Primary hyperparathyroidism (PHPT) is the most common cause of PTH- dependent hypercalcaemia. PHPT is a common endocrine disease, characterized by increased serum calcium and high or inappropriately normal serum levels of PTH. PHPT is prevalent in the sixth decade of life, with a female to male ratio of 3– 4:1, whereas there is no gender difference below the age of 40 years. PHPT generally occurs sporadically, but occasionally it may be part of familial syndromes: multiple endocrine neoplasia type 1, 2 A, and 4 (MEN1, MEN2A, and MEN4), hyperparathyroidism- jaw tumour syndrome (PHPT- JT), familial isolated PHPT (FIHP). In the majority of patients PHPT is due to a single parathyroid adenoma, rarely to a multiglandular disease and very rarely (less than 1%) to parathyroid carcinoma. In the latter case, hypercalcaemia is usually severe. During the last decades the clinical presentation of PHPT changed and in industrialized countries the disease commonly occurs as an asymptomatic disorder: patients rarely present hypercalcaemic symptoms, overt bone disease, and neuromuscular weakness; conversely silent nephrolithiasis is still rather common (up to 35%). Parathyroidectomy is the only definitive cure for PHPT and should be recommended in symptomatic patients. Moreover, parathyroidectomy should also be recommended in those with asymptomatic PHPT with target organs involvement, as suggested by international guidelines. Some important novel ties in patient’s evaluation and management were introduced in the lastly updated version in 2013, particularly regarding the evaluation of bone and kidney involvement and the impact of related abnormalities on patient’s management.
Tertiary hyperparathyroidism In patients with severe vitamin D deficiency, resistance to 1,25 (OH)2 vitamin D and endstage renal failure, parathyroid hyperplasia may be followed by autonomous overgrowth of a clone of parathyroid cells and development of adenomas and hypercalcaemia, a condition known as tertiary hyperparathyroidism.
Familial hypocalciuric hypercalcaemia FHH is a rare autosomal dominant disorder characterized by moderate hypercalcaemia and relative hypocalciuria, namely the urinary calcium excretion is low in relationship to the increased levels of serum calcium and renal calcium load. The reported prevalence of the disease is about 1 in 78 000 individuals, but it is probably underestimated, because of the subclinical picture and misdiagnosis. FHH is due to a genetic disorder associated in the most cases with a loss- of- function mutation in the calcium- sensing receptor (CaSR) gene. This accounts for lower sensitivity to the inhibitory effect of serum Ca2+ on the parathyroid synthesis, secretion of PTH and increased renal tubular reabsorption of calcium. Patients are generally asymptomatic. The diagnosis should be considered in asymptomatic patients with mild- to- moderate hypercalcaemia and inappropriately normal or slightly increased PTH levels. The clue for the diagnosis of FHH is the finding of a calcium to creatinine clearance ratio, less than 0.01 (in patients with PHPT this ratio is usually above 0.02– 0.03). Vitamin D deficiency, if present, should be corrected before urine collection. Laboratory testing (serum and urinary calcium) in relatives may be of value for supporting the diagnosis, which should be confirmed by genetic testing. It is important to remember that FHH is extremely rare as compared with PHPT and therefore in equivocal cases the latter diagnosis is the most likely one.
Authentic ectopic secretion of PTH. Since 1990 rare cases of patients with malignancies were reported, in whom hypercalcaemia was associated with authentic PTH secretion by the tumours. Streweler et al. for the first time described a patient with a neuroectodermal neck tumour shown to produce intact PTH [25]. Circulating PTH levels are usually particularly high in patients with a true intact PTH ectopic secretion. In the last 20 years 32 articles describing authentic ectopic secretion of PTH have been published. PTH secreting tumours can be found in the neck (medullary and papillary thyroid carcinoma, cervical paraganglioma, nasopharyngeal rhabdomyosarcoma, squamous tonsil carcinoma), in the thorax (lung carcinoma, thymoma), and in the gastrointestinal tract and pelvis (hepatocarcinoma, pancreatic adenocarcinoma, oesophageal carcinoma, pancreatic islet carcinoma, ovarian carcinoma, adenosquamous endometrium carcinoma). Ectopic PTH secretion should be considered when moderate- to- severe hypercalcaemia is found in a cancer patient, particularly if associated with high levels of PTH. When hypercalcaemia is mild, the diagnosis of PHPT, which is much more common than ectopic PTH secretion, should be considered, and therefore we cannot exclude that these two conditions may coexist in the same patient. Neck imaging studies and selective venous blood sampling for PTH measurement may be of help in selected cases.
