Education Resource from the Society for Endocrinology
Gordon C Wishart
Consultant Breast & Endocrine Surgeon & Associate Lecturer, University of Cambridge.
Summer School 11-14 July 2006
The Møller Centre, Storeys Way, Cambridge, UK
It is now almost 80 years since Felix Mandl performed the first operation for primary hyperparathyroidism (pHPT) (Mandl 1925). During that time the clinical profile has shifted from a symptomatic disorder, with classical symptoms and signs at presentation, towards a more asymptomatic condition. Primary HPT is now being diagnosed with increased frequency, with an annual incidence of approximately 0.1%, and diagnosis has been simplified by development of a whole molecule PTH assay. The annual incidence is higher, however, among middle-aged and elderly women (188 per 100,000 population) where the disorder is often associated with medical comorbities (Heath 1980).
The diagnosis of pHPT is made following detection of hypercalcaemia in the presence of inappropriately normal or elevated circulating parathyroid hormone levels. The hypercalcaemia is usually discovered on routine screening of patients with general symptoms including fatigue, depression, weakness or less commonly now during the investigation of osteopenia or nephrolithiasis, the two main complications of pHPT.
In 85-90% of patients, pHPT is due to a solitary parathyroid adenoma; in 10% of cases multiglandular hyperplasia is present which may be associated with multiple endocrine neoplasia (MEN) Type I (pancreatic tumours, pituitary tumours, pHPT ), sporadic or induced by long term lithium intake. A double adenoma or carcinoma each occurs in approximately 1% of cases of pHPT.
During the last decade, surgery for pHPT has been limited to those patients with symptoms or complications of the disease as well as younger patients under the age of 50. This approach was adopted following a National Institute of Health (NIH) consensus conference in 1990 (Potts 1991) which concluded that many patients did not require surgery as they were asymptomatic and their disease was not relentessly progressive (Potts et al 1991).
Two leading articles have now questioned this conservative approach suggesting that surgery should be considered following the initial diagnosis (Utiger 1999; Toft 2000). This is supported by two quality of life studies, which have shown that even patients with mild hypercalcaemia have physical or neuropsychological disabilities that improve following parathyroidectomy (Burney et al 1999; Chan et al 1995). In addition it is now recognised that the mortality among untreated patients with pHPT is increased, mainly from cardiovascular disease (Palmer 1987).
This paradigm shift in the threshold for surgical intervention has now led to a second NIH consensus conference that has reviewed the indications for surgery in pHPT (Bilezikian 2002). While these new guidelines go a small way towards supporting earlier surgical intervention they may not go far enough. At present surgery is the only curative treatment for patients with pHPT. With the introduction of unilateral or focused parathyroidectomy, often performed as a day-case procedure, the cost of surgical intervention may be less than any single hospital admission for a complication of the disease.
Familial hypocalciuric hypercalcaemia (FHH) is a rare disorder that can also present with hypercalcaemia and mildly elevated or inappropriately normal PTH levels and as a result it must be carefully distinguished from pHPT. FHH is transmitted in an autosomal dominant fashion and in the majority of cases is due to a heterozygous mutation in the calcium-sensing receptor (CaSR) gene that is the main regulator of parathyroid cell response to calcium. If the genetic disorder is homozygous, with two mutated CaSR genes, severe neonatal hyperparathyroidism results which requires emergency total parathyroidectomy.
FHH can be confirmed by measurement of urinary calcium concentration as well as the calcium/creatinine (Ca/Cr) clearance ratio in the patient and family members with hypercalcaemia. In FHH the Ca/Cr clearance ration is usually less than 0.01. In pHPT the Ca/Cr clearance ratio is typically greater than 0.02 (Bilezikian 2002).
Not all patients with pHPT have hypercalcaemia each time the serum calcium is measured. In some patients the serum calcium is at the upper end of the normal range and the PTH is inappropriately elevated. This condition, sometimes called normocalcaemic HPT (Bilzekian 2002), often comes to light when PTH is measured during the investigation of osteoporosis or intermittent hypercalcaemia. More recently there has been some evidence that the upper limit of normal for vitamin D-sufficient patients should be up to 30% lower than current values (Holick 2003). This is based on the assumption that the normal range for PTH was obtained from healthy adult volunteers, many of whom would have been vitamin D-deficient. Vitamin D deficiency may also explain a number of patients who have persistent elevation of PTH, despite normocalcaemia, following parathyroidectomy for pHPT (Denizot 2001).
In patients with normocalcaemia and elevation of PTH all potential causes of secondary hyperparathyroidism should be ruled out including renal insufficiency, vitamin D deficiency or hypercalciuria. In cases of vitamin D deficiency a trial of calcium and vitamin D supplements has been shown to markedly reduce PTH levels (Malabanan 1998) and may thus prevent unnecessary surgery.
For many years parathyroid surgery has relied on experienced surgeons to distinguish an adenoma from hyperplasia of all four glands. As a result bilateral cervical exploration has remained the preferred surgical approach with cure rates of at least 95% in experienced hands (Chen 1996). Proponents of this technique, currently used by 97% of UK endocrine surgeons (Ozbas 2003), suggest that cases of hyperplasia or double adenoma are easier to recognize if bilateral neck exploration is performed. . In the past frozen section was often performed on one or more glands and although currently performed routinely by at least 73% of endocrine surgeons in the UK (Ozbas 2003) it is becoming less popular in Europe and North America as other peroperative techniques are increasingly used.
In approximately 80-85% of cases however pHPT is caused by a single adenoma and this, together with improvements in pre-operative localisation techniques and the feasibility of intraoperative parathyroid hormone (iPTH) measurement, has increased the attraction of minimally invasive or unilateral surgery.
99mTc sestamibi is now the agent of choice for parathyroid imaging. It can be performed either as a subtraction technique with 123I (O’Doherty 1992) or as a sole agent with delayed/dual phase images (Taillefer 1992). The differential uptake and retention of 99mTc sestamibi in thyroid and parathyroid tissue, which allows identification of parathyroid tissue on delayed imaging, may be partly explained by the large numbers of mitochondria in parathyroid adenomas (Sandrock 1993). A number of techniques including use of collimation and single photon emission tomography (SPET) allow optimisation of the imaging technique to provide sensitivity in excess of 90% (Denham 1998). Over –expression of the multidrug resistance protein, P-glycoprotein (Kao 2002) and smaller adenoma size are both associated with false negative scintigraphy. The combination of 99mTc sestamibi and neck ultrasound is now recognised to be the optimum combination for pre-operative localisation, with a combined sensitivity of 94% (Lumachi 2001), and allows scan-directed selection of patients for either unilateral or bilateral surgery.
Other methods for parathyroid localisation have been used including CT, MRI and selective venous sampling. Although they can successfully identify adenomas the sensitivity of these techniques is extremely variable and their use is best reserved for those patients with persistent hypercalcaemia following failed neck exploration.
An increasing number of surgeons are now performing unilateral surgery for pHPT based on the fact that 85-90% of patients will have single gland disease. This change in practice has been made possible by improvements in preoperative localization techniques using 99mTc sestamibi scanning and/or ultrasound. A meta-analysis of 99mTc sestamibi scanning has revealed a sensitivity and specificity of 90.7% and 98.8% respectively suggesting that the majority of patients may be suitable for unilateral exploration (Denham 1998). A recent series of 184 patients who underwent scan-directed UNE reported a long term cure rate of 98.4% (Sidhu 2003).
Unilateral exploration relies not only on the ability to localise an adenoma pre-operatively but on careful patient selection also. Patients with mutigland disease, MEN-related hyperplasia, and renal disease are not suitable for this approach. Although a unilateral approach can be carried out through a collar incision a number of minimally invasive techniques are now available including focused parathyroidectomy, endoscopic parathyroidectomy and video-assisted parathyroidectomy.
Following accurate preoperative localisation of uniglandular disease FP is carried out through a small lateral neck incision. The patient is supine with the head in a neutral position. The technique develops the space between the lateral border of the strap muscles and sternomastoid to reach the retrothyroid space. This operation is suitable for day-case surgery and can be performed either under general or cervical block anaesthesia.
Comparison of this technique with bilateral neck exploration has shown less overall complications (1.2% versus 3.0%), a 50% reduction in operating time and a substantial reduction in post-operative stay (Udelsman 2002). These data have been confirmed by a further day-case study of fifty patients undergoing focused parathyroidectomy under general anaesthesia. This study demonstrated that this procedure was suitable for all ages (mean age 63, range 33-92), was completed under general anaesthesia in a mean operating time of 30 minutes (range 16-57), and allowed early discharge within two hours of surgery. Furthermore the cure rate, defined as normocalcaemia, was 100% when FP was combined with intra-operative PTH (iPTH) (Gurnell 2004).
The introduction of iPTH measurement by rapid PTH assay has been an important advance in the development of unilateral surgery, replacing the need for visualisation of all glands, and has been described as a biochemical “frozen section”. Several studies have now shown that a 50% reduction in baseline, pre-excision PTH within 5-10 minutes of adenoma excision accurately predict post-operative normocalcaemia (Inabnet 1999; Udelsman 2000). There is still some uncertainty with this technique, however, since a number of cases can take up to thirty minutes to fall by 50% (Gurnell 2004). Experience to date does suggest that failure to achieve a 50% drop in baseline PTH does seem to predict the presence of multigland disease or a second adenoma and can guide intra-operative decision making about further exploration. Intra-operative PTH measurement may not be necessary for all cases of focused parathyroidectomy. When there is concordance between pre-operative sestamibi and ultrasound scanning then the false-positive rate for adenoma localisation may be so low that iPTH measurement has little to add and is not cost-effective.
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The opinions expressed in this paper are those of the speaker and do not necessarily reflect the views of the Society
Revised:
24-Aug-2006