Review
Subclinical and asymptomatic parathyroid disease: implications of emerging data

https://doi.org/10.1016/S2213-8587(13)70083-4Get rights and content

Summary

Primary hyperparathyroidism, a disorder in which there is a tendency for hypercalcaemia caused by autonomous overproduction of parathyroid hormone, is common, especially in postmenopausal women. Although parathyroidectomy is indicated for symptomatic patients, most individuals with the disorder are asymptomatic and without classic complications, such as renal stones and osteoporosis, at diagnosis. Consensus guidelines suggest which individuals might be suitable for medical follow-up rather than parathyroidectomy, but there are no long-term randomised controlled trials to support the safety of medical surveillance, and some patients progress with time. Data from observational studies suggest that cardiovascular morbidity and mortality are increased in patients with primary hyperparathyroidism, and might be predicted by parathyroid hormone concentrations, even in individuals with asymptomatic primary hyperparathyroidism. Whether parathyroidectomy improves cardiovascular outcomes in patients with asymptomatic primary hyperparathyroidism is unproven, but data suggest that surgery decreases fracture risk and might improve neuropsychological symptoms. Studies also show that patients with normocalcaemic (subclinical) hyperparathyroidism and hypoparathyroidism have a low risk of progression to overt disease, but their long-term risks are not defined. In this Review, we explore the increasing range of asymptomatic parathyroid disorders, focusing on current evidence about their natural history and potential complications, with a particular emphasis on primary hyperparathyroidism.

Introduction

Parathyroid hormone works with 1,25-dihydroxyvitamin D to regulate calcium homoeostasis, ensuring plasma ionised calcium concentrations are maintained within a narrow range (1·1–1·3 mmol/L, or 2·2–2·6 mmol/L after adjustment for serum albumin) for optimum functioning of many physiological processes, including neural transmission, muscle contractility, and bone metabolism.1 The calcium-sensing receptor (CaSR) on the surface of parathyroid chief cells acts as a calciostat and mediates an increase in parathyroid hormone synthesis and secretion in response to falling ionised calcium concentrations, with parathyroid hormone maintaining calcium concentrations through several mechanisms (figure).2 Calcitonin, produced by the parafollicular C cells in the thyroid, is thought to have only a minor role in calcium homoeostasis, and lowers calcium through the inhibition of osteoclasts.1

Table 1 summarises disorders of parathyroid hormone secretion and signalling. Primary hyperparathyroidism is usually characterised by hypercalcaemia with a raised parathyroid hormone concentration, although parathyroid hormone concentrations might still lie within the upper half of the normal reference range (ie, inappropriately normal), and a normocalcaemic variant also exists.3, 4 A single parathyroid adenoma is the most common cause (∼85% of cases), and although the causal mechanism is unknown, investigators have noted several low-frequency somatic mutations in tumour tissue.5 Multiple adenomas, parathyroid gland hyperplasia, and (very rarely) parathyroid carcinoma might also cause primary hyperparathyroidism. A similar pattern can also be seen in patients given a thiazide diuretic or lithium, or in tertiary hyperparathyroidism when autonomous parathyroid hormone secretion develops after longstanding secondary hyperparathyroidism (a physiological increase in parathyroid hormone due to several possible causes; panel 1). Several familial and syndromic forms of primary hyperparathyroidism also exist and are reviewed in detail elsewhere.6

The role of the CaSR is shown in familial hypercalcaemic hypocalciuria, the main differential diagnosis for primary hyperparathyroidism, in which a heterozygous inactivating mutation of CASR leads to a changed setpoint for parathyroid hormone secretion. This change leads to mild hypercalcaemia (∼2·75 mmol/L) with inappropriately normal or mildly raised parathyroid hormone concentrations, and relative hypocalciuria (urinary calcium to creatinine ratio <0·01).7 By contrast, activating mutations in CASR lead to a decreased setpoint and autosomal-dominant hypocalcaemic hypercalciuria.8

Urinary calcium excretion can be difficult to interpret in patients receiving concomitant calcium and vitamin D analogue treatment. Generally, however, patients with autosomal-dominant hypocalcaemic hypercalciuria have a higher urinary calcium excretion than do those with hypoparathyroidism, despite the loss of the calcium-conserving effects of parathyroid hormone at the renal tubule in the latter condition. The higher fractional excretion of calcium in hypoparathyroidism, compared with individuals without parathyroid disease, increases susceptibility to hypercalciuria, especially while they are receiving calcium and vitamin D replacement, although urinary calcium excretion might still be inappropriately normal or low.9 In pseudohypoparathyroidism, urinary calcium excretion usually remains low because the effects of the raised parathyroid hormone concentrations on the distal tubule are conserved, despite resistance to parathyroid hormone in the proximal tubule.9

After the introduction of automated multichannel analysers to clinical biochemistry departments in the 1970s and, more recently, the ubiquity of vitamin D testing,10 more individuals are being diagnosed with disorders of calcium metabolism at a seemingly asymptomatic stage.11 These cases are likely to include individuals with CASR mutations, mild asymptomatic hypoparathyroidism, and previously unidentified vitamin D deficiency. Mild or asymptomatic disease is perhaps most apparent in primary hyperparathyroidism, in which the severity and pattern of complications has changed in the past 30–40 years.3, 11 In this Review, we discuss the increasingly recognised and increasing range of asymptomatic parathyroid disorders. We will focus on asymptomatic primary hyperparathyroidism, discuss its natural history with respect to potential complications, and debate whether this disorder is truly asymptomatic. We will also briefly discuss the newer entities of normocalcaemic, or subclinical, primary hyperparathyroidism and hypoparathyroidism.

Section snippets

Symptomatic versus asymptomatic primary hyperparathyroidism

Results of observational studies suggest that primary hyperparathyroidism is common. Studies from Scotland, UK,12 and Scandinavia13, 14 suggest a prevalence of about 1% in the general population, with the greatest prevalence in postmenopausal women (about 3%). These data suggest the prevalence is substantially higher than suggested by earlier studies,15, 16 and although this effect might initially have represented a catch-up effect from previously undiagnosed patients, most recent data suggest

Biochemical progression

Severe hypercalcaemia can be life-threatening. However, according to the most recent criteria, individuals with asymptomatic primary hyperparathyroidism have only mildly raised calcium—less than 0·25 mmol/L higher than the upper limit of the normal reference range (ie, about 2·85 mmol/L).24 Although studies of asymptomatic primary hyperparathyroidism have been limited by their observational nature, the risk of patients developing progressive hypercalcaemia seems to be small.12, 19

The

Prediction of adverse outcomes in primary hyperparathyroidism

Fulfilment of NIH surgical criteria at baseline did not predict clinical or biochemical progression in the Columbia University study,19 and although current guidelines do attempt to stratify patients on the basis of potential long-term risks, increasing accuracy of predictions or calculations of an individual's risk of complications would be desirable to inform clinicians of which patients would benefit most from parathyroidectomy.

Some epidemiological studies have shown an association between

Normocalcaemic primary hyperparathyroidism

Normocalcaemic primary hyperparathyroidism is defined as persistently raised parathyroid hormone concentrations with normal serum calcium concentrations, after the exclusion of causes of secondary hyperparathyroidism (panel 1).5 Until recently, studies of normocalcaemic primary hyperparathyroidism have been limited by their ability to exclude other causes of hyperparathyroidism and by potential bias from the inclusion of patients referred to specialist referral centres. Hence, although the

Subclinical hypoparathyroidism

Hypoparathyroidism (table 1) is much rarer than primary hyperparathyroidism, and most commonly results from removal or damage to the parathyroid glands or their blood supply during thyroid surgery, or from autoimmune destruction, often as part of a polyglandular autoimmune syndrome. Rarer causes include infiltration (eg, sarcoid) or congenital causes, either as part of a rare developmental syndrome such as DiGeorge's syndrome or from mutations in the gene that encodes parathyroid hormone.9, 88

Conclusion

In the past few decades, the phenotype of primary hyperparathyroidism has evolved into a disorder that is often thought of as a mild or asymptomatic disease compared with the traditional description. The prevalence of primary hyperparathyroidism has increased, especially in postmenopausal women, for reasons that are not clear. However, it is unlikely that this disorder is truly asymptomatic, as evidence suggests that subtle neuropsychological deficits and physical symptoms are attributable to

Search strategy and selection criteria

We searched Medline and PubMed for papers that were published in English from Jan 1, 1970, to June 1, 2013. We used the following search terms: “hyperparathyroidism”, “asymptomatic hyperparathyroidism”, “hyperparathyroidism and fractures”, “hyperparathyroidism and cardiovascular disease”, “subclinical hyperparathyroidism”, “normocalcaemic hyperparathyroidism”, “subclinical hypoparathyroidism”, and “normocalcaemic hypoparathyroidism”. We also searched the reference lists of articles identified

References (93)

  • H Al-Azem et al.

    Hypoparathyroidism

    Best Pract Res Clin Endocrinol Metab

    (2012)
  • C Marcocci et al.

    Clinical practice. Primary hyperparathyroidism

    N Engl J Med

    (2011)
  • R Eastell et al.

    Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop

    J Clin Endocrinol Metab

    (2009)
  • PJ Newey et al.

    Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas

    J Clin Endocrinol Metab

    (2012)
  • GN Hendy et al.

    Genetic defects associated with familial and sporadic hyperparathyroidism

    Front Horm Res

    (2013)
  • J Auwerx et al.

    Altered parathyroid set point to calcium in familial hypocalciuric hypercalcaemia

    Acta Endocrinol (Copenh)

    (1984)
  • SH Pearce et al.

    A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor

    N Engl J Med

    (1996)
  • JP Bilezikian et al.

    Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research

    J Bone Miner Res

    (2011)
  • WD Fraser et al.

    Vitamin D assays: past and present debates, difficulties, and developments

    Calcif Tissue Int

    (2013)
  • SJ Silverberg et al.

    Presentation of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop

    J Clin Endocrinol Metab

    (2009)
  • N Yu et al.

    The natural history of treated and untreated primary hyperparathyroidism: the Parathyroid Epidemiology and Audit Research Study

    QJM

    (2011)
  • M Palmer et al.

    Prevalence of hypercalcaemia in a health survey: a 14-year follow-up study of serum calcium values

    Eur J Clin Invest

    (1988)
  • CE Boonstra et al.

    Serum calcium survey for hyperparathyroidism: results in 50,000 clinic patients

    Am J Clin Pathol

    (1971)
  • T Christensson et al.

    Blood pressure in subjects with hypercalcaemia and primary hyperparathyroidism detected in a health screening programme

    Eur J Clin Invest

    (1977)
  • MW Yeh et al.

    Incidence and prevalence of primary hyperparathyroidism in a racially mixed population

    J Clin Endocrinol Metab

    (2013)
  • A Abood et al.

    Increasing incidence of primary hyperparathyroidism in Denmark

    Dan Med J

    (2013)
  • MR Rubin et al.

    The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years

    J Clin Endocrinol Metab

    (2008)
  • J Bollerslev et al.

    Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial

    J Clin Endocrinol Metab

    (2007)
  • G Hedback et al.

    Premature death in patients operated on for primary hyperparathyroidism

    World J Surg

    (1990)
  • Proceedings of the NIH Consensus Development Conference on diagnosis and management of asymptomatic primary hyperparathyroidism. Bethesda, Maryland, October 29–31, 1990

    J Bone Miner Res

    (1991)
  • JP Bilezikian et al.

    Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop

    J Clin Endocrinol Metab

    (2009)
  • SJ Silverberg et al.

    A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery

    N Engl J Med

    (1999)
  • DS Rao et al.

    Lack of biochemical progression or continuation of accelerated bone loss in mild asymptomatic primary hyperparathyroidism: evidence for biphasic disease course

    J Clin Endocrinol Metab

    (1988)
  • L Rejnmark et al.

    Nephrolithiasis and renal calcifications in primary hyperparathyroidism

    J Clin Endocrinol Metab

    (2011)
  • MD Walker et al.

    Effect of renal function on skeletal health in primary hyperparathyroidism

    J Clin Endocrinol Metab

    (2012)
  • MW Yeh et al.

    Surgery for primary hyperparathyroidism: are the consensus guidelines being followed?

    Ann Surg

    (2012)
  • F Tassone et al.

    Glomerular filtration rate and parathyroid hormone secretion in primary hyperparathyroidism

    J Clin Endocrinol Metab

    (2009)
  • N Yu et al.

    A record linkage study of outcomes in patients with mild primary hyperparathyroidism: The Parathyroid Epidemiology and Audit Research Study (PEARS)

    Clin Endocrinol (Oxf)

    (2011)
  • J Starup-Linde et al.

    Renal stones and calcifications in patients with primary hyperparathyroidism: associations with biochemical variables

    Eur J Endocrinol

    (2012)
  • J Wishart et al.

    Relationship between forearm and vertebral mineral density in postmenopausal women with primary hyperparathyroidism

    Arch Intern Med

    (1990)
  • Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. TR 843

    (1994)
  • LH VanderWalde et al.

    Effect of bone mineral density and parathyroidectomy on fracture risk in primary hyperparathyroidism

    World J Surg

    (2009)
  • DS Rao et al.

    Randomized controlled clinical trial of surgery versus no surgery in patients with mild asymptomatic primary hyperparathyroidism

    J Clin Endocrinol Metab

    (2004)
  • J Bollerslev et al.

    Effect of surgery on cardiovascular risk factors in mild primary hyperparathyroidism

    J Clin Endocrinol Metab

    (2009)
  • E Ambrogini et al.

    Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial

    J Clin Endocrinol Metab

    (2007)
  • EM Stein et al.

    Primary hyperparathyroidism is associated with abnormal cortical and trabecular microstructure and reduced bone stiffness in postmenopausal women

    J Bone Miner Res

    (2013)
  • Cited by (26)

    • Parathyroid Imaging

      2020, Radiologic Clinics of North America
      Citation Excerpt :

      The prevalence of PHPT is 1 to 7 cases per 1000 individuals, with higher incidence among female and Black individuals, and the older population.2 The highest prevalence of PHPT is among postmenopausal women and is estimated to be as high as 3%.3 Sporadic PHPT is associated with exposure to ionizing radiation in childhood and with chronic lithium use.4

    • Parathyroid hormone induces adipocyte lipolysis via PKA-mediated phosphorylation of hormone-sensitive lipase

      2016, Cellular Signalling
      Citation Excerpt :

      The association between insulin resistance and high levels of PTH is further supported by intervention studies with parathyroidectomy, which resulted in improved insulin sensitivity and normalized blood glucose levels [6–8]. High levels of PTH are not only associated with hallmarks of diabetes, but also with cardiovascular disease, as shown in several observational studies [9–11]. Primary hyperparathyroidism is a common endocrine disorder, especially among postmenopausal women.

    • Primary hyperparathyroidism and vitamin D deficiency

      2015, Annales d'Endocrinologie
      Citation Excerpt :

      Questions have been raised about the factors contributing to the severity and diversity of expression of the disease. Some significant factors include subject age, postmenopausal status, weight of parathyroid adenomas, the severity and time since diagnosis of parathyroid hormone overproduction, and the degree of tissue receptivity [3–6]. It has also emerged that the vitamin D (VD) load has a strong influence on the extent of intestinal calcium absorption, parathyroid hormone (PTH) levels, the effects on bones and the metabolic risk.

    View all citing articles on Scopus
    View full text