid tissue. Variable tumor biology and clinical progression may, therefore, depend on heterogeneity of tumor genetics.57 Occasionally, patients' metabolic problems progress rapidly and are then reflected in excessively raised serum calcium values. These patients may have parathyroid tissues that harbor exceptional and critical mutations with oncogene activation or recruitment of growth factors. A PRAD1 oncogene rearrangement has been described in this context and has been associated with the largest parathyroid adenomas, whereas a menin gene abnormality has also been evident in sporadic, mild HPT.58 Rare patients with initially mild hypercalcemia but rapidly advancing disease may have parathyroid carcinoma.40 In addition, stepwise "clinical" progression may occur during observation in patients with primary HPT, possibly representing development of secondary mutations that cause accelerated growth of the tumor. Thus, a history of mild primary HPT has been reported in up to one third of patients with hypercalcemic crisis. Because it is not yet possible to predict whether progressive disease will occur in any patient, extended follow-up is crucial if surgery is deferred in primary HPT.59 60 Younger patients seem to be at greater risk for progressive disease.

The absence of marked progression of complications in most patients with mild primary HPT allows medical surveillance in older persons with borderline hypercalcemia (i.e., with increments of serum calcium to less than 2.75 to 2.85 mmol/L, or 11.0 to 11.4 mg/dL) and in those with associated illnesses. Medical surveillance is probably inappropriate in younger patients and in those with more marked hypercalcemia. Nonoperative management in any circumstance requires that the presence of symptoms or complications be carefully excluded and that precise monitoring of symptoms and metabolic function be done.4 A new consensus statement46 has substantiated a risk for disease progression if patients with HPT are monitored without surgery and therefore issued a general recommendation for parathyroidectomy in patients with serum calcium values raised 0.25 mmol/L above the normal reference.


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