Asymptomatic primary hyperparathyroidism: a surgeon’s perspective A. J. Edis Surgeon, Mount Medical Centre, Perth, WA.
BACKGROUND For many years, primary hyperparathyroidism (HPT) was considered something of a medical curiosity - a rare disease characterised by severe, progressive skeletal gastrointestinal and renal manifestations. This perception changed however, with the introduction and widespread use of efficient, automated methods for multiple biochemical determinations in the mid 1960s. Large reservoirs of relatively asymptomatic patients were revealed in the population in some parts of the world. In the upper mid-west of the United States, for example, the incidence of primary H P T in men over the age of 60 years was found to approach one case per hundred of population per year; and in women in the same age group, it was twice as frequent.’ A similar high prevalence of the disease has been reported in England’ and S ~ e d e n . ~ The incidence of primary H P T in Australia is unknown. From a perusal of the available literature, however, it would appear that case finding falls far short of the figure anticipated from extrapolation of the US and European epidemiologic data. Perhaps this is because indiscriminate ‘routine multi-channel screening’ has never been adopted as standard practice in this country, or perhaps it is because the incidence of primary H P T is truly lower than that in the sunlight-starved climates of the northern US and Europe. Vitamin D has an important role in regulating the synthesis of parathyroid hormone via several feedback 1 0 0 ~ sIn . ~Sweden, there is insufficient sunlight to produce Vitamin D in the skin for almost six months of the year. This results in a relatively common Vitamin D deficiency in the elderly5 which according to Akerstrom et u Z . , ~ could contribute to the high frequency of parathyroid abnormalities and the high prevalence of HPT in that country. Conversely, the high levels of sunlight exposure in Australia presumably ensures a Vitamin D-replete population which may offer some measure of protection against the development of HPT.
Following the introduction of routine multichannel biochemical screening in the US, there was a dramatic increase in the number of operations performed for H P T and cervical exploration was no longer restricted to a few major referral centres with a special interest and expertise in the management of the disease. In the hands of experienced surgeons supported by experienced pathologists, the results of parathyroid surgery continued to be excellent - with a success rate of 95% or better, with negligible mortality and a very low morbidity.’ However, the involvement of surgeons and pathologists who were not fully initiated in the finer points of parathyroid anatomy and pathology was associated with an alarming increase in operative morbidity - especially postoperative hypoparathyroidism.* This prompted a review of the need for operation in all cases of primary H P T (especially those with no apparent symptoms or complications and only minor elevations in serum calcium) and a questioning of the assumption that H P T was a progressive disease in all patient^.^
NATURALHISTORYOFUNTREATED ASYMPTOMATIC HPT A prospective, randomised controlled trial should have been initiated at the outset to demonstrate whether the risks of parathyroidectomy exceeded those of persistent H P T in mild asymptomatic cases. However, this was not done and it is now unlikely that such a study will ever be conducted. Instead, workers from a dozen or so institutions around the world carried out pilot studies to characterise the natural history of untreated primary HPT. Those studies have so far yielded follow-up information from a collective patient group numbering from 750 to 1000 patients.” The quality and quantity of the patient data provided by these studies have been highly variable and follow-up has often been incomplete. Moreover, because different indications were used by surgical intervention, the patient groups cannot be compared readily. Neverthe-
Reprint requests to: Mr A. J. Edis, Suite 42 Mount Medical Centre, 146 Mounts Bay Road, Perth, WA 6000, Australia.
164
Aust NZ J Med 1992; 22
EDIS
- - -. 75 Years
65 Years ---.I
55 Yean
,
45 ........ Yeam
3.0Wative Risk
OP
5
10
I 15
Time after surgery. Years
Figure I : The relative risk of death depending on time after surgery for primary hyperparathyroidism; age at surgery 45-75 years. [Reproduced with permissionfrom Hedback et al. WorldJ Surg
- ---. OP1965
OPWO
- - -. ........ 0~1975
@I980
Relatlve Risk
i
I
0.51
op
5
x)
15
Time after surgery, Years
Figure 2: The relative risk of death after surgery for HPT with four different years of operation. [Reproduced with permission from Hedback et al. WorldJSurg 1991; 15: 399.1
1991; 15: 399.1
less, several conclusions have been drawn from these data: (1) The disease appears to have a non-progressive clinical course in many patients, while in others there may be increasing hypercalcaemia, deterioration in renal function, the development of kidney stones or progressive bone loss. (2) There are no clinical or laboratory criteria that can be used to predict which patients with mild, uncomplicated H P T will go on to develop complications of their disease. (3) Prolonged observation with careful medical follow-up is impracticable in many cases for various psychologic or logistical reasons and the cumulative costs of such surveillance may come to exceed those of initial diagnosis and surgery within a few years. T o evaluate these data and make recommendations concerning management, a Consensus Development Conference on the Diagnosis and Management of Asymptomatic Primary Hyperparathyroidism was convened in October 1990 by the US National Institutes of Health. The Consensus panel concluded that the 'current and acceptable treatment of primary H P T is operative intervention for cure', however, 'conscientious surveillance may be justified in patients whose calcium levels are only mildly elevated and whose renal and bone status are close to normal'." The panel reiterated the recommendation for a randomised multicentre clinical trial to compare operative versus non-operative management of asymptomatic H P T and it also made a plea for further pilot studies to better define the multisystem effects of HPT. NEW DATA ON MORTALITY IN HPT AND THE EFFECT OF SURGERY As if in response to the Consensus panel plea, several recent studies from Scandinavia have provided importHPT: TREATMENT BY SURGERY
ant new information about the natural history of H P T in terms of overall mortality (rather than disease progression) and how this is affected by successful parathyroidectomy . The first of these studies12examined the risk of death in patients with untreated HPT, many of whom had mild to moderate hypercalcaemia, as compared with concurrent age- and sex-matched controls in the normal population. Patients with H P T were found to have a significantly increased mortality (which continued to increase steadily with time), due predominantly to the same causes as in the general population - namely cardiovascular disease (50%) and malignancy (25%). R o n n i - S i ~ l a has ' ~ suggested that this phenomenon may be attributable to premature ageing caused by HPT. The effect of parathyroid surgery on this risk of premature death has now been examined by three independent Scandinavian groups in Hel~inki,'~ in Uppsala,I5 and most recently, in Gothenburg.16 The results have been remarkably consistent and demonstrate convincingly that the risk of death decreases with time after successful parathyroidectomy. The most recent, exacting study by Hedback et al., in Gothenburg, compared the mortality in a group of 896 patients followed up to 33 years (mean: 12.9 years) after successful parathyroidectomy, with individuals of corresponding age and sex in the Swedish population. The relative risk of death was substantially increased in all age groups (being highest in the group aged 55 to 70 years) but it improved progressively with time after operation (Figure 1).For those patients operated most recently (i.e. the 1982 cohort, Figure 2) the mortality rate actually normalised within five years. This new and unprecedented finding is particularly relevant to the present debate about the management of asymptomatic H P T because these patients tended Aust NZ J Med 1992; 22 165
to have disease of less severity and shorter duration. Notwithstanding the usual limitations of retrospective, non-randomised studies, these results are convincing and provide a persuasive argument in favour of offering surgery to all patients with H P T in whom the diagnosis is biochemically secure and who are otherwise fit for operation. The Scandinavian studies also underline the importance of early detection of H P T because they have shown that the earlier the disease is recognised, the more rapid the normalisation of mortality risk after operation. Perhaps there should be more systematic screening for HPT, especially in high risk groups, such as in women over 50 years of age. Of course, if we are going to make a more concerted effort to identify and treat patients with asymptomatic H P T it is imperative that they be treated by an experienced parathyroid surgeon to ensure a high success rate and negligible mortality.’.* These patients will usually have minimally enlarged glands which can be more troublesome to find at operation and which may present the surgeon greater difficulty in differentiating between tiny adenomas and nodular hyperplasia. l7 References 1. Heath H 111, Hodgson SF, Kennedy MA. Primary hyperparathyroidism, incidence, morbidity, and potential economic impact in a community. N Engl J Med 1980; 302: 189. 2. Mundy GR, Cove D H , Fisken R e t al. Primary hyperparathyroidism: changes in the pattern of clinical presentation. Lancet 1980; i: 1317. 3. Christensson T, Hellstrom K, Wengle B er al. Prevalence of hypercalcaemia in a health screening in Stockholm. Acta Med Scand 1976; 200: 131.
166
4. Reichel H, Koeffler HP, Norman AW. The role ofthe vitamin D endocrine system in health and disease. N Engl J Med 1989; 320: 980. 5. Toss G, Almqvist S, Larsson L et al. Vitamin D deficiency in welfare institutions for the aged. Acta Med Scad 1980; 208: 87. 6. Akerstrom G, Rudberg C, Grimelius L er al. Histologic parathyroid abnormalities in an autopsy series. Human Path 1986; 17: 520. 7. Russell CF, Edis AJ. Surgery for primary hyperparathyroidism: experience with 500 consecutive cases and evaluation of the role of surgery in the asymptomatic patient. Br J Surg 1982; 69: 244. 8. Edis AJ, Beahrs OH, van Heerden J et al. ‘Conservative’versus ‘liberal’ approach to parathyroid neck exploration. Surgery 1972; 82: 466. 9. Purnell DC, Smith LH, Scholz DA et al. Primary hvoerDarathvroidism: a urosoective clinical studv. Amer I Med 16?1;’50: 6?0. 10. Potts J T Jr. Management of asymptomatic hyperparathyroidism. J Clin Endocrinal Metab 1990; 70: 1489. 11. Diagnosis and management of asymptomatic primary hyperparathyroidism. Consensus Development Conference Statement. NIH Oct 1990. 12. Palmer M, Adami H-0, Bergstrom R et al. Survival and renal function in persons with untreated hypercalcemia: a populationbased cohort study with 14 years of follow-up. Lancet 1987; i: 59. 13. Ronni-Sivula H. Invited Commentary. World J Surg 1991; 15: 406. 14. Ronni-Sivula H. Causes of death in patients previously operated on four primary hyperparathyroidism. Ann Chir Gynecol 1985; 74: 13. 15. Palmer M, Adami H-0, Bergstrom R et al. Mortality after surgery for primary hyperparathyroidism: a follow-up of 44 1 patients operated on from 1956 to 1979. Surgery 1987; 102: 1. 16. Hedback G, Oden A, Tisell L-E. The influence of surgery on the risk of death in patients with primary hyperparathyroidism. World J Surg 1991; 15: 399. 17. Akerstrorn G, Bergstrom R, Grimelius Let al. Relation between changes in clinical and histopathological features of primary hyperparathyroidism. World J Surg 1986; 10: 696.
Aust NZ J Med 1992; 22
L
.
EDIS
BACKGROUND For many years, primary hyperparathyroidism (HPT) was considered something of a medical curiosity - a rare disease characterised by severe, progressive skeletal gastrointestinal and renal manifestations. This perception changed however, with the introduction and widespread use of efficient, automated methods for multiple biochemical determinations in the mid 1960s. Large reservoirs of relatively asymptomatic patients were revealed in the population in some parts of the world. In the upper mid-west of the United States, for example, the incidence of primary H P T in men over the age of 60 years was found to approach one case per hundred of population per year; and in women in the same age group, it was twice as frequent.’ A similar high prevalence of the disease has been reported in England’ and S ~ e d e n . ~ The incidence of primary H P T in Australia is unknown. From a perusal of the available literature, however, it would appear that case finding falls far short of the figure anticipated from extrapolation of the US and European epidemiologic data. Perhaps this is because indiscriminate ‘routine multi-channel screening’ has never been adopted as standard practice in this country, or perhaps it is because the incidence of primary H P T is truly lower than that in the sunlight-starved climates of the northern US and Europe. Vitamin D has an important role in regulating the synthesis of parathyroid hormone via several feedback 1 0 0 ~ sIn . ~Sweden, there is insufficient sunlight to produce Vitamin D in the skin for almost six months of the year. This results in a relatively common Vitamin D deficiency in the elderly5 which according to Akerstrom et u Z . , ~ could contribute to the high frequency of parathyroid abnormalities and the high prevalence of HPT in that country. Conversely, the high levels of sunlight exposure in Australia presumably ensures a Vitamin D-replete population which may offer some measure of protection against the development of HPT.
Following the introduction of routine multichannel biochemical screening in the US, there was a dramatic increase in the number of operations performed for H P T and cervical exploration was no longer restricted to a few major referral centres with a special interest and expertise in the management of the disease. In the hands of experienced surgeons supported by experienced pathologists, the results of parathyroid surgery continued to be excellent - with a success rate of 95% or better, with negligible mortality and a very low morbidity.’ However, the involvement of surgeons and pathologists who were not fully initiated in the finer points of parathyroid anatomy and pathology was associated with an alarming increase in operative morbidity - especially postoperative hypoparathyroidism.* This prompted a review of the need for operation in all cases of primary H P T (especially those with no apparent symptoms or complications and only minor elevations in serum calcium) and a questioning of the assumption that H P T was a progressive disease in all patient^.^
NATURALHISTORYOFUNTREATED ASYMPTOMATIC HPT A prospective, randomised controlled trial should have been initiated at the outset to demonstrate whether the risks of parathyroidectomy exceeded those of persistent H P T in mild asymptomatic cases. However, this was not done and it is now unlikely that such a study will ever be conducted. Instead, workers from a dozen or so institutions around the world carried out pilot studies to characterise the natural history of untreated primary HPT. Those studies have so far yielded follow-up information from a collective patient group numbering from 750 to 1000 patients.” The quality and quantity of the patient data provided by these studies have been highly variable and follow-up has often been incomplete. Moreover, because different indications were used by surgical intervention, the patient groups cannot be compared readily. Neverthe-
Reprint requests to: Mr A. J. Edis, Suite 42 Mount Medical Centre, 146 Mounts Bay Road, Perth, WA 6000, Australia.
164
Aust NZ J Med 1992; 22
EDIS
- - -. 75 Years
65 Years ---.I
55 Yean
,
45 ........ Yeam
3.0Wative Risk
OP
5
10
I 15
Time after surgery. Years
Figure I : The relative risk of death depending on time after surgery for primary hyperparathyroidism; age at surgery 45-75 years. [Reproduced with permissionfrom Hedback et al. WorldJ Surg
- ---. OP1965
OPWO
- - -. ........ 0~1975
@I980
Relatlve Risk
i
I
0.51
op
5
x)
15
Time after surgery, Years
Figure 2: The relative risk of death after surgery for HPT with four different years of operation. [Reproduced with permission from Hedback et al. WorldJSurg 1991; 15: 399.1
1991; 15: 399.1
less, several conclusions have been drawn from these data: (1) The disease appears to have a non-progressive clinical course in many patients, while in others there may be increasing hypercalcaemia, deterioration in renal function, the development of kidney stones or progressive bone loss. (2) There are no clinical or laboratory criteria that can be used to predict which patients with mild, uncomplicated H P T will go on to develop complications of their disease. (3) Prolonged observation with careful medical follow-up is impracticable in many cases for various psychologic or logistical reasons and the cumulative costs of such surveillance may come to exceed those of initial diagnosis and surgery within a few years. T o evaluate these data and make recommendations concerning management, a Consensus Development Conference on the Diagnosis and Management of Asymptomatic Primary Hyperparathyroidism was convened in October 1990 by the US National Institutes of Health. The Consensus panel concluded that the 'current and acceptable treatment of primary H P T is operative intervention for cure', however, 'conscientious surveillance may be justified in patients whose calcium levels are only mildly elevated and whose renal and bone status are close to normal'." The panel reiterated the recommendation for a randomised multicentre clinical trial to compare operative versus non-operative management of asymptomatic H P T and it also made a plea for further pilot studies to better define the multisystem effects of HPT. NEW DATA ON MORTALITY IN HPT AND THE EFFECT OF SURGERY As if in response to the Consensus panel plea, several recent studies from Scandinavia have provided importHPT: TREATMENT BY SURGERY
ant new information about the natural history of H P T in terms of overall mortality (rather than disease progression) and how this is affected by successful parathyroidectomy . The first of these studies12examined the risk of death in patients with untreated HPT, many of whom had mild to moderate hypercalcaemia, as compared with concurrent age- and sex-matched controls in the normal population. Patients with H P T were found to have a significantly increased mortality (which continued to increase steadily with time), due predominantly to the same causes as in the general population - namely cardiovascular disease (50%) and malignancy (25%). R o n n i - S i ~ l a has ' ~ suggested that this phenomenon may be attributable to premature ageing caused by HPT. The effect of parathyroid surgery on this risk of premature death has now been examined by three independent Scandinavian groups in Hel~inki,'~ in Uppsala,I5 and most recently, in Gothenburg.16 The results have been remarkably consistent and demonstrate convincingly that the risk of death decreases with time after successful parathyroidectomy. The most recent, exacting study by Hedback et al., in Gothenburg, compared the mortality in a group of 896 patients followed up to 33 years (mean: 12.9 years) after successful parathyroidectomy, with individuals of corresponding age and sex in the Swedish population. The relative risk of death was substantially increased in all age groups (being highest in the group aged 55 to 70 years) but it improved progressively with time after operation (Figure 1).For those patients operated most recently (i.e. the 1982 cohort, Figure 2) the mortality rate actually normalised within five years. This new and unprecedented finding is particularly relevant to the present debate about the management of asymptomatic H P T because these patients tended Aust NZ J Med 1992; 22 165
to have disease of less severity and shorter duration. Notwithstanding the usual limitations of retrospective, non-randomised studies, these results are convincing and provide a persuasive argument in favour of offering surgery to all patients with H P T in whom the diagnosis is biochemically secure and who are otherwise fit for operation. The Scandinavian studies also underline the importance of early detection of H P T because they have shown that the earlier the disease is recognised, the more rapid the normalisation of mortality risk after operation. Perhaps there should be more systematic screening for HPT, especially in high risk groups, such as in women over 50 years of age. Of course, if we are going to make a more concerted effort to identify and treat patients with asymptomatic H P T it is imperative that they be treated by an experienced parathyroid surgeon to ensure a high success rate and negligible mortality.’.* These patients will usually have minimally enlarged glands which can be more troublesome to find at operation and which may present the surgeon greater difficulty in differentiating between tiny adenomas and nodular hyperplasia. l7 References 1. Heath H 111, Hodgson SF, Kennedy MA. Primary hyperparathyroidism, incidence, morbidity, and potential economic impact in a community. N Engl J Med 1980; 302: 189. 2. Mundy GR, Cove D H , Fisken R e t al. Primary hyperparathyroidism: changes in the pattern of clinical presentation. Lancet 1980; i: 1317. 3. Christensson T, Hellstrom K, Wengle B er al. Prevalence of hypercalcaemia in a health screening in Stockholm. Acta Med Scand 1976; 200: 131.
166
4. Reichel H, Koeffler HP, Norman AW. The role ofthe vitamin D endocrine system in health and disease. N Engl J Med 1989; 320: 980. 5. Toss G, Almqvist S, Larsson L et al. Vitamin D deficiency in welfare institutions for the aged. Acta Med Scad 1980; 208: 87. 6. Akerstrom G, Rudberg C, Grimelius L er al. Histologic parathyroid abnormalities in an autopsy series. Human Path 1986; 17: 520. 7. Russell CF, Edis AJ. Surgery for primary hyperparathyroidism: experience with 500 consecutive cases and evaluation of the role of surgery in the asymptomatic patient. Br J Surg 1982; 69: 244. 8. Edis AJ, Beahrs OH, van Heerden J et al. ‘Conservative’versus ‘liberal’ approach to parathyroid neck exploration. Surgery 1972; 82: 466. 9. Purnell DC, Smith LH, Scholz DA et al. Primary hvoerDarathvroidism: a urosoective clinical studv. Amer I Med 16?1;’50: 6?0. 10. Potts J T Jr. Management of asymptomatic hyperparathyroidism. J Clin Endocrinal Metab 1990; 70: 1489. 11. Diagnosis and management of asymptomatic primary hyperparathyroidism. Consensus Development Conference Statement. NIH Oct 1990. 12. Palmer M, Adami H-0, Bergstrom R et al. Survival and renal function in persons with untreated hypercalcemia: a populationbased cohort study with 14 years of follow-up. Lancet 1987; i: 59. 13. Ronni-Sivula H. Invited Commentary. World J Surg 1991; 15: 406. 14. Ronni-Sivula H. Causes of death in patients previously operated on four primary hyperparathyroidism. Ann Chir Gynecol 1985; 74: 13. 15. Palmer M, Adami H-0, Bergstrom R et al. Mortality after surgery for primary hyperparathyroidism: a follow-up of 44 1 patients operated on from 1956 to 1979. Surgery 1987; 102: 1. 16. Hedback G, Oden A, Tisell L-E. The influence of surgery on the risk of death in patients with primary hyperparathyroidism. World J Surg 1991; 15: 399. 17. Akerstrorn G, Bergstrom R, Grimelius Let al. Relation between changes in clinical and histopathological features of primary hyperparathyroidism. World J Surg 1986; 10: 696.
Aust NZ J Med 1992; 22
L
.
EDIS
