Elsevier

The Lancet

Volume 391, Issue 10116, 13–19 January 2018, Pages 168-178
The Lancet

Seminar
Hyperparathyroidism

https://doi.org/10.1016/S0140-6736(17)31430-7Get rights and content

Summary

Primary hyperparathyroidism is a common endocrine disorder of calcium metabolism characterised by hypercalcaemia and elevated or inappropriately normal concentrations of parathyroid hormone. Almost always, primary hyperparathyroidism is due to a benign overgrowth of parathyroid tissue either as a single gland (80% of cases) or as a multiple gland disorder (15–20% of cases). Primary hyperparathyroidism is generally discovered when asymptomatic but the disease always has the potential to become symptomatic, resulting in bone loss and kidney stones. In countries where biochemical screening tests are not common, symptomatic primary hyperparathyroidism tends to predominate. Another variant of primary hyperparathyroidism has been described in which the serum calcium concentration is within normal range but parathyroid hormone is elevated in the absence of any obvious cause. Primary hyperparathyroidism can be cured by removal of the parathyroid gland or glands but identification of patients who are best advised to have surgery requires consideration of the guidelines that are regularly updated. Recommendations for patients who do not undergo parathyroid surgery include monitoring of serum calcium concentrations and bone density.

Introduction

Primary hyperparathyroidism is a common disorder of mineral metabolism that is due to excessive secretion of parathyroid hormone from one or more of the four parathyroid glands. The clinical consequences of abnormally active parathyroid tissue are typically hypercalcaemia and concentrations of parathyroid hormone that are either clearly elevated above the normal range or inappropriately normal in the context of hypercalcaemia.1 Primary hyperparathyroidism predominantly affects women, with studies reporting a female-to-male ratio of approximately 3–4:1.2, 3 Although several different clinical presentations of primary hyperparathyroidism are now commonly recognised, this was not always the case. In the 1930s, Albright first described the hypercalcaemic state caused by primary hyperparathyroidism as a disease of bones and stones.4 Although the clinical presentation of primary hyperparathyroidism has changed since the years of Albright, the central target organs for potential complications of this disorder continue to be the skeleton and kidneys. The typical diagnosis of primary hyperparathyroidism is no longer accompanied by overt skeletal and renal involvement. Rather, detection of skeletal or renal involvement requires proactive testing with technologies that were not available in Albright's day. The change in the clinical phenotype of primary hyperparathyroidism has fostered another dilemma—namely, for whom among the large number of individuals with only biochemical abnormalities associated with primary hyperparathyroidism should parathyroid surgery be recommended? The Fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism, held in 2013, addressed this question and other issues.5, 6

Section snippets

Clinical presentation

Asymptomatic primary hyperparathyroidism is the most common presentation in countries, such as the USA, Canada, and Germany, where biochemical screening is routinely implemented. Hypercalcaemia is usually not more than 0·25 mmol/L above the upper limit of the normal range (2·10–2·55 mmol/L). Overt kidney stone disease occurs in less than 20% of patients with primary hyperparathyroidism and radiologically evident bone disease is even less common.7 Conversely, target organ involvement at

North America

In the USA and Canada, primary hyperparathyroidism predominantly presents as an asymptomatic disorder.21 Overall, the prevalence of primary hyperparathyroidism in the USA was estimated at 0·86% in 2008–09.41 Consistent with the change in diagnostic strategies, in Southern California the incidence of primary hyperparathyroidism was reported to have tripled between 1995 and 2010.42 A 60% increase in the incidence of parathyroid cancer over this 15 year period was also reported in the USA.43 Some

Pathophysiology

The secretion and synthesis of parathyroid hormone is controlled by the ambient circulating ionised calcium concentration. Under normal conditions, an increase in circulating ionised calcium concentration, which might not be detected by biochemical methods, will instantly suppress parathyroid hormone secretion. Similarly, an imperceptible reduction in serum calcium concentration will immediately simulate parathyroid hormone secretion. This inverse sigmoidal association between parathyroid

Causes and risk factors

Primary hyperparathyroidism is most commonly due to a single benign parathyroid adenoma (approximately 80% of patients), with multiglandular disease seen in approximately 15–20% of patients.66 Multiglandular disease usually takes the form of four-gland parathyroid hyperplasia, but multiple parathyroid adenomas have also been described. Parathyroid cancer is rare and accounts for well under 1% of all cases of primary hyperparathyroidism.9 In most patients with primary hyperparathyroidism, the

Diagnosis

The albumin-corrected serum calcium concentration is usually elevated. To correct the calcium concentration for serum albumin, the measured serum calcium concentration is adjusted upward by 0·2 mmol/L for every 10 g/L by which the serum albumin is below 40 g/L. Ionised serum calcium concentration can be used for the measurement of serum calcium in centres that are equipped for accurate measurement with an instrument that has a proper ion-sensing electrode, which obviates the need for correction

Evaluation

Biochemical and imaging technology are used to determine whether, and the extent to which, primary hyperparathyroidism has involved the bone and kidney. Blood is obtained to analyse concentrations of serum calcium, phosphorus, parathyroid hormone, 25-hydroxyvitamin D, and bone turnover markers (typically one bone formation and one bone resorption index); a 24-h urine test for calcium and creatinine is also done.1, 42

Skeletal imaging depends on several modalities, the most common being dual

Hypercalcaemic primary hyperparathyroidism

The 15-year observational study by Rubin and colleagues94 indicates that the natural history of asymptomatic hypercalcaemia due to primary hyperparathyroidism can be associated with biochemical and densitometric stability. Many patients who were not candidates for parathyroid surgery at the time of evaluation continued to be stable over the study period. However, a substantial number of patients developed criteria for parathyroid surgery with a tendency for worsening hypercalcaemia and reduced

Acute management

Although primary hyperparathyroidism is considered to be a disorder of mild hypercalcaemia, a presentation of primary hyperparathyroidism with markedly high serum calcium concentrations exists that can be life-threatening. Most often these patients have a history, before their presentation with life-threatening hypercalcaemia, of only mildly elevated serum calcium concentration. Occasionally, patients with life-threatening primary hyperparathyroidism present de novo without any antecedent

Surgical management

Minimally invasive parathyroidectomy under local anaesthesia and conscious sedation is the procedure of choice in many centres, based on the assumption that the parathyroid gland or glands have been identified preoperatively. To identify abnormal parathyroid tissue, preoperative localisation approaches use ultrasound, 99mTc-sestamibi scintigraphy, CT, or four-dimensional CT. Imaging is strongly recommended for patients who are to have parathyroid surgery. The exact modality used depends on

Nutritional guidelines and medical management

Many patients with asymptomatic primary hyperparathyroidism do not have parathyroid surgery but are, instead, managed conservatively. Nutritional guidelines are important for all patients to consider.111 One notion that should be dispelled is that patients with primary hyperparathyroidism should restrict their intake of calcium. Conversely, restriction of calcium intake could provide a further stimulus to abnormal parathyroid tissue to produce parathyroid hormone. National guidelines112

Normocalcaemic primary hyperparathyroidism

The classification of normocalcaemic primary hyperparathyroidism as a primary disorder could be questioned because of the uncertainty related to an unknown secondary stimulus that might foster raised concentrations of parathyroid hormone. Furthermore, consideration of the normal distribution range for any analyte is important. The so-called normal range of parathyroid hormone spans two standard deviations about the mean (eg, 10–65 ng/L), and some patients with normocalcaemic primary

Conclusion

In this Seminar, we have provided an updated account of the new concepts related to the presentation, cause, and management of primary hyperparathyroidism. The disorder presents ongoing challenges as features of its clinical recognition continue to evolve. These changes require regular access to new investigative tools with particular reference to target and off-target manifestations as well as reconsideration of concepts of surgical and non-surgical management.

Search strategy and selection criteria

We searched PubMed between Jan 1, 2008, and Jan 1, 2016, for the terms “primary hyperparathyroidism”, “normocalcemic primary hyperparathyroidism”, “parathyroid surgery”, “parathyroid localization”, and “primary hyperparathyroidism international”. The time period for this search covers the years before and after the Fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism that was held in 2013. We limited the recovered entries to human patients in English. We

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