Primary hyperparathyroidism

Last reviewed: 28 Feb 2023

Last updated: 21 Sep 2021

Diagnosis of primary hyperparathyroidism is confirmed biochemically with synchronous elevation of serum calcium and inappropriate elevation of parathyroid hormone (PTH).

Normal serum intact PTH in the setting of hypercalcemia does not rule out disease.

Depression, cognitive changes, change in sleep pattern, fatigue, and myalgia or muscle weakness are nonspecific subjective complaints. There may be a history of nephrolithiasis or low bone mineral density.

Physical examination is usually normal, but examination of the neck is essential to look for a hard, dense mass, suggestive of parathyroid carcinoma.

Parathyroidectomy is the only definitive cure. Monitoring is an option for patients who have mild hypercalcemia without surgical indications, which include lack of ensured follow-up, renal stones, impaired renal function, or osteoporosis.

Definition

Primary hyperparathyroidism (PHPT) is an endocrine disorder in which autonomous overproduction of parathyroid hormone (PTH) results in derangement of calcium metabolism. In approximately 80% of cases, over-production of PTH is due to a single parathyroid adenoma and, less commonly, multi-gland involvement may occur. Diagnosis occurs through testing for a concurrent elevated serum calcium level with a higher or inappropriately normal (i.e., non-suppressed) plasma PTH level.[1][2] Inherited forms, affecting a minority of patients, lead to hyperfunctioning parathyroid glands. Importantly, hyperparathyroidism is rarely caused by parathyroid cancer characterized by severe hypercalcemia.[3]

Normocalcemic PHPT is recognized as a variant of PHPT, and has yet to be thoroughly characterized.[4] It presents with high levels of parathyroid hormone, in the setting of normal serum and ionized calcium levels, after secondary causes of PTH elevation have been excluded.[5] It is sometimes detected during the evaluation of patients with low bone mineral density.[6] Some, but not all, patients will go on to develop PHPT.[1][2][5]

History and exam

Key diagnostic factors

incidental finding on biochemical testing
history of osteoporosis or osteopenia
family history of hyperparathyroidism or features suggestive of hypercalcemia
nephrolithiasis

More key diagnostic factors

Other diagnostic factors

poor sleep
fatigue
myalgia
anxiety
depression
memory loss
overt neuromuscular dysfunction
cardiovascular and metabolic dysfunction
features suggestive of hypercalcemia
hard and dense neck mass

Other diagnostic factors

Risk factors

female sex
age ≥50-60 years
family history of PHPT
multiple endocrine neoplasia (MEN) 1, 2A, or 4
current or historical lithium treatment
hyperparathyroidism-jaw tumor syndrome
history of head and neck irradiation

More risk factors

Diagnostic investigations

1st investigations to order

serum calcium
serum intact PTH with immunoradiometric or immunochemical assay

More 1st investigations to order

Investigations to consider

25-hydroxyvitamin D level
serum alkaline phosphatase
serum phosphorus
24-hour urinary calcium
dual-energy x-ray absorptiometry (DXA) scan
trabecular bone score
Tc-99m sestamibi scanning and ultrasonography
single photon emission CT + sestamibi scanning
CT neck
4-Dimensional (4D) CT neck
MRI neck

More investigations to consider

Emerging tests

radiolabeled choline PET

Treatment algorithm

ONGOING

asymptomatic with surgical indications or symptomatic

asymptomatic with no surgical indications

Contributors

Authors

John Ayuk, MD

Consultant Endocrinologist

University Hospitals Birmingham

Birmingham

Disclosures

JA declares that he has no competing interests.

Neil Gittoes, MD, PhD

Consultant Endocrinologist and Honorary Professor of Endocrinology

Associate Medical Director

University Hospitals Birmingham

Birmingham

Disclosures

NG has contributed to advisory boards for Takedo and Shire pharmaceuticals.

Acknowledgements

Dr John Ayuk and Professor Neil Gittoes would like to gratefully acknowledge Dr Fausto Palazzo, Dr Swaroop Gantela, and Dr Nancy D. Perrier, the previous contributors to this topic. FP, SG, and NDP declare that they have no competing interests.

Peer reviewers

Bridget Sinnott, MD

Clinical Assistant

Professor of Medicine

University of Illinois at Chicago

Chicago

Disclosures

BS declares that she has no competing interests.

Udaya Kabadi, MD

Professor of Medicine

Department of Internal Medicine

University of Iowa

Iowa City

Disclosures

UK declares that she has no competing interests.

Leonard Egede, MD

Professor of Medicine

Medical University of South Carolina

Charleston

Disclosures

LE declares that he has no competing interests.

Petros Perros, BSc, MBBS, MD, FRCP

Department of Endocrinology

Elliott Building

Royal Victoria Infirmary

Newcastle-upon-Tyne

Disclosures

PP declares that he has no competing interests.

Differentials
- Familial hypocalciuric hypercalemia (FHH)
- Humoral hypercalcemia of malignancy
- Multiple myeloma
More Differentials
Guidelines
- The EANM practice guidelines for parathyroid imaging
- ACR–SPR Practice Parameter for the Performance of Parathyroid Scintigraphy
More Guidelines
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Primary hyperparathyroidism

Summary

Definition

History and exam

Key diagnostic factors

Other diagnostic factors

Risk factors

Diagnostic investigations

1st investigations to order

Investigations to consider

Emerging tests

Treatment algorithm

asymptomatic with surgical indications or symptomatic

asymptomatic with no surgical indications

Contributors

Authors

John Ayuk, MD

Disclosures

Neil Gittoes, MD, PhD

Disclosures

Acknowledgements

Peer reviewers

Bridget Sinnott, MD

Disclosures

Udaya Kabadi, MD

Disclosures

Leonard Egede, MD

Disclosures

Petros Perros, BSc, MBBS, MD, FRCP

Disclosures

Differentials

Guidelines

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