Elsevier

The Lancet

Volume 374, Issue 9684, 11–17 July 2009, Pages 145-158
The Lancet

Seminar
Hyperparathyroidism

https://doi.org/10.1016/S0140-6736(09)60507-9Get rights and content

Summary

Hyperparathyroidism is due to increased activity of the parathyroid glands, either from an intrinsic abnormal change altering excretion of parathyroid hormone (primary or tertiary hyperparathyroidism) or from an extrinsic abnormal change affecting calcium homoeostasis stimulating production of parathyroid hormone (secondary hyperparathyroidism). Primary hyperparathyroidism is the third most common endocrine disorder, with the highest incidence in postmenopausal women. Asymptomatic disease is common, and severe disease with renal stones and metabolic bone disease arises less frequently now than it did 20–30 years ago. Primary hyperparathyroidism can be cured by surgical removal of an adenoma, increasingly by minimally invasive parathyroidectomy. Medical management of mild disease is possible with bisphosphonates, hormone replacement therapy, and calcimimetics. Vitamin D deficiency is a common cause of secondary hyperparathyroidism, particularly in elderly people. However, the biochemical definition of vitamin D deficiency and its treatment are subject to much debate. Secondary hyperparathyroidism as the result of chronic kidney disease is important in the genesis of renal bone disease, and several new treatments could help achieve the guidelines set out by the kidney disease outcomes quality initiative.

Introduction

Ionised calcium in plasma is closely regulated and ranges from 1·1 mmol/L to 1·3 mmol/L (calcium adjusted for albumin 2·2–2·6 mmol/L). Precise control of ionised calcium is needed to ensure optimum function of physiological processes, particularly cell signalling, neural function, muscular function, and bone metabolism. Pivotal in regulation of ionised calcium is secretion of parathyroid hormone from the parathyroid glands, usually located in the neck, which respond to changes in circulating ionised calcium via the calcium-sensing receptor (CaSR) located on the surface of the chief cells.1 Parathyroid hormone has a major biological function in maintaining ionised calcium and phosphate within the reference range by stimulating specific receptor-mediated responses in cells throughout the body. If a decrease in circulating ionised calcium occurs, parathyroid hormone increases and has three major functions that help to restore a normal circulating concentration (figure 1): receptor-mediated tubular reabsorption of calcium (kidney); stimulation of osteoclast resorption to release skeletal calcium (bone); and increasing activity of renal 1 hydroxylase, resulting in production of 1,25-dihyroxyvitamin D and increasing calcium absorption (bowel). The increase in calcium in response to these effects mediated by parathyroid hormone acts via a classic endocrine feedback loop on the CaSR, decreasing secretion of parathyroid hormone.

Components in this regulatory system can cause excessive secretion of parathyroid hormone and hyperparathyroidism. Primary hyperparathyroidism can occur when one or more parathyroid glands secrete excess parathyroid hormone; secondary hyperparathyroidism arises when increased secretion of this hormone is a response to lowered ionised calcium as a result of kidney, liver, or bowel disease; and in tertiary hyperparathyroidism, a state of autonomous secretion of parathyroid hormone usually occurs as a result of longstanding chronic kidney disease.

In addition to parathyroid hormone, other major factors maintaining normocalcaemia are 1,25-dihydroxyvitamin D, which promotes calcium and phosphate absorption via the bowel; and calcitonin, produced by C cells of the thyroid, which acts on osteclasts, inhibiting their activity and reducing the release of calcium and phosphate from bone (figure 1).

Section snippets

Definition, pathology, cause, and epidemiology

In primary hyperparathyroidism, in the absence of a known or recognised stimulus, one or more of the four parathyroid glands secrete excess parathyroid hormone, resulting in hypercalcaemia (intrinsic abnormal change). Single gland adenoma is the most common cause (75–85%), multigland adenoma arises in a substantial proportion (two glands in 2–12% of cases, three glands in <1–2%, and four or more in <1–15%), and parathyroid carcinoma is rare (∼1%). Lower pole adenomas (in relation to the

Definition and causes

Secondary hyperparathyroidism is the result of failure of one or more components of the calcium homoeostatic mechanisms described previously (extrinsic abnormal change). When plasma ionised calcium decreases, the CaSR responds by increasing secretion of parathyroid hormone, resulting in a compensatory mechanism to restore normal function. Under normal circumstances, there is a transient state of relative or absolute secondary hyperparathyroidism. When the parathyroid hormone cannot correct the

Tertiary hyperparathyroidism

Although authors debate the existence of tertiary hyperparathyroidism, most believe that it represents a state of autonomous function of parathyroid tissue (intrinsic abnormal change) that is characterised by hypercalcaemic hyperparathyroidism. It is usually the outcome of longstanding secondary hyperparathyroidism and is characterised by a lack of suppression of parathyroid hormone by increasing calcium or vitamin D analogues. CaSR underexpression can be seen resulting in an increase in

Search strategy and selection criteria

The following terms were used to search PubMed, Medline, and the Web of Science for pertinent articles: “hyperparathyroidism”, “primary hyperparathyroidism”, “secondary hyperparathyroidism”, “tertiary hyperparathyroidism”, “chronic kidney disease”, “vitamin D deficiency”, and “familial benign hypercalcaemic hypocalciuria”. There was no restriction on language, and all years were searched. A computer link program was used to exclude duplicate articles, and linked articles were searched for

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