Clinical Review: Hyperparathyroidism

Contributed by Dr Angela Rogers, specialist registrar, Churchill Hospital, Oxford, and Professor John Wass, consultant endocrinologist, Churchill Hospital, and professor of endocrinology, University of Oxford.

An ultrasound scan of the neck is required prior to surgery to localise the parathyroid glands (Photograph: SPL)
An ultrasound scan of the neck is required prior to surgery to localise the parathyroid glands (Photograph: SPL)

Section 1: Epidemiology and aetiology
Hyperparathyroidism is defined as an excessive secretion of parathyroid hormone (PTH) by the parathyroid glands. The parathyroid glands are situated within the neck and are responsible for the production of PTH.

PTH secretion is regulated by the ionised plasma calcium concentration. PTH acts to increase the plasma calcium level by increasing calcium reabsorption by the kidneys, promoting calcium and phosphate release from bone and increasing calcium absorption from the gut via increased production of vitamin D.

Primary hyperparathyroidism
Hyperparathyroidism can be divided into primary, secondary and tertiary types. Primary hyperparathyroidism (PHP) is common, especially in women aged over 65 years. It is present in up to 1 in 500 of the general population.1

PHP is the most common cause of hypercalcaemia in non-hospitalised patients. The diagnosis is simple to make and the condition is treatable with minimal complications due to advances in imaging and surgical technique.

PHP is caused by a solitary parathyroid adenoma in 85 per cent of cases.

Approximately 15 per cent of cases are due to parathyroid hyperplasia and less than 1 per cent of all cases are due to a parathyroid carcinoma.

PHP is a feature of multiple endocrine neoplasia (MEN) syndromes 1 and 2a. MEN 1 is due to mutations in the MEN 1 gene located on the long arm of chromosome 11. It is characterised by PHP, anterior pituitary adenomas and pancreatic neuroendocrine tumours. PHP can also be seen as part of MEN 2a in association with medullary thyroid cancer and phaeochromocytomas. MEN 2a is caused by mutations in the C-RET proto-oncogene located on the long arm of chromosome 10.

Familial isolated PHP is rare and patients tend to present with severe hypercalcaemia. Familial hyperparathyroidism-jaw tumour syndrome, previously termed familial cystic parathyroid adenomatosis, is another rare genetic condition and is due to defects in the HRPT2 gene on chromosome 1. Affected individuals have a propensity to parathyroid cancer.


Radioactive tracer (orange/red) shows tumour cells around the parathyroid gland (Photograph: SPL)

Secondary hyperparathyroidism
Secondary hyperparathyroidism describes an appropriate increase in PTH secretion in response to hypocalcaemia. This is seen in chronic renal failure due to the effects of phosphate retention by the failing kidney and reduced renal synthesis of calcitriol resulting in reduced absorption of calcium from the gut.

Secondary hyperparathyroidism is seen in isolated vitamin D deficiency due to any cause, in patients on thiazide diuretics and lithium and in those with malabsorption.

Longstanding secondary hyperparathyroidism leads to autonomous hypersecretion of PTH, known as tertiary hyperparathyroidism.

Section 2: Making the diagnosis
It is now more common for PHP to be diagnosed incidentally than it is for patients to present with symptomatic hypercalcaemia. This is known as asymptomatic PHP. These patients typically have modest levels of hypercalcaemia.

There are few clinical signs on examination (see box, below).

Symptoms of hypercalcaemia
  • General Lethargy
  • Weakness
  • Anorexia
  • Gastrointestinal Nausea
  • Vomiting
  • Dyspepsia
  • Constipation
  • Renal Thirst, polyuria and polydipsia due to
  • nephrogenic diabetes insipidus.
  • Neurological Confusion
  • Drowsiness

Genetic testing for MEN 1 and 2a should be considered in all patients presenting with PHP under the age of 40 years and in those with a family history of PHP affecting one or more first degree relatives.1

Secondary hyperparathyroidism is characterised by a raised PTH and low or normal plasma calcium.

If the underlying cause is chronic renal failure, the phosphate will often be elevated. Vitamin D deficiency may be present.

Differential diagnoses
Differential diagnosis is from the other causes of hypercalcaemia. Malignancy is a common cause of hypercalcaemia in hospital inpatients. PTH is suppressed and the hypercalcaemia is often driven by parathyroid-related protein secreted by the tumour. Multiple bony metastases also cause hypercalcaemia.

Familial hypocalciuric hypercalcaemia is an autosomal dominant condition caused by an inactivating mutation in the calcium-sensing receptor. The parathyroid glands are less sensitive to calcium and higher calcium levels are required to alter PTH secretion.

Affected individuals present with hypercalcaemia, relatively low urinary calcium excretion, normal PTH level and normal or elevated magnesium levels.

End-organ damage
After a diagnosis of PHP, the patient must be investigated for evidence of end-organ damage. Renal complications include renal calculi, nephrocalcinosis and renal impairment. Osteoporosis is common. Hypercalcaemia is a known cause of pancreatitis. Pseudogout, chondrocalcinosis and osteitis fibrosa cystica are rarely seen.

Criteria for the diagnosis of PHP1
  • Adjusted calcium >2.65mmol/L on two separate samples.
  • Normal renal function (may be abnormal if adjusted Calcium >3mmol/L).
  • PTH >3pmol/L.
  • Urinary calcium >2.5mmol/24 hours.
  • Patient not taking thiazide diuretic or lithium.

Section: 3 Managing the condition
The threshold for referral to endocrine surgeons has lowered in recent years due to the use of minimally invasive techniques, which are associated with significantly lower complication rates.3 Current practice in some areas is to offer surgery to patients with asymptomatic PHP who have more modest hypercalcaemia.

Certainly, all patients with symptomatic PHP and/or evidence of end-organ damage should be considered for surgery.

Prior to surgery, the patient requires an ultrasound scan of the neck and 99mTc-sestamibi scan to localise the parathyroid glands and any tumours. Those with parathyroid hyperplasia are offered a partial parathyroidectomy. Those with a pre-operatively localised parathyroid adenoma are offered minimally invasive surgery. A two to 3cm incision is used, the operation lasts up to 60 minutes and the inpatient stay is around 24 hours.

Complications associated with parathyroid surgery are rare but include vocal cord paresis and hypocalcaemia. Following a total parathyroidectomy, the post operative hypocalcaemia is permanent and requires lifelong oral calcium and vitamin D supplementation. Following a partial parathyroidectomy or parathyroid adenomectomy, the hypocalcaemia is transient as the remaining normal parathyroid tissue recovers.

Conservative management
For patients who do not meet the criteria for surgery, monitoring alone is suitable. These patients require annual plasma calcium and renal function plus two yearly DXA and renal ultrasound scans.1 Two to 3 per cent of these patients per annum will develop new indications for surgery,1 so follow up is important.

These patients should be advised to maintain adequate hydration. Thiazide diuretics and lithium should be avoided.

Cinacalcet is a calcium-sensing receptor agonist. It increases the sensitivity of the calcium-sensing receptor leading to a reduction in PTH secretion and plasma calcium level. In the UK, it is only licensed for the treatment of secondary hyperparathyroidism and parathyroid carcinoma.

Consultant endocrinologists occasionally prescribe it off licence for patients with PHP with severe hypercalcaemia, who are unfit for surgery or in whom the parathyroid adenoma cannot be localised.

Emergency management
Any patient with a plasma calcium of 3mmol/L or greater requires admission to hospital for emergency treatment. They require IV fluid rehydration for 24 hours.

If the plasma calcium remains >3mmol/L at that stage, IV pamidronate is used to lower the calcium over the next 72 hours. Bisphosphonates can cause renal impairment and so the patient must be adequately hydrated prior to their administration.

Indications for Surgery in Asymptomatic PHP2
  • Plasma calcium 3mmol/L or greater
  • Urinary calcium 10mmol/24 hours or greater
  • Osteoporosis on bone densitometry
  • Age <50 years="" li="">

Section 4: Prognosis
Untreated PHP is associated with increased mortality due to cardiovascular disease and diabetes.

There is evidence that left ventricular hypertrophy, dyslipidaemia and impaired glucose metabolism may improve following successful parathyroid surgery, which may lower cardiovascular risk.3

Patients with asymptomatic PHP with no evidence of end-organ damage are generally managed conservatively. There are very little data assessing the impact of early surgical intervention in this group of patients with respect to quality of life, bone mineral density and, importantly, cardiovascular risk.

Mihai et al call for multicentre studies comparing long-term outcomes when these patients are treated conservatively verses early surgical intervention.3

Section 5: Case study

Bone densitometry showed osteoporosis of the left hip (Photograph: SPL)

A 72-year-old female was being investigated for fatigue. Adjusted calcium was elevated at 2.81mmol/L (reference range 2.12-2.62mmol/L) and PTH elevated at 8.9pmol/L (reference range 1.3-7.6pmol/L).

When she went to the endocrine clinic, she complained of constipation. Clinical examination was unremarkable. The results of the requested investigations were:

  • Adjusted plasma calcium: 2.74mmol/L.
  • Plasma phosphate: 0.67mmol/L.
  • PTH 9.4pmol/L.
  • Creatinine 129(mu)mol/L (70-150(mu)mol/L).
  • Alkaline phosphatase: 190IU/L (100-330IU/L).
  • Total 25-OH vitamin D 21.8ng/ml (indicates adequate vitamin D status).
  • Paired 24-hour urine collection: urine volume 1040ml; urine calcium 3.94mmol/L; 24-hour urinary calcium excretion 4.29mmol/24 hours (2.5-7.5).

The patient was diagnosed with PHP. She was investigated for evidence of end-organ damage. A renal ultrasound scan was normal. Bone densitometry showed osteoporosis with T-scores of -2.7 and -3.2 at the left hip and lumbar spine respectively.

The option of surgical management was discussed with the patient in view of end-organ damage. The patient agreed to surgery.

Ultrasound and nuclear medicine scans of the parathyroid glands were concordant, showing a left-sided 1.3cm parathyroid adenoma. The patient was referred to the endocrine surgeon and underwent a minimally invasive left parathyroid adenomectomy with no complications. Histology showed a benign parathyroid adenoma.

PTH returned to normal following surgery. The patient noticed an improvement in her energy levels. She was started on calcium, vitamin D supplementation and a bisphosphonate for her osteoporosis. She has been followed up for two years post-operatively. Her biochemistry has remained normal. A repeat bone densitometry scan showed an improvement in her bone density with T-scores of -2.4 and -3.0 at the left hip and lumbar spine respectively.


Renal ultrasound scans are a routine part of conservative management (Photograph: SPL)

Section 6 Evidence base
Clinical trials

  • Bollerslev J, Jansson S, Mollerup CL et al. Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial. J Clin Endocrinol Metab 2007; 92: 1687-92.

Guidelines

Curriculum

This topic is covered under section 15.6 of the RCGP curriculum 'Metabolic Problems'

Key texts

  • Turner HE, Wass JAH. Oxford Handbook of Endocrinology and Diabetes. Second edition. Oxford University Press, 2009.
  • Kennedy L, Basu A. Problem solving in endocrinology and metabolism. 1st edition. Clinical Publishing, 2007.

Online

  • Society for Endocrinology. www.endocrinology.org The education section of this site includes bone disorders.

Reflect on this article and add notes to your CPD Organiser on MIMS Learning

CPD IMPACT: Earn more credits

These further impact points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • Plan for future reviews of patients with PHP. Are they being monitored regularly? Check if they are using thiazide-like diuretics or lithium.
  • Review what constitutes evidence of parathyroid disease and consider this in osteoporosis patients.
  • Develop a practice protocol on how to investigate patients with hypercalcaemia.

References
1. HE Turner, JAH Wass. Oxford Handbook of Endocrinology and Diabetes. 2nd edition. Oxford University Press, 2009.

2. Garcia de la Torre N, Wass JAH, Turner HE. Parathyroid adenomas and cardiovascular risk. Endocr Relat Cancer 2003; 10: 309-22.

3. Mihai R, Wass JA, Sadler GP. Asymptomatic hyperparathyroidism - need for multicentre trials. Clin Endocrinol 2008; 68: 155-64.

  • Visit our GP Curriculum Centre for hundreds of articles linked to key topics in the RCGP curriculum.

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