Primary hyperparathyroidism

Contributed by Mr David Scott-Coombes, consultant endocrine surgeon at the University Hospital of Wales, Cardiff.

Section 1 Epidemiology and pathology
On the surface of every parathyroid cell is a calcium-sensing receptor (set to 2.20-2.60mmol/l). A fall in serum calcium or a rise in serum phosphate triggers the secretion of parathyroid hormone (PTH). PTH has effects on the intestines, bones and kidneys, which all result in an increase in serum calcium until the normal physiological concentration has been restored. A chronic excess secretion of PTH is termed hyperparathyroidism (HPT).

Classification of HPT
Primary hyperparathyroidism (1HPT) results from an inappropriate autonomous excess secretion of PTH. This may be due to a solitary adenoma (>85 per cent), four-gland hyperplasia (10 per cent), double adenoma (2 per cent) or, rarely, carcinoma (<1 per cent).1 The vast majority of cases of 1HPT are sporadic, but rarely it can be associated with multiple endocrine neoplasia type 1.

Secondary hyperparathyroidism (2HPT) results from an appropriate excess secretion of PTH in response to prolonged reduction in serum calcium. The patient has a high PTH with normal calcium. Vitamin D deficiency is the most common underlying cause, which may be either dietary or secondary to renal failure. Vitamin D replacement will rectify the former cause of 2HPT.

Tertiary hyperparathyroidism (3HPT) occurs in patients who, after a period of dialysis, undergo successful renal transplantation.

The previously appropriate excess secretion of PTH (2HPT) becomes inappropriate and results in hypercalcaemia. In an attempt to avoid confusion, alternative terms are normocalcaemic and hypercalcaemic renal hyperparathyroidism.

Primary HPT is the most common cause of hypercalcaemia. The annual incidence is estimated to be 20 per 100,0002 and more than 1 per cent of postmenopausal women have raised serum concentrations of calcium.3

Section 2 Diagnosis

Clinical features
Primary HPT is classically thought of as the somatic manifestation of hypercalcaemia. Patients suffer from a variety of complaints including osteopenia, nephrolithiasis, abdominal pain and mental status changes ('bones, stones, abdominal groans and psychic moans').

These days patients with 1HPT are relatively asymptomatic and are most often diagnosed when routine biochemical testing shows an elevated serum calcium level. Fewer than 20 per cent of patients satisfy the latest US National Institutes of Health (NIH) criteria for surgical intervention (see box).4 Surgery is performed if any one indicator is present.

A careful history will reveal many patients have subtle neurocognitive symptoms including fatigue, lethargy, muscle weakness, depression and cognitive impairment. Other symptoms include thirst, bone pains, joint pains and constipation.

Investigations
The diagnosis of HPT is confirmed from concurrent biochemical measurement of calcium and PTH. Typically, affected patients will have elevated serum calcium (corrected) and an elevated PTH. In the presence of hypercalcaemia, PTH within the normal range is 'inappropriately normal'. However, the sensitivity of the assay is now so great that we have seen patients with measurable PTH in the presence of severe hypercalcaemia from malignancy.

There are three potential pitfalls in the diagnosis of HPT.

Familial hypercalcaemic hypocalciuria: this is a rare (1 per 16,000) condition that derives from a genetic mutation of the calcium-sensing receptor such that it is 're-set' to a higher level (eg 2.40-2.80mmol/l). The condition is autosomal dominant and so a family history should be present. Affected patients are asymptomatic and do not benefit from surgery. The diagnosis is proven or excluded by measuring the urinary calcium excretion - derived from a calculation of the urinary calcium and creatinine ratio.

Vitamin D deficiency: co-existing vitamin D deficiency may cause the serum calcium level to fall into the normal range, which can lead to diagnostic uncertainty. Preoperative measurement of vitamin D status in all patients is essential.

Blood sample collection: PTH is unstable when stored in standard serum blood tubes. Therefore, a delay between venesection and biochemical analysis can result in a lower level of PTH. This enzymatic degradation is arrested if the blood sample is placed in EDTA tubes.Bone mineral density should be measured by DEXA scan in all patients. Parathyroid localisation is not a diagnostic test but a surgical aid. It should only be requested once a decision to operate has been made.

Surgical intervention in asymptomatic 1HPT4
IndexThreshold for surgery
AgeUnder 50 years
Serum calciumOver 2.75mmol/l
Creatinine clearanceReduced by 30%
24h urinary calciumOver 10mmol
Bone mineral densityt-score less than -2.5SD (at any site)

Section 3 Managing the condition

Vitamin D deficiency
Preliminary data on vitamin D repletion in patients with mild 1HPT suggest that correction of vitamin D deficiency can be achieved without worsening the underlying hypercalcaemia. Vitamin D-deficient patients undergoing parathyroidectomy are also at increased risk of postoperative hypocalcaemia and 'hungry bone syndrome', and so correction of this deficiency is recommended.

Surgery
Parathyroidectomy is currently the only curative treatment for 1HPT and is the mainstay of treatment for most patients.

Surgery is indicated in all symptomatic patients and those that meet the criteria set out by the NIH (see box, Section 2).4 Parathyroidectomy is safe and successful; the mortality is zero and the risk to the recurrent laryngeal nerve exceedingly low (0.4 per cent).5 In experienced hands surgery has a success rate that exceeds 95 per cent,6 although a cure rate of 70 per cent probably reflects general surgical practice more faithfully. Advances in the success of pre-operative parathyroid localisation using 99mTc-sestamibi (MIBI) scintigraphy and cervical ultrasound scanning have given surgeons the option to perform scan-directed (targeted) parathyroidectomy rather than bilateral neck dissection.

The approach favoured by most is via a 3cm lateral incision directly over the adenoma. This philosophy of minimalist surgery reduces post-operative discomfort, shortens hospital stay and may have a beneficial impact on cosmetic outcome. The ability to measure PTH during surgery (intra-operative PTH assay) is championed by some to prevent missing multiple gland disease, whereas others have not found that it provides any additional benefit.

The management of asymptomatic 1HPT is controversial. In the USA, surveys have shown that endocrinologists refer very few asymptomatic patients for surgery,7 whereas endocrine surgeons would operate on up to 80 per cent of such patients.8

The term 'asymptomatic HPT' is regarded by many as a misnomer, because when a careful history is taken nearly all patients have symptoms and so the term 'minimally symptomatic HPT' is preferred. In a recent study of 202 patients undergoing parathyroidectomy, symptoms were no different between those patients who met the NIH criteria for parathyroidectomy and those who did not; patients in both groups benefited symptomatically after successful parathyroidectomy.9

Many papers have demonstrated improvements following parathyroidectomy. A 25-year follow up of patients with untreated asymptomatic disease showed a noticeable increase in cardiovascular deaths compared with age-matched normocalcaemic controls.3 Certainly there is no data to suggest that a non-operative approach is beneficial to patients with 1HPT and as such a liberal attitude to parathyroidectomy is adopted by many endocrine surgeons.

Medical treatment
Patients with contraindications or refusal for surgery are managed conservatively, and should undergo long-term follow up for annual assessment of calcium, PTH, creatinine clearance and skeletal surveillance.

Calcimimetics reduce serum levels of PTH and calcium, with a leftward shift in the set-point for calcium-regulated PTH secretion. Currently, this class of drugs is not licensed for use outside renal 2HPT. Based on its unique mechanism of action, the calcimimetic cinacalcet may play a role in the medical treatment of 1HPT and 3HPT in the future.

Section 4 Follow-up and prognosis
Patients who have undergone resection of a parathyroid adenoma should be followed up with repeat serum calcium to six months and, if they remain normocalcaemic, they can be discharged. PTH does not return to normal limits in up to 16 per cent of patients.10 Patients undergoing subtotal parathyroidectomy for multiple gland disease need follow up for life as there is a risk of recurrent HPT.

Conclusion
Primary HPT is a common condition that is rarely asymptomatic. Surgery offers the only permanent cure and is both safe and successful in experienced hands. The role of surgery in minimally symptomatic patients is controversial owing to a lack of follow-up studies.

Pre-operative localisation should be undertaken after a decision to operate. The improved success of localisation studies have heralded minimally invasive techniques to resect solitary adenomas. Patients treated conservatively require long-term medical surveillance.

References
1. van Heerden J, Grant C. Surgical treatment of primary hyperparathyroidism: an institutional perspective. World J Surg 1991; 15: 688-92.

2. Melton L 3rd. Epidemiology of primary hyperparathyroidism. J Bone Miner Res 1991; 6 Suppl 2: S25-30.

3. Lundgren E, Lind L, Palmer M et al. Increased cardiovascular mortality and normalised serum calcium in patients with mild hypercalcaemia followed for 25 years. Surgery 2001; 130: 978-85.

4. Bilezikian J, Potts J Jr, Fuleihan Gel H et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st Century. J Clin Endocrinol Metabol 2002; 87: 5,353-61.

5. Scott-Coombes D, Kinsman R. The British Association of Endocrine Surgeons Second National Audit Report 2007; ISBN 1-903968-19-4.

6. Schell S, Dudly N. Clinical outcomes and fiscal consequences of bilateral neck exploration for primary idiopathic hyperpara-thyroidism without preoperative radionuclide imaging or minimally invasive techniques. Surgery 2003; 133: 32-9.

7. Mahadevia P, Sosa J, Levine M et al. Clinical management of primary hyperparathyroidism and thresholds for surgical referral. Endocr Pract 2003; 9: 494-503.

8. Kouvaraki M, Greer M, Sharma S et al. Indications for operative intervention in patients with asymptomatic primary hyperparathyroidism. Surgery 2006; 139: 527-34.

9. Eigelberger M, Cheah W, Ituarte P et al. The NIH criteria for parathyroidectomy in asymptomatic primary hyperpara-thyroidism: are they too limited? Ann Surg 2004; 239: 528-35.

10. Nordenstrom E, Westerdahl J, Bergenfelz A. Long-term follow-up of patients with elevated PTH levels following successful exploration for primary hyperparathyroidism. World J Surg 2004; 28: 570-5.

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