NIH
CONFERENCE
Diagnosis and Management of Asymptomatic Primary Hyperparathyroidism: Consensus Development Conference Statement Consensus Development Conference Panel*
Endocrinologists, surgeons, radiologists, epidemiologists, and primary health care providers convened to address both indications for surgery in asymptomatic patients with hyperparathyroidism as well as how patients who do not have surgery should be monitored and managed to minimize the risk for complications. The National Institutes of Health Consensus Development Conference Panel concluded that a diagnosis of hyperparathyroidism is established by showing persistent hypercalcemia and an elevated serum parathyroid hormone concentration; that the current and acceptable treatment for hyperparathyroidism is surgery; that the diagnosis of hyperparathyroidism in an asymptomatic patient does not in all cases mandate referral for surgery; that conscientious surveillance may be justified in patients whose calcium levels are only mildly elevated and whose renal and bone status are close to normal; and that preoperative localization in patients without previous neck operation is rarely indicated and has not proved to be cost effective.
Annals of Internal Medicine. 1991;114:593-597.
riyperparathyroidism is increasingly being recognized because of the widespread use of multiphasic screening for hypercalcemia. Women are affected twice as often as men, and the incidence of hyperparathyroidism increases with age. Approximately 100 000 new cases develop each year in the United States. Because the disease is now known to be more common than was previously appreciated, physicians are increasingly interested in the correct diagnosis and the proper management of patients with hyperparathyroidism. The increased recognition of hyperparathyroidism with the use of screening tests has disclosed a group of patients in whom symptoms are subtle or absent. A new clinical profile of hyperparathyroidism that is characterized by mild hypercalcemia has emerged. Presentation with bone disease that is evident from standard radiography or from the presence of nephrolithiasis or other An edited summary of a Consensus Development Conference held from 29 to 31 October 1990 at Masur Auditorium, Building 10, Bethesda, Maryland. The conference was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases and the Office of Medical Applications of Research, National Institutes of Health. Authors who wish to cite the conference may use this example for the form of reference: Consensus Development Conference Panel. Diagnosis and management of asymptomatic primary hyperparathyroidism: Consensus Development Conference statement. Ann Intern Med. 1991 ;114:593597. * For participating organizations and investigators, see end of text.
complications is now uncommon, yet it is not clear that incidentally discovered hyperparathyroidism is benign. Studies of the natural history of hyperparathyroidism are yielding information about how often and over what time course the mild syndrome remains benign. Silent loss of bone mass and changes in skeletal architecture in this asymptomatic patient group are being assessed with sensitive new techniques. The clinical importance of changes in bone density is uncertain, but it seems likely that progressive parathyroid-dependent bone loss is an additional risk factor for fractures. The potential for mild hyperparathyroidism to cause or to accelerate hypertension, renal deterioration, peptic ulcer disease, and psychiatric symptoms also is being evaluated. Parathyroidectomy is highly successful when done by experienced surgeons. The evidence suggests that some patients with asymptomatic primary hyperparathyroidism may have a prolonged benign course; perhaps such patients can be managed without operative intervention. If patients are not operated on, they must be monitored to detect progression of the disease. For these patients, the principal issue is how they can be best monitored, balancing the need to identify skeletal, renal, or other complications that are indications for operation with the burdens and expense of long-term monitoring. Evaluation of the long-term consequences of asymptomatic hyperparathyroidism with and without surgical treatment will answer questions about the optimal management of this condition. Predictive factors, if they can be discerned, would help to distinguish subgroups of patients who will develop adverse effects from those who will tolerate mild hyperparathyroidism without developing complications. The identification of such factors would substantially affect the justification for operative or nonoperative management. To address these issues, from 29 to 31 October 1990, the National Institute of Diabetes and Digestive and Kidney Diseases, together with the Office of Medical Applications of Research of the National Institutes of Health, convened a consensus development conference on the diagnosis and management of asymptomatic primary hyperparathyroidism. After experts in the relevant fields presented and the audience discussed the issues, a consensus panel comprising specialists and generalists from the medical and other related scientific disciplines considered the evidence and formulated a consensus statement in response to the following six previously stated questions: 1. What is the most accurate, cost-effective method of diagnosing hyperparathyroidism? 2. Are there patients with asymptomatic hyperpara-
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thyroidism who can safely be followed without surgery? Should they be? 3. If they are not operated on, how should asymptomatic patients be monitored and managed? 4. What are the indications for surgery in patients with asymptomatic hyperparathyroidism? 5. What is the role of gland localization technology in the management of patients with hyperparathyroidism? 6. What research should be done to clarify issues in the diagnosis and management of hyperparathyroidism? What Is the Most Accurate, Cost-Effective Method of Diagnosing Hyperparathyroidism? Primary hyperparathyroidism can best be diagnosed by showing persistent hypercalcemia with an elevated serum parathyroid hormone concentration. The measurement of total serum calcium concentration is a sensitive and cost-effective method for screening for primary hyperparathyroidism. When total serum calcium concentration is found to be elevated, the clinician should first confirm this finding under conditions that minimize the likelihood of false-positive values. The repeat blood sample should be obtained with minimal venous occlusion and, preferably, with the patient fasting. Drugs that can increase serum calcium concentration, such as thiazide diuretics, should be withdrawn for several days. Because small elevations in serum calcium concentration may be clinically important, clinicians should know the stated normal range for the laboratories used. Total calcium concentration values may be misleading in patients with decreased serum albumin levels, a problem that can be resolved with the use of an ionized serum calcium determination. Additional pertinent data may be available from multiphasic screening results. Low serum phosphorus, high chloride, low bicarbonate, and high alkaline phosphatase concentrations are consistent with, but are not diagnostic for, primary hyperparathyroidism; urea nitrogen and creatinine concentrations help in evaluating renal function. Immunoassays for intact parathyroid hormone using double-antibody methods represent a major advance in diagnosis. The majority of patients with primary hyperparathyroidism have unequivocally elevated parathyroid hormone levels according to these assays; the remainder have minimally elevated or high normal values. Patients with hypercalcemia from other causes, such as malignancy and sarcoidosis, have low normal or suppressed parathyroid hormone values. Because only rare instances of true ectopic secretion of parathyroid hormone by malignant tumors have been reported, this possibility need be considered only in patients with elevated parathyroid hormone levels and evidence of malignancy or in whom neck exploration for primary hyperparathyroidism has been unsuccessful. Borderline elevations or high normal values for intact parathyroid hormone may be found in familial hypocalciuric hypercalcemia, an uncommon, benign condition in which neck exploration is contraindicated. In this syndrome, hypercalcemia often is detected at an early age and is associated with low urinary calcium excre594
tion. The syndrome can be definitively diagnosed by measuring serum and urine calcium concentrations in family members. Family studies also are important for detecting kindreds with multiple endocrine neoplasia and familial hyperparathyroidism. Are There Patients with Asymptomatic Hyperparathyroidism Who Can Safely Be Followed without Surgery? Should They Be? The consensus panel agrees that there may be a subgroup of patients with primary hyperparathyroidism that can safely be followed without surgery. All patients with primary hyperparathyroidism should be considered to be candidates for surgery. Some patients with uncomplicated asymptomatic cases, however, may be considered for judicious nonsurgical medical monitoring. To identify patients who qualify for such management, physicians must have a clear understanding of ' 'asymptomatic" primary hyperparathyroidism and must use a rigorous evaluation and selection process. We use "asymptomatic primary hyperparathyroidism' ' to describe the clinical profile of patients with documented primary hyperparathyroidism without symptoms or signs that are commonly attributable to the disease. These patients are usually detected incidentally through multiphasic screening. Some patients may have one or several vague symptoms that cannot be definitively attributed to primary hyperparathyroidism and that may be nonspecific or that may arise from a coexisting condition. Nevertheless, for the purposes of this conference, such patients were considered to be "asymptomatic." In contrast, patients who present with important bone, renal, gastrointestinal, or neuromuscular symptoms that are typical of primary hyperparathyroidism were considered to be "symptomatic" and to require surgery. Our uncertainty about the natural history of asymptomatic primary hyperparathyroidism can be likened to the understanding of hypertension or hypercholesterolemia before large-scale epidemiologic and clinical studies were completed. No absolute clinical signs or laboratory criteria can be used to identify patients who are likely to develop complications. Decisions about surgical or medical management are based on clinical judgment on a case-by-case basis. The only acceptable treatment other than surgery for these patients is conscientious long-term medical surveillance. Indications for Medical Monitoring To qualify for nonsurgical management, a patient must have a serum calcium concentration that is only mildly elevated, no previous episodes of life-threatening hypercalcemia, and normal renal and bone status. Indications for Surgical Treatment Conversely, some asymptomatic patients have objective manifestations of primary hyperparathyroidism that are indications for surgery: a markedly elevated serum calcium concentration, a previous episode of life-threatening hypercalcemia, a reduced creatinine clearance,
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the presence of a kidney stone or stones (detected by abdominal radiography), a markedly elevated 24-hour urinary calcium excretion, or a substantially reduced bone mass (as determined by direct measurement). Mean bone density often is less than normal in patients with primary hyperparathyroidism. This diminished bone mass is most consistently noted at sites of cortical bone. Few long-term data are available about bone loss in patients with asymptomatic primary hyperparathyroidism. Further, no reported data or study presented to the conference had the requisite power, in terms of sample size or duration of follow-up, to compare the fracture rates of patients with asymptomatic primary hyperparathyroidism with those of normal persons. Because low bone mass in postmenopausal women is associated with an increased risk for fracture, we assumed that this relation would likely be valid in patients with primary hyperparathyroidism; this assumption remains to be established. The data were not sufficient to justify making precise quantitative recommendations for surgery for any of the above listed tests. Nevertheless, panel members thought that some examples should be offered as possible guidelines. Panel members considered the values mentioned below to warrant surgery. Clearly, many physicians will recommend surgery for less prominent elevations than the following: an elevation in serum calcium level of 1 to 1.6 mg/dL (0.25 to 0.4 mmol/L) above the accepted normal range (for example, 11.4 to 12 mg/dL [2.85 to 3.0 mmol/L]), given a normal range of 8.8 to 10.4 mg/dL (2.2 to 2.6 mmol/L); a creatinine clearance reduced by 30% compared with those of agematched normal persons, a confirmed 24-hour total urine calcium excretion of more than 400 mg, and a bone mass of more than 2 SDs less than those of age-, gender-, and race-matched control persons. In addition, surgery is indicated in those patients for whom medical surveillance is neither desirable nor suitable, including patients who request surgery, patients who are unlikely to return for consistent follow-up, patients whose co-existent illness complicates management, and young patients (< 50 years of age). Surgery is recommended for younger patients because the outcome of several decades of primary hyperparathyroidism is not known. In addition, for such patients, longterm compliance may be inadequate to ensure a safe outcome, and the cumulative expense and time invested in rigorous monitoring may greatly outweigh the expense and time invested in an operation. In patients with familial hypocalciuric hypercalcemia, surgery is inappropriate and should be avoided. Patients who decline recommended surgery should be followed at least as intensively as patients with asymptomatic uncomplicated hyperparathyroidism, in the manner described fn the next section. If They Are Not Operated on, How Should Asymptomatic Patients Be Monitored and Managed? Monitoring Procedures When a patient with asymptomatic hyperparathyroidism is followed without surgery, the patient must un-
derstand that forgoing parathyroid surgery is considered to be safe only with conscientious long-term monitoring. The goals of such follow-up include the early recognition of worsening hypercalcemia, bone deterioration, renal impairment, or the appearance or growth of renal stones. The patient should be seen at least semi-annually until the lack of disease progression has been established. Once the stability of the relevant variables has been established over 1 to 3 years, the intervals between observations can be safely extended. The patient should be queried specifically about neuromuscular weakness, depression, and symptoms related to the skeletal, gastrointestinal, and renal systems. The following variables should be measured at each visit: blood pressure, serum calcium concentration, and serum creatinine and creatinine clearance. In addition, the panel recommends that abdominal radiographs be obtained annually, that 24-hour urinary calcium concentration be measured in selected patients, and that bone mass measurement be repeated after 1 to 2 years. Bone mass should be remeasured after an interval that is adequate to assess whether a substantial amount of bone has been lost. The appropriate interval depends on the precision of the instrument available. The panel acknowledges that the ideal method for monitoring changes in bone mass in these patients has not been adequately identified. Some evidence suggests that measuring bone density in the forearm with single-photon absorptiometry may be useful in monitoring changes in bone density. Alternative densitometric methods, such as dual-energy x-ray absorptiometry, may soon become preferable in identifying subtle changes in cortical bone. Although a change to surgical therapy can be recommended solely on the basis of an abnormally low value of bone density, such a decision remains controversial in the management of patients with asymptomatic hyperparathyroidism. Management during Surveillance Some aspects of management should be advised for all patients being followed without surgery: Patients should avoid dehydration, immobilization, and a diet with inadequate or excessive calcium. Loop or thiazide diuretics should be used only with caution. Because of the risk for a hypercalcemic crisis, patients should be advised to seek immediate medical care when they develop a medical illness that may produce dehydration (for example, vomiting, diarrhea). All, even mild, hypertension should be adequately treated. Many physicians prescribe estrogen therapy for postmenopausal women, because of its beneficial effect on postmenopausal osteoporosis and cardiovascular risk factors. Although evidence suggests that estrogen therapy can reduce the action of parathyroid hormone on bone and can decrease serum calcium concentration without increasing parathyroid hormone level, the data on long-term estrogen therapy in postmenopausal patients with asymptomatic hyperparathyroidism are limited. The use of other drugs that modify the parathyroid hormone-induced stimulation of bone resorption, such
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as the bisphosphonates, oral phosphate, calcitonin, or mithramycin, is not presently indicated in patients with asymptomatic hyperparathyroidism. However, bisphosphonates or oral phosphate may be considered for use in the rare patient with symptomatic hyperparathyroidism who is not a surgical candidate because of severe concurrent diseases. What Are the Indications for Surgery in Patients with Asymptomatic Hyperparathyroidism? During monitoring of asymptomatic patients, the following developments may warrant consideration of operative intervention: typical parathyroid-related symptoms involving the skeletal, renal, or gastrointestinal systems; a sustained increase in serum calcium concentration of greater than 1.0 to 1.6 mg/dL (0.25 to 0.4 mmol/L) above the normal range; a substantial decline in renal function; the presence of nephrolithiasis or the worsening of calciuria; a substantial decline in bone mass; important neuromuscular or psychologic symptoms without other obvious causes; and the inability or the unwillingness of the patient to continue under medical supervision. In addition to the absolute level of serum calcium, clinicians need to consider the magnitude of the change over time. Renal function should be assessed by measuring creatinine clearance. Although the panel could not define precise values, a confirmed decrease of more than 30% was considered to be substantial. The importance of declining bone mass is controversial and a decrease to 2 SDs less than the mean for age-, sex-, and race-matched control persons was considered to be sufficient to warrant surgery. The relation between psychologic symptoms and hyperparathyroidism is uncertain. All investigators have suggested that neuromuscular symptoms are frequent and are often reversed by successful parathyroidectomy, but that other, less specific, somatic symptoms are rarely improved by operation. What Is the Role of Gland Localization Technology in the Management of Patients with Hyperparathyroidism? Imaging of the parathyroid glands before an initial neck exploration is not necessary. In the past 4 years, extensive experience has been acquired in nonoperative methods for localizing abnormal parathyroid glands. Both noninvasive methods (ultrasound, computed tomography, thallium-technetium scanning, magnetic resonance imaging) and invasive methods (arteriography, venous sampling, needle aspiration) are available. Such methods may be useful when a previous operation has failed. Because of their potential risks, however, invasive imaging techniques should never be used before the neck is first explored. The use of noninvasive imaging procedures before a first operation is controversial. Some surgeons never use these techniques, whereas others find them to be helpful in planning the sequence of an operation. The usefulness of all noninvasive imaging methods is diminished by their unreliability (approximately 15% of results are falsely positive and only 60% of results are 596
truly positive). In contrast, operative exploration of the neck by experienced surgeons has a proved success rate of 95%. No evidence indicates that preoperative imaging can substantially shorten surgical time, decrease surgical cost, decrease surgical complications, or prevent surgical failure. The results of imaging studies should seldom, if ever, be used as the basis for selecting patients for operative or nonoperative management. What Research Should Be Done To Clarify Issues in the Diagnosis and Management of Hyperparathyroidism? Ultimately, to predict outcomes in asymptomatic hyperparathyroidism and to decide on operative or nonoperative management, a multicenter, randomized, controlled trial of sufficient size and duration must be conducted to assess the long-term incidence and the progression of complications. Many specific issues that need to be resolved before such a trial can be designed, however, were identified during the conference. In particular, defining the neuromuscular, psychologic, cardiovascular, and gastrointestinal effects of primary hyperparathyroidism is important. The effects of asymptomatic hyperparathyroidism on bone mass and structure are being defined in ongoing studies, but the effects on bone strength and susceptibility to fracture also should be addressed. The case-control method might be a feasible initial approach. Patients with hyperparathyroidism having parathyroidectomy and carefully matched control patients having other elective surgical procedures, such as thyroidectomy, could be objectively analyzed before and after surgery. Epidemiologic studies using existing databases, such as the National Health and Nutrition Examination Survey, might identify conditions that are associated with primary hyperparathyroidism because the majority of patients who are identified with hypercalcemia would have hyperparathyroidism. In addition, collecting and organizing the data on fracture, change in bone mass and histomorphometry, and other complications of patients currently being followed in specialized centers may be desirable. A preliminary clinical trial assessing bone mass outcomes and biochemical measures of bone turnover in postmenopausal women with hyperparathyroidism who are randomly assigned to receive estrogen plus surgery compared with estrogen alone for a limited time might establish the feasibility of and guide the design of a large multicenter trial. Such a trial would permit analysis of the effects of hyperparathyroidism without the confounding effects of estrogen deficiency, yet would provide access to the patient group with the highest incidence of hyperparathyroidism. Basic studies are needed on the cause and molecular and cellular pathophysiology of hyperparathyroidism. The identification of the gene locus on the long arm of chromosome 11 for the multiple endocrine neoplasia I gene, the discovery of reciprocal translocations in parathyroid adenomas involving the parathyroid hormone gene, and evidence for deletions of one or both copies of the multiple endocrine neoplasia I gene in hyperplasia and adenomas (suggesting that this gene is antioncogenic) all provide an exciting opportunity to explore
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abnormal parathyroid function. The pathogenesis and complications also could be better understood through the development of animal models of hyperparathyroidism. Recent clinical studies using calcitriol and its analogs to treat secondary hyperparathyroidism suggest that parathyroid gland function may be controlled pharmacologically. The development of antagonists of parathyroid hormone synthesis, secretion, and end-organ effect would substantially increase therapeutic options for hyperparathyroidism and would influence the design of clinical trials. Conclusions and Recommendations The diagnosis of primary hyperparathyroidism is established by showing persistent hypercalcemia with an elevated serum parathyroid hormone concentration. Operative intervention for cure is the current and acceptable treatment for primary hyperparathyroidism. The diagnosis of asymptomatic primary hyperparathyroidism, however, does not in all cases mandate referral for imminent operative intervention; conscientious surveillance may be justified in patients whose calcium levels are only mildly elevated and whose renal and bone status are close to normal. During the long-term medical and nonoperative follow-up of these patients, a schedule of monitoring has been devised with assessment of specific symptoms and the measurement of biochemical variables and bone mineral content. Management guidelines are devised to minimize the risk for deterioration of renal, skeletal, or gastrointestinal complications of hyperparathyroidism. Changes that may warrant operative intervention during monitoring include an increase in serum calcium level, a deterioration in renal function, a decline in bone mass, and the onset of parathyroid-related symptoms. Preoperative localization in patients without previous neck operation is rarely indicated and has not proved to be cost effective. A randomized multicenter clinical trial is needed to compare the operative with the nonoperative management of asymptomatic hyperparathyroidism. Pilot studies would be useful to define this disease's multisystem effects, and further basic research is required to understand the disease's pathogenesis and to develop pharmacologic therapy. Consensus Development Conference Panel John T. Potts, Jr., MD, Chair, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. Irving P. Ackerman, MD, Southern California Permanente MedicaJ Group, Internal Medicine 5-A, 5th Floor, Module A, 4950 Sunset Boulevard, Los Angeles, CA 90027. Clyde F. Barker, MD, Department of Surgery, University of Pennsylvania Medical Center, 3400 Spruce Street, 4th Floor, Silverstein Pavilion, Philadelphia, PA 19104. Murray F. Brennan, MD, Department of Surgery, Memorial Sloan-
Kettering Cancer Center, Room C-1272, 1275 York Avenue, New York, NY 10021. Jack W. Coburn, MD, Department of Nephrology (W11IL), West Los Angeles Veterans Administration Medical Center, UCLA School of Medicine, Wilshire and Sawtelle Boulevards, West Los Angeles, CA 90073. Siu L. Hui, PhD, Division of Biostatistics, Indiana University School of Medicine, Rile Research, Room 135, 702 Barnhill Drive, Indianapolis, IN 46202. G. Leland Melson, MD, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway, St. Louis, MO 63110. Lawrence G. Raisz, MD, Division of Endocrinology and Metabolism, University of Connecticut Health Center, 163 Farmington Avenue, Farmington, CT 06032. Michael Rosenblatt, MD, Merck Sharp and Dohme Research Laboratories, West Point, PA 19486. Clinton T. Rubin, PhD, Musculoskeletal Research Laboratory, Department of Orthopedics, Health Science Center, State University of New York at Stony Brook, Tower 18, Room 030, Stony Brook, NY 117948181. Janet A. Schlechte, MD, Clinical Research Center, 157 MRF, University of Iowa College of Medicine, Iowa City, IA 52242. John L. Townsend, MD, Department of Medicine, Howard University College of Medicine, 2041 Georgia Avenue, NW, Suite 5C, Washington, DC 20060. Lawrence K. Wolfe, MD, Vanderbilt University School of Medicine, Suite 525 Street Thomas Medical Plaza East, 4230 Harding Road, Nashville, TN 37205. Glenda L. Wong, PhD, Department of Biology, University of Colorado at Colorado Springs, 1420 Austin Bluff Parkway, Colorado Springs, CO 80907.
Speakers Allen M. Spiegel, MD; Stephen J. Marx, MD; L. Joseph Melton III, MD; Jack H. Ladenson, PhD; Samuel R. Nussbaum, MD; Frederic W. Lafferty, MD; Hunter Heath III, MD; Susan M. Ott, MD; Munro Peacock, MD; John P. Bilezikian, MD; Phillip Clifton-Bligh, MBBS, BScMed; Don C. Purnell, MD; A. Michael Parfitt, MB, BChir; Robert M. Neer, MD; Sverker Ljunghall, MD, PhD; David A. Heath, MB, ChB; Robert Marcus, MD; Elizabeth Shane, MD; Orlo H. Clark, MD; Samuel A. Wells, Jr, MD; John L. Doppman, MD.
Planning Committee Judith E. Fradkin, MD, Chair, Endocrinology and Metabolic Diseases Programs Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Gerald D. Aurbach, MD, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Linda Blankenbaker, Office of Medical Applications of Research, National Institutes of Health, Bethesda, Maryland. Benjamin T. Burton, PhD, Office of Disease Prevention and Technology Transfer, National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health, Bethesda, Maryland. Jane Demouy, Information Office, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. John H. Ferguson, MD, Office of Medical Applications of Research, National Institutes of Health, Bethesda, Maryland. Willis R. Foster, MD, Office of Disease Prevention and Technology Transfer, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland William H. Hall, Office of Medical Applications of Research, National Institutes of Health, Bethesda, Maryland. Hunter Heath III, MD, Mayo Clinic, Mayo Medical School, Rochester, Minnesota. Stephen J. Marx, MD, Mineral Metabolism Section, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Susan M. Ott, MD, Department of Medicine, University of Washington, Seattle, Washington. John T. Potts, Jr, MD, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Samuel A. Wells, Jr, MD, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
1 April 1991 • Annals of Internal Medicine
• Volume 114 • Number 7
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CONFERENCE
Diagnosis and Management of Asymptomatic Primary Hyperparathyroidism: Consensus Development Conference Statement Consensus Development Conference Panel*
Endocrinologists, surgeons, radiologists, epidemiologists, and primary health care providers convened to address both indications for surgery in asymptomatic patients with hyperparathyroidism as well as how patients who do not have surgery should be monitored and managed to minimize the risk for complications. The National Institutes of Health Consensus Development Conference Panel concluded that a diagnosis of hyperparathyroidism is established by showing persistent hypercalcemia and an elevated serum parathyroid hormone concentration; that the current and acceptable treatment for hyperparathyroidism is surgery; that the diagnosis of hyperparathyroidism in an asymptomatic patient does not in all cases mandate referral for surgery; that conscientious surveillance may be justified in patients whose calcium levels are only mildly elevated and whose renal and bone status are close to normal; and that preoperative localization in patients without previous neck operation is rarely indicated and has not proved to be cost effective.
Annals of Internal Medicine. 1991;114:593-597.
riyperparathyroidism is increasingly being recognized because of the widespread use of multiphasic screening for hypercalcemia. Women are affected twice as often as men, and the incidence of hyperparathyroidism increases with age. Approximately 100 000 new cases develop each year in the United States. Because the disease is now known to be more common than was previously appreciated, physicians are increasingly interested in the correct diagnosis and the proper management of patients with hyperparathyroidism. The increased recognition of hyperparathyroidism with the use of screening tests has disclosed a group of patients in whom symptoms are subtle or absent. A new clinical profile of hyperparathyroidism that is characterized by mild hypercalcemia has emerged. Presentation with bone disease that is evident from standard radiography or from the presence of nephrolithiasis or other An edited summary of a Consensus Development Conference held from 29 to 31 October 1990 at Masur Auditorium, Building 10, Bethesda, Maryland. The conference was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases and the Office of Medical Applications of Research, National Institutes of Health. Authors who wish to cite the conference may use this example for the form of reference: Consensus Development Conference Panel. Diagnosis and management of asymptomatic primary hyperparathyroidism: Consensus Development Conference statement. Ann Intern Med. 1991 ;114:593597. * For participating organizations and investigators, see end of text.
complications is now uncommon, yet it is not clear that incidentally discovered hyperparathyroidism is benign. Studies of the natural history of hyperparathyroidism are yielding information about how often and over what time course the mild syndrome remains benign. Silent loss of bone mass and changes in skeletal architecture in this asymptomatic patient group are being assessed with sensitive new techniques. The clinical importance of changes in bone density is uncertain, but it seems likely that progressive parathyroid-dependent bone loss is an additional risk factor for fractures. The potential for mild hyperparathyroidism to cause or to accelerate hypertension, renal deterioration, peptic ulcer disease, and psychiatric symptoms also is being evaluated. Parathyroidectomy is highly successful when done by experienced surgeons. The evidence suggests that some patients with asymptomatic primary hyperparathyroidism may have a prolonged benign course; perhaps such patients can be managed without operative intervention. If patients are not operated on, they must be monitored to detect progression of the disease. For these patients, the principal issue is how they can be best monitored, balancing the need to identify skeletal, renal, or other complications that are indications for operation with the burdens and expense of long-term monitoring. Evaluation of the long-term consequences of asymptomatic hyperparathyroidism with and without surgical treatment will answer questions about the optimal management of this condition. Predictive factors, if they can be discerned, would help to distinguish subgroups of patients who will develop adverse effects from those who will tolerate mild hyperparathyroidism without developing complications. The identification of such factors would substantially affect the justification for operative or nonoperative management. To address these issues, from 29 to 31 October 1990, the National Institute of Diabetes and Digestive and Kidney Diseases, together with the Office of Medical Applications of Research of the National Institutes of Health, convened a consensus development conference on the diagnosis and management of asymptomatic primary hyperparathyroidism. After experts in the relevant fields presented and the audience discussed the issues, a consensus panel comprising specialists and generalists from the medical and other related scientific disciplines considered the evidence and formulated a consensus statement in response to the following six previously stated questions: 1. What is the most accurate, cost-effective method of diagnosing hyperparathyroidism? 2. Are there patients with asymptomatic hyperpara-
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thyroidism who can safely be followed without surgery? Should they be? 3. If they are not operated on, how should asymptomatic patients be monitored and managed? 4. What are the indications for surgery in patients with asymptomatic hyperparathyroidism? 5. What is the role of gland localization technology in the management of patients with hyperparathyroidism? 6. What research should be done to clarify issues in the diagnosis and management of hyperparathyroidism? What Is the Most Accurate, Cost-Effective Method of Diagnosing Hyperparathyroidism? Primary hyperparathyroidism can best be diagnosed by showing persistent hypercalcemia with an elevated serum parathyroid hormone concentration. The measurement of total serum calcium concentration is a sensitive and cost-effective method for screening for primary hyperparathyroidism. When total serum calcium concentration is found to be elevated, the clinician should first confirm this finding under conditions that minimize the likelihood of false-positive values. The repeat blood sample should be obtained with minimal venous occlusion and, preferably, with the patient fasting. Drugs that can increase serum calcium concentration, such as thiazide diuretics, should be withdrawn for several days. Because small elevations in serum calcium concentration may be clinically important, clinicians should know the stated normal range for the laboratories used. Total calcium concentration values may be misleading in patients with decreased serum albumin levels, a problem that can be resolved with the use of an ionized serum calcium determination. Additional pertinent data may be available from multiphasic screening results. Low serum phosphorus, high chloride, low bicarbonate, and high alkaline phosphatase concentrations are consistent with, but are not diagnostic for, primary hyperparathyroidism; urea nitrogen and creatinine concentrations help in evaluating renal function. Immunoassays for intact parathyroid hormone using double-antibody methods represent a major advance in diagnosis. The majority of patients with primary hyperparathyroidism have unequivocally elevated parathyroid hormone levels according to these assays; the remainder have minimally elevated or high normal values. Patients with hypercalcemia from other causes, such as malignancy and sarcoidosis, have low normal or suppressed parathyroid hormone values. Because only rare instances of true ectopic secretion of parathyroid hormone by malignant tumors have been reported, this possibility need be considered only in patients with elevated parathyroid hormone levels and evidence of malignancy or in whom neck exploration for primary hyperparathyroidism has been unsuccessful. Borderline elevations or high normal values for intact parathyroid hormone may be found in familial hypocalciuric hypercalcemia, an uncommon, benign condition in which neck exploration is contraindicated. In this syndrome, hypercalcemia often is detected at an early age and is associated with low urinary calcium excre594
tion. The syndrome can be definitively diagnosed by measuring serum and urine calcium concentrations in family members. Family studies also are important for detecting kindreds with multiple endocrine neoplasia and familial hyperparathyroidism. Are There Patients with Asymptomatic Hyperparathyroidism Who Can Safely Be Followed without Surgery? Should They Be? The consensus panel agrees that there may be a subgroup of patients with primary hyperparathyroidism that can safely be followed without surgery. All patients with primary hyperparathyroidism should be considered to be candidates for surgery. Some patients with uncomplicated asymptomatic cases, however, may be considered for judicious nonsurgical medical monitoring. To identify patients who qualify for such management, physicians must have a clear understanding of ' 'asymptomatic" primary hyperparathyroidism and must use a rigorous evaluation and selection process. We use "asymptomatic primary hyperparathyroidism' ' to describe the clinical profile of patients with documented primary hyperparathyroidism without symptoms or signs that are commonly attributable to the disease. These patients are usually detected incidentally through multiphasic screening. Some patients may have one or several vague symptoms that cannot be definitively attributed to primary hyperparathyroidism and that may be nonspecific or that may arise from a coexisting condition. Nevertheless, for the purposes of this conference, such patients were considered to be "asymptomatic." In contrast, patients who present with important bone, renal, gastrointestinal, or neuromuscular symptoms that are typical of primary hyperparathyroidism were considered to be "symptomatic" and to require surgery. Our uncertainty about the natural history of asymptomatic primary hyperparathyroidism can be likened to the understanding of hypertension or hypercholesterolemia before large-scale epidemiologic and clinical studies were completed. No absolute clinical signs or laboratory criteria can be used to identify patients who are likely to develop complications. Decisions about surgical or medical management are based on clinical judgment on a case-by-case basis. The only acceptable treatment other than surgery for these patients is conscientious long-term medical surveillance. Indications for Medical Monitoring To qualify for nonsurgical management, a patient must have a serum calcium concentration that is only mildly elevated, no previous episodes of life-threatening hypercalcemia, and normal renal and bone status. Indications for Surgical Treatment Conversely, some asymptomatic patients have objective manifestations of primary hyperparathyroidism that are indications for surgery: a markedly elevated serum calcium concentration, a previous episode of life-threatening hypercalcemia, a reduced creatinine clearance,
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the presence of a kidney stone or stones (detected by abdominal radiography), a markedly elevated 24-hour urinary calcium excretion, or a substantially reduced bone mass (as determined by direct measurement). Mean bone density often is less than normal in patients with primary hyperparathyroidism. This diminished bone mass is most consistently noted at sites of cortical bone. Few long-term data are available about bone loss in patients with asymptomatic primary hyperparathyroidism. Further, no reported data or study presented to the conference had the requisite power, in terms of sample size or duration of follow-up, to compare the fracture rates of patients with asymptomatic primary hyperparathyroidism with those of normal persons. Because low bone mass in postmenopausal women is associated with an increased risk for fracture, we assumed that this relation would likely be valid in patients with primary hyperparathyroidism; this assumption remains to be established. The data were not sufficient to justify making precise quantitative recommendations for surgery for any of the above listed tests. Nevertheless, panel members thought that some examples should be offered as possible guidelines. Panel members considered the values mentioned below to warrant surgery. Clearly, many physicians will recommend surgery for less prominent elevations than the following: an elevation in serum calcium level of 1 to 1.6 mg/dL (0.25 to 0.4 mmol/L) above the accepted normal range (for example, 11.4 to 12 mg/dL [2.85 to 3.0 mmol/L]), given a normal range of 8.8 to 10.4 mg/dL (2.2 to 2.6 mmol/L); a creatinine clearance reduced by 30% compared with those of agematched normal persons, a confirmed 24-hour total urine calcium excretion of more than 400 mg, and a bone mass of more than 2 SDs less than those of age-, gender-, and race-matched control persons. In addition, surgery is indicated in those patients for whom medical surveillance is neither desirable nor suitable, including patients who request surgery, patients who are unlikely to return for consistent follow-up, patients whose co-existent illness complicates management, and young patients (< 50 years of age). Surgery is recommended for younger patients because the outcome of several decades of primary hyperparathyroidism is not known. In addition, for such patients, longterm compliance may be inadequate to ensure a safe outcome, and the cumulative expense and time invested in rigorous monitoring may greatly outweigh the expense and time invested in an operation. In patients with familial hypocalciuric hypercalcemia, surgery is inappropriate and should be avoided. Patients who decline recommended surgery should be followed at least as intensively as patients with asymptomatic uncomplicated hyperparathyroidism, in the manner described fn the next section. If They Are Not Operated on, How Should Asymptomatic Patients Be Monitored and Managed? Monitoring Procedures When a patient with asymptomatic hyperparathyroidism is followed without surgery, the patient must un-
derstand that forgoing parathyroid surgery is considered to be safe only with conscientious long-term monitoring. The goals of such follow-up include the early recognition of worsening hypercalcemia, bone deterioration, renal impairment, or the appearance or growth of renal stones. The patient should be seen at least semi-annually until the lack of disease progression has been established. Once the stability of the relevant variables has been established over 1 to 3 years, the intervals between observations can be safely extended. The patient should be queried specifically about neuromuscular weakness, depression, and symptoms related to the skeletal, gastrointestinal, and renal systems. The following variables should be measured at each visit: blood pressure, serum calcium concentration, and serum creatinine and creatinine clearance. In addition, the panel recommends that abdominal radiographs be obtained annually, that 24-hour urinary calcium concentration be measured in selected patients, and that bone mass measurement be repeated after 1 to 2 years. Bone mass should be remeasured after an interval that is adequate to assess whether a substantial amount of bone has been lost. The appropriate interval depends on the precision of the instrument available. The panel acknowledges that the ideal method for monitoring changes in bone mass in these patients has not been adequately identified. Some evidence suggests that measuring bone density in the forearm with single-photon absorptiometry may be useful in monitoring changes in bone density. Alternative densitometric methods, such as dual-energy x-ray absorptiometry, may soon become preferable in identifying subtle changes in cortical bone. Although a change to surgical therapy can be recommended solely on the basis of an abnormally low value of bone density, such a decision remains controversial in the management of patients with asymptomatic hyperparathyroidism. Management during Surveillance Some aspects of management should be advised for all patients being followed without surgery: Patients should avoid dehydration, immobilization, and a diet with inadequate or excessive calcium. Loop or thiazide diuretics should be used only with caution. Because of the risk for a hypercalcemic crisis, patients should be advised to seek immediate medical care when they develop a medical illness that may produce dehydration (for example, vomiting, diarrhea). All, even mild, hypertension should be adequately treated. Many physicians prescribe estrogen therapy for postmenopausal women, because of its beneficial effect on postmenopausal osteoporosis and cardiovascular risk factors. Although evidence suggests that estrogen therapy can reduce the action of parathyroid hormone on bone and can decrease serum calcium concentration without increasing parathyroid hormone level, the data on long-term estrogen therapy in postmenopausal patients with asymptomatic hyperparathyroidism are limited. The use of other drugs that modify the parathyroid hormone-induced stimulation of bone resorption, such
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as the bisphosphonates, oral phosphate, calcitonin, or mithramycin, is not presently indicated in patients with asymptomatic hyperparathyroidism. However, bisphosphonates or oral phosphate may be considered for use in the rare patient with symptomatic hyperparathyroidism who is not a surgical candidate because of severe concurrent diseases. What Are the Indications for Surgery in Patients with Asymptomatic Hyperparathyroidism? During monitoring of asymptomatic patients, the following developments may warrant consideration of operative intervention: typical parathyroid-related symptoms involving the skeletal, renal, or gastrointestinal systems; a sustained increase in serum calcium concentration of greater than 1.0 to 1.6 mg/dL (0.25 to 0.4 mmol/L) above the normal range; a substantial decline in renal function; the presence of nephrolithiasis or the worsening of calciuria; a substantial decline in bone mass; important neuromuscular or psychologic symptoms without other obvious causes; and the inability or the unwillingness of the patient to continue under medical supervision. In addition to the absolute level of serum calcium, clinicians need to consider the magnitude of the change over time. Renal function should be assessed by measuring creatinine clearance. Although the panel could not define precise values, a confirmed decrease of more than 30% was considered to be substantial. The importance of declining bone mass is controversial and a decrease to 2 SDs less than the mean for age-, sex-, and race-matched control persons was considered to be sufficient to warrant surgery. The relation between psychologic symptoms and hyperparathyroidism is uncertain. All investigators have suggested that neuromuscular symptoms are frequent and are often reversed by successful parathyroidectomy, but that other, less specific, somatic symptoms are rarely improved by operation. What Is the Role of Gland Localization Technology in the Management of Patients with Hyperparathyroidism? Imaging of the parathyroid glands before an initial neck exploration is not necessary. In the past 4 years, extensive experience has been acquired in nonoperative methods for localizing abnormal parathyroid glands. Both noninvasive methods (ultrasound, computed tomography, thallium-technetium scanning, magnetic resonance imaging) and invasive methods (arteriography, venous sampling, needle aspiration) are available. Such methods may be useful when a previous operation has failed. Because of their potential risks, however, invasive imaging techniques should never be used before the neck is first explored. The use of noninvasive imaging procedures before a first operation is controversial. Some surgeons never use these techniques, whereas others find them to be helpful in planning the sequence of an operation. The usefulness of all noninvasive imaging methods is diminished by their unreliability (approximately 15% of results are falsely positive and only 60% of results are 596
truly positive). In contrast, operative exploration of the neck by experienced surgeons has a proved success rate of 95%. No evidence indicates that preoperative imaging can substantially shorten surgical time, decrease surgical cost, decrease surgical complications, or prevent surgical failure. The results of imaging studies should seldom, if ever, be used as the basis for selecting patients for operative or nonoperative management. What Research Should Be Done To Clarify Issues in the Diagnosis and Management of Hyperparathyroidism? Ultimately, to predict outcomes in asymptomatic hyperparathyroidism and to decide on operative or nonoperative management, a multicenter, randomized, controlled trial of sufficient size and duration must be conducted to assess the long-term incidence and the progression of complications. Many specific issues that need to be resolved before such a trial can be designed, however, were identified during the conference. In particular, defining the neuromuscular, psychologic, cardiovascular, and gastrointestinal effects of primary hyperparathyroidism is important. The effects of asymptomatic hyperparathyroidism on bone mass and structure are being defined in ongoing studies, but the effects on bone strength and susceptibility to fracture also should be addressed. The case-control method might be a feasible initial approach. Patients with hyperparathyroidism having parathyroidectomy and carefully matched control patients having other elective surgical procedures, such as thyroidectomy, could be objectively analyzed before and after surgery. Epidemiologic studies using existing databases, such as the National Health and Nutrition Examination Survey, might identify conditions that are associated with primary hyperparathyroidism because the majority of patients who are identified with hypercalcemia would have hyperparathyroidism. In addition, collecting and organizing the data on fracture, change in bone mass and histomorphometry, and other complications of patients currently being followed in specialized centers may be desirable. A preliminary clinical trial assessing bone mass outcomes and biochemical measures of bone turnover in postmenopausal women with hyperparathyroidism who are randomly assigned to receive estrogen plus surgery compared with estrogen alone for a limited time might establish the feasibility of and guide the design of a large multicenter trial. Such a trial would permit analysis of the effects of hyperparathyroidism without the confounding effects of estrogen deficiency, yet would provide access to the patient group with the highest incidence of hyperparathyroidism. Basic studies are needed on the cause and molecular and cellular pathophysiology of hyperparathyroidism. The identification of the gene locus on the long arm of chromosome 11 for the multiple endocrine neoplasia I gene, the discovery of reciprocal translocations in parathyroid adenomas involving the parathyroid hormone gene, and evidence for deletions of one or both copies of the multiple endocrine neoplasia I gene in hyperplasia and adenomas (suggesting that this gene is antioncogenic) all provide an exciting opportunity to explore
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abnormal parathyroid function. The pathogenesis and complications also could be better understood through the development of animal models of hyperparathyroidism. Recent clinical studies using calcitriol and its analogs to treat secondary hyperparathyroidism suggest that parathyroid gland function may be controlled pharmacologically. The development of antagonists of parathyroid hormone synthesis, secretion, and end-organ effect would substantially increase therapeutic options for hyperparathyroidism and would influence the design of clinical trials. Conclusions and Recommendations The diagnosis of primary hyperparathyroidism is established by showing persistent hypercalcemia with an elevated serum parathyroid hormone concentration. Operative intervention for cure is the current and acceptable treatment for primary hyperparathyroidism. The diagnosis of asymptomatic primary hyperparathyroidism, however, does not in all cases mandate referral for imminent operative intervention; conscientious surveillance may be justified in patients whose calcium levels are only mildly elevated and whose renal and bone status are close to normal. During the long-term medical and nonoperative follow-up of these patients, a schedule of monitoring has been devised with assessment of specific symptoms and the measurement of biochemical variables and bone mineral content. Management guidelines are devised to minimize the risk for deterioration of renal, skeletal, or gastrointestinal complications of hyperparathyroidism. Changes that may warrant operative intervention during monitoring include an increase in serum calcium level, a deterioration in renal function, a decline in bone mass, and the onset of parathyroid-related symptoms. Preoperative localization in patients without previous neck operation is rarely indicated and has not proved to be cost effective. A randomized multicenter clinical trial is needed to compare the operative with the nonoperative management of asymptomatic hyperparathyroidism. Pilot studies would be useful to define this disease's multisystem effects, and further basic research is required to understand the disease's pathogenesis and to develop pharmacologic therapy. Consensus Development Conference Panel John T. Potts, Jr., MD, Chair, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. Irving P. Ackerman, MD, Southern California Permanente MedicaJ Group, Internal Medicine 5-A, 5th Floor, Module A, 4950 Sunset Boulevard, Los Angeles, CA 90027. Clyde F. Barker, MD, Department of Surgery, University of Pennsylvania Medical Center, 3400 Spruce Street, 4th Floor, Silverstein Pavilion, Philadelphia, PA 19104. Murray F. Brennan, MD, Department of Surgery, Memorial Sloan-
Kettering Cancer Center, Room C-1272, 1275 York Avenue, New York, NY 10021. Jack W. Coburn, MD, Department of Nephrology (W11IL), West Los Angeles Veterans Administration Medical Center, UCLA School of Medicine, Wilshire and Sawtelle Boulevards, West Los Angeles, CA 90073. Siu L. Hui, PhD, Division of Biostatistics, Indiana University School of Medicine, Rile Research, Room 135, 702 Barnhill Drive, Indianapolis, IN 46202. G. Leland Melson, MD, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway, St. Louis, MO 63110. Lawrence G. Raisz, MD, Division of Endocrinology and Metabolism, University of Connecticut Health Center, 163 Farmington Avenue, Farmington, CT 06032. Michael Rosenblatt, MD, Merck Sharp and Dohme Research Laboratories, West Point, PA 19486. Clinton T. Rubin, PhD, Musculoskeletal Research Laboratory, Department of Orthopedics, Health Science Center, State University of New York at Stony Brook, Tower 18, Room 030, Stony Brook, NY 117948181. Janet A. Schlechte, MD, Clinical Research Center, 157 MRF, University of Iowa College of Medicine, Iowa City, IA 52242. John L. Townsend, MD, Department of Medicine, Howard University College of Medicine, 2041 Georgia Avenue, NW, Suite 5C, Washington, DC 20060. Lawrence K. Wolfe, MD, Vanderbilt University School of Medicine, Suite 525 Street Thomas Medical Plaza East, 4230 Harding Road, Nashville, TN 37205. Glenda L. Wong, PhD, Department of Biology, University of Colorado at Colorado Springs, 1420 Austin Bluff Parkway, Colorado Springs, CO 80907.
Speakers Allen M. Spiegel, MD; Stephen J. Marx, MD; L. Joseph Melton III, MD; Jack H. Ladenson, PhD; Samuel R. Nussbaum, MD; Frederic W. Lafferty, MD; Hunter Heath III, MD; Susan M. Ott, MD; Munro Peacock, MD; John P. Bilezikian, MD; Phillip Clifton-Bligh, MBBS, BScMed; Don C. Purnell, MD; A. Michael Parfitt, MB, BChir; Robert M. Neer, MD; Sverker Ljunghall, MD, PhD; David A. Heath, MB, ChB; Robert Marcus, MD; Elizabeth Shane, MD; Orlo H. Clark, MD; Samuel A. Wells, Jr, MD; John L. Doppman, MD.
Planning Committee Judith E. Fradkin, MD, Chair, Endocrinology and Metabolic Diseases Programs Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Gerald D. Aurbach, MD, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Linda Blankenbaker, Office of Medical Applications of Research, National Institutes of Health, Bethesda, Maryland. Benjamin T. Burton, PhD, Office of Disease Prevention and Technology Transfer, National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health, Bethesda, Maryland. Jane Demouy, Information Office, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. John H. Ferguson, MD, Office of Medical Applications of Research, National Institutes of Health, Bethesda, Maryland. Willis R. Foster, MD, Office of Disease Prevention and Technology Transfer, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland William H. Hall, Office of Medical Applications of Research, National Institutes of Health, Bethesda, Maryland. Hunter Heath III, MD, Mayo Clinic, Mayo Medical School, Rochester, Minnesota. Stephen J. Marx, MD, Mineral Metabolism Section, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Susan M. Ott, MD, Department of Medicine, University of Washington, Seattle, Washington. John T. Potts, Jr, MD, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Samuel A. Wells, Jr, MD, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
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