Primary hyperparathyroidism

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Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia, is most often identified in postmenopausal women with hypercalcemia and parathyroid hormone (PTH) levels that are either frankly elevated or inappropriately normal. The clinical presentation of PHPT includes three phenotypes: target organ involvement of the renal and skeletal systems; mild asymptomatic hypercalcemia; and more recently, high PTH levels in the context of persistently normal albumin-corrected and ionized serum calcium values. The factors that determine which of these three clinical presentations is more likely to predominate in a given country include the extent to which biochemical screening is employed, the prevalence of vitamin D deficiency, and whether a medical center or practitioner tends to routinely measure PTH levels in the evaluation of low bone density or frank osteoporosis. When biochemical screening is common, asymptomatic primary hyperparathyroidism is the most likely form of the disease. In countries where vitamin D deficiency is prevalent and biochemical screening is not a feature of the health care system, symptomatic disease with skeletal abnormalities is likely to predominate. Finally, when PTH levels are part of the evaluation for low bone mass, the normocalcemic variant is seen. Guidelines for surgical removal of hyperfunctioning parathyroid tissue apply to all three clinical forms of the disease. If guidelines for surgery are not met, parathyroidectomy can also be an appropriate option if there are no medical contraindications to surgery. In settings where either the serum calcium or bone mineral density is of concern, and surgery is not an option, pharmacological approaches are available and effective. Referencing in this article the most current published articles, we review the different presentations of PHPT, with particular emphasis on recent advances in our understanding of target organ involvement and management.

Introduction

Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia, is most often identified in postmenopausal women with hypercalcemia and parathyroid hormone (PTH) levels that are either frankly elevated or inappropriately normal. It is caused by excessive synthesis and secretion of PTH by one or more of the four parathyroid glands [1], [2].

When PHPT was first described almost a century ago, in the 1930's, the disease was associated with severe hypercalcemia and serious skeletal and renal complications. The indelible association of PHPT with signs (kidney stones and fractures) and symptoms (due to hypercalcemia) persisted until the 1970's when biochemical screening tests became routinely employed, first in the United States and then elsewhere. The clinical phenotype of PHPT changed from overt bone and renal involvement to asymptomatic hypercalcemia. These patients were discovered essentially in the context of biochemical screening and not for any signs or symptoms that would have prompted the health care provider to measure the serum calcium. Four more decades passed when yet another phenotype of PHPT emerged, namely a normocalcemic variant in which albumin-corrected and ionized serum calcium concentrations were persistently normal but the PTH level was persistently elevated. Of course, all known secondary causes for a high PTH have to be ruled out [3]. Not the subject of this discussion, but it is noteworthy that patients have recently been recognized with PHPT but only by pathological examination of parathyroid tissue. The calcium and PTH levels are normal [4], [5].

These different clinical phenotypes of PHPT have raised many issues with regard to parathyroid surgery, the definitive management of the disease. In the hands of expert parathyroid surgeons, parathyroidectomy (PTX) offers very high cure rates [6], but in patients who are completely asymptomatic, a surgical option is not necessarily the obvious one. The normocalcemic variant of PHPT presents yet another challenge in the decision to recommend parathyroid surgery or not. To this end, the Fourth International Workshop on Asymptomatic PHPT [7], recently revisited by others [8], [9], [10], offers reasonable evidence-based guidance as to who is best advised to have parathyroid surgery.

In this article, we review these different profiles of PHPT with particular emphasis on recent publications.

Section snippets

Epidemiology

The peak incidence of PHPT is in the early postmenopausal years, coincident with the loss of estrogen [11]. Many more women than men develop this disease with a ratio of approximately 4:1. In the United States, the prevalence is 0.86% [12]. Racial predilection favors African Americans [13]. While there is wide variability in prevalence estimates for the classic hypercalcemic form of PHPT, there are even more widely variant prevalence estimates of normocalcemic PHPT (0.4–11%). To a certain

Etiology and risk factors

The vast majority of patients with PHPT harbor a single, benign, parathyroid adenoma. It accounts for approximately 80% of cases of PHPT. Multiglandular disease, in which 4-gland parathyroid hyperplasia is the predominant form, is seen in 15–20% of cases. Multiglandular disease can also be manifest as two and, very rarely, three adenomas. Parathyroid carcinoma accounts for well under 1% of all cases of PHPT [2]. Parathyroid cancer presents in a very different manner than its benign counterpart.

Clinical presentation

When hypercalcemia is high enough, generally over 12 mg/dL, or if it rises rapidly, over several days, signs and symptoms of PHPT may be due to the hypercalcemia itself. Symptoms include polyuria, polydipsia, constipation, anorexia, vomiting, dehydration, arrhythmias, and altered mental status.

The clinical presentation of PHPT can also include the key target organs, kidney and bone. With regard to the kidney, any combination of hypercalciuria, nephrolithiasis, nephrocalcinosis and reduced renal

A world view of how PHPT can present

These three different presentations of PHPT were described chronologically with the symptomatic variant described first, following by the discovery of asymptomatic PHPT via the use of biochemical screening, and most recently by the normocalcemic variant in which the routine measurement of PTH among those with normal serum calcium levels was prompted initially by the proactive approach to the evaluation of low bone density. However, these three forms of PHPT exist concurrently in the world

Diagnosis and evaluation

Classical PHPT is diagnosed readily by hypercalcemia in association with a frankly elevated PTH or inappropriately ‘normal’ PTH. A PTH level within the normal range is clearly not a normal value physiologically when someone is hypercalcemic. The question then arises, how low can the PTH be when hypercalcemia is present and have it still be compatible with the diagnosis of PHPT? A level of 20–25 pg/mL or higher in the setting of hypercalcemia is considered to be compatible with the diagnosis of

Surgical management

The definitive cure of PHPT is surgical removal of hyperfunctioning parathyroid tissue. Successful PTX leads to normalization of all biochemical indices and eventually to higher BMD, reduced fracture risk and reduced risk of kidney stones *[21], [55], [56], [57], *[75], *[76]. Even in NPHPT, PTX has been associated with beneficial outcomes [77], [78]. In patients who are symptomatic of hypercalcemia or who have sustained target organ issues (e.g., fractures, stones), surgery is clearly

Natural history of PHPT with and without surgery

Based upon a number of studies, comparing PTX with non-operative management *[21], [55], [56], [57], *[75], *[76], BMD significantly improves after PTX while it remains stable or declines in those without surgical intervention. The longest observational study to date followed patients with or without PTX for 15 years. In the non-surgical group [21], biochemical indices remained stable for 15 years, the only exception being the serum calcium that trended upwards between years 13 and 15. After

Summary

The three clinical forms of PHPT present in frequency as a function of several factors: the presence of routine biochemical screening; endogenous vitamin D deficiency; the use of PTH in the evaluation of reduced bone mass even if the serum calcium is normal. Even among those whose PHPT is discovered incidentally, signs of skeletal and renal involvement can often be demonstrated. Successful PTX cures the disease. It is recommended in those with symptomatic disease and for those who are

Acknowledgments

This work was supported, in part, by NIH grant DK 32333.

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