PHPT is almost always a benign expression of excessive production and secretion of PTH. In 80% of adult patients, the cause is a single parathyroid adenoma while in the remaining 20%, all four parathyroid glands are involved with a hyperplastic histology. Double parathyroid adenomas are seen infrequently. Classically, PHPT is a hypercalcaemic disorder. In patients whose serum albumin is low, the total serum calcium measurement will read lower than it would if the level were 4.0 g/ dl. The serum calcium is adjusted up wards by 0.8 mg/ dl for every gram by which the albumin is below 4.0 g/ dl. In centres where the ionized calcium is routinely measured, it will be elevated and, of course, no adjustment for albumin is needed. In PHPT, the PTH level is elevated but not infrequently, the PTH level will be within the normal reference range for the assay. The hypercalcaemic state defines that ‘normal’ PTH level as abnormal because normal parathyroid tissue would instantly reduce PTH secretion to undetectable levels if the cause of the hypercalcaemia were not parathyroid hormone dependent. Theoretically, any detectable level of PTH in the context of frank hypercalcaemia is compatible with a diagnosis of PHPT. Since second generation PTH assays, that are most commonly used, can detect inactive circulating fragments, it is helpful to set a lower limit of detectability below which one would look for other causes of hypercalcaemia. Well- documented PHPT has been described with levels of PTH as low as 20– 25 pg/ ml, assuming a normal reference range of 10– 65 pg/ ml. A PTH con centration of 20 pg/ ml would seem to be a reasonable lower limit below which non PTH- dependent hypercalcaemia becomes more plausible. Bear in mind that PTH levels increase with age. While reference ranges have not been completely established by age, in those under the age of 45, an upper limit of 45 pg/ ml, not 65 pg/ ml would seem to be reasonable.
The recent controversy over normal reference ranges for 25- hydroxyvitamin D has stimulated discussion about normal reference ranges for PTH. The generally accepted reference ranges for PTH, as noted earlier, do not take into account the levels of 25- hydroxyvitamin D. Since there is a linear, inverse relationship between 25- hydroxyvitamin D levels and PTH, the reference range for PTH may well be lower in a vitamin D replete population.
In addition, the PTH assay can read low, in certain assays, by virtue of moieties that interfere with the assay, such as biotin [30]. If a patient who reports the use of biotin is rechecked after discontinuing it, the level PTH may become more compatible with the diagnosis of PHPT.
Thiazides and lithium can be associated with PTH- dependent hypercalcaemia, that is with elevated calcium and PTH levels. Most of these patients have PHPT and, if one were able to discontinue the thiazide or lithium, the serum calcium would remain elevated in the clear majority of patients. If there is doubt, thiazides can be substituted for other agents, but stopping or substituting lithium should only be done under careful supervision.
In the differential diagnosis of PTH- dependent hypercalcaemia, familial hypocalciuric hypercalcaemia (FHH) is often considered. This is clearly appropriate because one does not want to mistake PHPT for FHH, particularly if parathyroid surgery is being considered for the patient. The consideration of FHH is highly relevant in young patients under the age of 30 because the disease has high penetrance by then. If there is family history of hypercalcaemia, particularly if it includes members who have had unsuccessful parathyroid surgery one should consider FHH. These patients represent a very small proportion of the hyperparathyroid universe. Since most patients with PHPT are postmenopausal women whose serum calcium was known to be normal years before, the development of hypercalcaemia in their adult years virtually rules out FHH. It should be emphasized that FHH is a rare disorder and, from a statistical point of view, a postmenopausal woman who develops hypercalcaemia and elevated levels of PTH does not have FHH. A key point of distinction between PHPT and FHH, as the name implies, is that urinary excretion of calcium is very low. When compared to the creatinine clearance, the ratio of the calcium clearance:creatinine clearance (CCCR) is less than 0.01. Patients with PHPT can also have a low urinary excretion of calcium because PTH is a calcium- conserving hormone. For any amount of calcium filtered at the glomerulus, under the influence of PTH, there will be greater tubular reabsorption and less calcium excretion. A CCCR less than 0.01 can, therefore, be compatible with PHPT particularly if the patient is on a low calcium diet. If there is doubt, genetic testing for an inactivating mutation in the calcium- sensing receptor can be done readily.
Patients with PHPT can demonstrate a normal albumin- corrected serum calcium level from time to time. As noted just now, if the albumin is low, the total serum calcium can read normal. If the patient has severe vitamin D deficiency, the serum calcium can read normal. If the patient has PHPT, correction of the vitamin D deficiency can unmask the hypercalcaemia of PHPT.
