Update on Genetic and Clinical Aspects of Primary Hyperparathyroidism: Update on Genetic and Clinical Aspects of Primary Hyperparathyroidism

S. Miedlich, K. Krohn, R. Paschke


Clin Endocrinol. 2003;59(5) 

In This Article

Summary and Introduction

Primary hyperparathyroidism (pHPT) is a common endocrine disorder that predominantly affects postmenopausal women. It is mostly caused by solitary tumours within the parathyroid glands. Although the pathophysiology of pHPT is still incompletely understood, recent studies provide new clues on the development and cellular growth of tumours within the parathyroids associated with hypersecretion of parathyroid hormone and hypercalcaemia. The natural course of pHPT is rather benign. Nowadays, it has become an oligo- or asymptomatic disease often only detected by routine blood tests. These facts raise the question whether to perform parathyroidectomy on oligo- and asymptomatic patients with pHPT or whether it is possible to monitor these patients without surgery. The aim of this article is to review the literature as regards (i) the pathophysiological mechanisms that underlie parathyroid neoplasia and (ii) the defective calcium-sensing in patients with pHPT (iii) environmental and/or genetic risk factors that predispose to or promote parathyroid neoplasia, as well as (iv) alternative approaches to treat oligo- and asymptomatic patients with pHPT medically.

Maintenance of a normal extracellular calcium concentration (2·2-2·6 mmol/l) depends on the integrated co-ordination of calcium fluxes with respect to intestinal tract, kidneys and bone. Changes in extracellular calcium levels are mainly regulated by parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (reviewed in Bushinsky & Monk, 1998). Secretion of PTH is regulated by extracellular calcium, via a G protein-coupled calcium-sensing receptor (CaR; Brown et al., 1993). Small increments in extracellular calcium levels above normal inhibit PTH secretion. Subsequently, calcium uptake from intestine, renal reabsorption and release of calcium from bone are reduced to re-establish the normal value (see Fig. 1). If serum calcium concentration falls by only a few per cent, secretion of PTH is stimulated, and calcium uptake from the intestines, release from bone and reabsorption from the kidneys are increased (reviewed in Bushinsky & Krieger, 1992a, 1992b). In part, these effects are mediated by 1,25-dihydroxyvitamin D, whose synthesis is tightly regulated by PTH, as well as by calcium, phosphate and 1,25-dihydroxyvitamin D itself (Kumar, 1984; Breslau, 1988). In patients with primary hyperparathyroidism (pHPT), the normal regulation of PTH secretion is disrupted. In spite of increased levels of total and ionized serum calcium, its biologically active compound, hypersecretion of PTH is observed. In general, measurement of serum calcium and intact PTH (1-84 amino acids) levels confirm the diagnosis.

Regulation of calcium fluxes respect to intestinal tract, kidneys and bone. For better clarity, the aspects of phosphate regulation were omitted in this scheme. PTH, parathyroid hormone; 1,25-D3, 1,25-dihydroxyvitamin D; 25-D3, 25-hydroxyvitamin D; Ca2+e, extracellular calcium; CaR, calcium-sensing receptor; PO4, extracellular phosphate; circle with cross, stimulatory effect; Ø, inhibitory effect.

Newly developed PTH assays, which specifically recognize the biologically active form of the peptide (1-84), seem to be more sensitive compared to standard immunoassays that also bind to smaller fragments of PTH (Gao et al., 2001; Nakanishi et al., 2001). However, these amino-terminally truncated PTH fragments confer biological activity, mediated by a distinct receptor (Murray et al., 1991; Kaji et al., 1994; Inomata et al., 1995; Divieti et al., 2001; Nguyen-Yamamoto et al., 2001). As their percentage in the plasma of patients with various hyperparathyroid disorders has been found higher than in normal subjects (Gao et al., 2001), their determination might be of diagnostic value. Thus, it remains to be determined which PTH assay provides the highest diagnostic sensitivity in patients with pHPT. In ambiguous cases, increased levels of ionized serum calcium, decreased levels of serum phosphate, as well as elevated renal calcium and phosphate excretion are further indicative of pHPT, with ionized serum calcium being the most sensitive parameter (88-99% sensitivity; Edmondson & Li, 1976; McLeod et al., 1984; Forster et al., 1988; Glendenning et al., 1998).

Whereas it was formerly known as a disease of 'bones, stones, groans and psychic moans' (Albright & Reifenstein, 1948; Bilezikian et al., 1994), nowadays pHPT, at least in western countries, is usually an asymptomatic disorder often only diagnosed by routine biochemical screening of serum total and ionized calcium concentrations. However, the majority of the patients with pHPT report at least a few symptoms related to the disease if specifically asked. Surprisingly, in a case-control study of elderly women in Sweden, fewer patients than controls reported classical symptoms. However, patients complained more often than controls of nonspecific symptoms, such as lassitude, fatigue, lack of sexual and emotional interest (Lundgren et al., 1998). Complete absence of classical and associated symptoms has been reported in 21-25% of patients with pHPT (Harrison & Wheeler, 1991; Lundgren et al., 1998; Hasse et al., 2000). In Beijing, China, patients with pHPT not only were significantly younger, had higher serum calcium and PTH levels, but also showed much more severe symptoms (renal stones, osteoporosis and osteitis fibrosa cystica) when compared to a matched group of patients with pHPT in New York City, USA (Bilezikian et al., 2000). Different genetic and ethnic backgrounds of the groups investigated, calcium as well as vitamin D deficiency may account for the observed differences in China and the USA (Bilezikian et al., 2000).

The classical treatment of pHPT is parathyroidectomy of the diseased glands. However, is surgery also indicated in oligo- and asymptomatic patients with pHPT? To date, the decision to perform parathyroidectomy on an asymptomatic patient with pHPT is made according to guidelines established in 1990 on the NIH Consensus Development Conference (Anonymous, 1991) and updated in 2002 (Bilezikian et al., 2002). Thus, parathyroidectomy should be performed if the total serum calcium concentration exceeds 0·25 mmol/l of the upper normal value, if the creatinine clearance is reduced by > 30%, if the urinary calcium excretion exceeds 400 mg/day, and if bone mineral density (BMD) is reduced by more than 2·5 SD of the peak bone mass (T-score). Furthermore, parathyroidectomy is indicated in patients who request surgery, patients who are unlikely to return for regular follow-up, patients whose coexistent illnesses complicate management and younger patients (< 50 years). In addition, patients with nonspecific psychic complaints should be considered for parathyroidectomy as symptoms in the majority of these patients will resolveafter surgery (Lundgren et al., 1998; Hasse et al., 2000). Other reasons that have more recently been suggested as indications for surgery in patients with asymptomatic pHPT are a history of fracture at any site in the absence of a major trauma (independent of bone mass), vertebral osteopenia, vitamin D deficiency and perimenopause (Bilezikian, 2000).

The course of pHPT is rather benign. During a 10-year follow-up, only 27% of initially asymptomatic patients had evidence of disease progression, defined as the development of one or more new indications for parathyroidectomy (Silverberg et al., 1999b). Younger patients and women entering menopause appeared to be at risk for disease progression and should therefore be considered for surgery.

Both observations, a growing percentage of oligo- and asymptomatic patients with pHPT in the western population and a slow progression of the disease, raise the question whether it is safe to monitor patients without surgery. Besides, it would be of great interest to have clinical and/or geneticmarkers in order to identify patients at risk for more severe progression of the disease. Third, small studies have demonstrated beneficial effects of oestrogens, selective oestrogen receptor modulators (SERMs), bisphosphonates, vitamin D and phosphate in patients with pHPT. Fourth, new insights into the pathophysiology of parathyroid neoplasia initiated the development of new drugs to treat patients with pHPT medically. Allosteric modulators of CaR, NPS R-568 and NPS R-467, have been shown to significantly reduce PTH levels in patients with pHPT and have been subject of clinical trials (Silverberg et al., 1997; Nemeth et al., 1998). The aim of this article is to review the literature as regards (i) the pathophysiological mechanisms that underlie parathyroid neoplasia; (ii) the defective calcium-sensing in patients with pHPT; and (iii) environmental and/or genetic risk factors that predispose to or promote parathyroid neoplasia. Better understanding of the pathophysiology underlying parathyroid neoplasia may disclose new treatment options, which would be especially useful for patients with mild disease. (iv) Studies applying alternative medical approaches to treat oligo- and asymptomatic patients with pHPT medically are presented.