0021 -972X/90/7006-1489$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1990 by The Endocrine Society
Vol. 70, No. 6 Printed in U.S.A.
CLINICAL REVIEW 9 Management of Asymptomatic Hyperparathyroidism JOHN T. POTTS, JR. The Department of Medicine, Harvard Medical School, and the Massachusetts General Hospital, Boston, Massachusetts 02114
T
HE ACCURATE diagnosis and proper management of asymptomatic hyperparathyroidism is a topic that has become of increasing interest for several reasons: the disease is more common than was previously appreciated, many of the patients with the disease are recognized in medical practice because of the widespread use of multiphasic screening tests that lead to detection of hypercalcemia, and the lack of symptoms raises obvious questions about the necessity of surgical correction of hyperparathyroidism. At the same time, it is not clear that the course of asymptomatic hyperparathyroidism is necessarily benign; as with many other disorders, such as hypercholesterolemia or hypertension, there is an appreciation that the condition may be a risk factor for disease processes that have significant morbidity and mortality. A survey of published reports dealing with the topic leads to the conclusion that in the opinion of many, but by no means all, it is reasonable to recommend medical surveillance in older patients rather than surgical correction of their hyperparathyroidism, but only with the provision that medical surveillance involves monitoring of bone mass as well as serum calcium and other laboratory parameters. There are a number of published reports dealing with long-term follow-up of patients but the approach used by different groups is quite variable, the available data about the natural history of the disease is still limited, and few firm conclusions can be drawn, although some trends and general principles are evident. It should be emphasized that whenever the overall health of the patient permits, surgical correction of hyperparathyroidism is a reasonable medical recommendation; the success rate is high (greater than 90%), mortality is very low, morbidity is minimal and cure, persisting for many years, is common. Many patients,
however, wish to avoid surgery if possible. There are still unresolved issues with either course, surgery us. medical surveillance, namely convenience, medical cost, and safety. The morbidity and initially higher cost of hospitalization and surgery are to be compared with potentially years of medical surveillance requiring periodic testing of mineral metabolism and bone status. It is clear, however, from the published reports that hundreds of patients have elected periods of some years of medical surveillance rather than surgery. If formal comparisons are made of the two approaches in randomized trials, it will be possible to compare and contrast the overall economic and personal consequences of the two approaches. The importance of the topic coupled with the incompleteness of the data base has led the National Institutes of Health to plan a Consensus Conference on the Management of Asymptomatic Hyperparathyroidism to emphasize what interim conclusions are possible and to suggest the directions in which further studies could improve the data base from which more general and firm recommendations could be made regarding disease management. The principal questions facing a physician responsible for the management of a patient with confirmed hypercalcemia who lacks symptoms, can be stated as follows: 1) Can the physician confidently establish the diagnosis of hyperparathyroidism as the cause of the hypercalcemia rather than a disease with life-threatening potential such as malignancy with hypercalcemia; what are most reliable and cost-effective methods for diagnosis? 2) How often, if ever, is the course of the disease benign and for how long? 3) When and why should surgery be recommended? 4) If surgery is not recommended, what are the medical issues for which hyperparathyroidism could be a risk factor, and how should the patient be followed to detect silent organ deterioration or other unwanted problems?
Received December 10,1989. Address requests for reprints to: John T. Potts, Jr., MD, Chief of Medical Services, Massachusetts General Hospital, Boston, Massachusetts 02114.
Diagnosis Establishing the diagnosis of primary hyperparathyroidism with high accuracy and in a cost effective manner 1489
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1490
POTTS JR.
is obviously quite important, given the increased incidence of the disease especially in older men and women. The incidence of the disease in men over the age of 60 is one new case per thousand of the population per year; the disease frequency in women over the age of 60 is twice the estimated rate in men (1). It is generally agreed that hyperparathyroidism and malignancy account for over 90% of the cases of confirmed hypercalcemia (1). Logically, the immunoassay for a PTH should be the most useful diagnostic test. If malignancy or any cause of hypercalcemia other than hyperparathyroidism is present, normal parathyroid glands should be suppressed and immunoassayable PTH undectable or low; if hyperparathyroidism is the cause, there should be an elevated PTH. Unfortunately, although the PTH assay has been useful as a diagnostic tool since its original introduction nearly three decades ago, there has generally not been a clear separation between hyperparathyroidism and hypercalcemia of malignancy, and there have been numerous problems in application and interpretation of PTH immunoassays. Fortunately, the introduction of double antibody assay methods by several academic and commercial groups recently has led to a dramatic improvement in the specificity and sensitivity of the PTH immunoassay in the differential diagnosis of hypercalcemia (2). Assays based on double antibody techniques have theoretical advantages that can be shown to result in greater sensitivity, speed of performance, and freedom from nonspecific effects. These newer assays give clear separation between primary hyperparathyroidism and other causes of hypercalcemia with a high degree of reliability and, in fact, are the method of choice in the differential diagnosis of hypercalcemia. There are, of course, many issues to consider in the differential diagnosis of hypercalcemia and the use and pitfalls in the application and interpretation of any PTH immunoassays as well as other laboratory tests in hypercalcemic subjects, which are beyond the scope of this review. However, physicians can confidently establish the diagnosis of hyperparathyroidism in most cases with a combination of clinical perspective and judicious use of the new type PTH immunoassay (other laboratory tests can be regarded as secondary in importance). In over 90% of patients, hypercalcemia will be due to hyperparathyroidism or malignancy. Patients with malignancy typically have a rapid course of illness and associated specific symptoms. One can conclude clinically that if the patient's hypercalcemia is asymptomatic and/or is known to be chronic (more than 6 months in duration), it is likely that the diagnosis is hyperparathyroidism. The PTH assay can be applied to aid in definitive diagnosis. If PTH is elevated in the presence of hypercalcemia, confirmed more than once, then hyper-
JCE & M • 1990 Vol 70 • No 6
parathyroidism is present with a high probability. On the other hand, if PTH levels are suppressed and the duration of the hypercalcemia is unknown, then a careful screen for malignancy is indicated. If hypercalcemia is known to be chronic, as well as asymptomatic, and PTH levels are suppressed, then one of the rarer causes of hypercalcemia, such as sarcoidosis, is likely.
Natural History of Hyperparathyroidism How often is the course of hyperparathyroidism benign and over what time period? A survey of published reports dealing with the natural history of the disease provides information that is highly variable in its content both with respect to quality and quantity of patient data and length of follow-up but does provide, in aggregate, useful information in a dozen or more published reports that collectively represent data from 750 to 1000 patients. Variable indications have been purposed for surgery and, therefore, the groups can not be readily compared. There is a high loss of follow-up. Patients were operated upon after initial periods of medical surveillance for a variety of reasons, such as the development of renal calculi, ulcer disease, and worsening hypercalcemia, or more subjective criteria relating to the patient's overall sense of well being. These studies clearly were not planned as formal, randomized, controlled prospective studies with uniform criteria for evaluation; rather, the efforts were pilot studies to establish whether the disease can run a benign course over years. Results, with the limitations cited above, do indicate that the disease can have an apparently benign clinical course. For example, in a recent report that lists many of the earlier studies, it is concluded through the follow-up of 175 patients for a mean period of 4 y, that hyperparathyroidism can be benign with little change in bone density, function of other organs, or PTH or blood calcium levels (3).
How to Follow Patients Medically and When and Why to Recommend Surgery What is necessary to assure that the course of the disease in an asymptomatic patient is truly benign? In the published reports, the issues of greatest concern, include the following: 1) silent bone deterioration in the absence of symptoms: a parathyroid-dependent osteopenia, leading to premature fractures before the onset of generalized age-dependent or postmenopausal osteoporosis; 2) hypertension, parathyroid dependent and/or aggravated; 3) silent renal deterioration in the absence of kidney stones: a reduction in glomerular or tubular function; and 4) psychiatric symptoms: depression, subtle degrees of impairment in energy level, and reduction in mental concentrating power. Clearly, hyperparathyroidism can be associated with
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CLINICAL REVIEW clear-cut organ and tissue damage, such as osteitis fibrosas cystica; gastrointestinal manifestations, including ulcer disease and pancreatitis; a reversible neuromuscular syndrome; and recurrent nephrolithiasis and other conditions which, when present, lead the physician to recommend surgery at the time of initial diagnosis. Surgery may be needed, however, to arrest or reverse silent deleterious effects of hyperparathyroidism. The majority of studies suggest that renal function remains unimpaired in the absence of renal stones (3). Bone density measured by single photon absorptiometry of the forearm, which measures cortical bone density principally, has been shown to be stable for protracted periods of time in a number of patients (3). In the experience of the author and his colleagues, however, there is sometimes an abrupt loss of bone after periods of stability. The overall evidence, however, provides reassurance that silent bone deterioration need not be an invariable consequence of hyperparathyroidism. Obviously, further study with larger numbers of individuals and multiple techniques will be required to provide definitive answers regarding cortical bone loss in hyperparathyroidism: How many patients show a stable bone pattern and for how long? Can one predict early which patients will lose bone? Although some have claimed that hypertension is more common in the hyperparathyroid population than in agematched control populations and that hypertension improves in about 50% of patients after parathyroidectomy, other reports (4) indicate that there is little persistent change in the majority of patients. These studies have been limited in scope, and it is difficult to come to any general conclusions. Ascertainment bias (more careful evaluation of patients once hyperparathyroidism is suspected), the nonspecific but transient beneficial effects on hypertension of surgical intervention and hospitalization of any type due to improved patient management, plus the variable results reported, suggest that there is insufficient data to recommend surgical correction of hyperparathyroidism in the expectation of reversing hypertension. There is the possibility that patients with psychiatric symptoms, ranging from depression to mild fatigue and impaired mental concentrating ability, will benefit from parathyroid surgery, but there is no conclusive data in published reports to suggest a cause-and-effect relationship between hyperparathyroidism and psychiatric symptoms. If, in truly asymptomatic patients, the issue of parathyroid-dependent osteopenia and increased fracture risk may influence a physician to recommend parathyroid surgery, we need to know what happens after surgery. Does further loss stop and/or is there reversal? Again only limited data exists (5). Bone mass after parathyroid
1491
surgery generally improves, although only modestly, and the improvement does not continue beyond 6 months to 1 yr after surgery; study design did not separately treat other factors that affect bone density, such as vitamin D and estrogen status. Nonetheless, it supports the conclusion that there is a parathyroid-dependent osteopenia and that surgical correction of hyperparathyroidism stops the process, even if improvement is very limited. These conclusions would indicate that even in the absence of symptoms, a patient with low or falling bone mass would benefit from surgical correction of hyperparathyroidism. It has generally been held that it is cortical bone and not trabecular bone that is principally lost in patients whose skeleton is susceptible to the effects of untreated hyperparathyroidism; hence, most investigators have tended to follow only single photon absorptiometry, for example in the forearm, as a measure of cortical bone loss (3, 5). Recently, there has been an intensive focus on the question of trabecular bone loss as a complication of undetected or untreated hyperparathyroidism based principally on evidence that there is a considerably higher instance of vertebral crush factors in patients with hyperparathyroidism than in what appeared to be an appropriate control group of the same age. The data so far reported is confusing but disturbing. A recent report (6) summarizes most of the earlier data. The original US report indicated a fracture incidence of the vertebral bodies of approximately 4% in patients with hyperparathyroidism compared with a control incidence of 0.2%. The recent review (6) disputes the fact that there is an increased incidence of vertebral fractures in hyperparathyroidism in the US, quoting an incidence of 1.7% in hyperparathyroidism us. 2.9% in what is believed to be a more appropriate control population. Unquestioned, however, is a much higher incidence of vertebral fractures in Great Britain and Western Europe in patients with hyperparathyroidism as compared to control populations; in one study, the incidence was 15% in hyperparathyroidism us. approximately 2% in the control population (6). Much stricter criteria were used to define the presence of vertebral crush fractures in the European studies. Hence, it must be concluded thathyperparathyroidism is much more likely to cause vertebral crush fractures in some countries even if not clearly established in the US. Why should this be? There is obvious speculation about the great difference in vitamin D intake which is much lower in Britain, but many other factors such as nutritional, racial, and/or environmental could be involved (6). This newer issue, the possibility of increased risk of vertebral crush fractures in hyperparathyroidism, must be much more carefully evaluated despite the findings by one group (6) that there is not an increased incidence of vertebral fractures in the
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JCE & M • 1990 Vol70«No6
POTTS JR.
TABLE 1. Indications for surgery in hyperparathyroidism Usually no
Usually yes
1. Hypertension
1. Hypercalcemia > 12 mg/dL
2. Hypercalcemia < 12 mg/dL 3. ?Silent renal impairment
2. Osteitis fibrosa 3. Reduced and falling cortical or trabecular bone mass 4. Refractory ulcer disease
4. Psychiatric symptoms
US. If a principal issue that remains to be evaluated in asymptomatic hyperparathyroidism is the risk of parathyroid-dependent osteopenia of either cortical or trabecular bone, what are the best techniques for measuring bone mass of either type? Fortunately, there has been a proliferation of techniques for measurement of spinal bone mass as well as cortical bone. Quantitative computerized tomography, available in at least many medical centers, seems to be a reliable technique for spinal bone. The method permits the measurement of trabecular bone without interference from the outer rim of cortical bone in the vertebral body. A number of techniques featuring dual energy photon absorptiometry and dual energy xray absorptiometry have been introduced. A discussion of the relative strengths and limitations of each technique, their radiation burden, cost, and overall reliability is beyond the scope of this review. It can be concluded, however, that there is growing availability and reliability of techniques for monitoring cortical and trabecular bone mass. The interim conclusion is that single photon absorptiometry, which is relatively inexpensive and widely available, can be used to monitor cortical bone mass in those patients whom physicians elect to follow without surgical intervention. Given the current confusion regarding fractures of the spine, we would recommend that trabecular bone in the spine also be followed. In summary, certain general recommendations can be made about the indications for surgery in hyperparathyroidism; conditions that would be generally accepted as indications for surgery are distinguished from potential problems associated with hyperparathyroidism which current evidence does not indicate conclusive indicators (Table 1). Other conditions listed as probable indications for surgery reflect the need for individual judgement on the part of the physician and patient. Clearly, if bone mass cannot be adequately evaluated, surgery may be the wiser course of action rather than run the risk of silent osteopenia. Perhaps premenopausal women should always have their hyperparathyroidism corrected since they still face the potential risk of estrogen-dependent spinal osteopenia. There certainly have been patients with one kidney stone who have not had a recurrence and not all forms of pancreatitis are attributable to hyperparathyroidism.
Probable indication 1. Low cortical or trabecular bone mass (>2-2.5 SD below mean for age) 2. Premenopausal status 3. Kidney stones (recurrent) 4. Pancreatitis
There is disagreement about the level of serum calcium above which one would automatically recommend surgery. Earlier reports suggested 11 mg/dL, but, more recently, 12 mg/dL has been suggested as the safe upper limit (3). Clearly, many issues remain unsettled and detailed data in longitudinal studies is needed to provide greater confidence in making recommendations concerning management of asymptomatic hyperparathyroidism. There may be surprises as well as reassurances if prospective controlled studies are undertaken. A Swedish group has reported in a study of several hundred patients followed for a decade or more, that mortality in patients with hypercalcemia (presumed to have hyperparathyroidism on reasonable grounds) had an overall survival less than that of aged matched controls without hypercalcemia; increased mortality was due to cardiovascular death. The mortality difference noted, 32% in hyperparathyroid patients vs. 23% in eucalcemic controls, seemed statistically significant but for a study of this type the sample size is small and the usual problems inherent in a retrospective report rather than a randomized and prospective study exist. In conclusion, several points should be emphasized. It is now relatively easy to establish a definitive, presumptive diagnosis of hyperparathyroidism. Once the diagnosis has been established, surgical correction of the hyperparathyroidism is a valid and reasonable approach for the physician and patient to select, especially in younger patients. The advantages are a high likelihood of cure, low complications, and a minimal requirement for further monitoring. It could well be, however, that primary hyperparathyroidism is benign in many, especially older, patients in whom the diagnosis is established, and hence election of medical surveillance is an alternative to surgery. Controlled prospective randomized studies clearly seem needed to more definitively answer questions regarding whether the disease is benign and how often and to determine the spectrum of disease, especially whether predictive indices could be developed regarding ultimate course. A goal would be to develop criteria that indicated early which patients appeared likely to require surgery, eventually sparing much unnecessary surveillance.
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CLINICAL REVIEW
References 1. Heath H, Hodgson SF, Kennedy MA. Primary hyperparathyroidism, incidence, morbidity, and potential economic impact in a community. NEJM. 1980;302:189-193. 2. Nussbaum SR, Zahradnik RJ, Lavigne JR, Brennan, GL, NozawaUng, K, Kim LY, Keutmann HT, Wang CA, Potts Jr JT, Segre GV. Highly sensitive two-site immunoradiometric assay of parathyrin, and its clinical utility in evaluating patients with hypercalcemia. Clin Chem. 1987;8:1364-1367. 3. Rao DS, Wilson RJ, Kleerekoper M, and Parfitt AM. Lack of biochemical progression or continuation of accelerated bone loss in mild asymptomatic primary hyperparathyroidism: evidence for biphasic disease course. J Clin Endocrinol Metab. 1988;67:6:1294-
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1298. 4. Lafferty, FW. Primary hyperparathyroidism, changing clinical spectrum, prevalence of hypertension, and discriminant analysis of laboratory tests. Arch Intern Med. 1981;141:1761-1766. 5. Martin P, Bergmann P, Gillet C, Fuss M, Kinnaert P, Corvilain J, van Geertruyden J. Partially reversible osteopenia after surgery for primary hyperparathyroidism. Arch Intern Med. 1986; 146:689691. 6. Wilson RJ, Sudhaker D, Ellis B, Kleerekoper M, Parfitt M. Mild asymptomatic primary hyperparathyroidism is not a risk factor for vertebral fractures. Ann Intern Med. 1988;109:959-962. 7. Palmer M, Adami HO, Bergstrom R, Akerstrom G, and Ljunghall S. Mortality after surgery for primary hyperparathyroidism: a follow-up of 441 patients operated on from 1956 to 1979. Surgery. 1987;102:l:l-7.
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Vol. 70, No. 6 Printed in U.S.A.
CLINICAL REVIEW 9 Management of Asymptomatic Hyperparathyroidism JOHN T. POTTS, JR. The Department of Medicine, Harvard Medical School, and the Massachusetts General Hospital, Boston, Massachusetts 02114
T
HE ACCURATE diagnosis and proper management of asymptomatic hyperparathyroidism is a topic that has become of increasing interest for several reasons: the disease is more common than was previously appreciated, many of the patients with the disease are recognized in medical practice because of the widespread use of multiphasic screening tests that lead to detection of hypercalcemia, and the lack of symptoms raises obvious questions about the necessity of surgical correction of hyperparathyroidism. At the same time, it is not clear that the course of asymptomatic hyperparathyroidism is necessarily benign; as with many other disorders, such as hypercholesterolemia or hypertension, there is an appreciation that the condition may be a risk factor for disease processes that have significant morbidity and mortality. A survey of published reports dealing with the topic leads to the conclusion that in the opinion of many, but by no means all, it is reasonable to recommend medical surveillance in older patients rather than surgical correction of their hyperparathyroidism, but only with the provision that medical surveillance involves monitoring of bone mass as well as serum calcium and other laboratory parameters. There are a number of published reports dealing with long-term follow-up of patients but the approach used by different groups is quite variable, the available data about the natural history of the disease is still limited, and few firm conclusions can be drawn, although some trends and general principles are evident. It should be emphasized that whenever the overall health of the patient permits, surgical correction of hyperparathyroidism is a reasonable medical recommendation; the success rate is high (greater than 90%), mortality is very low, morbidity is minimal and cure, persisting for many years, is common. Many patients,
however, wish to avoid surgery if possible. There are still unresolved issues with either course, surgery us. medical surveillance, namely convenience, medical cost, and safety. The morbidity and initially higher cost of hospitalization and surgery are to be compared with potentially years of medical surveillance requiring periodic testing of mineral metabolism and bone status. It is clear, however, from the published reports that hundreds of patients have elected periods of some years of medical surveillance rather than surgery. If formal comparisons are made of the two approaches in randomized trials, it will be possible to compare and contrast the overall economic and personal consequences of the two approaches. The importance of the topic coupled with the incompleteness of the data base has led the National Institutes of Health to plan a Consensus Conference on the Management of Asymptomatic Hyperparathyroidism to emphasize what interim conclusions are possible and to suggest the directions in which further studies could improve the data base from which more general and firm recommendations could be made regarding disease management. The principal questions facing a physician responsible for the management of a patient with confirmed hypercalcemia who lacks symptoms, can be stated as follows: 1) Can the physician confidently establish the diagnosis of hyperparathyroidism as the cause of the hypercalcemia rather than a disease with life-threatening potential such as malignancy with hypercalcemia; what are most reliable and cost-effective methods for diagnosis? 2) How often, if ever, is the course of the disease benign and for how long? 3) When and why should surgery be recommended? 4) If surgery is not recommended, what are the medical issues for which hyperparathyroidism could be a risk factor, and how should the patient be followed to detect silent organ deterioration or other unwanted problems?
Received December 10,1989. Address requests for reprints to: John T. Potts, Jr., MD, Chief of Medical Services, Massachusetts General Hospital, Boston, Massachusetts 02114.
Diagnosis Establishing the diagnosis of primary hyperparathyroidism with high accuracy and in a cost effective manner 1489
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1490
POTTS JR.
is obviously quite important, given the increased incidence of the disease especially in older men and women. The incidence of the disease in men over the age of 60 is one new case per thousand of the population per year; the disease frequency in women over the age of 60 is twice the estimated rate in men (1). It is generally agreed that hyperparathyroidism and malignancy account for over 90% of the cases of confirmed hypercalcemia (1). Logically, the immunoassay for a PTH should be the most useful diagnostic test. If malignancy or any cause of hypercalcemia other than hyperparathyroidism is present, normal parathyroid glands should be suppressed and immunoassayable PTH undectable or low; if hyperparathyroidism is the cause, there should be an elevated PTH. Unfortunately, although the PTH assay has been useful as a diagnostic tool since its original introduction nearly three decades ago, there has generally not been a clear separation between hyperparathyroidism and hypercalcemia of malignancy, and there have been numerous problems in application and interpretation of PTH immunoassays. Fortunately, the introduction of double antibody assay methods by several academic and commercial groups recently has led to a dramatic improvement in the specificity and sensitivity of the PTH immunoassay in the differential diagnosis of hypercalcemia (2). Assays based on double antibody techniques have theoretical advantages that can be shown to result in greater sensitivity, speed of performance, and freedom from nonspecific effects. These newer assays give clear separation between primary hyperparathyroidism and other causes of hypercalcemia with a high degree of reliability and, in fact, are the method of choice in the differential diagnosis of hypercalcemia. There are, of course, many issues to consider in the differential diagnosis of hypercalcemia and the use and pitfalls in the application and interpretation of any PTH immunoassays as well as other laboratory tests in hypercalcemic subjects, which are beyond the scope of this review. However, physicians can confidently establish the diagnosis of hyperparathyroidism in most cases with a combination of clinical perspective and judicious use of the new type PTH immunoassay (other laboratory tests can be regarded as secondary in importance). In over 90% of patients, hypercalcemia will be due to hyperparathyroidism or malignancy. Patients with malignancy typically have a rapid course of illness and associated specific symptoms. One can conclude clinically that if the patient's hypercalcemia is asymptomatic and/or is known to be chronic (more than 6 months in duration), it is likely that the diagnosis is hyperparathyroidism. The PTH assay can be applied to aid in definitive diagnosis. If PTH is elevated in the presence of hypercalcemia, confirmed more than once, then hyper-
JCE & M • 1990 Vol 70 • No 6
parathyroidism is present with a high probability. On the other hand, if PTH levels are suppressed and the duration of the hypercalcemia is unknown, then a careful screen for malignancy is indicated. If hypercalcemia is known to be chronic, as well as asymptomatic, and PTH levels are suppressed, then one of the rarer causes of hypercalcemia, such as sarcoidosis, is likely.
Natural History of Hyperparathyroidism How often is the course of hyperparathyroidism benign and over what time period? A survey of published reports dealing with the natural history of the disease provides information that is highly variable in its content both with respect to quality and quantity of patient data and length of follow-up but does provide, in aggregate, useful information in a dozen or more published reports that collectively represent data from 750 to 1000 patients. Variable indications have been purposed for surgery and, therefore, the groups can not be readily compared. There is a high loss of follow-up. Patients were operated upon after initial periods of medical surveillance for a variety of reasons, such as the development of renal calculi, ulcer disease, and worsening hypercalcemia, or more subjective criteria relating to the patient's overall sense of well being. These studies clearly were not planned as formal, randomized, controlled prospective studies with uniform criteria for evaluation; rather, the efforts were pilot studies to establish whether the disease can run a benign course over years. Results, with the limitations cited above, do indicate that the disease can have an apparently benign clinical course. For example, in a recent report that lists many of the earlier studies, it is concluded through the follow-up of 175 patients for a mean period of 4 y, that hyperparathyroidism can be benign with little change in bone density, function of other organs, or PTH or blood calcium levels (3).
How to Follow Patients Medically and When and Why to Recommend Surgery What is necessary to assure that the course of the disease in an asymptomatic patient is truly benign? In the published reports, the issues of greatest concern, include the following: 1) silent bone deterioration in the absence of symptoms: a parathyroid-dependent osteopenia, leading to premature fractures before the onset of generalized age-dependent or postmenopausal osteoporosis; 2) hypertension, parathyroid dependent and/or aggravated; 3) silent renal deterioration in the absence of kidney stones: a reduction in glomerular or tubular function; and 4) psychiatric symptoms: depression, subtle degrees of impairment in energy level, and reduction in mental concentrating power. Clearly, hyperparathyroidism can be associated with
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 00:51 For personal use only. No other uses without permission. . All rights reserved.
CLINICAL REVIEW clear-cut organ and tissue damage, such as osteitis fibrosas cystica; gastrointestinal manifestations, including ulcer disease and pancreatitis; a reversible neuromuscular syndrome; and recurrent nephrolithiasis and other conditions which, when present, lead the physician to recommend surgery at the time of initial diagnosis. Surgery may be needed, however, to arrest or reverse silent deleterious effects of hyperparathyroidism. The majority of studies suggest that renal function remains unimpaired in the absence of renal stones (3). Bone density measured by single photon absorptiometry of the forearm, which measures cortical bone density principally, has been shown to be stable for protracted periods of time in a number of patients (3). In the experience of the author and his colleagues, however, there is sometimes an abrupt loss of bone after periods of stability. The overall evidence, however, provides reassurance that silent bone deterioration need not be an invariable consequence of hyperparathyroidism. Obviously, further study with larger numbers of individuals and multiple techniques will be required to provide definitive answers regarding cortical bone loss in hyperparathyroidism: How many patients show a stable bone pattern and for how long? Can one predict early which patients will lose bone? Although some have claimed that hypertension is more common in the hyperparathyroid population than in agematched control populations and that hypertension improves in about 50% of patients after parathyroidectomy, other reports (4) indicate that there is little persistent change in the majority of patients. These studies have been limited in scope, and it is difficult to come to any general conclusions. Ascertainment bias (more careful evaluation of patients once hyperparathyroidism is suspected), the nonspecific but transient beneficial effects on hypertension of surgical intervention and hospitalization of any type due to improved patient management, plus the variable results reported, suggest that there is insufficient data to recommend surgical correction of hyperparathyroidism in the expectation of reversing hypertension. There is the possibility that patients with psychiatric symptoms, ranging from depression to mild fatigue and impaired mental concentrating ability, will benefit from parathyroid surgery, but there is no conclusive data in published reports to suggest a cause-and-effect relationship between hyperparathyroidism and psychiatric symptoms. If, in truly asymptomatic patients, the issue of parathyroid-dependent osteopenia and increased fracture risk may influence a physician to recommend parathyroid surgery, we need to know what happens after surgery. Does further loss stop and/or is there reversal? Again only limited data exists (5). Bone mass after parathyroid
1491
surgery generally improves, although only modestly, and the improvement does not continue beyond 6 months to 1 yr after surgery; study design did not separately treat other factors that affect bone density, such as vitamin D and estrogen status. Nonetheless, it supports the conclusion that there is a parathyroid-dependent osteopenia and that surgical correction of hyperparathyroidism stops the process, even if improvement is very limited. These conclusions would indicate that even in the absence of symptoms, a patient with low or falling bone mass would benefit from surgical correction of hyperparathyroidism. It has generally been held that it is cortical bone and not trabecular bone that is principally lost in patients whose skeleton is susceptible to the effects of untreated hyperparathyroidism; hence, most investigators have tended to follow only single photon absorptiometry, for example in the forearm, as a measure of cortical bone loss (3, 5). Recently, there has been an intensive focus on the question of trabecular bone loss as a complication of undetected or untreated hyperparathyroidism based principally on evidence that there is a considerably higher instance of vertebral crush factors in patients with hyperparathyroidism than in what appeared to be an appropriate control group of the same age. The data so far reported is confusing but disturbing. A recent report (6) summarizes most of the earlier data. The original US report indicated a fracture incidence of the vertebral bodies of approximately 4% in patients with hyperparathyroidism compared with a control incidence of 0.2%. The recent review (6) disputes the fact that there is an increased incidence of vertebral fractures in hyperparathyroidism in the US, quoting an incidence of 1.7% in hyperparathyroidism us. 2.9% in what is believed to be a more appropriate control population. Unquestioned, however, is a much higher incidence of vertebral fractures in Great Britain and Western Europe in patients with hyperparathyroidism as compared to control populations; in one study, the incidence was 15% in hyperparathyroidism us. approximately 2% in the control population (6). Much stricter criteria were used to define the presence of vertebral crush fractures in the European studies. Hence, it must be concluded thathyperparathyroidism is much more likely to cause vertebral crush fractures in some countries even if not clearly established in the US. Why should this be? There is obvious speculation about the great difference in vitamin D intake which is much lower in Britain, but many other factors such as nutritional, racial, and/or environmental could be involved (6). This newer issue, the possibility of increased risk of vertebral crush fractures in hyperparathyroidism, must be much more carefully evaluated despite the findings by one group (6) that there is not an increased incidence of vertebral fractures in the
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1492
JCE & M • 1990 Vol70«No6
POTTS JR.
TABLE 1. Indications for surgery in hyperparathyroidism Usually no
Usually yes
1. Hypertension
1. Hypercalcemia > 12 mg/dL
2. Hypercalcemia < 12 mg/dL 3. ?Silent renal impairment
2. Osteitis fibrosa 3. Reduced and falling cortical or trabecular bone mass 4. Refractory ulcer disease
4. Psychiatric symptoms
US. If a principal issue that remains to be evaluated in asymptomatic hyperparathyroidism is the risk of parathyroid-dependent osteopenia of either cortical or trabecular bone, what are the best techniques for measuring bone mass of either type? Fortunately, there has been a proliferation of techniques for measurement of spinal bone mass as well as cortical bone. Quantitative computerized tomography, available in at least many medical centers, seems to be a reliable technique for spinal bone. The method permits the measurement of trabecular bone without interference from the outer rim of cortical bone in the vertebral body. A number of techniques featuring dual energy photon absorptiometry and dual energy xray absorptiometry have been introduced. A discussion of the relative strengths and limitations of each technique, their radiation burden, cost, and overall reliability is beyond the scope of this review. It can be concluded, however, that there is growing availability and reliability of techniques for monitoring cortical and trabecular bone mass. The interim conclusion is that single photon absorptiometry, which is relatively inexpensive and widely available, can be used to monitor cortical bone mass in those patients whom physicians elect to follow without surgical intervention. Given the current confusion regarding fractures of the spine, we would recommend that trabecular bone in the spine also be followed. In summary, certain general recommendations can be made about the indications for surgery in hyperparathyroidism; conditions that would be generally accepted as indications for surgery are distinguished from potential problems associated with hyperparathyroidism which current evidence does not indicate conclusive indicators (Table 1). Other conditions listed as probable indications for surgery reflect the need for individual judgement on the part of the physician and patient. Clearly, if bone mass cannot be adequately evaluated, surgery may be the wiser course of action rather than run the risk of silent osteopenia. Perhaps premenopausal women should always have their hyperparathyroidism corrected since they still face the potential risk of estrogen-dependent spinal osteopenia. There certainly have been patients with one kidney stone who have not had a recurrence and not all forms of pancreatitis are attributable to hyperparathyroidism.
Probable indication 1. Low cortical or trabecular bone mass (>2-2.5 SD below mean for age) 2. Premenopausal status 3. Kidney stones (recurrent) 4. Pancreatitis
There is disagreement about the level of serum calcium above which one would automatically recommend surgery. Earlier reports suggested 11 mg/dL, but, more recently, 12 mg/dL has been suggested as the safe upper limit (3). Clearly, many issues remain unsettled and detailed data in longitudinal studies is needed to provide greater confidence in making recommendations concerning management of asymptomatic hyperparathyroidism. There may be surprises as well as reassurances if prospective controlled studies are undertaken. A Swedish group has reported in a study of several hundred patients followed for a decade or more, that mortality in patients with hypercalcemia (presumed to have hyperparathyroidism on reasonable grounds) had an overall survival less than that of aged matched controls without hypercalcemia; increased mortality was due to cardiovascular death. The mortality difference noted, 32% in hyperparathyroid patients vs. 23% in eucalcemic controls, seemed statistically significant but for a study of this type the sample size is small and the usual problems inherent in a retrospective report rather than a randomized and prospective study exist. In conclusion, several points should be emphasized. It is now relatively easy to establish a definitive, presumptive diagnosis of hyperparathyroidism. Once the diagnosis has been established, surgical correction of the hyperparathyroidism is a valid and reasonable approach for the physician and patient to select, especially in younger patients. The advantages are a high likelihood of cure, low complications, and a minimal requirement for further monitoring. It could well be, however, that primary hyperparathyroidism is benign in many, especially older, patients in whom the diagnosis is established, and hence election of medical surveillance is an alternative to surgery. Controlled prospective randomized studies clearly seem needed to more definitively answer questions regarding whether the disease is benign and how often and to determine the spectrum of disease, especially whether predictive indices could be developed regarding ultimate course. A goal would be to develop criteria that indicated early which patients appeared likely to require surgery, eventually sparing much unnecessary surveillance.
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CLINICAL REVIEW
References 1. Heath H, Hodgson SF, Kennedy MA. Primary hyperparathyroidism, incidence, morbidity, and potential economic impact in a community. NEJM. 1980;302:189-193. 2. Nussbaum SR, Zahradnik RJ, Lavigne JR, Brennan, GL, NozawaUng, K, Kim LY, Keutmann HT, Wang CA, Potts Jr JT, Segre GV. Highly sensitive two-site immunoradiometric assay of parathyrin, and its clinical utility in evaluating patients with hypercalcemia. Clin Chem. 1987;8:1364-1367. 3. Rao DS, Wilson RJ, Kleerekoper M, and Parfitt AM. Lack of biochemical progression or continuation of accelerated bone loss in mild asymptomatic primary hyperparathyroidism: evidence for biphasic disease course. J Clin Endocrinol Metab. 1988;67:6:1294-
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1298. 4. Lafferty, FW. Primary hyperparathyroidism, changing clinical spectrum, prevalence of hypertension, and discriminant analysis of laboratory tests. Arch Intern Med. 1981;141:1761-1766. 5. Martin P, Bergmann P, Gillet C, Fuss M, Kinnaert P, Corvilain J, van Geertruyden J. Partially reversible osteopenia after surgery for primary hyperparathyroidism. Arch Intern Med. 1986; 146:689691. 6. Wilson RJ, Sudhaker D, Ellis B, Kleerekoper M, Parfitt M. Mild asymptomatic primary hyperparathyroidism is not a risk factor for vertebral fractures. Ann Intern Med. 1988;109:959-962. 7. Palmer M, Adami HO, Bergstrom R, Akerstrom G, and Ljunghall S. Mortality after surgery for primary hyperparathyroidism: a follow-up of 441 patients operated on from 1956 to 1979. Surgery. 1987;102:l:l-7.
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