Educational Article Scottish Medical Journal 58(4) 251–253 ! The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0036933013507845 scm.sagepub.com
The management of primary hyperparathyroidism J Hinnie
Keywords Primary hyperparathyroidism, hyperparathyroidism, parathyroid adenoma, parathyroidectomy
The exact prevalence of primary hyperparathyroidism (PHP) is not known but it may be as high as 1 in 47 women aged 55–75 years. This would equate to 1 in 333 of the general population.1,2 The female to male ratio is 2:1 with most presenting between 50 and 60 years of age,1,3 although it can present at any age. Traditionally described as the symptomatic disease of ‘bones, stones, groans and moans’, with the advent of widespread biochemical testing cases are now often picked up when the patient is asymptomatic. This leads to the dilemma of whether or not to treat. Most cases (85%) are due to a solitary benign parathyroid adenoma, while two adenomas occur in 2–5% of cases and hyperplasia of all four glands in 10–15%. Parathyroid carcinoma is a rare cause, constituting less than 1% of cases. The four parathyroid glands normally lie along the posterior border of the thyroid – one inferiorly and one superiorly on each side. However, ectopic glands (and hence ectopic adenomas) can be found in various locations (e.g. in the mediastinum or thymus or in a paraoesophageal location).4 Diagnosis is made on the basis of biochemical findings. Calcium is raised and parathyroid hormone (PTH) is inappropriately high (i.e. high normal or raised). Initial investigations should be serum calcium, PTH, alkaline phosphatase, vitamin D, U and Es, eGFR and urine calcium. At presentation a detailed family history should be taken to check for the hereditary forms of PHP, most notably multiple endocrine neoplasia (MEN) types 1 and 2A. PHP is often the presenting condition in both of these. The possibility of MEN in the face of no obvious family history should be borne in mind. This is unlikely in the elderly, but especially in younger patients it should be considered. The author routinely arranges genetic screening for MEN in patients presenting at the age of 50 or below. Familial benign hypocalciuric hypercalcaemia (FBHH) represents the main differential diagnosis for PHP. The possibility of FBHH will be flagged up by one or both of family history and low urine calcium. This benign cause of hypercalcaemia is inherited as an
autosomal dominant condition that mimics PHP.5 Its prevalence in Scotland has been estimated as between 1 in 16,0006 and 1 in 77,0007. It is important to obtain a full drug history from the patient asking in particular about thiazide diuretics and lithium, since both can cause increases in serum calcium. Thiazides decrease urinary calcium excretion, which can therefore lead to hypercalcaemia. In this situation PTH is not usually inappropriately high for the observed serum calcium and differentiation from hyperparathyroidism is usually straight forward. If in doubt, then the drug should be discontinued and the patient reassessed after 3 months. Lithium is a calcium sensing receptor antagonist, and thus decreases the receptor’s sensitivity to calcium. Since this receptor controls PTH release, higher calcium concentrations are needed to suppress PTH levels. This leads to increases in serum calcium and PTH8 and can induce parathyroid hyperplasia with prolonged use. In the author’s experience it is (understandably) very rarely that agreement can be reached with the patient’s psychiatrist to discontinue lithium, even for a trial period, so that it is best to regard such patients as having PHP. It is important that all PHP patients are vitamin D replete. Not only will this ensure that PTH secretion is not exacerbated by low vitamin D levels, but it will also ensure that misleadingly low urine calcium is not found, as this may lead to a misdiagnosis of FBHH. Urine calcium is often low in patients deficient in vitamin D, but rises to normal levels when the patient is rendered vitamin D replete. Until recently, vitamin D supplementation was problematic in the UK because of difficulty in obtaining supplies. However in the last year, two options have become freely available in the form of Fultium-D3 capsules and Desunin tablets. One Clinic L, The New Victoria Hospital, Glasgow, UK Corresponding author: John Hinnie, Clinic L, The New Victoria Hospital, Grange Road, Glasgow G42 9LF, UK. Email: [email protected]
Downloaded from scm.sagepub.com at UNIVERSITY OF ALBERTA LIBRARY on June 29, 2015
252
Scottish Medical Journal 58(4)
capsule or tablet per day will give 800 IU of colecalciferol and is usually sufficient. The author aims for serum 25-hydroxyvitamin D levels of 60 nmol/L or above. Once the diagnosis of PHP has been reached, then a decision must be made regarding whether to proceed to parathyroidectomy, since this should be regarded as the definitive treatment for PHP. Patients with PHP may present with signs and/or symptoms such as nephrolithiasis, osteoporosis and/or fragility fracture, nonspecific psychiatric symptoms, mild myalgia/arthralgia, abdominal discomfort, polyuria or constipation, or they may be asymptomatic with no clinical hint of the diagnosis. This latter presentation is the more common today with hypercalcaemia being picked up during testing carried out as part of the assessment of other conditions. As can be seen, the symptoms of PHP are varied and non-specific and it should therefore be borne in mind that even in a patient with confirmed PHP, such symptoms may not necessarily be due to this disease. When discussing the prospect of parathyroidectomy, it is important therefore to point out that parathyroidectomy may not lead to resolution of symptoms. However symptoms are not the only consideration when assessing whether parathyroidectomy should be carried out. Guidelines on management of asymptomatic PHP have recently been developed9 and the criteria which, it is believed, are likely to make surgery beneficial are outlined in Table 1. Note that it is not suggested that all these criteria need to be fulfilled before surgery is considered. Unfortunately, even using these criteria, the decision as to whether to proceed to surgery is not always clear cut. Surgery may not be realistic in many frail elderly patients for instance, even though they have severe osteoporosis with multiple fractures. The author therefore recommends (with due deference to his surgical colleagues) that assessment by a physician should be carried out prior to referring for parathyroidectomy, in order both to confirm the diagnosis and to discuss the pros and cons of surgery. Where parathyroidectomy would be desirable, but not feasible, the physician can then assess the patients’ needs in terms of medical management. Table 2 lists recommendations for medical surveillance in asymptomatic PHP.9 Since the diagnosis of PHP is a biochemical one, it is only once the decision has been made to refer the patient for parathyroidectomy that imaging studies should be undertaken. Indeed the author has recently demonstrated that considerable resources are wasted imaging PHP patients who do not proceed to parathyroidectomy.10 Imaging will help to localise the adenoma and so guide the surgical approach. The most widely used imaging techniques are probably neck ultrasound and sestamibi-SPECT (single-photon emission
computed tomography), although MRI and fourdimensional CT are also used. A recent meta-analysis of neck ultrasound and sestamibi-SPECT studies showed similar sensitivity and positive predictive value for the two methods. Neck ultrasound had a pooled sensitivity of 76.1% (95% CI 70.4–81.4%) and positive predictive value of 93.2% (90.7–95.3%), while for sestamibi-SPECT the values were 78.9% (64– 90.6%) and 90.7% (83.5–96.0%) respectively.11 The optimal preoperative localisation technique in each hospital will be dependent on local resources and experience and is best decided in discussions between surgeon and radiologist. As discussed above, in many cases surgery will not be appropriate and in this situation medical management should be considered. Medical management falls into two broad categories, namely drugs which will decrease bone resorption (antiresorptive drugs) and Cinacalcet. This is a calcium sensing receptor agonist – sometimes termed a ‘calcimimetic’ – which decreases both serum calcium and PTH in patients with PHP. Some evidence is available for the effects of antiresorptive drugs in PHP. Such data is available for the bisphosphonate Alendronate, the selective oestrogen receptor modulator Raloxifene and Oestrogen. All studies were small but some did show increases in bone density. Although studies involving Cinacalcet did show a fall in serum calcium and PTH, they did not show a significant effect on bone density. None of the studies with antiresorptive drugs or Cinacalcet provided fracture
Table 1. Criteria for parathyroidectomy in asymptomatic primary hyperparathyroidism.9 Adjusted serum calcium Urinary calcium Creatinine clearance DXA scan result Age
>0.25 mmol/L above reference range Not indicated
The management of primary hyperparathyroidism J Hinnie
Keywords Primary hyperparathyroidism, hyperparathyroidism, parathyroid adenoma, parathyroidectomy
The exact prevalence of primary hyperparathyroidism (PHP) is not known but it may be as high as 1 in 47 women aged 55–75 years. This would equate to 1 in 333 of the general population.1,2 The female to male ratio is 2:1 with most presenting between 50 and 60 years of age,1,3 although it can present at any age. Traditionally described as the symptomatic disease of ‘bones, stones, groans and moans’, with the advent of widespread biochemical testing cases are now often picked up when the patient is asymptomatic. This leads to the dilemma of whether or not to treat. Most cases (85%) are due to a solitary benign parathyroid adenoma, while two adenomas occur in 2–5% of cases and hyperplasia of all four glands in 10–15%. Parathyroid carcinoma is a rare cause, constituting less than 1% of cases. The four parathyroid glands normally lie along the posterior border of the thyroid – one inferiorly and one superiorly on each side. However, ectopic glands (and hence ectopic adenomas) can be found in various locations (e.g. in the mediastinum or thymus or in a paraoesophageal location).4 Diagnosis is made on the basis of biochemical findings. Calcium is raised and parathyroid hormone (PTH) is inappropriately high (i.e. high normal or raised). Initial investigations should be serum calcium, PTH, alkaline phosphatase, vitamin D, U and Es, eGFR and urine calcium. At presentation a detailed family history should be taken to check for the hereditary forms of PHP, most notably multiple endocrine neoplasia (MEN) types 1 and 2A. PHP is often the presenting condition in both of these. The possibility of MEN in the face of no obvious family history should be borne in mind. This is unlikely in the elderly, but especially in younger patients it should be considered. The author routinely arranges genetic screening for MEN in patients presenting at the age of 50 or below. Familial benign hypocalciuric hypercalcaemia (FBHH) represents the main differential diagnosis for PHP. The possibility of FBHH will be flagged up by one or both of family history and low urine calcium. This benign cause of hypercalcaemia is inherited as an
autosomal dominant condition that mimics PHP.5 Its prevalence in Scotland has been estimated as between 1 in 16,0006 and 1 in 77,0007. It is important to obtain a full drug history from the patient asking in particular about thiazide diuretics and lithium, since both can cause increases in serum calcium. Thiazides decrease urinary calcium excretion, which can therefore lead to hypercalcaemia. In this situation PTH is not usually inappropriately high for the observed serum calcium and differentiation from hyperparathyroidism is usually straight forward. If in doubt, then the drug should be discontinued and the patient reassessed after 3 months. Lithium is a calcium sensing receptor antagonist, and thus decreases the receptor’s sensitivity to calcium. Since this receptor controls PTH release, higher calcium concentrations are needed to suppress PTH levels. This leads to increases in serum calcium and PTH8 and can induce parathyroid hyperplasia with prolonged use. In the author’s experience it is (understandably) very rarely that agreement can be reached with the patient’s psychiatrist to discontinue lithium, even for a trial period, so that it is best to regard such patients as having PHP. It is important that all PHP patients are vitamin D replete. Not only will this ensure that PTH secretion is not exacerbated by low vitamin D levels, but it will also ensure that misleadingly low urine calcium is not found, as this may lead to a misdiagnosis of FBHH. Urine calcium is often low in patients deficient in vitamin D, but rises to normal levels when the patient is rendered vitamin D replete. Until recently, vitamin D supplementation was problematic in the UK because of difficulty in obtaining supplies. However in the last year, two options have become freely available in the form of Fultium-D3 capsules and Desunin tablets. One Clinic L, The New Victoria Hospital, Glasgow, UK Corresponding author: John Hinnie, Clinic L, The New Victoria Hospital, Grange Road, Glasgow G42 9LF, UK. Email: [email protected]
Downloaded from scm.sagepub.com at UNIVERSITY OF ALBERTA LIBRARY on June 29, 2015
252
Scottish Medical Journal 58(4)
capsule or tablet per day will give 800 IU of colecalciferol and is usually sufficient. The author aims for serum 25-hydroxyvitamin D levels of 60 nmol/L or above. Once the diagnosis of PHP has been reached, then a decision must be made regarding whether to proceed to parathyroidectomy, since this should be regarded as the definitive treatment for PHP. Patients with PHP may present with signs and/or symptoms such as nephrolithiasis, osteoporosis and/or fragility fracture, nonspecific psychiatric symptoms, mild myalgia/arthralgia, abdominal discomfort, polyuria or constipation, or they may be asymptomatic with no clinical hint of the diagnosis. This latter presentation is the more common today with hypercalcaemia being picked up during testing carried out as part of the assessment of other conditions. As can be seen, the symptoms of PHP are varied and non-specific and it should therefore be borne in mind that even in a patient with confirmed PHP, such symptoms may not necessarily be due to this disease. When discussing the prospect of parathyroidectomy, it is important therefore to point out that parathyroidectomy may not lead to resolution of symptoms. However symptoms are not the only consideration when assessing whether parathyroidectomy should be carried out. Guidelines on management of asymptomatic PHP have recently been developed9 and the criteria which, it is believed, are likely to make surgery beneficial are outlined in Table 1. Note that it is not suggested that all these criteria need to be fulfilled before surgery is considered. Unfortunately, even using these criteria, the decision as to whether to proceed to surgery is not always clear cut. Surgery may not be realistic in many frail elderly patients for instance, even though they have severe osteoporosis with multiple fractures. The author therefore recommends (with due deference to his surgical colleagues) that assessment by a physician should be carried out prior to referring for parathyroidectomy, in order both to confirm the diagnosis and to discuss the pros and cons of surgery. Where parathyroidectomy would be desirable, but not feasible, the physician can then assess the patients’ needs in terms of medical management. Table 2 lists recommendations for medical surveillance in asymptomatic PHP.9 Since the diagnosis of PHP is a biochemical one, it is only once the decision has been made to refer the patient for parathyroidectomy that imaging studies should be undertaken. Indeed the author has recently demonstrated that considerable resources are wasted imaging PHP patients who do not proceed to parathyroidectomy.10 Imaging will help to localise the adenoma and so guide the surgical approach. The most widely used imaging techniques are probably neck ultrasound and sestamibi-SPECT (single-photon emission
computed tomography), although MRI and fourdimensional CT are also used. A recent meta-analysis of neck ultrasound and sestamibi-SPECT studies showed similar sensitivity and positive predictive value for the two methods. Neck ultrasound had a pooled sensitivity of 76.1% (95% CI 70.4–81.4%) and positive predictive value of 93.2% (90.7–95.3%), while for sestamibi-SPECT the values were 78.9% (64– 90.6%) and 90.7% (83.5–96.0%) respectively.11 The optimal preoperative localisation technique in each hospital will be dependent on local resources and experience and is best decided in discussions between surgeon and radiologist. As discussed above, in many cases surgery will not be appropriate and in this situation medical management should be considered. Medical management falls into two broad categories, namely drugs which will decrease bone resorption (antiresorptive drugs) and Cinacalcet. This is a calcium sensing receptor agonist – sometimes termed a ‘calcimimetic’ – which decreases both serum calcium and PTH in patients with PHP. Some evidence is available for the effects of antiresorptive drugs in PHP. Such data is available for the bisphosphonate Alendronate, the selective oestrogen receptor modulator Raloxifene and Oestrogen. All studies were small but some did show increases in bone density. Although studies involving Cinacalcet did show a fall in serum calcium and PTH, they did not show a significant effect on bone density. None of the studies with antiresorptive drugs or Cinacalcet provided fracture
Table 1. Criteria for parathyroidectomy in asymptomatic primary hyperparathyroidism.9 Adjusted serum calcium Urinary calcium Creatinine clearance DXA scan result Age
>0.25 mmol/L above reference range Not indicated
