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Surgical exploration in asymptomatic hypercalcemia
Surgical Exploration in Asymptomatic
Hypercalcemia
Ea.rly Treatment of Hyperparathyroidism Joseph N. Attle, MD, New Hyde Park, New York Rene A. Khafif, MD, New Hyde Park, New York
Fifty years have elapsed since the first report of removal of a parathyroid tumor in a patient with osteitis fibrosa cystica [I]. During the next ten years hyperparathyroidism was rarely recognized. In 1934, Albright, Aub, and Bauer [2] demonstrated the frequency of renal calculi as the presenting feature of the disease. During the ensuing years the condition was recognized more frequently and several syndromes besides skeletal and renal were found to occur with hyperparathyroidism. These included peptic ulcer, pancreatitis, and mental and neurologic symptoms. Furthermore, the increasing alertness of physicians to the disease led to frequent chemical evaluations in patients with ‘minimal symptoms, such as polydipsia, fatigue, nausea, and polyuria, and to the earlier diagnosis and treatment of hyperparathyroidism. The introduction of the -serum autoanalyzer (SMA-12) has resulted in a marked increase in the diagnosis of hyperparathyroidism in the absence of symptoms. There has been considerable debate concerning the indications for surgery in such patients. During the past seven years, we have explored seventy-five patients with asymptomatic hypercalcemia: sixty-eight with solitary adenomas, six with multiple adenomas, and one with diffuse hyperplasia. Postoperatively, all the patients reverted to normocalcemia and there were no complications or fatalities in this group of patients. Material and Methods The clinical material reviewed includes 248 cases explored by us over a period of twenty-five years. In 237 of these, hyperparathyroidism was confirmed at surgery and From the Department of Surgery, Long island Jewish Medical Center, New Hyde Park, New York. Reprint requests shouu be addressed to Joseph N. Attie, MD, 105 South Middle Neck Road. Great Neck, New York 11021. Presented at the Joint Meeting of tha Society of Head and Neck Surgeons and the American Society for Head and Neck Swgery, San Diego, Califcmia. April 1 l-15. 1976.
successfully treated. The various presenting manifestations in these 237 patients included: renal calculi (87 patients), skeletal manifestations (12), gastrointestinal (ulcer, pancreatitis) (9), insulinoma (2), neurologic or psychotic manifestations (6), coma (7), minimal symptoms (fatigue, frequency) (6), asymptomatic hypercalcemia @MA-12 finding) (75), incidental (during thyroid explorations) (16), and secondary hyperplasia (17). The operative findings included: single adenoma (195 patients), two adenomas (ll), three adenomas (3), carcinoma (4), primary hyperplasia (7), and secondary hyperplasia (17). In the first twenty years of our experience (1951 to 1970), only 107 patients were explored. Ninety-seven patients had positive findings. Eight patients were explored for hypercalcemia and found to have four normal parathyroids; these patients proved not to have hyperparathyroidism. Intwo additional patients, exploration failed to reveal abnormal parathyroids; one was later explored elsewhere and a tumor was removed; the other patient refused reexploration and has been lost to follow-up. During that same period, five of our patients are known to have died of renal failure and several others suffered from permanent bony deformities and other complications despite successful removal of a parathyroid adenoma and return of the serum calcium level to normal limits. In addition, two patients of six operated on in coma for acute parathyroid crisis died postoperatively despite removal of the parathyroid adenoma. During the last five years, 141 patients were explored for hypercalcemia. Since 1971, we have had only one negative exploration (the patient has not yet been reexplored), and only one patient with acute parathyroid crisis was operated on in coma (a carcinoma of the parathyroid was found and removed, but the patient expired two weeks postoperatively). A comparison of the presenting symptoms during the two periods, 1951 to 1970 and 1971 to 1976, reveals a distinct trend toward earlier diagnosis and treatment and a progressively greater number of patients diagnosed with minor symptoms or discovered on routine screening. As a result, morbidity and mortality have been significantly reduced. In contrast to the earlier series, none of the patients undergoing operation during the last five years died of renal failure or other complications of the disease and only two of the last 140 treated had osseous manifestations.
449
Attie and Khafif
Seventy-five patients were explored in whom persistent hypercalcemia was discovered on routine SMA-12 examination. The criteria for exploration were repeated elevated values for serum calcium, with two or more greater than 11.0 mg/lOO ml, and exclusion of all other causes for hypercalcemia, such as malignant tumors, prolonged bed rest, sarcoidosis, milk alkali syndrome, and hypervitaminosis D. Although other laboratory tests were performed, none was consistently found to be abnormal-many of the patients had levels of serum phosphorus, alkaline phosphatase, urinary excretion of calcium, or tubular reabsorption of phosphates within normal limits. During the past three years, nearly all the patients treated had radioimmunoassay of parathyroid hormone (PTH); this revealed elevated or normal values. A low PTH value on assay would seem to rule out hyperparathyroidism. Although the hypercalcemia was discovered by routine chemical studies in patients who presented with unrelated diseases or no complaints, careful retrospective questioning revealed that about 20 per cent of the patients had minimal symptoms (fatigue, constipation, nausea, polydipsia, polyuria, or gastrointestinal distress) or a prior history of conditions probably related to the hyperparathyroidism (renal colic, peptic ulcer, bone pain). The remaining 80 per cent were completely asymptomatic. Furthermore, an additional number of patients who presented with the classic renal or bone findings at the time of surgery were known to be hypercalcemic for a variable period of time prior to the onset of symptoms. Of the seventy-five patients explored, one had diffuse hyperplasia of five glands and had four and a half parathyroids removed, four patients had two adenomas, two patients had three adenomas, and sixty-eight had a solitary adenoma with three normal glands identifled in each case. There were no negative explorations in this group of patients. In all the patients operated on, the serum calcium level returned to normal range and remained at this level. There were no deaths or operative complications in the series, no instances of recurrent nerve injury or hypocalcemia, and no recurrences to date. Our policy in all cases of hyperparathyroidism has been to remove only enlarged or abnormal parathyroid glands. We do not agree with those who have suggested the removal of three or more parathyroids regardless of their gross appearance. The permanent hypocalcemia that might result in many of these patients would constitute a serious and unwarranted complication. All four parathyroids must be identified in every case, if possible. The exposure of normal parathyroids in all our thyroid operations had trained us to recognize the color, shape, and consistency of the normal glandules, thus permitting us to identify the abnormal. Normal appearing parathyroids are not biopsied unless there is a question about their state. In such instances, only a minute biopsy with frozen section should be done to avoid sacrificing a normal gland. The average size of the parathyroid adenomas in the patients explored for asymptomatic hypercalcemia has been relatively small compared with the size of tumors removed in symptomatic patients or in those with very high serum calcium levels. Even the smallest adenomas, how-
450
ever, appeared grossly different from the normal glands in several respects and they were generally diagnosed as tumors when exposed in the wound, the histologic study later confirming the diagnosis. The task undertaken by the surgeon in these cases is therefore a very difficult one-the need to be very sure of the diagnosis prior to exploration, thorough familiarity with the anatomy of the region and the appearance of normal and abnormal parathyroids, and finally the removal of only diseased glands, often small in size and difficult to find in patients who are otherwise healthy and have no symptoms related to the disease. Although the pathologist can be of great assistance in distinguishing a normal from a diseased gland and frozen section frequently used to confirm the surgeon’s impression, the pathologist is often unable to distinguish histologically between adenomatous and hyperplastic parathyroid glands. The gross appearance of the gland at operation is often the only way to make this determination, especially if one or more normal parathyroids have been identified, thus ruling out hyperplasia. Many papers have been written concerning the technic to be followed in parathyroid exploration. It is not the purpose of this paper to discuss the operative procedure at length. A detailed description of our technic to identify and dissect parathyroid glands during thyroid surgery was recently reported [3]. Several points concerning our approach, however, should be mentioned. No vessels are divided except possibly the middle thyroid veins, in order not to disturb the anatomy or the blood supply to the normal parathyroids. The recurrent laryngeal nerve is always exposed both to avoid injury and to aid in identification of the parathyroids; the superior glands are posterior to the nerve and the inferiors are anterior to it. The strap muscles are retracted rather than divided. We have never had to split the sternum, even when the parathyroid adenomas were in the superior mediastinum; all of these glands were brought up into the neck and removed through a cervical approach. The superior parathyroids are more constant in position than the inferior and are generally exposed first. They are usually found either on the posterior wall of the upper pole of the thyroid, on the cricothyroid, or pharyngoesophageal muscles, or in the retropharyngeal space. The inferior glands are more difficult to find and should be sought on the anterolateral surface of the lower pole of the thyroid, in the paratracheal area, adjacent to the recurrent laryngeal nerve and the inferior thyroid artery branches, or in the superior mediastinum and in close relation to the thymus. If the exploration is unsuccessful after a thorough search through the cervical incision, we would then close the wound and only reexplore the patient after reconfirming the diagnosis and utilizing some method of localization preferably by selective venous catheterization and differential radioimmunossay of parathormone. If three normal glands are identified and no tumor found, the thyroid lobe on the side of the missing parathyroid should be removed; the tumor can at times be intrathyroid in position. The location of the tumors found in our cases were almost equal in all four positions: of the sixty-eight patients
The AmericanJournal of Surgery
Asymptomatic
with solitary adenomas there were sixteen right superior, twenty-one right inferior, sixteen left superior, and fifteen left inferior. Although several tumors dipped partially into the superior mediastinum and three of the tumors were found completely substernal in position, all were removed via the cervical incision. The patient with diffuse hyperplasia had five enlarged glands; four and a half were removed with a return to normocalcemia. Comments
Detection of hyperparathyroidism in the absence of symptoms was first reported by Randall and Keating [4] when they recorded twenty cases in which the diagnosis of hyperparathyroidism was made by “serendipity” during the investigation of other conditions. Boonstra [5], in an attempt to determine the incidence of hyperparathyroidism in the general population, performed routine serum calcium determinations in 25,847 consecutive individuals during a sixty-five month period; thirty-one patients had persistent hypercalcemia, twienty-six had parathyroid adenomas removed, and five others were not explored but no follow-up is recorded. Eight of the thirty-one had signs and symptoms that would have suggested the diagnosis of hyperparathyroidism and a few others had vague symptoms that were attributable to hypercalcemia. After the installation of the multiple channel analyzer, hypercalcemia was discovered more frequently. Reece [6] discovered eighty-eight hypercalcemia values in 4,000 serum samples. Collen [7] found an incidence of 1 parathyroid tumor per 5,000 examinations. Esselstyn and Crile [8] reported a series of 114 cases of hyperparathyroidism of which 60 per cent were picked up by automated laboratory tests. Haff, Black, and Ballinger [9] reported that in the thirty months after the installation of an SMA12, forty-seven patients were operated on for primary hyperparathyroidism in contrast to only thirty-nine such operations in the previous ten years. One fourth of these forty-seven patients were completely asymptomatic and another fourth were mildly symptomatic, even though the hypercalcemia was found on routine chemical studies. During this thirty month period serum examinations were made in 87,500 patients, representing 1 case of hyperparathyroidism per 4,000 studies. The clinical picture presenting in patients with hyperparathyroidism has been gradually changing over the years as a result of early diagnosis and treatment. Goldman, Gordan, and Chambers [IO] had thirty-three patients in the past twenty-three years. During the first twenty-one years all but one patient had skeletal disease, whereas in the next two
Volume
132,October1976
Hypercalcemia
years only one of twenty-three patients undergoing operation had osseous manifestations. Krementz et al [11] reported on 100 patients with hyperparathyroidism during a thirty year period. In the first nine years, only one patient was operated on and one fourth of the patients during that time were discovered at autopsy. In the last five years, only four were found at postmortem examination, an indication of earlier diagnosis and treatment. Although there are occasional patients with primary hyperparathyroidism who have lived for many years with no evidence of progressive disease [12], there is mounting evidence that a significant percentage of individuals with asymptomatic hypercalcemia will proceed to complications if left untreated. In 1971, Purnell et al [13] reported from the Mayo Clinic on a prospective study of 147 subjects with asymptomatic or biochemical hypercalcemia in whom surgery was not performed. These patients had elevated serum calcium levels less than 11.0 mg/lOO ml, elevated or normal PTH values, no roentgenologic evidence of bone involvement, normal renal function, and no renal calculi. Of eighty-five subjects who remained in the study for five years, twenty-nine (34 per cent of the total) had since been operated on. The reasons for surgery were an increase in the level of serum calcium, development of bone changes, psychological reasons, or decreasing renal function. Of the twenty-nine surgical explorations, parathyroid lesions were resected in twenty-six; the other three patients remained hypercalcemic postoperatively, either due to failure to find the responsible parathyroid tumor or because the hypercalcemia was due to some other cause. The authors state that there is no criterion permitting recognition of the patient whose disease will become progressive. They concluded that medical follow-up of such patients is time-consuming, expensive, and unreliable, since 40 per cent of the subjects dropped out of the study and could not be followed. In a later publication, Purnell et al [14] emphasize the importance of thorough exploration by experienced parathyroid surgeons in patients with hypercalcemia. They state: “It requires not only identification and recording of the location and size of all parathyroid tissue possible, but also judgment on the part of the operating surgeon as to gross normality or abnormality of a given parathyroid gland on the basis of its size. Because the disease is being treated in earlier stages, the clear-cut criteria for differentiating adenoma and hyperplasia are no longer valid” [14]. Reiss and Canterbury [15] suggest that “the old nomenclature of primary hyperparathyroidism due to adenoma be supplanted by hypercalcemic hy-
451
Attie and Khafif
perparathyroidism, one enlarged gland, three normal glands.” In our experience, several patients who were operated on for symptomatic hyperparathyroidism were known to be hypercalcemic and asymptomatic prior to the onset of symptoms. It is apparent that a significant number of patients with asymptomatic hypercalcemia will go on to have one or more of the complications of hyperparathyroidism-manifestations that are generally considered the “syndromes” of the disease. It is also evident that the beneficial results of surgery in cases of symptomatic hyperparathyroidism are limited by the degree of permanent damage to bone or kidneys. Furthermore, the morbidity and mortality of the surgery are directly related to the severity of the disease. On the other hand, surgery for asymptomatic hyperparathyroidism carries practically no morbidity or mortality and will undoubtedly prevent the development of the serious complications of prolonged hypercalcemia. Therefore, we strongly recommend thorough evaluation of any patient found to be hypercalcemic and that surgical exploration be carried out as soon as the diagnosis of hyperparathyroidism is made.
Summary
The use of the serum auto-analyzer (SMA-12) has resulted in a marked increase in the diagnosis of hyperparathyroidism. Seventy-five patients with asymptomatic hypercalcemia were explored: sixtyeight with solitary adenomas, six with multiple adenomas, and one with diffuse hyperplasia. Postoperatively, all patients reverted to normocalcemia. Surgical exploration of asymptomatic hypercalcemia
452
is advocated to reduce surgical morbidity and mortality and to prevent the development of renal and osseous complications of hyperparathyroidism. References 1. Mandl F: Klinisches und experimentelles zur Frage der lokalisierten und generalisierten Osteitis Fibrosa. Aich k/in Chir 143: 1. 1926. 2. Albright F, Aub JC, Bauer W: Hyperparathyroidism: a common and polymorphic condition as illustrated by 17 cases from one clinic. JAMA 102: 1276, 1934. 3. Attie JN, Khafif IRA: Preservation of parathyroid glands during total thyroidectomy. Am J Surg 130: 399, 1975. 4. Randall RV, Keating FR Jr: Serendipity in the diagnosis of primary hyperparathyroidism. Am J Med Sci 236: 575, 1956. 5. Boonstra CE, Jackson CE: Hyperparathyroidism detected by routine serum calcium analysis. Ann lntem Med 63: 466, 1965. 6. Reece RL: An analysis of 4,000 chemistry graphs. Minn Med 51: 351, 1966. 7. Collen MF: Value of multiphasic health checkups. Nfngl JMed 260: 1072, 1969. 6. Esselstyn CB, Crile G: Hyperparathyroidism-epidemic or endemic? Diagnosis and treatment. C/eve Chin 0 37: 67, 1970. 9. Haff RC, Black WC, Ballinger WF: Primary hyperparathyroidism: changing clinical, surgical and pathologic aspects. Ann Surg 171: 65, 1970. 10. Goldman L, Gordan GS, Chambers EL Jr: Chahging diagnostic criteria for hyperparathyroidism. Ann Surg 146: 407, 1957. 11. Krementz ET, Yeager R, Hawley W, Weichert R: The first 100 cases of parathyroid tumor from Charity Hospital of Louisiana. Ann Surg 173: 672, 1971. 12. Keating FR: The clinical problem of hyperparathyroidism. A&d C/in North Am54: 511, 1970. 13. Purnell DC, Smith LH, Scholz DA, Elveback LR, Arnaud CD: Primary hyperparathyroidism: a prospective clinical study. Am J Med50: 670, 1971. 14. Purnell DC, Scholz DA, Smith LH, Sizemore GW, Black BM, Goldsmith RS, Arnaud CD: Treatment of primary hyperparathyroidism.Am J Med 56: 600, 1974. 15. Reiss E, Canterbury JM: Spectrum of hyperparathyroidism. Am J Med 56: 794, 1974.
The American Journal of Surgery
Hypercalcemia
Ea.rly Treatment of Hyperparathyroidism Joseph N. Attle, MD, New Hyde Park, New York Rene A. Khafif, MD, New Hyde Park, New York
Fifty years have elapsed since the first report of removal of a parathyroid tumor in a patient with osteitis fibrosa cystica [I]. During the next ten years hyperparathyroidism was rarely recognized. In 1934, Albright, Aub, and Bauer [2] demonstrated the frequency of renal calculi as the presenting feature of the disease. During the ensuing years the condition was recognized more frequently and several syndromes besides skeletal and renal were found to occur with hyperparathyroidism. These included peptic ulcer, pancreatitis, and mental and neurologic symptoms. Furthermore, the increasing alertness of physicians to the disease led to frequent chemical evaluations in patients with ‘minimal symptoms, such as polydipsia, fatigue, nausea, and polyuria, and to the earlier diagnosis and treatment of hyperparathyroidism. The introduction of the -serum autoanalyzer (SMA-12) has resulted in a marked increase in the diagnosis of hyperparathyroidism in the absence of symptoms. There has been considerable debate concerning the indications for surgery in such patients. During the past seven years, we have explored seventy-five patients with asymptomatic hypercalcemia: sixty-eight with solitary adenomas, six with multiple adenomas, and one with diffuse hyperplasia. Postoperatively, all the patients reverted to normocalcemia and there were no complications or fatalities in this group of patients. Material and Methods The clinical material reviewed includes 248 cases explored by us over a period of twenty-five years. In 237 of these, hyperparathyroidism was confirmed at surgery and From the Department of Surgery, Long island Jewish Medical Center, New Hyde Park, New York. Reprint requests shouu be addressed to Joseph N. Attie, MD, 105 South Middle Neck Road. Great Neck, New York 11021. Presented at the Joint Meeting of tha Society of Head and Neck Surgeons and the American Society for Head and Neck Swgery, San Diego, Califcmia. April 1 l-15. 1976.
successfully treated. The various presenting manifestations in these 237 patients included: renal calculi (87 patients), skeletal manifestations (12), gastrointestinal (ulcer, pancreatitis) (9), insulinoma (2), neurologic or psychotic manifestations (6), coma (7), minimal symptoms (fatigue, frequency) (6), asymptomatic hypercalcemia @MA-12 finding) (75), incidental (during thyroid explorations) (16), and secondary hyperplasia (17). The operative findings included: single adenoma (195 patients), two adenomas (ll), three adenomas (3), carcinoma (4), primary hyperplasia (7), and secondary hyperplasia (17). In the first twenty years of our experience (1951 to 1970), only 107 patients were explored. Ninety-seven patients had positive findings. Eight patients were explored for hypercalcemia and found to have four normal parathyroids; these patients proved not to have hyperparathyroidism. Intwo additional patients, exploration failed to reveal abnormal parathyroids; one was later explored elsewhere and a tumor was removed; the other patient refused reexploration and has been lost to follow-up. During that same period, five of our patients are known to have died of renal failure and several others suffered from permanent bony deformities and other complications despite successful removal of a parathyroid adenoma and return of the serum calcium level to normal limits. In addition, two patients of six operated on in coma for acute parathyroid crisis died postoperatively despite removal of the parathyroid adenoma. During the last five years, 141 patients were explored for hypercalcemia. Since 1971, we have had only one negative exploration (the patient has not yet been reexplored), and only one patient with acute parathyroid crisis was operated on in coma (a carcinoma of the parathyroid was found and removed, but the patient expired two weeks postoperatively). A comparison of the presenting symptoms during the two periods, 1951 to 1970 and 1971 to 1976, reveals a distinct trend toward earlier diagnosis and treatment and a progressively greater number of patients diagnosed with minor symptoms or discovered on routine screening. As a result, morbidity and mortality have been significantly reduced. In contrast to the earlier series, none of the patients undergoing operation during the last five years died of renal failure or other complications of the disease and only two of the last 140 treated had osseous manifestations.
449
Attie and Khafif
Seventy-five patients were explored in whom persistent hypercalcemia was discovered on routine SMA-12 examination. The criteria for exploration were repeated elevated values for serum calcium, with two or more greater than 11.0 mg/lOO ml, and exclusion of all other causes for hypercalcemia, such as malignant tumors, prolonged bed rest, sarcoidosis, milk alkali syndrome, and hypervitaminosis D. Although other laboratory tests were performed, none was consistently found to be abnormal-many of the patients had levels of serum phosphorus, alkaline phosphatase, urinary excretion of calcium, or tubular reabsorption of phosphates within normal limits. During the past three years, nearly all the patients treated had radioimmunoassay of parathyroid hormone (PTH); this revealed elevated or normal values. A low PTH value on assay would seem to rule out hyperparathyroidism. Although the hypercalcemia was discovered by routine chemical studies in patients who presented with unrelated diseases or no complaints, careful retrospective questioning revealed that about 20 per cent of the patients had minimal symptoms (fatigue, constipation, nausea, polydipsia, polyuria, or gastrointestinal distress) or a prior history of conditions probably related to the hyperparathyroidism (renal colic, peptic ulcer, bone pain). The remaining 80 per cent were completely asymptomatic. Furthermore, an additional number of patients who presented with the classic renal or bone findings at the time of surgery were known to be hypercalcemic for a variable period of time prior to the onset of symptoms. Of the seventy-five patients explored, one had diffuse hyperplasia of five glands and had four and a half parathyroids removed, four patients had two adenomas, two patients had three adenomas, and sixty-eight had a solitary adenoma with three normal glands identifled in each case. There were no negative explorations in this group of patients. In all the patients operated on, the serum calcium level returned to normal range and remained at this level. There were no deaths or operative complications in the series, no instances of recurrent nerve injury or hypocalcemia, and no recurrences to date. Our policy in all cases of hyperparathyroidism has been to remove only enlarged or abnormal parathyroid glands. We do not agree with those who have suggested the removal of three or more parathyroids regardless of their gross appearance. The permanent hypocalcemia that might result in many of these patients would constitute a serious and unwarranted complication. All four parathyroids must be identified in every case, if possible. The exposure of normal parathyroids in all our thyroid operations had trained us to recognize the color, shape, and consistency of the normal glandules, thus permitting us to identify the abnormal. Normal appearing parathyroids are not biopsied unless there is a question about their state. In such instances, only a minute biopsy with frozen section should be done to avoid sacrificing a normal gland. The average size of the parathyroid adenomas in the patients explored for asymptomatic hypercalcemia has been relatively small compared with the size of tumors removed in symptomatic patients or in those with very high serum calcium levels. Even the smallest adenomas, how-
450
ever, appeared grossly different from the normal glands in several respects and they were generally diagnosed as tumors when exposed in the wound, the histologic study later confirming the diagnosis. The task undertaken by the surgeon in these cases is therefore a very difficult one-the need to be very sure of the diagnosis prior to exploration, thorough familiarity with the anatomy of the region and the appearance of normal and abnormal parathyroids, and finally the removal of only diseased glands, often small in size and difficult to find in patients who are otherwise healthy and have no symptoms related to the disease. Although the pathologist can be of great assistance in distinguishing a normal from a diseased gland and frozen section frequently used to confirm the surgeon’s impression, the pathologist is often unable to distinguish histologically between adenomatous and hyperplastic parathyroid glands. The gross appearance of the gland at operation is often the only way to make this determination, especially if one or more normal parathyroids have been identified, thus ruling out hyperplasia. Many papers have been written concerning the technic to be followed in parathyroid exploration. It is not the purpose of this paper to discuss the operative procedure at length. A detailed description of our technic to identify and dissect parathyroid glands during thyroid surgery was recently reported [3]. Several points concerning our approach, however, should be mentioned. No vessels are divided except possibly the middle thyroid veins, in order not to disturb the anatomy or the blood supply to the normal parathyroids. The recurrent laryngeal nerve is always exposed both to avoid injury and to aid in identification of the parathyroids; the superior glands are posterior to the nerve and the inferiors are anterior to it. The strap muscles are retracted rather than divided. We have never had to split the sternum, even when the parathyroid adenomas were in the superior mediastinum; all of these glands were brought up into the neck and removed through a cervical approach. The superior parathyroids are more constant in position than the inferior and are generally exposed first. They are usually found either on the posterior wall of the upper pole of the thyroid, on the cricothyroid, or pharyngoesophageal muscles, or in the retropharyngeal space. The inferior glands are more difficult to find and should be sought on the anterolateral surface of the lower pole of the thyroid, in the paratracheal area, adjacent to the recurrent laryngeal nerve and the inferior thyroid artery branches, or in the superior mediastinum and in close relation to the thymus. If the exploration is unsuccessful after a thorough search through the cervical incision, we would then close the wound and only reexplore the patient after reconfirming the diagnosis and utilizing some method of localization preferably by selective venous catheterization and differential radioimmunossay of parathormone. If three normal glands are identified and no tumor found, the thyroid lobe on the side of the missing parathyroid should be removed; the tumor can at times be intrathyroid in position. The location of the tumors found in our cases were almost equal in all four positions: of the sixty-eight patients
The AmericanJournal of Surgery
Asymptomatic
with solitary adenomas there were sixteen right superior, twenty-one right inferior, sixteen left superior, and fifteen left inferior. Although several tumors dipped partially into the superior mediastinum and three of the tumors were found completely substernal in position, all were removed via the cervical incision. The patient with diffuse hyperplasia had five enlarged glands; four and a half were removed with a return to normocalcemia. Comments
Detection of hyperparathyroidism in the absence of symptoms was first reported by Randall and Keating [4] when they recorded twenty cases in which the diagnosis of hyperparathyroidism was made by “serendipity” during the investigation of other conditions. Boonstra [5], in an attempt to determine the incidence of hyperparathyroidism in the general population, performed routine serum calcium determinations in 25,847 consecutive individuals during a sixty-five month period; thirty-one patients had persistent hypercalcemia, twienty-six had parathyroid adenomas removed, and five others were not explored but no follow-up is recorded. Eight of the thirty-one had signs and symptoms that would have suggested the diagnosis of hyperparathyroidism and a few others had vague symptoms that were attributable to hypercalcemia. After the installation of the multiple channel analyzer, hypercalcemia was discovered more frequently. Reece [6] discovered eighty-eight hypercalcemia values in 4,000 serum samples. Collen [7] found an incidence of 1 parathyroid tumor per 5,000 examinations. Esselstyn and Crile [8] reported a series of 114 cases of hyperparathyroidism of which 60 per cent were picked up by automated laboratory tests. Haff, Black, and Ballinger [9] reported that in the thirty months after the installation of an SMA12, forty-seven patients were operated on for primary hyperparathyroidism in contrast to only thirty-nine such operations in the previous ten years. One fourth of these forty-seven patients were completely asymptomatic and another fourth were mildly symptomatic, even though the hypercalcemia was found on routine chemical studies. During this thirty month period serum examinations were made in 87,500 patients, representing 1 case of hyperparathyroidism per 4,000 studies. The clinical picture presenting in patients with hyperparathyroidism has been gradually changing over the years as a result of early diagnosis and treatment. Goldman, Gordan, and Chambers [IO] had thirty-three patients in the past twenty-three years. During the first twenty-one years all but one patient had skeletal disease, whereas in the next two
Volume
132,October1976
Hypercalcemia
years only one of twenty-three patients undergoing operation had osseous manifestations. Krementz et al [11] reported on 100 patients with hyperparathyroidism during a thirty year period. In the first nine years, only one patient was operated on and one fourth of the patients during that time were discovered at autopsy. In the last five years, only four were found at postmortem examination, an indication of earlier diagnosis and treatment. Although there are occasional patients with primary hyperparathyroidism who have lived for many years with no evidence of progressive disease [12], there is mounting evidence that a significant percentage of individuals with asymptomatic hypercalcemia will proceed to complications if left untreated. In 1971, Purnell et al [13] reported from the Mayo Clinic on a prospective study of 147 subjects with asymptomatic or biochemical hypercalcemia in whom surgery was not performed. These patients had elevated serum calcium levels less than 11.0 mg/lOO ml, elevated or normal PTH values, no roentgenologic evidence of bone involvement, normal renal function, and no renal calculi. Of eighty-five subjects who remained in the study for five years, twenty-nine (34 per cent of the total) had since been operated on. The reasons for surgery were an increase in the level of serum calcium, development of bone changes, psychological reasons, or decreasing renal function. Of the twenty-nine surgical explorations, parathyroid lesions were resected in twenty-six; the other three patients remained hypercalcemic postoperatively, either due to failure to find the responsible parathyroid tumor or because the hypercalcemia was due to some other cause. The authors state that there is no criterion permitting recognition of the patient whose disease will become progressive. They concluded that medical follow-up of such patients is time-consuming, expensive, and unreliable, since 40 per cent of the subjects dropped out of the study and could not be followed. In a later publication, Purnell et al [14] emphasize the importance of thorough exploration by experienced parathyroid surgeons in patients with hypercalcemia. They state: “It requires not only identification and recording of the location and size of all parathyroid tissue possible, but also judgment on the part of the operating surgeon as to gross normality or abnormality of a given parathyroid gland on the basis of its size. Because the disease is being treated in earlier stages, the clear-cut criteria for differentiating adenoma and hyperplasia are no longer valid” [14]. Reiss and Canterbury [15] suggest that “the old nomenclature of primary hyperparathyroidism due to adenoma be supplanted by hypercalcemic hy-
451
Attie and Khafif
perparathyroidism, one enlarged gland, three normal glands.” In our experience, several patients who were operated on for symptomatic hyperparathyroidism were known to be hypercalcemic and asymptomatic prior to the onset of symptoms. It is apparent that a significant number of patients with asymptomatic hypercalcemia will go on to have one or more of the complications of hyperparathyroidism-manifestations that are generally considered the “syndromes” of the disease. It is also evident that the beneficial results of surgery in cases of symptomatic hyperparathyroidism are limited by the degree of permanent damage to bone or kidneys. Furthermore, the morbidity and mortality of the surgery are directly related to the severity of the disease. On the other hand, surgery for asymptomatic hyperparathyroidism carries practically no morbidity or mortality and will undoubtedly prevent the development of the serious complications of prolonged hypercalcemia. Therefore, we strongly recommend thorough evaluation of any patient found to be hypercalcemic and that surgical exploration be carried out as soon as the diagnosis of hyperparathyroidism is made.
Summary
The use of the serum auto-analyzer (SMA-12) has resulted in a marked increase in the diagnosis of hyperparathyroidism. Seventy-five patients with asymptomatic hypercalcemia were explored: sixtyeight with solitary adenomas, six with multiple adenomas, and one with diffuse hyperplasia. Postoperatively, all patients reverted to normocalcemia. Surgical exploration of asymptomatic hypercalcemia
452
is advocated to reduce surgical morbidity and mortality and to prevent the development of renal and osseous complications of hyperparathyroidism. References 1. Mandl F: Klinisches und experimentelles zur Frage der lokalisierten und generalisierten Osteitis Fibrosa. Aich k/in Chir 143: 1. 1926. 2. Albright F, Aub JC, Bauer W: Hyperparathyroidism: a common and polymorphic condition as illustrated by 17 cases from one clinic. JAMA 102: 1276, 1934. 3. Attie JN, Khafif IRA: Preservation of parathyroid glands during total thyroidectomy. Am J Surg 130: 399, 1975. 4. Randall RV, Keating FR Jr: Serendipity in the diagnosis of primary hyperparathyroidism. Am J Med Sci 236: 575, 1956. 5. Boonstra CE, Jackson CE: Hyperparathyroidism detected by routine serum calcium analysis. Ann lntem Med 63: 466, 1965. 6. Reece RL: An analysis of 4,000 chemistry graphs. Minn Med 51: 351, 1966. 7. Collen MF: Value of multiphasic health checkups. Nfngl JMed 260: 1072, 1969. 6. Esselstyn CB, Crile G: Hyperparathyroidism-epidemic or endemic? Diagnosis and treatment. C/eve Chin 0 37: 67, 1970. 9. Haff RC, Black WC, Ballinger WF: Primary hyperparathyroidism: changing clinical, surgical and pathologic aspects. Ann Surg 171: 65, 1970. 10. Goldman L, Gordan GS, Chambers EL Jr: Chahging diagnostic criteria for hyperparathyroidism. Ann Surg 146: 407, 1957. 11. Krementz ET, Yeager R, Hawley W, Weichert R: The first 100 cases of parathyroid tumor from Charity Hospital of Louisiana. Ann Surg 173: 672, 1971. 12. Keating FR: The clinical problem of hyperparathyroidism. A&d C/in North Am54: 511, 1970. 13. Purnell DC, Smith LH, Scholz DA, Elveback LR, Arnaud CD: Primary hyperparathyroidism: a prospective clinical study. Am J Med50: 670, 1971. 14. Purnell DC, Scholz DA, Smith LH, Sizemore GW, Black BM, Goldsmith RS, Arnaud CD: Treatment of primary hyperparathyroidism.Am J Med 56: 600, 1974. 15. Reiss E, Canterbury JM: Spectrum of hyperparathyroidism. Am J Med 56: 794, 1974.
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