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Hypercalcaemia and primary hyperparathyroidism
CALCIUM AND BONE
Hypercalcaemia and primary hyperparathyroidism
What’s new? C
Matthew E Fenech Jeremy JO Turner
Abstract Hypercalcaemia is most commonly caused by primary hyperparathyroidism (PHPT) or malignancy. PHPT is common, affects more women than men, and is usually due to a solitary parathyroid adenoma. Nowadays, the most common presentation is an incidental finding on blood testing. The only curative treatment is parathyroidectomy. In 2009 the Third International Workshop on the management of asymptomatic primary hyperparathyroidism updated their guidance on management of asymptomatic PHPT. They recommend surgery in: all symptomatic patients; asymptomatic patients with hypercalcaemia above the upper limit of the reference range by more than 0.25 mmol/litre, evidence of end-organ damage, including impaired renal function, and reduced bone mineral density; and patients under 50 years old. In other patients, conservative management with regular monitoring is an acceptable management strategy. Defining ‘asymptomatic’ is not always easy and there is growing awareness of the prevalence of reduced quality-of-life scores among patients with ‘asymptomatic’ PHPT, but there is a lack of definitive evidence showing benefit in these domains following parathyroidectomy. Therefore, careful clinical decision-making is required in this group of patients.
C
C
C
C
C
The guidelines updated in 2009 by the Third International Workshop on the management of asymptomatic primary hyperparathyroidism (PHPT), on which groups of patients with asymptomatic PHPT should undergo parathyroidectomy, now have a firmer evidence base, particularly with respect to the sequelae of reduced renal function on skeletal disease in PHPT, and regarding improvements in bone mineral density and fracture risk following parathyroidectomy There is still a role for clinical judgement when assessing the risks and benefits of parathyroidectomy in the ‘no indication for surgery’ group, as emphasized by the American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons in their position statement on the diagnosis and management of primary hyperparathyroidism published in 2005 Guidelines for the treatment of PHPT in MEN-1 were released in 2012 There is a growing recognition of the multiple ways in which vitamin D deficiency and PHPT can interact Where it is available, and when imaging results concur, minimally invasive parathyroidectomy is becoming the preferred surgical option The calcimimetic, cinacalcet, is now licensed for use in PHPT where surgery is inappropriate, along with its original licence for use in secondary hyperparathyroidism in chronic renal disease and for parathyroid carcinoma
Keywords cinacalcet; hypercalcaemia; parathyroidectomy; primary hyperparathyroidism; vitamin D Guidelines for the management of PHPT and other clinical features in MEN-1 have been published recently.4 Hypercalcaemia due to other causes (Figure 1) is distinguished from PHPT by suppressed PTH concentration.
Aetiology Of the numerous causes of hypercalcaemia, primary hyperparathyroidism (PHPT) is the most common in outpatient settings and malignancy is most common amongst inpatients. PHPT is characterized by hypercalcaemia with elevated or inappropriately normal concentrations of parathyroid hormone (PTH) and elevated urinary calcium excretion. The prevalence is 1e3/1000. It is more common in women (3:1) and most commonly presents after the age of 50 years. The main causes of PHPT are outlined in Table 1. PHPT is usually sporadic, but may be associated with inherited syndromes, most commonly multiple endocrine neoplasia (MEN) type 1 and type 2,1 familial isolated hyperparathyroidism2 and hyperparathyroidismejaw tumour syndrome.3 These inherited forms tend to present at a younger age.
Clinical features Patients are commonly asymptomatic at diagnosis, with serum calcium less than 0.25 mmol/litre above the reference range. Classical symptoms include polyuria, polydipsia, depression, peptic ulcer disease, musculoskeletal aches and pains and renal colic (‘moans, bones, stones and groans’). Some reports have linked asymptomatic PHPT to reduced quality-of-life scores but this does not consistently improve after parathyroidectomy.5,6 Likewise, although an association of PHPT with hypertension has been described, it is not thought consistently to improve following parathyroidectomy.7 Features of end-organ damage include osteoporosis, osteitis fibrosa cystica, nephrolithiasis and nephrocalcinosis. Classical skeletal changes (Brown tumours, osteitis fibrosa cystica) occur in fewer than 2% of patients, but osteoporosis is a common feature of hyperparathyroidism and predominantly affects cortical bone (e.g. distal radius) more than trabecular bone (e.g. vertebral bodies).
Matthew E Fenech MD MRCP is a BHF Clinical Research Fellow in Diabetes and Endocrinology at the University of East Anglia, Norwich, UK. Competing interests: none declared.
Diagnosis and investigations
Jeremy JO Turner DPhil FRCP is a Consultant Endocrinologist at the Norfolk and Norwich University Hospitals, Norwich, UK. Competing interests: none declared.
MEDICINE 41:10
Elevated or inappropriately ‘normal’ plasma PTH with elevated serum calcium (corrected for serum albumin concentration) is
573
Ó 2013 Published by Elsevier Ltd.
CALCIUM AND BONE
PHPT,8 and may drive the hyperparathyroid state, increasing skeletal disease activity in PHPT.9 An assessment of vitamin D status should therefore be performed whenever calcium or PTH biochemistry are abnormal. Elevated PTH with normal calcium, so-called normocalcaemic hyperparathyroidism, is an increasingly common biochemical finding; it is diagnosed by excluding causes of secondary hyperparathyroidism, such as vitamin D deficiency and renal disease, and may represent ‘early’ PHPT before serum calcium has had time to rise.10 However, its natural history is not well described.
Aetiology of primary hyperparathyroidism Cause
Proportion of PHPT cases
Single parathyroid adenoma Multiple parathyroid adenomata; four-gland hyperplasia Parathyroid carcinoma
80e85% 15e20% <0.5%
Table 1
Management almost diagnostic of PHPT (see Figure 1). The exception is familial hypocalciuric hypercalcaemia (FHH), which can mimic the serum biochemistry of PHPT and is distinguishable only by urine biochemistry. FHH is an autosomal dominant condition caused by inactivating mutations in the calcium-sensing receptor gene. It is characterized by a modest increase in serum calcium with an inappropriately normal plasma PTH (slight elevation in 5e10% of patients). The calcium:creatinine clearance ratio is used to distinguish PHPT from FHH. This ratio is calculated from simultaneous measurements of urine and serum calcium and creatinine concentrations. A value of less than 0.01 is indicative of FHH. The interaction of PHPT with vitamin D deficiency has received much attention. Vitamin D deficiency may mask hypercalcaemic
Surgery is the only curative treatment for PHPT, but is not appropriate in all patients; the potential benefits must be weighed against the risks in each case. This process has been simplified by the publication of guidelines from the Third International Workshop on the management of asymptomatic primary hyperparathyroidism (Table 2). However, these guidelines do not apply in the familial PHPT syndromes described above.
Surgery Surgery is indicated in all symptomatic patients and asymptomatic patients with evidence of end-organ damage, specifically: impaired renal function age under 50 years (as they are the most likely to progress)
Investigation of hypercalcaemia High calcium (on two occasions)
Ensure no drug causes (e.g. thiazides, lithium) Normal renal function
Low
Check PTH
Malignancy (most common in hospital setting) Multiple myeloma Bony metastases Humoral hypercalcaemia
Normal
Sarcoidosis (high levels of 1,25-dihydroxyvitamin D lead to increased gastrointestinal calcium absorption) and other granulomatous disease
High
Measure calcium:creatinine clearance ratio
Vitamin D toxicity Milk–alkali syndrome
<0.01
>0.01
Familial hypocalciuric hypercalcaemia
Primary hyperparathyroidism
Addison’s disease High-turnover bone disease with immobilization • Paget’s disease • Thyrotoxicosis Vitamin A toxicity PTH, parathyroid hormone.
Figure 1
MEDICINE 41:10
574
Ó 2013 Published by Elsevier Ltd.
CALCIUM AND BONE
below 60 ml/minute per 1.73 m2 is now stronger, following the publication of a study showing poorer bone health with worsening renal function in PHPT.13
2009 Third International Workshop on the management of asymptomatic primary hyperparathyroidism guidelines
Choice of surgery: the standard operation has been full neck exploration, with identification of all four glands. However, minimally invasive surgery is now performed in many centres. If technetium sestamibi scanning (Figure 2) and ultrasonography show an adenoma in the same location (i.e. are ‘concordant’), a localized surgical approach, under local anaesthetic, with or without intraoperative PTH monitoring, may be used.14 Patients in whom the imaging findings are non-concordant, who have multi-gland disease or who have already undergone surgery are generally not candidates for minimally invasive surgery. Recurrent PHPT and cases complicated by ectopic parathyroid adenoma (mediastinal, intrathyroid, lateral neck and retrooesophageal) require more extensive preoperative imaging that may include magnetic resonance imaging, computed tomography, angiography and selective venous sampling. Patients with four-gland hyperplasia are treated with subtotal or total parathyroidectomy, followed by medical treatment for hypoparathyroidism. Total parathyroidectomy and surgical reimplantation of parathyroid tissue in the forearm is an alternative still practised in some centres.
Indications for surgery in primary hyperparathyroidism Symptomatic Asymptomatic C Serum calcium >0.25 mmol/litre above upper limit of normal C Creatinine clearance reduced to <60 ml/minute C Bone mineral density T score < 2.5 at any site and/or previous fragility fracture C Age <50 years C Patients in whom medical surveillance is not practical or desired
C C C
Follow-up of primary hyperparathyroidism managed conservatively Serum calcium: annually Serum creatinine: annually Bone mineral density: 1e2-yearly (hip, spine, forearm)
Table 2
reduced bone mineral density (BMD), T score less than 2.5. Results post-surgery show an increase in BMD11 and reduced fracture risk.12 Furthermore, the evidence favouring surgical treatment of PHPT when calculated creatinine clearance drops
Figure 2 Technicium (99mTc) sestamibi scan showing a persistent focus of tracer uptake in the region of the lower pole of the right lobe of thyroid in keeping with a parathyroid adenoma (Image courtesy of Dr D Pawaroo, Norfolk & Norwich University Hospital, Norwich, UK).
MEDICINE 41:10
575
Ó 2013 Published by Elsevier Ltd.
CALCIUM AND BONE
2 Pannett AA, Kennedy AM, Turner JJ, et al. Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. Clin Endocrinol (Oxf) 2003; 58: 639e46. 3 Carpten JD, Robbins CM, Villablanca A, et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet 2002; 32: 676e80. 4 Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 2012; 97: 2990e3011. 5 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: 1687e92. 6 Ambrogini E, Cetani F, Cianferotti L, et al. Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin Endocrinol Metab 2007; 92: 3114e21. 7 Farahnak P, Ring M, Caidahl K, Farnebo LO, Eriksson MJ, Nilsson IL. Cardiac function in mild primary hyperparathyroidism and the outcome after parathyroidectomy. Eur J Endocrinol 2010; 163: 461e7. 8 Bilezikian JP. Primary hyperparathyroidism. Endoc Pract 2012; 18: 781e90. 9 Stein EM, Dempster DW, Udesky J, et al. Vitamin D deficiency influences histomorphometric features of bone in primary hyperparathyroidism. Bone 2011; 48: 557e61. 10 Cusano NE, Silverberg SJ, Bilezikian JP. Normocalcaemic primary hyperparathyroidism. J Clin Densitom 2013; 16: 33e9. 11 Sankaran S, Gamble G, Bolland M, et al. Skeletal effects of interventions in mild primary hyperparathyroidism: a meta-analysis. J Clin Endocrinol Metab 2010; 95: 1653e62. 12 Vanderwalde LH, Liu ILA, O’Connell TX, et al. The effect of parathyroidectomy on bone fracture risk in patients with primary hyperparathyroidism. Arch Surg 2006; 141: 885e91. 13 Walker MD, Dempster DW, McMahon DJ, et al. Effect of renal function on skeletal health in primary hyperparathyroidism. J Clin Endocrinol Metab 2012; 97: 1501e7. 14 Udelsman R, Lin Z, Donovan P. The superiority of minimally invasive parathyroidectomy based on 1650 consecutive patients with primary hyperparathyroidism. Ann Surg 2011; 253: 585e91. 15 Peacock M, Bilezikian JP, Klassen PS, et al. Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2005; 90: 135e41.
Complications: postoperative transient hypoparathyroidism may develop in up to 70% of patients, as a consequence of suppression of the remaining glands. This usually resolves within 1 week but may require oral calcium supplements. More severe hypocalcaemia may arise from ‘hungry bones’; it occurs in patients with pre-existing bone disease and may require intravenous calcium to correct the hypocalcaemia. Permanent hypoparathyroidism is rare unless total parathyroidectomy has been performed. These patients require life-long calcium supplements and 1a-hydroxylated vitamin D metabolites.
Medical management In patients with hyperparathyroidism who have only moderately elevated serum calcium, general advice includes ensuring adequate fluid intake and normal dietary calcium (1000e1200 mg/day) and vitamin D (400e800 IU/day) intake, and avoiding thiazide diuretics. Regular monitoring with annual serum calcium, annual serum creatinine and 1e2-yearly BMD measurements is recommended (Table 2). About 25% of PHPT patients managed conservatively for 10 years develop an indication for surgery; the rest remain well. However, fracture risk may be higher in this group12 and operation appears to reduce this. Accordingly, in recent years there has been a shift of emphasis in the literature favouring parathyroidectomy in an increasing proportion of such cases. Patients with severe hyperparathyroidism with symptomatic hypercalcaemia require large volumes of intravenous fluid (e.g. sodium chloride 0.9%, 3e6 litres over the first 24 hours). Once the patient is adequately hydrated, a loop diuretic may be added to encourage calciuresis. Administration of intravenous bisphosphonate (e.g. disodium pamidronate, 30e90 mg or zoledronic acid 4 mg) results in a decline in serum calcium over 3e5 days, but should be avoided if surgery is imminent because bisphosphonates can lead to profound postoperative hypocalcaemia. Antiresorptive agents in PHPT managed conservatively: studies of alendronic acid in PHPT show an increase in BMD at 2 years in the lumbar spine, with lesser gains at the hip and radius. Calcimimetic agents in PHPT managed conservatively: cinacalcet is a calcimimetic agent that increases the sensitivity of calciumsensing receptors to extracellular calcium, thereby reducing PTH secretion directly. Along with its licence for the management of secondary hyperparathyroidism in renal disease and for the management of hypercalcaemia in parathyroid carcinoma, it has recently been licensed for use in PHPT when parathyroidectomy is inappropriate. In this situation, cinacalcet reduces calcium and PTH, but produces no change in BMD at 12 months.15 A
FURTHER READING AACE/AAES Task Force on Primary Hyperparathyroidism. The American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Pract 2005; 11: 49e54. Bilezikian JP, Brandi ML, Rubin M, et al. Primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features. J Intern Med 2005; 257: 6e17. Bilezikian JP, Khan AA, Potts JT, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab 2009; 94: 335e9.
REFERENCES 1 Turner JJ, Leotlela PD, Pannett AA, et al. Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 2002; 87: 2688e93.
MEDICINE 41:10
576
Ó 2013 Published by Elsevier Ltd.
Hypercalcaemia and primary hyperparathyroidism
What’s new? C
Matthew E Fenech Jeremy JO Turner
Abstract Hypercalcaemia is most commonly caused by primary hyperparathyroidism (PHPT) or malignancy. PHPT is common, affects more women than men, and is usually due to a solitary parathyroid adenoma. Nowadays, the most common presentation is an incidental finding on blood testing. The only curative treatment is parathyroidectomy. In 2009 the Third International Workshop on the management of asymptomatic primary hyperparathyroidism updated their guidance on management of asymptomatic PHPT. They recommend surgery in: all symptomatic patients; asymptomatic patients with hypercalcaemia above the upper limit of the reference range by more than 0.25 mmol/litre, evidence of end-organ damage, including impaired renal function, and reduced bone mineral density; and patients under 50 years old. In other patients, conservative management with regular monitoring is an acceptable management strategy. Defining ‘asymptomatic’ is not always easy and there is growing awareness of the prevalence of reduced quality-of-life scores among patients with ‘asymptomatic’ PHPT, but there is a lack of definitive evidence showing benefit in these domains following parathyroidectomy. Therefore, careful clinical decision-making is required in this group of patients.
C
C
C
C
C
The guidelines updated in 2009 by the Third International Workshop on the management of asymptomatic primary hyperparathyroidism (PHPT), on which groups of patients with asymptomatic PHPT should undergo parathyroidectomy, now have a firmer evidence base, particularly with respect to the sequelae of reduced renal function on skeletal disease in PHPT, and regarding improvements in bone mineral density and fracture risk following parathyroidectomy There is still a role for clinical judgement when assessing the risks and benefits of parathyroidectomy in the ‘no indication for surgery’ group, as emphasized by the American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons in their position statement on the diagnosis and management of primary hyperparathyroidism published in 2005 Guidelines for the treatment of PHPT in MEN-1 were released in 2012 There is a growing recognition of the multiple ways in which vitamin D deficiency and PHPT can interact Where it is available, and when imaging results concur, minimally invasive parathyroidectomy is becoming the preferred surgical option The calcimimetic, cinacalcet, is now licensed for use in PHPT where surgery is inappropriate, along with its original licence for use in secondary hyperparathyroidism in chronic renal disease and for parathyroid carcinoma
Keywords cinacalcet; hypercalcaemia; parathyroidectomy; primary hyperparathyroidism; vitamin D Guidelines for the management of PHPT and other clinical features in MEN-1 have been published recently.4 Hypercalcaemia due to other causes (Figure 1) is distinguished from PHPT by suppressed PTH concentration.
Aetiology Of the numerous causes of hypercalcaemia, primary hyperparathyroidism (PHPT) is the most common in outpatient settings and malignancy is most common amongst inpatients. PHPT is characterized by hypercalcaemia with elevated or inappropriately normal concentrations of parathyroid hormone (PTH) and elevated urinary calcium excretion. The prevalence is 1e3/1000. It is more common in women (3:1) and most commonly presents after the age of 50 years. The main causes of PHPT are outlined in Table 1. PHPT is usually sporadic, but may be associated with inherited syndromes, most commonly multiple endocrine neoplasia (MEN) type 1 and type 2,1 familial isolated hyperparathyroidism2 and hyperparathyroidismejaw tumour syndrome.3 These inherited forms tend to present at a younger age.
Clinical features Patients are commonly asymptomatic at diagnosis, with serum calcium less than 0.25 mmol/litre above the reference range. Classical symptoms include polyuria, polydipsia, depression, peptic ulcer disease, musculoskeletal aches and pains and renal colic (‘moans, bones, stones and groans’). Some reports have linked asymptomatic PHPT to reduced quality-of-life scores but this does not consistently improve after parathyroidectomy.5,6 Likewise, although an association of PHPT with hypertension has been described, it is not thought consistently to improve following parathyroidectomy.7 Features of end-organ damage include osteoporosis, osteitis fibrosa cystica, nephrolithiasis and nephrocalcinosis. Classical skeletal changes (Brown tumours, osteitis fibrosa cystica) occur in fewer than 2% of patients, but osteoporosis is a common feature of hyperparathyroidism and predominantly affects cortical bone (e.g. distal radius) more than trabecular bone (e.g. vertebral bodies).
Matthew E Fenech MD MRCP is a BHF Clinical Research Fellow in Diabetes and Endocrinology at the University of East Anglia, Norwich, UK. Competing interests: none declared.
Diagnosis and investigations
Jeremy JO Turner DPhil FRCP is a Consultant Endocrinologist at the Norfolk and Norwich University Hospitals, Norwich, UK. Competing interests: none declared.
MEDICINE 41:10
Elevated or inappropriately ‘normal’ plasma PTH with elevated serum calcium (corrected for serum albumin concentration) is
573
Ó 2013 Published by Elsevier Ltd.
CALCIUM AND BONE
PHPT,8 and may drive the hyperparathyroid state, increasing skeletal disease activity in PHPT.9 An assessment of vitamin D status should therefore be performed whenever calcium or PTH biochemistry are abnormal. Elevated PTH with normal calcium, so-called normocalcaemic hyperparathyroidism, is an increasingly common biochemical finding; it is diagnosed by excluding causes of secondary hyperparathyroidism, such as vitamin D deficiency and renal disease, and may represent ‘early’ PHPT before serum calcium has had time to rise.10 However, its natural history is not well described.
Aetiology of primary hyperparathyroidism Cause
Proportion of PHPT cases
Single parathyroid adenoma Multiple parathyroid adenomata; four-gland hyperplasia Parathyroid carcinoma
80e85% 15e20% <0.5%
Table 1
Management almost diagnostic of PHPT (see Figure 1). The exception is familial hypocalciuric hypercalcaemia (FHH), which can mimic the serum biochemistry of PHPT and is distinguishable only by urine biochemistry. FHH is an autosomal dominant condition caused by inactivating mutations in the calcium-sensing receptor gene. It is characterized by a modest increase in serum calcium with an inappropriately normal plasma PTH (slight elevation in 5e10% of patients). The calcium:creatinine clearance ratio is used to distinguish PHPT from FHH. This ratio is calculated from simultaneous measurements of urine and serum calcium and creatinine concentrations. A value of less than 0.01 is indicative of FHH. The interaction of PHPT with vitamin D deficiency has received much attention. Vitamin D deficiency may mask hypercalcaemic
Surgery is the only curative treatment for PHPT, but is not appropriate in all patients; the potential benefits must be weighed against the risks in each case. This process has been simplified by the publication of guidelines from the Third International Workshop on the management of asymptomatic primary hyperparathyroidism (Table 2). However, these guidelines do not apply in the familial PHPT syndromes described above.
Surgery Surgery is indicated in all symptomatic patients and asymptomatic patients with evidence of end-organ damage, specifically: impaired renal function age under 50 years (as they are the most likely to progress)
Investigation of hypercalcaemia High calcium (on two occasions)
Ensure no drug causes (e.g. thiazides, lithium) Normal renal function
Low
Check PTH
Malignancy (most common in hospital setting) Multiple myeloma Bony metastases Humoral hypercalcaemia
Normal
Sarcoidosis (high levels of 1,25-dihydroxyvitamin D lead to increased gastrointestinal calcium absorption) and other granulomatous disease
High
Measure calcium:creatinine clearance ratio
Vitamin D toxicity Milk–alkali syndrome
<0.01
>0.01
Familial hypocalciuric hypercalcaemia
Primary hyperparathyroidism
Addison’s disease High-turnover bone disease with immobilization • Paget’s disease • Thyrotoxicosis Vitamin A toxicity PTH, parathyroid hormone.
Figure 1
MEDICINE 41:10
574
Ó 2013 Published by Elsevier Ltd.
CALCIUM AND BONE
below 60 ml/minute per 1.73 m2 is now stronger, following the publication of a study showing poorer bone health with worsening renal function in PHPT.13
2009 Third International Workshop on the management of asymptomatic primary hyperparathyroidism guidelines
Choice of surgery: the standard operation has been full neck exploration, with identification of all four glands. However, minimally invasive surgery is now performed in many centres. If technetium sestamibi scanning (Figure 2) and ultrasonography show an adenoma in the same location (i.e. are ‘concordant’), a localized surgical approach, under local anaesthetic, with or without intraoperative PTH monitoring, may be used.14 Patients in whom the imaging findings are non-concordant, who have multi-gland disease or who have already undergone surgery are generally not candidates for minimally invasive surgery. Recurrent PHPT and cases complicated by ectopic parathyroid adenoma (mediastinal, intrathyroid, lateral neck and retrooesophageal) require more extensive preoperative imaging that may include magnetic resonance imaging, computed tomography, angiography and selective venous sampling. Patients with four-gland hyperplasia are treated with subtotal or total parathyroidectomy, followed by medical treatment for hypoparathyroidism. Total parathyroidectomy and surgical reimplantation of parathyroid tissue in the forearm is an alternative still practised in some centres.
Indications for surgery in primary hyperparathyroidism Symptomatic Asymptomatic C Serum calcium >0.25 mmol/litre above upper limit of normal C Creatinine clearance reduced to <60 ml/minute C Bone mineral density T score < 2.5 at any site and/or previous fragility fracture C Age <50 years C Patients in whom medical surveillance is not practical or desired
C C C
Follow-up of primary hyperparathyroidism managed conservatively Serum calcium: annually Serum creatinine: annually Bone mineral density: 1e2-yearly (hip, spine, forearm)
Table 2
reduced bone mineral density (BMD), T score less than 2.5. Results post-surgery show an increase in BMD11 and reduced fracture risk.12 Furthermore, the evidence favouring surgical treatment of PHPT when calculated creatinine clearance drops
Figure 2 Technicium (99mTc) sestamibi scan showing a persistent focus of tracer uptake in the region of the lower pole of the right lobe of thyroid in keeping with a parathyroid adenoma (Image courtesy of Dr D Pawaroo, Norfolk & Norwich University Hospital, Norwich, UK).
MEDICINE 41:10
575
Ó 2013 Published by Elsevier Ltd.
CALCIUM AND BONE
2 Pannett AA, Kennedy AM, Turner JJ, et al. Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. Clin Endocrinol (Oxf) 2003; 58: 639e46. 3 Carpten JD, Robbins CM, Villablanca A, et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet 2002; 32: 676e80. 4 Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 2012; 97: 2990e3011. 5 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: 1687e92. 6 Ambrogini E, Cetani F, Cianferotti L, et al. Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin Endocrinol Metab 2007; 92: 3114e21. 7 Farahnak P, Ring M, Caidahl K, Farnebo LO, Eriksson MJ, Nilsson IL. Cardiac function in mild primary hyperparathyroidism and the outcome after parathyroidectomy. Eur J Endocrinol 2010; 163: 461e7. 8 Bilezikian JP. Primary hyperparathyroidism. Endoc Pract 2012; 18: 781e90. 9 Stein EM, Dempster DW, Udesky J, et al. Vitamin D deficiency influences histomorphometric features of bone in primary hyperparathyroidism. Bone 2011; 48: 557e61. 10 Cusano NE, Silverberg SJ, Bilezikian JP. Normocalcaemic primary hyperparathyroidism. J Clin Densitom 2013; 16: 33e9. 11 Sankaran S, Gamble G, Bolland M, et al. Skeletal effects of interventions in mild primary hyperparathyroidism: a meta-analysis. J Clin Endocrinol Metab 2010; 95: 1653e62. 12 Vanderwalde LH, Liu ILA, O’Connell TX, et al. The effect of parathyroidectomy on bone fracture risk in patients with primary hyperparathyroidism. Arch Surg 2006; 141: 885e91. 13 Walker MD, Dempster DW, McMahon DJ, et al. Effect of renal function on skeletal health in primary hyperparathyroidism. J Clin Endocrinol Metab 2012; 97: 1501e7. 14 Udelsman R, Lin Z, Donovan P. The superiority of minimally invasive parathyroidectomy based on 1650 consecutive patients with primary hyperparathyroidism. Ann Surg 2011; 253: 585e91. 15 Peacock M, Bilezikian JP, Klassen PS, et al. Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2005; 90: 135e41.
Complications: postoperative transient hypoparathyroidism may develop in up to 70% of patients, as a consequence of suppression of the remaining glands. This usually resolves within 1 week but may require oral calcium supplements. More severe hypocalcaemia may arise from ‘hungry bones’; it occurs in patients with pre-existing bone disease and may require intravenous calcium to correct the hypocalcaemia. Permanent hypoparathyroidism is rare unless total parathyroidectomy has been performed. These patients require life-long calcium supplements and 1a-hydroxylated vitamin D metabolites.
Medical management In patients with hyperparathyroidism who have only moderately elevated serum calcium, general advice includes ensuring adequate fluid intake and normal dietary calcium (1000e1200 mg/day) and vitamin D (400e800 IU/day) intake, and avoiding thiazide diuretics. Regular monitoring with annual serum calcium, annual serum creatinine and 1e2-yearly BMD measurements is recommended (Table 2). About 25% of PHPT patients managed conservatively for 10 years develop an indication for surgery; the rest remain well. However, fracture risk may be higher in this group12 and operation appears to reduce this. Accordingly, in recent years there has been a shift of emphasis in the literature favouring parathyroidectomy in an increasing proportion of such cases. Patients with severe hyperparathyroidism with symptomatic hypercalcaemia require large volumes of intravenous fluid (e.g. sodium chloride 0.9%, 3e6 litres over the first 24 hours). Once the patient is adequately hydrated, a loop diuretic may be added to encourage calciuresis. Administration of intravenous bisphosphonate (e.g. disodium pamidronate, 30e90 mg or zoledronic acid 4 mg) results in a decline in serum calcium over 3e5 days, but should be avoided if surgery is imminent because bisphosphonates can lead to profound postoperative hypocalcaemia. Antiresorptive agents in PHPT managed conservatively: studies of alendronic acid in PHPT show an increase in BMD at 2 years in the lumbar spine, with lesser gains at the hip and radius. Calcimimetic agents in PHPT managed conservatively: cinacalcet is a calcimimetic agent that increases the sensitivity of calciumsensing receptors to extracellular calcium, thereby reducing PTH secretion directly. Along with its licence for the management of secondary hyperparathyroidism in renal disease and for the management of hypercalcaemia in parathyroid carcinoma, it has recently been licensed for use in PHPT when parathyroidectomy is inappropriate. In this situation, cinacalcet reduces calcium and PTH, but produces no change in BMD at 12 months.15 A
FURTHER READING AACE/AAES Task Force on Primary Hyperparathyroidism. The American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Pract 2005; 11: 49e54. Bilezikian JP, Brandi ML, Rubin M, et al. Primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features. J Intern Med 2005; 257: 6e17. Bilezikian JP, Khan AA, Potts JT, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab 2009; 94: 335e9.
REFERENCES 1 Turner JJ, Leotlela PD, Pannett AA, et al. Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 2002; 87: 2688e93.
MEDICINE 41:10
576
Ó 2013 Published by Elsevier Ltd.