Normocalcaemic primary hyperparathyroidism. The entity now known as normocalcaemic PHPT was discovered over 15 years ago. During evaluation, but not necessarily long- term, these patients demonstrate normal corrected serum calcium levels. Discover of this phenotype of PHPT is due, in large part, to the proactive approach to low bone mass with regard to testing in which the PTH is measured even when the serum calcium is normal. When these patients are confirmed to have normal serum calcium levels and elevated PTH, a consideration of secondary causes for an elevated PTH level becomes mandatory. One of the most important secondary causes to rule out is vitamin D deficiency. The Institute of Medicine has stated that vitamin D insufficiency can be defined when the 25- hydroxyvitamin D level is less than 20 ng/ ml and that levels between 20 and 30 are acceptable. It stated, furthermore, that levels from 30 to 20 ng/ ml are not reliably associated with elevated levels of PTH. It is also true, though, that some patients will show an inflection upwards in their PTH levels when the 25- hydroxyvitamin D level is between 30 and 20 ng/ ml. In order to be sure that vitamin D insufficiency is not contributing to the elevated PHT, a level of more than 30 ng/ ml seems reasonable. In some situations, a goal might be to set the 25- hydroxyvitamin D level at 40 ng/ ml, on the chance that this form of PHPT may be as sociated with an element of vitamin D resistance.
When considering the diagnosis of normocalcaemic PHPT, other secondary causes for an elevated PTH, besides vitamin D insufficiency, should be considered. Renal insufficiency with an eGFR of less than 60 cc/ min can be associated with an elevated PTH level, but PTH levels do not tend to show levels in the abnormal range until renal function has declined to chronic kidney disease has reached stage 3B (i.e. <45 cc/ min).
Medications, as noted earlier with regard to thiazide diuretics and lithium, can be associated with a high PTH. While not generally appreciated, bisphosphonates and denosumab can be associated with elevated levels of PTH. Patients with other metabolic bone disease such as Paget’s disease can occasionally show elevated levels of PTH.
The diagnosis of normocalcaemic PHPT depends upon ruling out secondary causes of elevated PTH levels. Even with due diligence, one may miss a secondary cause such as a subclinical malabsorption syndrome.
The discussion of normocalcaemic PHPT should take into account also the possibility that the patient doesn’t have a disease at all but that the PTH level is merely representing the fringe of the normal distribution curve. The normal distribution curve captures about 95% of the normal population with about 2.5% falling either above or below those defined limits. Such patients are not necessarily abnormal. Another consideration in the discussion of normocalcaemic PHPT is the ‘normal’ serum calcium level. Is the serum calcium normal for that patient? For an analyte like calcium, the control in a given individual is much tighter than it is for the entire population. If patients have spent most of their years with serum calcium levels averaging 9.0 mg/ dl and develops PHPT, the serum calcium might increase to10.0 mg/ dl. Without a history of those patients’ earlier serum calcium levels, the measured calcium appears to be normal. If one had a history of those patients’ earlier calcium levels, the levels measured as ‘normal’ would not be normal for that patient. The 1 mg/ dl increase in serum calcium would still be within the normal population range but for that given patient, it is decidedly high. We describe the patient as one with normocalcaemic PHPT but in fact the patient is hypercalcaemic with regard to her own calcium homeostasis.
Finally, a form of abnormal parathyroid tissue has been described with a normal serum calcium and PTH concentration made only by pathological examination of abnormal parathyroid tissue has been proposed.
Acute Primary Hyperparathyroidism
The onset of marked hypercalcaemia and elevated levels of PTH can occur in patients with a history of mild hypercalcaemia. Typically, mild hypercalcaemia due to PHPT is not likely to lead to acute, symptomatic hypercalcaemia, the incidence of which is less than 1%. If there is an antecedent history of mild hypercalcaemia, the possibility of acute PHPT becomes likely. The inciting factors are not understood but an intercurrent illness in which the patient does not maintain good hydration and is bed ridden is a typical scenario. Haemorrhage or infarction of the offending parathyroid gland is almost never seen at the time of parathyroidectomy. A previous history of mild hypercalcaemia is not always obtained, leading to the possibility that the patient has parathyroid cancer. While this is certainly a possibility, the rarity of parathyroid cancer makes acute primary hyperparathyroidism statistically more likely.
Parathyroid carcinoma
The differential diagnosis of marked hypercalcaemia and very high levels of PTH usually comes down to either acute PHPT or parathyroid cancer. Because parathyroid cancer is so unlikely, the patient presenting with acute symptomatic hypercalcaemia is more likely to have a benign parathyroid adenoma. Among patients with PHPT, malignant disease constitutes less than 0.5%. In parathyroid cancer, the serum calcium tends to high (>14 mg/ dl) and associated with hypercalcaemic symptoms, along with markedly elevated levels of PTH. It is not unusual for levels of PTH to be 20 times normal. It is exceedingly rare for a parathyroid cancer to be non- secretory. There are other differentiating features when parathyroid cancer becomes a consideration. For example, the carcinoma can present with a neck mass that is easily palpable. They are 40– 50 years old, on average, about a decade younger than patients with benign dis ease. Different from its benign counterpart, there is no difference in incidence by gender. The natural history of parathyroid cancer can be cure, if surgery if successful at the outset. But many patients are not cured but follow, rather, a slow, indolent clinical course. Patients will typically live for several decades after the diagnosis is made. Recurrent parathyroid cancer can resurface 20 years later. While parathyroid cancer is typically a sporadic disease, it has seen in association with the hyperparathyroid- jaw tumour syndrome. That presentation and other aspects of parathyroid cancer genetics are covered elsewhere in this chapter.
Hyperparathyroidism due to true ectopic PTH production. While malignancies have been associated with hypercalcaemia, it is very rare for the tumour to be producing authentic PTH. Much more common is the situation in which the patient has both a malignancy and PHPT. The production of parathyroid hormone related peptide (PTHrP) by the tumour is very well described but this peptide does not cross- react in the commercially available immunoassays for PTH. Thus, in this setting, the PTH level will be undetectable.
Hereditary Primary Hyperparathyroidism: Forms and Genetics
The Multiple Endocrine Neoplasia (MEN) syndromes, known classically as type 1 and type 2, are autosomal disorders. Of the glands that can be involved in MEN 1 or 2, PHPT is the most common and often the first to be involved. By the age of 50, penetrance is virtually complete with rare de novo cases seen thereafter. In MEN 1, the other common glands that are involved include the pancreas and the anterior pituitary. In MEN 2, PHPT is seen with medullary thyroid cancer and pheochromocytoma. In the syndrome known as MEN 2b or MEN 3, PHPT is not seen. Along with medullary thyroid cancer and pheochromocytoma, MEN 2b (MEN 3), can feature mucosal neuromas, autonomic ganglia dysfunction of the gastrointestinal (GI) tract and a marfanoid habitus. In MEN 4, PHPT is seen in as sociation with anterior pituitary, gonadal, adrenal, or renal tumours. PHPT, which can be a frank parathyroid malignancy or as part of the hyperparathyroidism- jaw tumour (HPT- JT) syndrome.
These genetic disorders are of great interest, in part, because they have helped to elucidate genetic controls of normal endocrine glands. But, they constitute a small percentage of patients with PHPT. One is advised to pursue a genetic aetiology only when setting is suggestive such as PHPT in those less than 30 years old or in those with a family history of PHPT or other hypersecretory endocrine syndromes. Familial isolated PHPT has also been well- described in the absence of any other endocrine disorder.
The tumour suppressor gene known as MENIN is inactivated in MEN 1. Mutations in the RET proto- oncogene are responsible for MEN2 and MEN 2b (MEN3). The gene that controls the cyclin- dependent kinase inhibitor (p27kip1), CKNK1B, is affected in MEN 4. The HRPT2 gene (CDC73) is abnormal in the HPT- JT syndrome. This gene directs the production of parafibromin which can be immunochemically detected in parathyroid tissue.
Other familial syndromes cannot be neatly classified. Familial isolated hyperparathyroidism (FIH), for example, can be as sociated with multiglandular syndromes. It will be of great interest when these genes are identified and compared to regulatory aspects of the genes that have already been characterized in the familial syndromes of PHPT. Thakker et al. presents a well- reasoned approach to questions related to the genetic basis for the hyperparathyroid states.
Familial hypocalciuric hypercalcaemia (FHH). The clinical aspects of FHH have already been discussed. The genetic basis of this disease is inactivation of the calcium- sensing receptor (CaSR).
Neonatal severe primary hyperparathyroidism (NSHPT). This rare but life- threatening presentation in newborns is identified by marked hypercalcaemia, very high levels of PTH, hypotonia, and respiratory distress. A homozygous mutation of the CaSR gene is responsible for this disease.
