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

S. Miedlich, K. Krohn, R. Paschke

Disclosures

Clin Endocrinol. 2003;59(5) 

In This Article

Are There Environmental and/or Genetic Risk Factors That Predispose to or Promote Parathyroid Neoplasia?

Previous neck irradiation isa possible risk factor for the development of neoplasms within the parathyroids. In a series of 74 consecutive cases with pHPT, 25% of the patients gave a history of prior neck irradiation in comparison to 8% in a matched control group (Russ et al., 1979). However, the latency interval can be as long as 38 years (Fiorica & Males, 1979).

Chronic application of lithium, used to treat psychiatric disorders, can induce hypercalcaemia, hypersecretion of PTHand hyperplasia of the parathyroid glands (reviewed by Brochier et al., 1994). As these patients may develop severe cardiac arrhythmias, regular monitoring of serum calcium levels is mandatory during treatment with lithium (Wolf et al., 1997). In vitro studies have shown that application of lithium negatively interfers with G protein-coupled signalling in various cell systems, by direct or indirect effects on second messenger cascades (adenylyl cyclase, phosphoinositide hydrolysis, intracellular calcium release; Salata & Klein, 1987; Berridge, 1989; Mork, 1993; Tritsaris et al., 2001). In bovine parathyroid cells, intracellular calcium, but not inositol 1,4,5-trisphosphate, increases in response to increments of extracellular calcium, magnesium and adenosine triphosphate (ATP) were blunted in lithium-pretreated cells (Racke et al., 1994; McHenry et al., 1995). Furthermore, lithium potentiated PTH secretion at physiological extracellular calcium concentrations in vitro and in vivo (McHenry et al., 1991; Haden et al., 1997). However, the precise mechanisms by which lithium application leads to hyperparathyroidism and whether it induces or rather promotes the development of parathyroid adenomas are not known to date.

Women are more frequently affected by pHPT than men (ratio female : male = 2-3 : 1; Palmer et al., 1987; Jorde et al., 2000). Three other observations point to a pathophysiological role of the hormonal status for the development and progression of pHPT. First, in most female patients, pHPT is diagnosed after the menopause. Second, in a 10-year prospective study of patients with initially asymptomatic pHPT, 27% of the cases showed significant progression of the disease, with entry into menopause being a risk factor (Silverberg et al., 1999b). Third, postmenopausal patients with pHPT have been treated successfully with oestrogen replacement therapy (Selby & Peacock, 1986; Horowitz et al., 1987; McDermott et al., 1994; Diamond et al., 1996; Grey et al., 1996; Guo et al., 1996; Orr-Walker et al., 2000). Thus, female gender and menopause clearly represent risk factors for the development and a more progressive course of pHPT. However, the underlying pathophysiological mechanisms have yet to be determined.

PTH secretion and cellular proliferation in the parathyroids are inversely regulated by extracellular calcium. Via activation of CaR, high extracellular calcium inhibits and low extracellular calcium stimulates secretion and gene expression of PTH in parathyroid cells in vitro and in vivo (Russell et al., 1983; LeBoff et al., 1983; Naveh-Many et al., 1989, 1995; Ishimi et al., 1990; Tsukamoto et al., 1995). Calcium deficiency also stimulates cellular proliferation in rat parathyroid glands (Naveh-Many et al., 1989, 1995). As the median intake of calcium in elderly American women has been reported to be below the recommended 37·5 mmol/day (1500 mg/day; Anonymous, 1994), elderly women may have a relative calcium deficiency that could increase PTH secretion/gene expression as well as stimulate cellular proliferation (McKane et al., 1996).

Synthesis of 1,25-dihydroxyvitamin D is stimulated by PTH. Vice versa, 1,25-dihydroxyvitamin D inhibits gene expression of PTH and cellular growth of the parathyroid glands. The active form of vitamin D acts via a nuclear receptor. The hormone-receptor complex binds to specific DNA sequences of the promotor region of genes and regulates their expression (Nygren et al., 1988; Kremer et al., 1989; Demay et al., 1992). Vitamin D deficiency influences the course of pHPT as patients with lower vitamin D levels had significantly higher serum calcium and PTH levels as well as larger tumours than patients with vitamin D levels within the normal range. Moreover, serum alkaline phosphatase levels were significantly higher in patients with vitamin D deficiency as defined by values < 15 ng/ml (Rao et al., 2000). Others found higher PTH and alkaline phosphatase levels in patients with vitamin D deficiency but no correlation between 25-hydroxyvitamin D levels and parathyroid gland weight (Silverberg et al., 1999a). Furthermore, treatment of patients with pHPT and coexisting vitamin D deficiency with vitamin D significantly increased the BMD in spine and hip despite elevated serum calcium and PTH levels (Kantorovich et al., 2000). Thus, the vitamin D status clearly affects the course of pHPT. In addition, a reduced conversion of 25-hydroxyvitamin D to the active metabolite 1,25-dihydroxyvitamin D, and a reduced responsiveness to 1,25-dihydroxyvitamin D, as reported for the elderly, could contribute to the above-described effects (Clemens et al., 1986; Ebeling et al., 1992). Whether vitamin D deficiency also triggers the development of tumours within the parathyroids, for instance by increasing the probability of somatic mutations in hyperplastic parathyroid glands, is not known to date.

The search for germline genetic variations that could predispose to or influence the course of diseases has gained much interest during the last decades. However, the data regarding pHPT is inconclusive (summarized in Table 1 ).

Investigation of allelic variants of the vitamin D receptor (VDR) gained considerable interest when they were shown to predict differences in BMD in postmenopausal women (Morrison et al., 1994). A number of studies investigated these genetic polymorphisms within intron 8 (Bb, Aa) and exon 9 (Tt) of the VDR in patients with pHPT. Presence of the restriction sites was denoted as bat, absence as BAT. In one study, the prevalence of the genotype baT was significantly higher in female patients with sporadic pHPT than in age-matched controls (Carling et al., 1995). Serum calcium, PTH levels, BMDs at femur and spine of the patients with different genotypes did not differ. Other studies of the VDR polymorphism within intron 8 (Bb) could not confirm the above-described differences in prevalence of the disease (Kobayashi et al., 1998; Pacheco et al., 2000; Sosa et al., 2000) but found significantly lower BMDs in patients with the VDR genotype bb compared to the genotypes BB and Bb (Kobayashi et al., 1998). Meta-analysis of three major European studies of the prevalence of the VDR genotypes BB, Bb and bb in postmenopausal women with pHPT and matched controls discloses no significant differences in the frequency of the genotype bb in patients as compared to controls (P = 0·1, Table 2 ). Likewise, another genetic variation within the start codon of the VDR gene cannot clearly be associated with a higher prevalence of pHPT (Correa et al., 1999; Sosa et al., 2000).

Carling et al. (1997) could not find a higher prevalence of genetic variations within the oestrogen receptor gene in 101 patients with pHPT. However, the authors report an association of the oestrogen receptor genotypes to lower serum calcium, higher PTH levels and lower BMDs at the lumbar spine.

A recent study investigatedthe frequency of polymorphisms of the PTH gene in 79 patients with pHPT without finding significant differences of the allelotypes between patients and controls (Kanzawa et al., 1999). Specific allelotypes were associated with higher serum calcium and PTH levels, respectively.

We have studied the prevalence of calcium-sensing receptor variants in 50 patients with pHPT. In female patients, the frequency of the genetic variant A986S, which has been found to be linked to higher serum calcium levels in young healthy women (Cole et al., 1999), did not differ significantly from that in an age-matched control group. Although, in male patients, the heterozygous variant A986S was found more frequently than in male controls, these groups were too small to draw clear conclusions (Miedlich et al., 2001a).

In general, association studies of specific genetic variations have their limitations. Gene-gene and gene-environment interactions may mask the effect of a disease-associated polymorphism and, when there are multiple trait-causing loci in a population, the association with any particular polymorphism may be overshadowed by the effects of other genes (Hobson & Ralston, 2001). False positive results may also occur as a result of inappropriate selection of cases and controls and because of population stratification (Lander & Schork, 1994). As regards pHPT, there does not seem to be a single genetic polymorphism, which clearly represents a risk factor for the development of pHPT. Reports about associations to clinical markers (calcium, PTH, BMDs) are inconsistent, and have not been investigated in the control groups. Further work is needed to determine whether the above-described or other genetic polymorphisms are truly associated with the prevalence and clinical phenotype of pHPT. One could assume that a number of genetic variations together with other predisposing factors such as previous neck irradiation, calcium/vitamin D deficiency or postmenopausal status may indeed increase the risk of parathyroid neoplasia.

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