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Asymptomatic primary hyperparathyroidism: the case for conservative management S. Posen Emeritus Professor of Medicine, University of Sydney, Consulting Physician, Royal North Shore Hospital, St Leonards, NSW
Standard textbooks of medicine and endocrinology fail to emphasise three major features of primary hyperparathyroidism: (1) The ‘benign’ and ‘accelerated’ forms of the disease’ differ so greatly in their clinical presentations, biochemical findings and prognosis that they almost constitute two separate ‘entities’ (Table 1). Remarkably, very few cases convert from the mild to the severe form, even over long periods of observation.2 (2) Spontaneous remissions of biochemical abnormalities are sometimes seen in patients with the mild form of the d i ~ e a s e(3) . ~ The majority of hyperparathyroid patients are not healthy, young individuals, but middle aged and elderly women (Figure 1). Some of these patients are physically and emotionally frail and suffer from symptoms that cannot by any stretch of the imagination be linked to hyperparathyroidism. There is no doubt that patients with the ‘accelerated’ form of primary hyperparathyroidism (who currently constitute less than 10% of the hyperparathyroid population) require parathyroidectomy. The situation is less clear in relation to the other 90%. Many patients with mild primary hyperparathyroidism appear to suffer no ill effects through being left untreated and there is continuing controversy as to whether such patients benefit from parathyroidectomy,2 especially as the operation, even in major centres, is not entirely free of m ~ r b i d i t y . ~ Palmer et al. showed that untreated hypercalcaemia due to presumptive hyperparathyroidism is associated with a diminished life expectancy in patients under the age of 70. However, there are no data to show that parathyroidectomy improves this life expectancy. In a retrospective study comparing operated and unoperated patients there was no difference between the survival of the two groups.* Hypertension is present in some 40% of patients with primary hyperparathyroidi~m.~-~ There are no data to show that in patients with the mild form of the disease, parathyroidectomy lowers blood pressure or improves creatinine clearance in the long term.
Indeed, several ~ t u d i e sshowed ~ - ~ that at follow-up, two to six years after the decision to operate or not to operate, hypertension persisted amongst operated as well as amongst unoperated patients. The presence of renal calculi is generally held to be an indication for parathyroidectomy. However, while a successful operation reduces urine calcium excretioq2 there are no controlled studies to indicate it diminishes the rate of stone formation. On the contrary, the numbers of stone ‘episodes’ (colic, haematuria, passage of stone, surgical or endoscopic intervention) were similar in operated and unoperated patients.2 It is well known that in cross-sectional studies, hyperparathyroid patients have a lower forearm mineral content than age-matched controls. Moreover, in a longitudinal study of hyperparathyroid patients Warner et aLbfound that parathyroidectomy led to an increase in forearm bone mineral content while unoperated patients continued to lose bone. However, the differences between the two groups were slight and most of the gain in bone mineral in the operated patients occurred in the first year. There have been valiant attempts over the years particularly by the Uppsala group to show that ‘neuromuscular’ and psychiatric symptoms improve after parathyroidect~my.~,~ Joborn et aZ. in a semiquantitative study, found that psychiatric symptoms were more common in a group of incidentally discovered hyperparathyroid patients than in a group of controls and that these symptoms improved after parathyroidectomy. This study by Joborn et al.’ is flawed for two reasons: (1) It ignores the powerful placebo effect of a surgical operation (2) As Joborn et aL7 themselves point out, a group of patients with presumptive hyperparathyroidism who were treated conservatively had psychiatric symptom scores which were not significantly different from those of the controls. One therefore wonders whether in the patients described by Joborn et aL7 the decision to operate was
Reprinr requests to: Dr S. Posen, North Shore Medical Centre, 66 Pacific Highway, St Leonards, NSW 2065, Australia. HPT: CONSERVATIVE MANAGEMENT
Aust NZ J Med 1992; 22
161
Hyperparathyroidism RNSH 1983 - 1986
TABLE 1 Two Forms of Primary Hyperparathyroidism
Presentation
Serum calcium Serum PTH
Serum alkaline phosphatase Prevalence Need for surgery
'Benign'
'Accelerated'
No symptoms Non-specific symptoms Renal calculi 3.0 mmol/L or less Less than 3 times upper limit of reference range Normal
Dehydration Classical skeletal lesions 3.1 mmol/L or more 3 times upper limit of reference range or greater Elevated
Males CN
1961
Qaince
> 90% Questionable
< 10% Definite
influenced, at least in part, by the patients' persistent non-organic complaints. In other studies, Joborn et ~ 1showed . ~ that muscle hnction (as assessed by objective criteria) was impaired in patients with primary hyperparathyroidism and that muscle strength improved after parathyroide~tomy.~ Jansson et al. l o recently conducted a thorough study into muscle function before and after parathyroidectomy. Using kinetic, morphological, enzymatic and electrophysiological methods Jansson er al. lo showed that parathyroidectomy indeed caused a slight but significant increase in muscle strength. However, a group of patients undergoing thyroid surgery also showed such a postoperative increase.'O The work of Jansson et al.1° throws considerable doubt on 'before and after' parathyroidectomy studies purporting to show subtle changes in neurologic or psychiatric parameters. Joborn et al." even went so far as to perform preand postoperative lumbar punctures on patients with primary hyperparathyroidism in an attempt to demonstrate changes in the concentrations of monoamine metabolites of the cerebrospinal fluid. Joborn et al." actually found a reduction in CSF 5-hydroxyindoleacetic acid concentrations in hyperparathyroidism, with a postoperative rise. The significance of these findings is currently obscure and their relevance to clinical medicine problematical. There are no data relating to pre- and postoperative monoamine metabolites in the CSF of patients undergoing operations other than parathyroidectomy. Potts'* formulated four reservations concerning the conservative management of hyperparathyroid patients. (1) Might the patients lose more bone than age-matched controls? (2) Might the hyperparathyroid 162 Aust NZ J Med
-
24)
0Females (N = 79)
19511060
19411950
10311840
nI I
n
19211930
19111920
1910
orbefae
DATE OF BIRTH
Figure I : The age- and sex-distribution of surgically proven hyperparathyroidism amongst 103 patients treated at Royal North Shore Hospital, Sydney, over a period of four years. An additional 8 1 hyperparathyroid patients seen at this hospital over the same period were not submitted to neck exploration because of age, associated disorders or unwillingness to undergo a surgical operation. The largest age group (patients born 1921-1930) consisted of five men and 31 women while the next largest group (1911-1920) comprised five men and 16 women.
state aggravate hypertension? (3)Might renal function deteriorate? (4)Might there be subtle parathyroid hormone-induced or calcium-induced psychiatric changes? More importantly for the patient and the physician, are these undesirable trends likely to be reversed by parathyroidectomy!. Long-term controlled studies to answer these questions are not available. The recent concensus conference at B e t h e ~ d a 'therefore ~ came up with a series of compromise recommendations. In 'young' patients surgery is usually recommended. In patients with 'severe' hypercalcaemia surgery is usually recommended. Renal stones are taken as an indication for surgery - not because there is evidence that parathyroid surgery reduces the formation, the passage or the complications of renal calculi, but because it seems reasonable to reduce urinary calcium excretion in such patients. A low bone density constitutes an indication for parathyroidectomy. There is evidence6 that the bone mineral gain after surgery (both in absolute and in percentage terms) is significantly greater in patients with low baseline values. Indeed, the recent concensus conference13reached the conclusion that 'all patients with primary hyperparathyroidism should be considered candidates for surgery'. All of this makes good sense in the case of a young and otherwise healthy woman of 35 with a serum calcium concentration of 3.4 mmol/L. However, this 1992; 22
POSEN
description does not fit the majority of hyperparathyroid patients who are older women with serum calcium values around 2.7 mmollL. Such individuals frequently suffer from cardiovascular, pulmonary, neurological and/or non-organic disorders and there is little evidence that a reduction of serum calcium from 2.7 mmol/L to 2.4 mmol/L will improve the life expectancy or the quality of life of these individuals. On the other hand, there is now sufficient experience, worldwide, indicating that most of these patients will not come to any harm by a conservative approach.. References 1. Lloyd HM. Primary hyperparathyroidism: an analysis of the role of the parathyroid tumor. Medicine (Baltimore) 1968; 47: 53-71. 2. Posen S, Clifton-Bligh P, Reeve T, Wagstaffe C, Wilkinson M. Is parathyroidectomyof benefit in primary hyperparathyroidwm? Quart J Med 1985; 54: 241-51. 3. Lind L, Jacobsson S , Palmer M, Lithell H, Wengle B, Ljunghall S. Cardiovascular risk factors in primary hyperparathyroidism: a 15 year follow up of operated and unoperated cases. J Internal Med 1991; 230: 29-35. 4. Lafferty FW,Hubay CA. Primary hyperparathyroidism: a review of the long term surgical and non-surgical morbidities as a basis for a rational approach to treatment. Arch Int Med 1989; 149: 789-96.
HPT: CONSERVATIVE MANAGEMENT
5. Palmer M, Adami HO, Bergstrom R, Jakobsson S, Akerstrom G, Ljunghall S. Survival and renal function in untreated hypercalcaemia. Lancet 1987; i: 59-62. 6. Warner J, Clifton-Bligh P, Posen S, McElduff A, Delbridge L, Reeve T. Longitudinal changes in forearm bone mineral content in primary hyperparathyroidism. J Bone Min Res 1991; ~ ( S U P P2):~ S91495. 7. Joborn C, Hetta J, Lind L, Rastad J, Akerstrom G, Ljunghall S. Self-rated psychiatric symptoms in patients operated on because of primary hyperparathyroidism and in patients with long-standing mild hypercalcemia. Surgery 1989; 105: 72-8. 8. Joborn C, Rastad J, Stalberg E, Akerstrom G, Ljunghall S. Muscle function in patients with primary hyperparathyroidism. Muscle and Nerve 1989; 12: 87-94. 9. Joborn C, Joborn H, Rastad J, Akerstrom G, Ljunghall S. Maximal isokinetic muscle strength in patients with primary hyperparathyroidism before and after parathyroid surgery. Brit J Surg 1988; 75: 77-80. 10. Jansson S, Grimby G, Hague I, Hedman I, Tisell LE. Muscle structure and function before and after surgery for primary hyperparathyroidism. Eur J Surg 1991; 157: 13-6. 11. Joborn C, Hetta J, Rastad J, Agren H, Akerstrom G, Ljunghall S . Psychiatric symptoms and cerebrospinal monoamine metabolites in primary hyperparathyroidism. Biol Psychiatry 1988; 23: 149-58. 12. Potts JT. Management of asymptomatic hyperparathyroidism. J Clin Endocrinol Metabl 1990; 70: 1489-93. 13. Potts J T (Chairman). Concensus Development Conference Statement. J Bone Min Res 1991; 6 (Suppl 2): S9-Sl3.
Aust NZ J Med 1992; 22
163
Asymptomatic primary hyperparathyroidism: the case for conservative management S. Posen Emeritus Professor of Medicine, University of Sydney, Consulting Physician, Royal North Shore Hospital, St Leonards, NSW
Standard textbooks of medicine and endocrinology fail to emphasise three major features of primary hyperparathyroidism: (1) The ‘benign’ and ‘accelerated’ forms of the disease’ differ so greatly in their clinical presentations, biochemical findings and prognosis that they almost constitute two separate ‘entities’ (Table 1). Remarkably, very few cases convert from the mild to the severe form, even over long periods of observation.2 (2) Spontaneous remissions of biochemical abnormalities are sometimes seen in patients with the mild form of the d i ~ e a s e(3) . ~ The majority of hyperparathyroid patients are not healthy, young individuals, but middle aged and elderly women (Figure 1). Some of these patients are physically and emotionally frail and suffer from symptoms that cannot by any stretch of the imagination be linked to hyperparathyroidism. There is no doubt that patients with the ‘accelerated’ form of primary hyperparathyroidism (who currently constitute less than 10% of the hyperparathyroid population) require parathyroidectomy. The situation is less clear in relation to the other 90%. Many patients with mild primary hyperparathyroidism appear to suffer no ill effects through being left untreated and there is continuing controversy as to whether such patients benefit from parathyroidectomy,2 especially as the operation, even in major centres, is not entirely free of m ~ r b i d i t y . ~ Palmer et al. showed that untreated hypercalcaemia due to presumptive hyperparathyroidism is associated with a diminished life expectancy in patients under the age of 70. However, there are no data to show that parathyroidectomy improves this life expectancy. In a retrospective study comparing operated and unoperated patients there was no difference between the survival of the two groups.* Hypertension is present in some 40% of patients with primary hyperparathyroidi~m.~-~ There are no data to show that in patients with the mild form of the disease, parathyroidectomy lowers blood pressure or improves creatinine clearance in the long term.
Indeed, several ~ t u d i e sshowed ~ - ~ that at follow-up, two to six years after the decision to operate or not to operate, hypertension persisted amongst operated as well as amongst unoperated patients. The presence of renal calculi is generally held to be an indication for parathyroidectomy. However, while a successful operation reduces urine calcium excretioq2 there are no controlled studies to indicate it diminishes the rate of stone formation. On the contrary, the numbers of stone ‘episodes’ (colic, haematuria, passage of stone, surgical or endoscopic intervention) were similar in operated and unoperated patients.2 It is well known that in cross-sectional studies, hyperparathyroid patients have a lower forearm mineral content than age-matched controls. Moreover, in a longitudinal study of hyperparathyroid patients Warner et aLbfound that parathyroidectomy led to an increase in forearm bone mineral content while unoperated patients continued to lose bone. However, the differences between the two groups were slight and most of the gain in bone mineral in the operated patients occurred in the first year. There have been valiant attempts over the years particularly by the Uppsala group to show that ‘neuromuscular’ and psychiatric symptoms improve after parathyroidect~my.~,~ Joborn et aZ. in a semiquantitative study, found that psychiatric symptoms were more common in a group of incidentally discovered hyperparathyroid patients than in a group of controls and that these symptoms improved after parathyroidectomy. This study by Joborn et al.’ is flawed for two reasons: (1) It ignores the powerful placebo effect of a surgical operation (2) As Joborn et aL7 themselves point out, a group of patients with presumptive hyperparathyroidism who were treated conservatively had psychiatric symptom scores which were not significantly different from those of the controls. One therefore wonders whether in the patients described by Joborn et aL7 the decision to operate was
Reprinr requests to: Dr S. Posen, North Shore Medical Centre, 66 Pacific Highway, St Leonards, NSW 2065, Australia. HPT: CONSERVATIVE MANAGEMENT
Aust NZ J Med 1992; 22
161
Hyperparathyroidism RNSH 1983 - 1986
TABLE 1 Two Forms of Primary Hyperparathyroidism
Presentation
Serum calcium Serum PTH
Serum alkaline phosphatase Prevalence Need for surgery
'Benign'
'Accelerated'
No symptoms Non-specific symptoms Renal calculi 3.0 mmol/L or less Less than 3 times upper limit of reference range Normal
Dehydration Classical skeletal lesions 3.1 mmol/L or more 3 times upper limit of reference range or greater Elevated
Males CN
1961
Qaince
> 90% Questionable
< 10% Definite
influenced, at least in part, by the patients' persistent non-organic complaints. In other studies, Joborn et ~ 1showed . ~ that muscle hnction (as assessed by objective criteria) was impaired in patients with primary hyperparathyroidism and that muscle strength improved after parathyroide~tomy.~ Jansson et al. l o recently conducted a thorough study into muscle function before and after parathyroidectomy. Using kinetic, morphological, enzymatic and electrophysiological methods Jansson er al. lo showed that parathyroidectomy indeed caused a slight but significant increase in muscle strength. However, a group of patients undergoing thyroid surgery also showed such a postoperative increase.'O The work of Jansson et al.1° throws considerable doubt on 'before and after' parathyroidectomy studies purporting to show subtle changes in neurologic or psychiatric parameters. Joborn et al." even went so far as to perform preand postoperative lumbar punctures on patients with primary hyperparathyroidism in an attempt to demonstrate changes in the concentrations of monoamine metabolites of the cerebrospinal fluid. Joborn et al." actually found a reduction in CSF 5-hydroxyindoleacetic acid concentrations in hyperparathyroidism, with a postoperative rise. The significance of these findings is currently obscure and their relevance to clinical medicine problematical. There are no data relating to pre- and postoperative monoamine metabolites in the CSF of patients undergoing operations other than parathyroidectomy. Potts'* formulated four reservations concerning the conservative management of hyperparathyroid patients. (1) Might the patients lose more bone than age-matched controls? (2) Might the hyperparathyroid 162 Aust NZ J Med
-
24)
0Females (N = 79)
19511060
19411950
10311840
nI I
n
19211930
19111920
1910
orbefae
DATE OF BIRTH
Figure I : The age- and sex-distribution of surgically proven hyperparathyroidism amongst 103 patients treated at Royal North Shore Hospital, Sydney, over a period of four years. An additional 8 1 hyperparathyroid patients seen at this hospital over the same period were not submitted to neck exploration because of age, associated disorders or unwillingness to undergo a surgical operation. The largest age group (patients born 1921-1930) consisted of five men and 31 women while the next largest group (1911-1920) comprised five men and 16 women.
state aggravate hypertension? (3)Might renal function deteriorate? (4)Might there be subtle parathyroid hormone-induced or calcium-induced psychiatric changes? More importantly for the patient and the physician, are these undesirable trends likely to be reversed by parathyroidectomy!. Long-term controlled studies to answer these questions are not available. The recent concensus conference at B e t h e ~ d a 'therefore ~ came up with a series of compromise recommendations. In 'young' patients surgery is usually recommended. In patients with 'severe' hypercalcaemia surgery is usually recommended. Renal stones are taken as an indication for surgery - not because there is evidence that parathyroid surgery reduces the formation, the passage or the complications of renal calculi, but because it seems reasonable to reduce urinary calcium excretion in such patients. A low bone density constitutes an indication for parathyroidectomy. There is evidence6 that the bone mineral gain after surgery (both in absolute and in percentage terms) is significantly greater in patients with low baseline values. Indeed, the recent concensus conference13reached the conclusion that 'all patients with primary hyperparathyroidism should be considered candidates for surgery'. All of this makes good sense in the case of a young and otherwise healthy woman of 35 with a serum calcium concentration of 3.4 mmol/L. However, this 1992; 22
POSEN
description does not fit the majority of hyperparathyroid patients who are older women with serum calcium values around 2.7 mmollL. Such individuals frequently suffer from cardiovascular, pulmonary, neurological and/or non-organic disorders and there is little evidence that a reduction of serum calcium from 2.7 mmol/L to 2.4 mmol/L will improve the life expectancy or the quality of life of these individuals. On the other hand, there is now sufficient experience, worldwide, indicating that most of these patients will not come to any harm by a conservative approach.. References 1. Lloyd HM. Primary hyperparathyroidism: an analysis of the role of the parathyroid tumor. Medicine (Baltimore) 1968; 47: 53-71. 2. Posen S, Clifton-Bligh P, Reeve T, Wagstaffe C, Wilkinson M. Is parathyroidectomyof benefit in primary hyperparathyroidwm? Quart J Med 1985; 54: 241-51. 3. Lind L, Jacobsson S , Palmer M, Lithell H, Wengle B, Ljunghall S. Cardiovascular risk factors in primary hyperparathyroidism: a 15 year follow up of operated and unoperated cases. J Internal Med 1991; 230: 29-35. 4. Lafferty FW,Hubay CA. Primary hyperparathyroidism: a review of the long term surgical and non-surgical morbidities as a basis for a rational approach to treatment. Arch Int Med 1989; 149: 789-96.
HPT: CONSERVATIVE MANAGEMENT
5. Palmer M, Adami HO, Bergstrom R, Jakobsson S, Akerstrom G, Ljunghall S. Survival and renal function in untreated hypercalcaemia. Lancet 1987; i: 59-62. 6. Warner J, Clifton-Bligh P, Posen S, McElduff A, Delbridge L, Reeve T. Longitudinal changes in forearm bone mineral content in primary hyperparathyroidism. J Bone Min Res 1991; ~ ( S U P P2):~ S91495. 7. Joborn C, Hetta J, Lind L, Rastad J, Akerstrom G, Ljunghall S. Self-rated psychiatric symptoms in patients operated on because of primary hyperparathyroidism and in patients with long-standing mild hypercalcemia. Surgery 1989; 105: 72-8. 8. Joborn C, Rastad J, Stalberg E, Akerstrom G, Ljunghall S. Muscle function in patients with primary hyperparathyroidism. Muscle and Nerve 1989; 12: 87-94. 9. Joborn C, Joborn H, Rastad J, Akerstrom G, Ljunghall S. Maximal isokinetic muscle strength in patients with primary hyperparathyroidism before and after parathyroid surgery. Brit J Surg 1988; 75: 77-80. 10. Jansson S, Grimby G, Hague I, Hedman I, Tisell LE. Muscle structure and function before and after surgery for primary hyperparathyroidism. Eur J Surg 1991; 157: 13-6. 11. Joborn C, Hetta J, Rastad J, Agren H, Akerstrom G, Ljunghall S . Psychiatric symptoms and cerebrospinal monoamine metabolites in primary hyperparathyroidism. Biol Psychiatry 1988; 23: 149-58. 12. Potts JT. Management of asymptomatic hyperparathyroidism. J Clin Endocrinol Metabl 1990; 70: 1489-93. 13. Potts J T (Chairman). Concensus Development Conference Statement. J Bone Min Res 1991; 6 (Suppl 2): S9-Sl3.
Aust NZ J Med 1992; 22
163
