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Parathyroid hormone and hypertension

Nyirenda, Moffat J; Padfield, Paul L

doi: 10.1097/01.hjh.0000179508.84479.90
Editorial commentaries

Department of Medical Sciences, Western General Hospital, Edinburgh, UK

Correspondence and requests for reprints to Moffat J. Nyirenda, Department of Medical Sciences, Western General Hospital, Edinburgh EH4 2XU, UK. E-mail:

Numerous studies in humans and experimental models have shown that alterations in calcium homeostasis are associated with an increased risk of cardiovascular complication. In particular, changes in systemic calcium metabolism are thought to play an important role in the regulation of blood pressure. One hypothesis for this link implicates parathyroid hormone (PTH). Serum calcium level is tightly regulated by PTH in a classic negative-feedback system. A small decrease in serum calcium stimulates an abrupt increase in PTH secretion, which leads to calcium mobilization from bone, increased renal tubular calcium reabsorption and increased renal hydroxylation of 25-hydroxyvitamin D to the biologically more active 1,25-dihydroxyvitamin D (which enhances calcium absorption from the intestine). Factors that tend to reduce the serum calcium levels (i.e. vitamin D deficiency) induce secondary hyperparathyroidism. In primary hyperparathyroidism, there is an autonomous increase in PTH secretion resulting in hypercalcaemia. Several studies have reported a positive correlation between serum PTH levels and hypertension [1]. This relationship has been demonstrated in patients with primary hyperparathyroidism as well as in those with secondary hyperparathyroidism [1]. Moreover, some studies have shown that patients with essential hypertension have a higher serum concentration of PTH than normotensive individuals. These data have led to the speculation that PTH may be involved in the pathogenesis of hypertension.

In this issue of the journal, Jorde et al. [2] provide further evidence for an association between serum PTH levels and hypertension. In a prospective study involving 1784 patients over a 7-year period, the authors observed that the serum PTH levels at baseline (or the change in PTH levels over the study period) were a positive predictor of a change in systolic blood pressure over the study period in men. This association was not significant in women. The reasons for this apparent sexual diamorphism in the relationship between PTH levels and change blood pressure are unclear, although, in a previous report on this population, the authors found that PTH was a predictor of systolic and diastolic blood pressure in females [3]. Such a discrepancy may relate to differences in statistical power between the two studies. The current study has several other limitations, and these are freely acknowledged by the authors. In particular, the baseline samples for PTH estimation had been stored for a number of years before analysis, and may have been subjected to degradation, thus influencing the results.

Despite the compelling evidence linking PTH with hypertension, the important question that remains unanswered is whether this relationship is causal or not. Several studies have demonstrated that PTH has vasoactive properties. For example, an acute fall in circulating PTH induced by calcium infusion increases systolic blood pressure in normal individuals, but not in thyroparathyroidectomized subjects [4]. Conversely, acute administration of PTH has been shown to cause vasodilation and blood pressure reduction. In sharp contrast to the acute effects, chronic PTH infusion results in persistent hypercalcaemia and hypertension in normal subjects [5]. Furthermore, patients with primary hyperparathyroidism have enhanced responsiveness to pressor agents, such as angiotensin II or norepinephrine [6], suggesting that PTH may provide a ‘permissive’ effect on blood pressure control. PTH has also been shown to increase renin secretion [7]. Additionally, PTH may cause hypertension by its direct effects on arteries and myocytes to promote arterial stiffness and left ventricular hypertrophy, respectively [8]. These data suggest a mechanistic coupling of PTH to hypertension. However, this relationship has remained controversial mainly because, unlike in most causes of secondary hypertension, there is no evidence that correction of PTH (and hypercalcaemia) with parathyroidectomy in patients with primary hyperparathyroidism improves blood pressure [9,10]. Similarly, although normalization of PTH after parathyroidectomy for primary hyperparathyroidism decreases left ventricular hypertrophy, this does not lower blood pressure [8,11].

The nature of the association between essential hypertension and PTH has also been questioned. Several studies have noted disturbances of calcium metabolism in patients with essential hypertension. These include increased urinary calcium excretion, a tendency for a low serum ionized calcium level, a raised PTH level and an increase in 1,25-dihydroxyvitamin D levels [12]. Essential hypertension is also associated with renal stones and osteoporosis [12]. Whether the alterations in calcium metabolism are primary or merely secondary to the elevated blood pressure remains unclear. There is evidence that hypertension increases urinary calcium excretion, and that this primary renal calcium leak results in a transient fall in serum ionized calcium, subsequently causing a compensatory rise in PTH [13]. In support of this hypothesis, similar alterations in calcium homeostasis have been observed in animal models of hypertension, such as in spontaneously hypertensive rats (SHR) [14] and mineralocorticoid-salt (DOCA-salt)-hypertensive rats [15]. Under these conditions, elevated PTH levels would be the consequence of hypertension, rather than the mediator of hypertension. Indeed, treating hypertension with diuretics or β-blockers has been shown to reverse changes in calcium and PTH levels [16]. On the other hand, dietary calcium supplementation (which lowers PTH levels) has also been shown to lower blood pressure in patients with essential hypertension and in animal models of hypertension, including SHR and DOCA-salt hypertension. This would support the notion that derangements in calcium metabolism may, at least in part, play a role in the development of hypertension. Clearly, other components of the calcium metabolic pathway, notably serum concentrations of ionized calcium and 1,25-dihydroxyvitamin D levels, rather than PTH per se, may also be important in the relationship between calcium homeostasis and the regulation of blood pressure. Thus, if such a mechanistic link exists, it will be difficult to differentiate indirect markers from actual mediator(s) of this relationship.

The presentation of primary hyperparathyroidism has changed from a classical multisystem disease, characterized by severe hypercalcemia with significant bone, renal and neurological manifestations, to a disorder with mild hypercalcaemia in largely asymptomatic patients. These have resulted in a revision of the management guidelines, such that most asymptomatic patients with primary hyperparathyroidism are usually followed without parathyroidectomy [17]. With the increasing evidence implicating PTH in the pathogenesis of hypertension and cardiovascular risk, further studies will be required to critically examine this relationship, as well as to evaluate the long-term cardiovascular outcome of parathyroidectomy in asymptomatic patients with primary hyperparathyroidism, which might necessitate a reappraisal of current management strategies.

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