Asymptomatic Primary Hyperparathyroidism David State, MD, Torrance, California George S. Hill, MD, Torrance, California
In the past, patients with primary hyperparathyroidism were diagnosed only when overt classic clinical findings usually relating to pathology of the kidney (lithiasis, calcinosis) and/or bone (osteoporosis, von Recklinghausen’s disease) directed attention to the problem. The few operations performed annually for this condition at most medical centers were the occasion of considerable interest on the part of the surgical, medical, and pathology staffs, and too frequently, even though an adenoma was discovered, the usual extensive damage to the kidneys was not followed by a return to normal function of this organ. With the advent of automated equipment for blood chemistry determinations, the diagnosis of primary hyperparathyroidism has been made much earlier in symptomatic patients, but in addition hypercalcemia has been uncovered in patients who are asymptomatic. The frequency with which the latter occurred raised questions as to whether primary hyperparathyroidism was a much more common disease than anticipated, and what should be done for these patients-perform surgery or observe them for future developments? We have taken the former course and our experience is reported herein. Material and Methods The records of 136 patients who underwent surgery for hyperparathyroidism were reviewed. Of this group, fiftythree patients were considered to be asymptomatic. They were patients seen for a variety of medical reasons, such as routine periodic physical examinations, varicose veins, hernias, uterine fibroids, and benign breast masses. Attention was drawn to the possibility of hyperparathyroidism only by an unexpected presence of an elevated blood calcium level on a sequential multiple analyzer (SMA-12) print out. The upper normal limit of serum calcium level was considered to be 10.8 mg/lOO ml when accompanied by normal plasma proteins and albumin. A serum phosphorus level of 3.0 mg/lOO ml or less was considered corroborative, but not diagnostic when associated From the Lkpertment of Surgery, Harbor Qeneral Hospital. Twance, California. and WA School of Medicine. Los Andes. California. Repint requests should be ad&&sad to 6avM’State~ MD. Chairman, Depertment of swgery. Mbor General Hospital. 1000 west carsc+l Street. Torrance, California 90509. Presented at the Forty-Seventh Annual Meeting of the Pacific Coast Surgical Association, Monterey. California. February 15-18. 1976.
Volume 132. Au*
1976
with hypercalcemia. Blood calcium, plasma protein, and albumin determinations were repeated on two separate occasions, and if hypercalcemia persisted, the diagnosis of hyperparathyroidism was tentatively made. A careful history and physical examination were carried out and every attempt was made to rule out other potential causes of hypercalcemia, such as hyperthyroidism, sarcoidosis, multiple myeloma, milk-alkali syndrome, thiaxide medication, and metastatic malignancies. X-ray films of the chest, skeleton, and urinary tracts were taken to rule out a pathologic condition in these organ systems. As part of a protocol study, the majority of these patients had prior to surgery a steroid suppression test consisting of 100 to 200 mg of cortisone per day for five to six days. Failure of the elevated serum calcium level to decrease to within normal limits was considered indicative of primary hyperparathyroidism. Determinations of calcium balance and tubular reabsorption of phosphorus were not carried out. Parathyroid hormone assays only became available late in the study and were infrequently done. Parathyroid exploration was performed with the use of general anesthesia. The usual accepted surgical principles for this type of surgery-careful dissection of tissues, meticulous hemostasis, and adequate exposure-were adhered to. In all instances an attempt to identify all four parathyroids was made regardless of the pathologic features of the parathyroids. If a single adenoma was discovered, it was removed, and at least one other parathyroid was biopsied. When two enlarged glands were encountered, both were removed and a third gland was biopsied. With hyperplasia of four glands, three of the glands and a portion of the fourth were removed, leaving a well vascularized remnant of approximately 50 mg which was tagged with a silk suture. Results
In the group of 136 patients operated on for hyperparathyroidism, fifty-three (20 male, 33 female) were considered to be asymptomatic. Ages ranged from twenty to greater than sixty years (2 patients, 20 to 40 years; 40,40 to 60 years; and 11, greater than 60 years). Operative findings included forty-four patients with single adenoma, four patients with multiple adenomas, and three patients with hyperplasia. In two patients no adenoma or hyperplasia was noted. In one patient, a forty-five year old female with persistent hypercalcemia (11.1 mg/lOO ml), three parathyroids were observed, biopsied, and re-
231
State and Hill
AGE Upper Values 20
Calcium mg / lOOmI M
Phosphorous mg/ IOOml MIF
IO. 20
10.01
4.45
4.74
30
IO.14
10.02
4.34
4.24
40 30
IO.08
10.02
10.0 I
10.03
4.24 4.14
4.25 4.43
60
9.95
10.03
4.04
4.65
70
9.88
IQ04
3.94
4.84
20
9.09
882
2.55
2.85
30
9.03
683
2.45
2.55
40
8.96
883
2.35
2.55
50
8.90
8.84
2.24
2.66
8.84
2. 14
2.79
8.85
2.04
2.90
Lower Values
60
8.83
70
8.77
Maximal S.E.
0.05
0.10
Figwe 1. Upper and lower values of serum calcium and @osphmws In normal adults. (Modlfkd from [S] wnh pennlsshn~ of publfsfw. )
ported as normal. One gland, the right superior, could
not be found in the neck, and it was decided not to split the sternum. Postoperatively, the patient continued to be hypercalcemic, but she refused further surgery. We believe that a hyperfunctioning tumor was missed in this patient. The second patient a forty-two year old male had maximal serum calcium levels of 10.8 mg/lOO ml. Exploration of the neck revealed four parathyroid glands, which were biopsied and reported as normal. Up to one year postoperatively, all calcium levels did not exceed 10.4 mg/lOO ml. In this patient, we presume that an error in diagnosis had been made. Comments
A significant increase in the frequency of hyperparathyroidism in North America and Europe has been reported [1,2]. Whether this represents an absolute increase in the frequency of the disease or whether it is a result of greater awareness and uncovering of unexpected hypercalcemia by means of automated blood analysis equipment is moot. Jackson and Boonstra [3] saw proved hyperparathyroidism in one of every 834 patients when serum calcium level was routinely measured in all ambulatory patients admitted to the hospital [2]. At the Mayo Clinic, Purnell and his colleagues observed from January 1,1968 through June 30,197O 401 patients with disorders of calcium metabolism [3]. The provisional diagnosis of hyperparathyroidism was made initially in 322 of these patients, and of this 232
group 171 patients had surgical explorations. However, 147 patients with a provisional diagnosis of primary hyperparathyroidism but who were asymptomatic were followed for a five year period, and twenty-one patients had clinical signs and symptoms warranting surgical explorations. Eight additional patients required surgery for other reasons (41. The sine qua non for the diagnosis of hyperparathyroidism, as demonstrated in our study and in others reported in the recent literature, is the presence of hypercalcemia. Keating et al [5] stated: “The estimation of the precise level of serum calcium is the most effective screening for this condition.” Results of their carefully performed studies to determine the upper (97.5 percentile) limit of the normal range of serum calcium level for each decade from twenty to seventy years of age are shown in Figure 1. Keating et al [5] further stated that it was advisable for each laboratory to provide its own reliable and documented range of normal values. In establishing precise values for normal limits, slight elevations of serum calcium levels become important. Thus, Keating [S] reported on fifty-two patients with serum calcium values of less than 11.0 mg/lOO ml, forty-six of whom had nephrolithiasis. The disease was recurrent, bilateral, and severe in twenty-one. In our series, any serum calcium level of 10.8 mg/lOO ml or higher on two or more occasions was considered to be due to primary hyperparathyroidism. Serum phosphorus levels were obtained in our study, but they are of limited value in the diagnosis of hyperparathyroidism [I]. Values of serum phosphorus are quite labile, being affected in patients by exercise, standing, sleeping, and eating; furthermore, there is an endogenous rhythm that parallels the welI defined daily urinary excretion rhythm. Careful determination also shows that the lower range of normal values in both males and females between the second and seventh decades may decrease to less than 3.0 mg/lOO ml [5]. In ruling out other possible causes of hypercalcemia, such entities as hyperthyroidism, Cushing’s syndrome, milk-alkali syndrome, vitamin D intoxication, sarcoidosis, Paget’s disease, thiazide medication, and occult malignancies must be considered. In differential diagnosis of hypercalcemia, Edis, Ayala, and Egdahl [4] reported a 20 per cent incidence of primary hyperparathyroidism, 55 per cent skeletal metastases and myeloma, and 15 per cent ectopic hyperparathyroidism; the remaining 10 per cent included thiazide medication, vitamin D intoxication, sarcoidosis, milk-alkali syndrome, and thyrotoxicosis. In asymptomatic patients the greatest diagnostic challenge is in ruling out hidden maligrho Amwkan
Journal 04 !Zurgery
Hyperparathyroidism
nancies. As part of an investigation to determine the efficacy of the steroid suppression test [7] to differentiate primary from secondary hyperparathyroidism, the majority but not all of the patients were given a five to six day trial of 100 to 200 mg of cortisone. This test was helpful to us, but there have been other reports showing both false-positive and falsenegative results with this test [8]. We did not use other tests such as tubular reabsorption of phosphorus [9] or calcium infusion test [IO] in this study. Immunoreactive assays of parathormone (PTH) were not readily available to us and were used infrequently. There is no doubt that as technics for determination of PTH become fully developed and particularly as human parathyroid material for immunization replaces beef parathyroid, PTH determination will be extremely helpful in differentiating primary from secondary hyperparathyroidism [11,12]. It is also anticipated that PTH determinations in conjunction with catheterization of draining veins of the thyroid will be a great aid in locating previously missed parathyroid adenomas or carcinomas [13,14]. It is of interest to note, however, the degree of accuracy in diagnosis we were able to obtain without the aid of PTH determination. Preoperate localization by noninvasive technics would be most helpful to the surgeon. Selenium methionine has been suggested as a radionucleotide technic for this purpose [15]. In the present series it was attempted in nineteen patients but only localized the tumor preoperatively in two. We have not had any experience with ultrasonography or thermography, but these technics have been reported as being successful in preoperative localization of parathyroid pathologic conditions [4]. The surgical technic we used in exploring our patients followed the principles promulgated by Cope [16,17] and Goldman, Gordon, and Roof [13,18]. A thorough knowledge of the embryology and anatomy is essential. Dissection must be performed with meticulous attention to hemostasis and adequate exposure. Some specific details that we have found useful in this type of surgery are complete mobilization of the superior poles of the thyroid to identify superior parathyroids and routine identification of the recurrent laryngeal nerves throughout their cervical course. Furthermore, in a little more than half of our patients, the identification of a unilaterally enlarged inferior thyroid artery [19] or the identification of a prominent branch arising from an inferior or superior thyroid artery of almost normal size has been helpful in locating an otherwise hidden parathyroid adenoma as in Figures 2 and 3. In the present series five patients had adenomas inferior to the level of the clavicles, but in each instance the Volume 132, August 1976
\,
Inferior Thyroic
Adenoma
Figure 2. Schematk drawing of asymptomatic hyperparath~tdhwn showing ankrgsd lnferkr thymid artery on sideof ademmaNotenotmal size of infarkr thyroid artery on 0pposMe side.
Large Inf. Thyroid Artery
Figure 3. Schematic drawing of asympkmatk hyperparathyroidm demonstrating large branch from Merkr thyrohi arteryto parathyroid adenoma.
tumor could be delivered into the neck without the need for a sternal split. As indicated previously, forty-four patients in the present series had a single adenoma, four patients had multiple adenomas, and three had hyperplasia of four glands. The 85 per cent incidence of single adenoma is thus quite similar to that reported by the group at Massachusetts General Hospital [20]. Others [1,21], however, have reported a much greater incidence of chief cell hyperplasia. Furthermore, from more recent reports in which electron 233
State and Hill
microscopy has been used, it appears that differentiation between adenoma and hyperplasia may be extremely difficult if not impossible (221. Thus it becomes important, whenever possible, to identify, biopsy if necessary, and assess the size of all parathyroid tissue in the exposed surgical field. Paloyan Lawrence, and Straus [I] recommend outright resection of three and a half glands in all patients with primary hyperparathyroidism regardless of the findings at operation. We have not followed this policy; rather, we have excised single adenomas when present with biopsy of at least one additional gland. When all four glands were enlarged, we have resected three and part of the fourth, leaving approximately 50 mg of parathyroid tissue, being certain to identify the remnant with a silk suture. In patients with two adenomas, rather than simply remove the adenomas and biopsy a third (as we had done) we would now, in light of newer information concerning the pathology of hyperparathyroidism, remove three glands and salvage only a part of the fourth, as with four gland hyperplasia. Summary With the advent of automated equipment for blood chemistry determinations, many patients are presenting with asymptomatic or “biochemical” hyperparathyroidism. In the present series, of 136 patients operated on for hyperparathyroidism, fifty-three were considered asymptomatic. In fiftyone patients, parathyroid pathologic conditions were found; in one patient, it is probable that an adenoma had been missed, and in the other, it is presumed that an error in diagnosis was made. We recommend that surgical exploration be considered as an acceptable alternative to watchful waiting for patients with asymptomatic hyperparathyroidism. References 1. Paloyan E, Lawrence AM, Straus FH: Hyperparathyroidism. Modem Surgical Moncqaphs. New York, Grune & Stratton, 1973. 2. Adams P. Chalmers TM, Hill LF, Truscott B&N: idiopathic hypercalcemia and hyperparathyroidism. & Med./ 4: 582, 1970. 3. Jackson CE, Boon&a CE: The hyperparathyroidism detected by routfne serum calctum analysis. Ann lntem A&d 83: 488, 1965. 4. Edis AJ, Ayata LA, Egdahl RH: Manual of Endocrine Sugery. New York, Heidelberg, Berlin, Springer-Verlag, 1975. 5. Keatlng FR Jr, Jones JD. Etveback LR, Randall RV: The relation of age and sex to distribution of values in healthy adults of serum cabium, incqfanic phosphorus, magnesium atkalina phosphatase, total proteins, albumin and blood urea. JLe6 Clin h&d 73: 825. 1969. 6. Keating FR Jr: D@nostt of primary hyperpamthyrofdtsm. JAMA 178: 547, 1961.
234
7. Dent CE: Cortisone test for hyperparathyroidism. Br h&d J 1: 230, 1956. 8. Danowski TS: Phosphorus pools in the body. Clinical Endocrinology, vol Ill. Baltimore, Williams 8 Wilkins, 1962. 9. Sirota JH: Renal tubufar reabsorption of phosphate in hyperparathyroidism before and after removal of parathyroid adenoma. fed Pfoc 12: 133, 1953. 10. Howard JE, Hopkins TR, Connor TB: Use of intravenous calcium as a measure of activity of the parathyroM gland. J C//n Endocrinol Metab 12: 927. 1952. 11. Silverman R, Yaflow RS: Heterogenefty of parathyrofd hantone: clinical and physiologic implications. J C/in invest 52: 1958, 1973. 12. Reiss E, Canterbug JM: Application of radioimmunoassay to differentiation of adenoma and hyperptasia and to preoperative localization of hyperfunctioning parathyrold glands. N EnglJMed280: 1381, 1969. 13. Goldman L, Gordon GS, Roof BS: The parathyrotds: progress, problems and practice. Chicago, Year Book Medical, Curr Probl Surg August 197 1. 14. Eisenberg H, Paltotta J, Sherwood LM: Selective arterlography, venography and venous hormone assay in diagnosis and localization of parathyroid lesions. Am J Ahd 56: 810, 1974. 15. Potchen EJ, Wilson RE. Dealy JB Jr: External parathyroid scanning with Se75 selenomethionine. Ann Surg 162: 492, 1965. 16. CopeO:Thestoryofhypaqamthyroklismattheh4assachusetts GeneralHospital. NEnglJMed274: 1174, 1966. 17. Cope 0: Hyparp%athyroidlsm: d-is and management. Am J Surg 99: 394, 1960. 18. Goldman L: Unusual manifestations of hyperparathyrokflsm. Surg Gynecol Obstet 100: 675, 1955. 19. State D: The enlarged inferior thyroM artery: a valuable guide in surgery of parathyroid adenomas. Surgery 56: 461, 1964. 20. St Goar WT, Roth SI: Ccfreqxndence. N Eng/ JAM 297: 913, 1974. 21. Roth SL: Recent advance in parathyroid gland pathology. Am JMed50: 612, 1971. 22. Shannon WA, Roth SI: An ultrastructural study of acM phosphatase activity in normal, adenomatous and hyperpiastlc (chief cell type) human parathyrokf glands. Am J P&o/77: 493, 1974.
Discussion H. Earl Gordon (Los Angeles, CA): As indicated by the authors, an increasing number of patients with primary hyperparathyroidism are being encountered who lack the classic clinical features usually associated with this disease. Despite this, I was surprised that 40 per cent of the authors’ patients were considered asymptomatic. Therefore, I would question whether some of the more subtle clinical manifestations may have been overlooked. The changing clinical picture of the disease seems to parallel the increased incidence. Many symptoms that were previously considered relatively nonspecific may now be the presenting complaint. These include such symptoms as easy fatigability, muscle weakness (particularly of the proximal muscles), headaches, neuropsychiatric changes, weight loss, and arthralgia. Abdominal pain, particularly epigastric distress in the absence of demonstrable peptic ulcer disease, is not uncommon. I have been increasingly impressed by the number of patients who are relieved of these nonspecific complaints after operation. Recently, anemia has been recognized as another clinical manifestation. We have had
lha Amuka
Jaurnal 04 8urgwy
Hyperparathyroidism
two patients with refractory anemia who responded only after the correction of their hyperparathyroid state. In establishing a diagnosis, I am somewhat concerned about the authors’ reliance primarily on the level of serum calcium and the cortisone suppression test. In our hands, the cortisone test has proved of limited value, since in a few patients with hyperparathyroidism, hypercalcemia has been abolished by steroids, and secondly, the hypercalcemia of some malignancies does not respond to corticoids. In reaching a decision on an asymptomatic patient with hypercalcemia, I feel more secure with a complete biochemical evaluation including the immunoassay of PTH. In regard to one of the common procedures, tubular reabsorption of phosphate can be a valuable discriminatory test if preceded for six days by a high phosphate intake. After establishing the diagnosis with reasonable certainty, I strongly support the authors’ recommendation for surgical exploration in all good risk patients with asymptomatic primary hyperparathyroidism. If uncorrected, the condition will inevitably lead to hypertension, renal impairment, and other complications in a significant number of patients. I also concur with their conservative approach in regard to biopsy of grossly normal glands. Biopsy of all four glands, as recommended by many surgeons, carries a definite risk of prolonged or permanent hypocalcemia. When confronted with hyperplasia of all glands, there in always the potential risk that the remnant of parathyroid gland left behind may be inadequate to sustain the patient at normocalcemic levels. For this reason, we now routinely preserve some of the excised tissue for transplantation if hypoparathyroidism should subsequently develop. With the technic of Wells et al (Surgery 75:49,1974), parathyroid tissue can be preserved for six to nine months by rapid freezing in tissue culture medium and storage in a liquid nitrogen freezer. When indicated, transplantation is carried out in the flexor muscles of the forearm using microsurgical technic. Assay of the antecubital blood draining the graft site can then be used as an index of graft function. Although we have been fortunate in not having a patient who has required transplantation, it is reassuring to have the tissue available should the need arise. Willard E. Goodwin (Los Angeles, CA): Hugh Cabot was reported to have said that the way to suspect a right ureteral stone is to look for the footprints or handprints of the surgeon who removed the normal appendix. Here is such a patient. She was a fourteen year old girl, hospitalized with right lower quadrant pain and normal urine. The scout x-ray film was interpreted as normal, but in fact a shadow near the bladder represented a lower ureteral stone. Her normal appendix was removed and an intravenous urogram was wisely ordered. These films looked normal except that the right ureter was dilated. Retrograde pyelogram proved there was a lower ureteral stone on the right side, which she later passed after further colic. It is rare for a fourteen year old girl to have a stone in this country. The serum calcium value was 14 mg/lOO ml. The same surgeon, Doctor Eric Fonkalsrud, later removed a parathyroid adenoma. I have
Volume 132, August 1976
never seen one in a fourteen year old child, and I noticed that the authors had none less than age twenty. Frederic P. Shidler (Menlo Park, CA): My personal experience is not extensive, but in fourteen patients I have been impressed that the asymptomatic patient does not really have the urgency for neck exploration as the patient with renal stone, duodenal ulcer, or fatigability. I am one member of this Association who would not operate on an asymptomatic patient until the patient has been observed for a year or so. Our practice is to observe the serum calcium level, which may fluctuate and in some months may be within normal range. I do not think the patient is at risk with serum calcium levels of 11.0 to 11.3 mg/lOO ml. During the observation period we have an opportunity to reassure ourselves that we are really dealing with hyperparathyroidism and not with some other systemic disease that produces the hypercalcemia. All the patients we have operated on have had adenoma or hyperplasia. Robert W. Rand (Los Angeles, CA): Certain types of tumors in the head and neck lend themselves to embolization by ferrosilicone-particularly if they are supplied by the external carotid circulation. We have used this on some occasions and I am aware of at least one patient who has had successful embolization of a parathyroid tumor. I am wondering if Doctor State would make a comment as to arteriography especially with subtraction technic and the identification of the particular artery going to the adenoma, which I think could be readily injected and possibly avoid an open operation. David State (closing): I think Doctor Gordon is absolutely correct in his point regarding the term “asymptomatic.” However, I think we would have to admit that none of us is completely asymptomatic in the strict sense of the word. In the pragmatic aspect, in my patients no thought was ever given to the possibility of hyperparathyroidism clinically, and the diagnosis was made primarily on biochemical determinations. As to Doctor Goodwin’s remarks, we did not find any patient with hypercalcemia less than twenty years old. As far as I know, very few patients younger than twenty years have been reported with primary hyperparathyroidism. Doctor Shidler, I cannot argue with your conservative approach. As a matter of fact, it is one advocated by the Mayo Clinic group. It is interesting to note, however, that Keating reported a series of patients who had mild elevations of serum calcium levels but still below 11 mg/lOO ml, and in that group of fifty-two patients, forty-six had significant renal disease. I think, therefore, the onus is on the individual who makes the decision to follow them. However, hyperparathyroidism is a slow process, and if the patient is watched carefully, there should be time to operate. However, the results of this study indicate that if you adopt a more aggressive attitude, you can find parathyroid lesions before they produce symptoms and presumably pathologic changes that one would hope to avoid.
235
In the past, patients with primary hyperparathyroidism were diagnosed only when overt classic clinical findings usually relating to pathology of the kidney (lithiasis, calcinosis) and/or bone (osteoporosis, von Recklinghausen’s disease) directed attention to the problem. The few operations performed annually for this condition at most medical centers were the occasion of considerable interest on the part of the surgical, medical, and pathology staffs, and too frequently, even though an adenoma was discovered, the usual extensive damage to the kidneys was not followed by a return to normal function of this organ. With the advent of automated equipment for blood chemistry determinations, the diagnosis of primary hyperparathyroidism has been made much earlier in symptomatic patients, but in addition hypercalcemia has been uncovered in patients who are asymptomatic. The frequency with which the latter occurred raised questions as to whether primary hyperparathyroidism was a much more common disease than anticipated, and what should be done for these patients-perform surgery or observe them for future developments? We have taken the former course and our experience is reported herein. Material and Methods The records of 136 patients who underwent surgery for hyperparathyroidism were reviewed. Of this group, fiftythree patients were considered to be asymptomatic. They were patients seen for a variety of medical reasons, such as routine periodic physical examinations, varicose veins, hernias, uterine fibroids, and benign breast masses. Attention was drawn to the possibility of hyperparathyroidism only by an unexpected presence of an elevated blood calcium level on a sequential multiple analyzer (SMA-12) print out. The upper normal limit of serum calcium level was considered to be 10.8 mg/lOO ml when accompanied by normal plasma proteins and albumin. A serum phosphorus level of 3.0 mg/lOO ml or less was considered corroborative, but not diagnostic when associated From the Lkpertment of Surgery, Harbor Qeneral Hospital. Twance, California. and WA School of Medicine. Los Andes. California. Repint requests should be ad&&sad to 6avM’State~ MD. Chairman, Depertment of swgery. Mbor General Hospital. 1000 west carsc+l Street. Torrance, California 90509. Presented at the Forty-Seventh Annual Meeting of the Pacific Coast Surgical Association, Monterey. California. February 15-18. 1976.
Volume 132. Au*
1976
with hypercalcemia. Blood calcium, plasma protein, and albumin determinations were repeated on two separate occasions, and if hypercalcemia persisted, the diagnosis of hyperparathyroidism was tentatively made. A careful history and physical examination were carried out and every attempt was made to rule out other potential causes of hypercalcemia, such as hyperthyroidism, sarcoidosis, multiple myeloma, milk-alkali syndrome, thiaxide medication, and metastatic malignancies. X-ray films of the chest, skeleton, and urinary tracts were taken to rule out a pathologic condition in these organ systems. As part of a protocol study, the majority of these patients had prior to surgery a steroid suppression test consisting of 100 to 200 mg of cortisone per day for five to six days. Failure of the elevated serum calcium level to decrease to within normal limits was considered indicative of primary hyperparathyroidism. Determinations of calcium balance and tubular reabsorption of phosphorus were not carried out. Parathyroid hormone assays only became available late in the study and were infrequently done. Parathyroid exploration was performed with the use of general anesthesia. The usual accepted surgical principles for this type of surgery-careful dissection of tissues, meticulous hemostasis, and adequate exposure-were adhered to. In all instances an attempt to identify all four parathyroids was made regardless of the pathologic features of the parathyroids. If a single adenoma was discovered, it was removed, and at least one other parathyroid was biopsied. When two enlarged glands were encountered, both were removed and a third gland was biopsied. With hyperplasia of four glands, three of the glands and a portion of the fourth were removed, leaving a well vascularized remnant of approximately 50 mg which was tagged with a silk suture. Results
In the group of 136 patients operated on for hyperparathyroidism, fifty-three (20 male, 33 female) were considered to be asymptomatic. Ages ranged from twenty to greater than sixty years (2 patients, 20 to 40 years; 40,40 to 60 years; and 11, greater than 60 years). Operative findings included forty-four patients with single adenoma, four patients with multiple adenomas, and three patients with hyperplasia. In two patients no adenoma or hyperplasia was noted. In one patient, a forty-five year old female with persistent hypercalcemia (11.1 mg/lOO ml), three parathyroids were observed, biopsied, and re-
231
State and Hill
AGE Upper Values 20
Calcium mg / lOOmI M
Phosphorous mg/ IOOml MIF
IO. 20
10.01
4.45
4.74
30
IO.14
10.02
4.34
4.24
40 30
IO.08
10.02
10.0 I
10.03
4.24 4.14
4.25 4.43
60
9.95
10.03
4.04
4.65
70
9.88
IQ04
3.94
4.84
20
9.09
882
2.55
2.85
30
9.03
683
2.45
2.55
40
8.96
883
2.35
2.55
50
8.90
8.84
2.24
2.66
8.84
2. 14
2.79
8.85
2.04
2.90
Lower Values
60
8.83
70
8.77
Maximal S.E.
0.05
0.10
Figwe 1. Upper and lower values of serum calcium and @osphmws In normal adults. (Modlfkd from [S] wnh pennlsshn~ of publfsfw. )
ported as normal. One gland, the right superior, could
not be found in the neck, and it was decided not to split the sternum. Postoperatively, the patient continued to be hypercalcemic, but she refused further surgery. We believe that a hyperfunctioning tumor was missed in this patient. The second patient a forty-two year old male had maximal serum calcium levels of 10.8 mg/lOO ml. Exploration of the neck revealed four parathyroid glands, which were biopsied and reported as normal. Up to one year postoperatively, all calcium levels did not exceed 10.4 mg/lOO ml. In this patient, we presume that an error in diagnosis had been made. Comments
A significant increase in the frequency of hyperparathyroidism in North America and Europe has been reported [1,2]. Whether this represents an absolute increase in the frequency of the disease or whether it is a result of greater awareness and uncovering of unexpected hypercalcemia by means of automated blood analysis equipment is moot. Jackson and Boonstra [3] saw proved hyperparathyroidism in one of every 834 patients when serum calcium level was routinely measured in all ambulatory patients admitted to the hospital [2]. At the Mayo Clinic, Purnell and his colleagues observed from January 1,1968 through June 30,197O 401 patients with disorders of calcium metabolism [3]. The provisional diagnosis of hyperparathyroidism was made initially in 322 of these patients, and of this 232
group 171 patients had surgical explorations. However, 147 patients with a provisional diagnosis of primary hyperparathyroidism but who were asymptomatic were followed for a five year period, and twenty-one patients had clinical signs and symptoms warranting surgical explorations. Eight additional patients required surgery for other reasons (41. The sine qua non for the diagnosis of hyperparathyroidism, as demonstrated in our study and in others reported in the recent literature, is the presence of hypercalcemia. Keating et al [5] stated: “The estimation of the precise level of serum calcium is the most effective screening for this condition.” Results of their carefully performed studies to determine the upper (97.5 percentile) limit of the normal range of serum calcium level for each decade from twenty to seventy years of age are shown in Figure 1. Keating et al [5] further stated that it was advisable for each laboratory to provide its own reliable and documented range of normal values. In establishing precise values for normal limits, slight elevations of serum calcium levels become important. Thus, Keating [S] reported on fifty-two patients with serum calcium values of less than 11.0 mg/lOO ml, forty-six of whom had nephrolithiasis. The disease was recurrent, bilateral, and severe in twenty-one. In our series, any serum calcium level of 10.8 mg/lOO ml or higher on two or more occasions was considered to be due to primary hyperparathyroidism. Serum phosphorus levels were obtained in our study, but they are of limited value in the diagnosis of hyperparathyroidism [I]. Values of serum phosphorus are quite labile, being affected in patients by exercise, standing, sleeping, and eating; furthermore, there is an endogenous rhythm that parallels the welI defined daily urinary excretion rhythm. Careful determination also shows that the lower range of normal values in both males and females between the second and seventh decades may decrease to less than 3.0 mg/lOO ml [5]. In ruling out other possible causes of hypercalcemia, such entities as hyperthyroidism, Cushing’s syndrome, milk-alkali syndrome, vitamin D intoxication, sarcoidosis, Paget’s disease, thiazide medication, and occult malignancies must be considered. In differential diagnosis of hypercalcemia, Edis, Ayala, and Egdahl [4] reported a 20 per cent incidence of primary hyperparathyroidism, 55 per cent skeletal metastases and myeloma, and 15 per cent ectopic hyperparathyroidism; the remaining 10 per cent included thiazide medication, vitamin D intoxication, sarcoidosis, milk-alkali syndrome, and thyrotoxicosis. In asymptomatic patients the greatest diagnostic challenge is in ruling out hidden maligrho Amwkan
Journal 04 !Zurgery
Hyperparathyroidism
nancies. As part of an investigation to determine the efficacy of the steroid suppression test [7] to differentiate primary from secondary hyperparathyroidism, the majority but not all of the patients were given a five to six day trial of 100 to 200 mg of cortisone. This test was helpful to us, but there have been other reports showing both false-positive and falsenegative results with this test [8]. We did not use other tests such as tubular reabsorption of phosphorus [9] or calcium infusion test [IO] in this study. Immunoreactive assays of parathormone (PTH) were not readily available to us and were used infrequently. There is no doubt that as technics for determination of PTH become fully developed and particularly as human parathyroid material for immunization replaces beef parathyroid, PTH determination will be extremely helpful in differentiating primary from secondary hyperparathyroidism [11,12]. It is also anticipated that PTH determinations in conjunction with catheterization of draining veins of the thyroid will be a great aid in locating previously missed parathyroid adenomas or carcinomas [13,14]. It is of interest to note, however, the degree of accuracy in diagnosis we were able to obtain without the aid of PTH determination. Preoperate localization by noninvasive technics would be most helpful to the surgeon. Selenium methionine has been suggested as a radionucleotide technic for this purpose [15]. In the present series it was attempted in nineteen patients but only localized the tumor preoperatively in two. We have not had any experience with ultrasonography or thermography, but these technics have been reported as being successful in preoperative localization of parathyroid pathologic conditions [4]. The surgical technic we used in exploring our patients followed the principles promulgated by Cope [16,17] and Goldman, Gordon, and Roof [13,18]. A thorough knowledge of the embryology and anatomy is essential. Dissection must be performed with meticulous attention to hemostasis and adequate exposure. Some specific details that we have found useful in this type of surgery are complete mobilization of the superior poles of the thyroid to identify superior parathyroids and routine identification of the recurrent laryngeal nerves throughout their cervical course. Furthermore, in a little more than half of our patients, the identification of a unilaterally enlarged inferior thyroid artery [19] or the identification of a prominent branch arising from an inferior or superior thyroid artery of almost normal size has been helpful in locating an otherwise hidden parathyroid adenoma as in Figures 2 and 3. In the present series five patients had adenomas inferior to the level of the clavicles, but in each instance the Volume 132, August 1976
\,
Inferior Thyroic
Adenoma
Figure 2. Schematk drawing of asymptomatic hyperparath~tdhwn showing ankrgsd lnferkr thymid artery on sideof ademmaNotenotmal size of infarkr thyroid artery on 0pposMe side.
Large Inf. Thyroid Artery
Figure 3. Schematic drawing of asympkmatk hyperparathyroidm demonstrating large branch from Merkr thyrohi arteryto parathyroid adenoma.
tumor could be delivered into the neck without the need for a sternal split. As indicated previously, forty-four patients in the present series had a single adenoma, four patients had multiple adenomas, and three had hyperplasia of four glands. The 85 per cent incidence of single adenoma is thus quite similar to that reported by the group at Massachusetts General Hospital [20]. Others [1,21], however, have reported a much greater incidence of chief cell hyperplasia. Furthermore, from more recent reports in which electron 233
State and Hill
microscopy has been used, it appears that differentiation between adenoma and hyperplasia may be extremely difficult if not impossible (221. Thus it becomes important, whenever possible, to identify, biopsy if necessary, and assess the size of all parathyroid tissue in the exposed surgical field. Paloyan Lawrence, and Straus [I] recommend outright resection of three and a half glands in all patients with primary hyperparathyroidism regardless of the findings at operation. We have not followed this policy; rather, we have excised single adenomas when present with biopsy of at least one additional gland. When all four glands were enlarged, we have resected three and part of the fourth, leaving approximately 50 mg of parathyroid tissue, being certain to identify the remnant with a silk suture. In patients with two adenomas, rather than simply remove the adenomas and biopsy a third (as we had done) we would now, in light of newer information concerning the pathology of hyperparathyroidism, remove three glands and salvage only a part of the fourth, as with four gland hyperplasia. Summary With the advent of automated equipment for blood chemistry determinations, many patients are presenting with asymptomatic or “biochemical” hyperparathyroidism. In the present series, of 136 patients operated on for hyperparathyroidism, fifty-three were considered asymptomatic. In fiftyone patients, parathyroid pathologic conditions were found; in one patient, it is probable that an adenoma had been missed, and in the other, it is presumed that an error in diagnosis was made. We recommend that surgical exploration be considered as an acceptable alternative to watchful waiting for patients with asymptomatic hyperparathyroidism. References 1. Paloyan E, Lawrence AM, Straus FH: Hyperparathyroidism. Modem Surgical Moncqaphs. New York, Grune & Stratton, 1973. 2. Adams P. Chalmers TM, Hill LF, Truscott B&N: idiopathic hypercalcemia and hyperparathyroidism. & Med./ 4: 582, 1970. 3. Jackson CE, Boon&a CE: The hyperparathyroidism detected by routfne serum calctum analysis. Ann lntem A&d 83: 488, 1965. 4. Edis AJ, Ayata LA, Egdahl RH: Manual of Endocrine Sugery. New York, Heidelberg, Berlin, Springer-Verlag, 1975. 5. Keatlng FR Jr, Jones JD. Etveback LR, Randall RV: The relation of age and sex to distribution of values in healthy adults of serum cabium, incqfanic phosphorus, magnesium atkalina phosphatase, total proteins, albumin and blood urea. JLe6 Clin h&d 73: 825. 1969. 6. Keating FR Jr: D@nostt of primary hyperpamthyrofdtsm. JAMA 178: 547, 1961.
234
7. Dent CE: Cortisone test for hyperparathyroidism. Br h&d J 1: 230, 1956. 8. Danowski TS: Phosphorus pools in the body. Clinical Endocrinology, vol Ill. Baltimore, Williams 8 Wilkins, 1962. 9. Sirota JH: Renal tubufar reabsorption of phosphate in hyperparathyroidism before and after removal of parathyroid adenoma. fed Pfoc 12: 133, 1953. 10. Howard JE, Hopkins TR, Connor TB: Use of intravenous calcium as a measure of activity of the parathyroM gland. J C//n Endocrinol Metab 12: 927. 1952. 11. Silverman R, Yaflow RS: Heterogenefty of parathyrofd hantone: clinical and physiologic implications. J C/in invest 52: 1958, 1973. 12. Reiss E, Canterbug JM: Application of radioimmunoassay to differentiation of adenoma and hyperptasia and to preoperative localization of hyperfunctioning parathyrold glands. N EnglJMed280: 1381, 1969. 13. Goldman L, Gordon GS, Roof BS: The parathyrotds: progress, problems and practice. Chicago, Year Book Medical, Curr Probl Surg August 197 1. 14. Eisenberg H, Paltotta J, Sherwood LM: Selective arterlography, venography and venous hormone assay in diagnosis and localization of parathyroid lesions. Am J Ahd 56: 810, 1974. 15. Potchen EJ, Wilson RE. Dealy JB Jr: External parathyroid scanning with Se75 selenomethionine. Ann Surg 162: 492, 1965. 16. CopeO:Thestoryofhypaqamthyroklismattheh4assachusetts GeneralHospital. NEnglJMed274: 1174, 1966. 17. Cope 0: Hyparp%athyroidlsm: d-is and management. Am J Surg 99: 394, 1960. 18. Goldman L: Unusual manifestations of hyperparathyrokflsm. Surg Gynecol Obstet 100: 675, 1955. 19. State D: The enlarged inferior thyroM artery: a valuable guide in surgery of parathyroid adenomas. Surgery 56: 461, 1964. 20. St Goar WT, Roth SI: Ccfreqxndence. N Eng/ JAM 297: 913, 1974. 21. Roth SL: Recent advance in parathyroid gland pathology. Am JMed50: 612, 1971. 22. Shannon WA, Roth SI: An ultrastructural study of acM phosphatase activity in normal, adenomatous and hyperpiastlc (chief cell type) human parathyrokf glands. Am J P&o/77: 493, 1974.
Discussion H. Earl Gordon (Los Angeles, CA): As indicated by the authors, an increasing number of patients with primary hyperparathyroidism are being encountered who lack the classic clinical features usually associated with this disease. Despite this, I was surprised that 40 per cent of the authors’ patients were considered asymptomatic. Therefore, I would question whether some of the more subtle clinical manifestations may have been overlooked. The changing clinical picture of the disease seems to parallel the increased incidence. Many symptoms that were previously considered relatively nonspecific may now be the presenting complaint. These include such symptoms as easy fatigability, muscle weakness (particularly of the proximal muscles), headaches, neuropsychiatric changes, weight loss, and arthralgia. Abdominal pain, particularly epigastric distress in the absence of demonstrable peptic ulcer disease, is not uncommon. I have been increasingly impressed by the number of patients who are relieved of these nonspecific complaints after operation. Recently, anemia has been recognized as another clinical manifestation. We have had
lha Amuka
Jaurnal 04 8urgwy
Hyperparathyroidism
two patients with refractory anemia who responded only after the correction of their hyperparathyroid state. In establishing a diagnosis, I am somewhat concerned about the authors’ reliance primarily on the level of serum calcium and the cortisone suppression test. In our hands, the cortisone test has proved of limited value, since in a few patients with hyperparathyroidism, hypercalcemia has been abolished by steroids, and secondly, the hypercalcemia of some malignancies does not respond to corticoids. In reaching a decision on an asymptomatic patient with hypercalcemia, I feel more secure with a complete biochemical evaluation including the immunoassay of PTH. In regard to one of the common procedures, tubular reabsorption of phosphate can be a valuable discriminatory test if preceded for six days by a high phosphate intake. After establishing the diagnosis with reasonable certainty, I strongly support the authors’ recommendation for surgical exploration in all good risk patients with asymptomatic primary hyperparathyroidism. If uncorrected, the condition will inevitably lead to hypertension, renal impairment, and other complications in a significant number of patients. I also concur with their conservative approach in regard to biopsy of grossly normal glands. Biopsy of all four glands, as recommended by many surgeons, carries a definite risk of prolonged or permanent hypocalcemia. When confronted with hyperplasia of all glands, there in always the potential risk that the remnant of parathyroid gland left behind may be inadequate to sustain the patient at normocalcemic levels. For this reason, we now routinely preserve some of the excised tissue for transplantation if hypoparathyroidism should subsequently develop. With the technic of Wells et al (Surgery 75:49,1974), parathyroid tissue can be preserved for six to nine months by rapid freezing in tissue culture medium and storage in a liquid nitrogen freezer. When indicated, transplantation is carried out in the flexor muscles of the forearm using microsurgical technic. Assay of the antecubital blood draining the graft site can then be used as an index of graft function. Although we have been fortunate in not having a patient who has required transplantation, it is reassuring to have the tissue available should the need arise. Willard E. Goodwin (Los Angeles, CA): Hugh Cabot was reported to have said that the way to suspect a right ureteral stone is to look for the footprints or handprints of the surgeon who removed the normal appendix. Here is such a patient. She was a fourteen year old girl, hospitalized with right lower quadrant pain and normal urine. The scout x-ray film was interpreted as normal, but in fact a shadow near the bladder represented a lower ureteral stone. Her normal appendix was removed and an intravenous urogram was wisely ordered. These films looked normal except that the right ureter was dilated. Retrograde pyelogram proved there was a lower ureteral stone on the right side, which she later passed after further colic. It is rare for a fourteen year old girl to have a stone in this country. The serum calcium value was 14 mg/lOO ml. The same surgeon, Doctor Eric Fonkalsrud, later removed a parathyroid adenoma. I have
Volume 132, August 1976
never seen one in a fourteen year old child, and I noticed that the authors had none less than age twenty. Frederic P. Shidler (Menlo Park, CA): My personal experience is not extensive, but in fourteen patients I have been impressed that the asymptomatic patient does not really have the urgency for neck exploration as the patient with renal stone, duodenal ulcer, or fatigability. I am one member of this Association who would not operate on an asymptomatic patient until the patient has been observed for a year or so. Our practice is to observe the serum calcium level, which may fluctuate and in some months may be within normal range. I do not think the patient is at risk with serum calcium levels of 11.0 to 11.3 mg/lOO ml. During the observation period we have an opportunity to reassure ourselves that we are really dealing with hyperparathyroidism and not with some other systemic disease that produces the hypercalcemia. All the patients we have operated on have had adenoma or hyperplasia. Robert W. Rand (Los Angeles, CA): Certain types of tumors in the head and neck lend themselves to embolization by ferrosilicone-particularly if they are supplied by the external carotid circulation. We have used this on some occasions and I am aware of at least one patient who has had successful embolization of a parathyroid tumor. I am wondering if Doctor State would make a comment as to arteriography especially with subtraction technic and the identification of the particular artery going to the adenoma, which I think could be readily injected and possibly avoid an open operation. David State (closing): I think Doctor Gordon is absolutely correct in his point regarding the term “asymptomatic.” However, I think we would have to admit that none of us is completely asymptomatic in the strict sense of the word. In the pragmatic aspect, in my patients no thought was ever given to the possibility of hyperparathyroidism clinically, and the diagnosis was made primarily on biochemical determinations. As to Doctor Goodwin’s remarks, we did not find any patient with hypercalcemia less than twenty years old. As far as I know, very few patients younger than twenty years have been reported with primary hyperparathyroidism. Doctor Shidler, I cannot argue with your conservative approach. As a matter of fact, it is one advocated by the Mayo Clinic group. It is interesting to note, however, that Keating reported a series of patients who had mild elevations of serum calcium levels but still below 11 mg/lOO ml, and in that group of fifty-two patients, forty-six had significant renal disease. I think, therefore, the onus is on the individual who makes the decision to follow them. However, hyperparathyroidism is a slow process, and if the patient is watched carefully, there should be time to operate. However, the results of this study indicate that if you adopt a more aggressive attitude, you can find parathyroid lesions before they produce symptoms and presumably pathologic changes that one would hope to avoid.
235
