World J. Surg. 1,739-746, 1977
9 1977 by the Soci6t6 Internationale de Chirurgie
Hyperparathyroidism with Asymptomatic Hypercalcemia and Symptomatic Normocalcemia LARS THORI~N, M . D .
Department of Surgery, University Hospital, Uppsala, Sweden
Asymptomatic hyperparathyroidism has been found with increasing frequency as serum calcium determinations have become routine. Normocalcemic hyperparathyroidism has been diagnosed in patients who have recurrent urinary tract stones in combination with hypercalciuria. The indications for surgery in asymptomatic hyperparathyroidism are difficult to evaluate. Three treatment options for dealing with verified asymptomatic hyperparathyroidism are discussed. The option of neck exploration is advocated for the purpose of preventing the complications of renal impairment, persistent hypertension, and skeletal disease. The presence of urinary tract stones is the main reason for suspecting normocalcemic hyperparathyroidism. Although various tests can be used, the final diagnosis is often made at neck exploration. The recurrence of urinary tract stones and the possibility of kidney damage are the main reasons for surgery. Further study is needed to evaluate fully the results of parathyroid surgery in normocalcemic hyperparathyroidism.
because of the routine calcium determinations for hospitalized patients and the wider use of health screening programs. So-called normocalcemic hyperparathyroidism is diagnosed mainly in patients who have recurrent urinary tract stones in combination with hypercalciuria. In these cases a thorough evaluation of the type of hypercalciuria is essential before surgical intervention is considered. These types are absorptive hypercalciuria caused by increased uptake of calcium from the intestine; bone resorptive hypercalciuria caused by hyperparathyroidism itsclf; and renal hypercalciuria related to increased renal calcium loss. Recurrent urinary tract stones and hypercalciuria of the absorptive type seem to dominate this syndrome [1-3]. The indications for surgery in asymptomatic hyperparathyroidism and in so-called normocalcemic hyperparathyroidism are difficult to evaluate and will be dealt with in detail.
The diagnosis of hyperparathyroidism is now made much earlier and more frequently in symptomatic patients than it was 10 to 15 years ago. The common use of automated equipment for blood chemistry determinations has increased the detection of hypercalcemia in patients without other symptoms related to the function of the parathyroid glands. As a result, asymptomatic hyperparathyroidism is encountered with increasing frequency
Asymptomatic Hypercaleemic Hyperparathyroidism
In the last decade hyperparathyroidism has been diagnosed with increasing frequency because of growing interest in the disease. The sometimes diffuse symptoms, especially in older age groups, are now considered carefidly. As a result, many patients have had earlier operative treatment for parathyroid disease than would have been truc a decade ago. New diagnostic methods have made it obvious that primary hyperparathyroidism may occur without the symptoms usually attributed to the disease. The per-
Reprint requests: Lars Thor6n, M.D., Department of Surgery, University of Uppsala, Uppsala, Sweden.
739
740
centage of these asymptomatic cases varies from 1% to 74%, depending upon the criteria used [1, 4-9]. Routine measurements of serum calcium have shown that a proportion of the population has hypercalcemia [10]. When other causes of hypercalcemia, such as Cushing's syndrome, Paget's disease, and medication with thiazide drugs, have been excluded, a group of patients with hyperparathyroidism still remains, many of them without clinical symptoms [11, 12]. In the differential diagnosis of patients with hypercalcemia, Edis et al. reported that 20% of patients had primary hyperparathyroidism, 55% had skeletal metastases and myeloma, and 15% had a tumor with ectopic parathyroid hormone-like activity [13]. The remaining 10% included the other diseases mentioned above. The cost-benefit problem in screening hospitalized patients has been discussed [14]. Christensson studied the prevalence of hypercalcemia in a health screening program and reported 95 patients with verified hypercalcemia on repeated measurements (~>11.1 mg/100 ml) among 15,903 subjects (employees aged 20 to 36 years, 0.6%) [15]. The highest prevalence of verified hypercalcemia, 1.3%, was noted in women 60 to 63 years of age. Primary hyperparathyroidism was the most common cause of hypercalcemia in this series, and in 57 of 59 subjects undergoing exploratory neck surgery, parathyroid adenomas (usually single) were found (0.36% of the examined population). The findings of renal calculi, constipation, and mental depression were taken as evidence of symptomatic disease. These symptoms were not found in 48 subjects (71%) defined as having asymptomatic hyperparathyroidism. Approximately 0.3% of the examined population appeared to have asymptomatic hyperparathyroidism, in hypercalcemic subjects the mean systolic and diastolic blood pressures were significantly higher than in matched normocalcemic subjects. The difference was not related to impaired renal function or other factors associated with hypertension. Early diagnosis and treatment may save patients from symptoms and progressive disease. No criteria are available to predict and identify the patients who are to remain asymptomatic or ultimately will require surgical intervention. The few patients who have refused surgery have been followed for several years without signs of progressive disease [16], and most patients with hyperparathyroidism demonstrate long periods with moderate symptoms before turning up for examination and treatment. The prospective study of this problem by Purnell and associates at the Mayo Clinic is of particular interest [5, 17]. In the total series of patients with
World J. Surg. Vol. 1, No. 6, November, 1977
hypercalcemia and a tentative diagnosis of hyperparathyroidism, the patients with asymptomatic and uncomplicated disease and mild hypercalcemia (not above 11 mg/100 ml) were studied prospectively. At the end of the 5-year study, 20% of the original group of 147 had sufficient progression of their disease to require surgical treatment during the first 4 years of the study. However, the study is not complete, since 27 patients were removed from the series during the second 30 months because of inability to cooperate in the follow-up program. Sufficient data are not available concerning these patients to assess any development of complications in this group. Because of different opinions in this field, there are several options for treating verified asymptomatic hyperparathyroidism, as follows: (a) neck exploration on broad indications; (b) observation and thorough follow-up to detect early symptoms or complications; (c) observation of patients with moderate hypercalcemia and neck exploration of patients with serum calcium above a certain level. At our institution we have performed neck exploration (option a) when the patient's status was not clear. We have applied this policy to younger patients as well as older ones. Subtle clinical manifestations may be overlooked, such as the nonspecific symptoms of muscle weakness, muscular fatigability, mental changes, and gastrointestinal problems. The patients may not be aware of their symptoms until they are relieved of them by operation. The relief of unrecognized symptoms is illustrated by the case of a 35-year-old man with a fractured wrist. On x-ray examination a small bone cyst near the elbow was found incidentally. Serum calcium determinations showed moderate hypercalcemia. Otherwise, the patient was fully employed and without symptoms. Neck exploration revealed a parathyroid adenoma, which was removed. The patient became normocalcemic after the operation. A few months later I met him skating. He then mentioned that he had been very fond of that sport up to the age of 25, but was forced to give it up because of weakness in his ankle joints. He thought this was caused by increasing age. After the operation he was able to take up skating again with the same muscle strength as 10 years earlier. This kind of information is difficult to elicit in taking a routine case history. in elderly people many symptoms such as decreased muscle strength, muscular fatigue, and mental disorders are ascribed to the aging per se. Gastrointestinal symptoms and arterial hypertension can be difficult to evaluate. Often these symptoms are discovered by the patient and appreciated by the surgeon after operation when the patient becomes
L. Thor~n: Asymptomatic and Normocalcemic Hyperparathyroidism
aware of the disappearance of symptoms such as muscular weakness, fatigue, and gastrointestinal disturbances. The elderly patient often says, " I feel much stronger now and can get up from an armchair without help." Because of this kind of clinical experience, we follow a policy of surgical exploration of the neck. The Mayo Clinic program reported by Purnell et al. adhered to the third option [5, 17]. However, certain unnecessary difficulties can arise in a program of long-term observation. Asymptomatic patients tend to discount the potential seriousness of their disease and do not cooperate adequately. Some of these patients are at risk for complications such as renal impairment and even hypercalcemic crisis [18]. In the Mayo Clinic study this serious event did not occur during the 5 years of observation. However, we have recently seen a fatal case of hyperparathyroid crisis (pernicious hyperparathyroidism) [19] in an elderly woman about 2 years after her refusal to have a neck exploration which was suggested for hyperparathyroidism with very few symptoms. The metabolic effects of parathyroidectomy in asymptomatic cases have been evaluated objectively [20]. Six patients with asymptomatic hyperparathyroidism on a standardized diet were investigated regarding levels of serum calcium, phosphorous, magnesium, creatinine, cyclic AMP, and parathormone before and after surgery, and were compared to a symptomatic group. The asymptomatic patients were younger than the symptomatic ones. After parathyroidectomy the biochemical evidence of hyperparathyroidism was reversed in both groups. There was no difference between the groups in the morphology of resected parathyroid tissue. There was no x-ray evidence of skeletal disease or excessive bone resorption in the asymptomatic patients, but 4 of 6 had signs of low bone density when measured by 1251photon absorption in the distal third of the radius. Despite lack of symptoms, and with normal routine skeletal x-ray films and normal serum alkaline phosphatase levels, bone disease may be present in asymptomatic patients with so-called biochemical hyperparathyroidism. An appreciable loss of mineral from the skeleton, after hyperparathyroidism has been present for some time, is necessary for detection by ordinary x-ray examination [21]. In summary, neck exploration on rather broad indications is advocated in patients with asymptomatic hyperparathyroidism. This may avoid complications such as renal impairment, persistent hypertension, and skeletal disease, and may relieve symptoms that have been neglected or misinterpreted.
741
Normocalcemic Hyperparathyroidism
The serum calcium level in each individual is stable, but there is a range of variation between individuals. One individual can start at the lower border of the " n o r m a l " range and increase his serum value to the upper border and still be considered to have a normal serum calcium level, taking the albumin level into account. This is the logical background of so-called normocalcemic hyperparathyroidism. The main reason for suspecting the existence of this type of disease is the recurrence of urinary tract stones. The serum calcium values are usually in the upper quartile of the normal distribution curve or occasionally slightly above the upper limit [22, 23]. When patients with stones in the urinary tract are observed over prolonged periods of time, hypercalcemia may supervene [24]. In the diagnostic examination of these patients several tests can be used. Preoperatively, the surgeon needs reasonably satisfactory biochemical evidence in order to suspect primary hyperparathyroidism. In many cases the diagnosis is supported by serial estimations of serum calcium and phosphate, phosphate deprivation combined with thiazide administration [25], determination of ionized calcium [26], parathormone assay [27-30], cAMP in urine [31, 32], a calcium infusion test, a calcium loading test with determination of calcium, cAMP, and creatinine [2], and T R P (tubular reabsorption of phosphate). However, in several instances of normocalcemic hyperparathyroidism, the results of these tests have fallen within the normal range. The final diagnosis is often made at neck exploration. The surgeon must take the responsibility as diagnostician during parathyroid exploration. During the procedure microscopic analysis of material from the parathyroid glands is essential; here the judgment of the surgeon and the pathologist experienced in endocrine pathology is of the utmost importance. All 4 parathyroid glands should be identified. However, all the glands should not be biopsied regardless of the findings at exploration. If one gland is affected, it is removed and a normal gland is biopsied. When 2 glands are enlarged and removed, a third gland is examined. In hyperplasia 3 glands are removed, and a well-vascularlzed portion of the fourth is left tagged with a silk suture or a metallic clip in the adjacent thyroid capsule. The size of the remnant should be approximately 60 to 70 mg. Subtotal parathyroidectomy has been advocated regardless of pathologic findings [33-36] because of the rising incidence of hyperplasia in surgical series, the difficulties in establishing the diagnosis of hyper-
742
plasia at the time of surgery [37], and the published figures of high recurrence rates [33, 38, 39]. We continue to use the approach described above because of the low recurrence rate in our series (2%) [40] and in that of Clark and Goldman (2.2%) [8]. If persistent hyperparathyroidism is excluded, recurrent hyperparathyroidism appears to be unusual [8]. This conclusion is supported by the results of Romanus, et al. [41]. However, in patients with familial hyperparathyroidism, multiple parathyroid adenoma, or a multiple endocrine adenomatosis syndrome, a subtotal parathyroidectomy is advocated regardless of pathology because of the high risk of recurrence [42]. Because preoperative diagnosis is sometimes difficult, the surgeon may find normal parathyroid glands. In our series of 84 patients explored on the provisional diagnosis of normocalcemic hyperparathyroidism [22, 23, 43], we found 26 patients with normal glands, 39 patients with hyperplasia, and 19 with adenomatons diseases. In other studies the incidence of normal findings at neck exploration in patients with normocalcemia and urinary tract stones has been higher [41]. The adenomas did not differ histologically from those causing hypercalcemic hyperparathyroidism. The hyperplasia was of the chief cell type and was slight in most cases [43]. The results following neck exploration in symptomatic normocalcemic hyperparathyroidism, mostly related to urinary tract stones, are relevant to the discussion. In our series the recurrence rate of urinary tract stone disease at follow-up 2 to 5 years postoperatively was about 48% in the group with normal parathyroids at exploration, and 24% in the group with hyperplasia. There were no recurrences in the patients with parathyroid adenoma [23, 43]. However, to be conclusive this series must be followed for a longer period of time. The main reasons for advocating surgery in these cases are the problems of recurrent urinary tract stones and the possibility of concomitant kidney damage. Patients with normocalcemic hyperparathyroidism have developed hypercalcemic crisis [18], but this is exceptional. A prospective randomized series is required to evaluate the results of parathyroid surgery in normocalcemic hyperparathyroidism. R~sum~
Depuis que le dosage de la calcdmie est devenu un examen de routine, de nombreux cas d'hyperparathyroidie asymptomatique ont 6t6 decouverts. Chez des malades atteints de lithiase urinaire recidivante avec hypercalciurie, on a pu diagnostiquer l'hyperparathyroidie normocalcemique.
World J. Surg. Vol. 1, No. 6, November, 1977
I1 est difficile de pr6ciser les indications operatoires de l'hyperparathyroidie asymptomatique. Nous discutons trois options thdrapeutiques et conseillons l'exploration cervicale pour prevenir les complications d'insuffisance rdnale, d'hypertension persistante et d'atteinte osseuse. En presence d'une lithiase renale faisant suspecter une hyperparathyroidie normocalc6mique, on peut utiliser divers tests de diagnostic. Mais, souvent, c'est l'exploration cervicale qui donne la certitude. Ces malades doivent etre operes pour 6viter la lithiase recidivante et le risque de lesion r6nale. A l'heure actuelle, faute d'dtudes completes, il est encore difficile d'6valuer les resultats de la chirurgie des parathyroides pour l'hyperparathyroidie normocalcemique.
References
1. Pak, C.Y.C., Ohata, M., Lawrence, E.C., Snyder, W.: The hypercalcurias: causes, parathyroid functions and diagnostic criteria. J. Clin. Invest. 54:387, 1974 2. Pak, C.Y.C., Kaplan, R., Bone, H., Townsend, J., Waters, O.: A simple test for the diagnosis of absorptive, resorptive and renal hypercalciurias. N. Engl. J. Med. 292:497, 1975 3. LjunghaU, S.: Renal stone disease. Studies on epidemiology and calcium metabolism. Scand. J. Urol. Nephrol. [Suppl.] 41:1, 1977 4. Boonstra, C.E., Jackson, C.E.: Hyperparathyroidism detected by routine serum calcium analysis. Ann. Intern. Med. 63:468, 1963 5. Purnell, D.C., Smith, L.H., Scholz, D.A., Elveback, L.R., Arnaud, C.D.: Primary hyperparathyroidism: a prospective clinical study. Am. J. Med. 50:670, 1971 6. Mallette, L.E., Bilezikian, J.P., Heath, D.A., Aurbach, G.D.: Primary hyperparathyroidism: clinical and biochemical features. Medicine 53:127, 1974 7. Attie, J.N., Khafif, R.A.: Surgical exploration in asymptomatic hypercalcemia. Am. J. Surg. 132:449, 1976 8. Clark, O.H., Goldman, L.: Prophylactic subtotal parathyroidectomy should be discouraged. In Controversy in Surgery, R.L. Varco and J.P. Delaney, editors. Philadelphia-London-Toronto, W.B. Saunders Co., 1976, p. 53 9. State, D., Hill, G.S.: Asymptomatic primary hyperparathyroidism. Am. J. Surg. 132:231, 1976 10. Boonstra, C.E., Jackson, C.E.: Serum calcium survey for hyperparathyroidism. Am. J. Clin. Pathol. 55:523, 1971 11. Lamberg, B.-A., Kuhlbfick, B.: Effect of chlorthiazide on the excretion of calcium in urine. Scand. J. Clin. Lab. Invest. I1:351, 1959 12. Middler, S., Pak, C.Y.C., Murad, F., Bartter, F.C.: Thiazide diuretics and calcium metabolism. Metabolism 22:139, 1973 13. Edis, A.J., Ayala, L.A., Egdahl, R.H.: Manual of Endocrine Surgery. New York-Heidelberg-Berlin, Springer-Verlag, 1975
L. Thor6n: Asymptomatic and Normocalcemic Hyperparathyroidism
14. Williamson, E., van Peenen, H.J.: Patient benefit in discovering occult hyperparathyroidism. Arch. Intern. Med. 133:430, 1974 15. Christensson, T.: Hypercalcemiain ahealth screening. Thesis. Stockhohn, 1975 16. Keating, F.R.: The clinical problem of primary hyperparathyroidism. Med. Clin. North Am. 54:511, 1970 17. Purnell, D.C., Schaltz, D.A., Smith, L.H., Sizemore, G.V., Black, B.M., Goldsmith, R.S., Arnaud, C.D.: Treatment of primary hyperparathyroidism. Am. J. Med. 56:800, 1974 18. Eisenberg, E., Gotch, F.A.: Normocalcemic hyperparathyroidism culminating in hypercalcemic crisis. Arch. Intern. Med. 122:258, 1968 19. Johansson, H., Thor6n, L., Warner, I.: Pernicious hyperparathyroidism. Acta Chir. Scand. 139:37, 1973 20. Kaplan, R.A., Snyder, W.H., Stewart, A., Pak, C.Y.~2.: Metabolic effects of parathyroidectomy in asymptomatic primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 42:4t5, 1976 21. Dal6n, N., Hjern, B.: Bone mineral content in patients with primary hyperparathyroidism without radiological evidence of skeletal changes. Acta Endocrinol. 75:297, 1974 22. Grimelius, L., Johansson, H., Lindquist, B., Thor6n, L., Werner, I.: Normocalcemic primary hyperparathyroidism. Acta Chit. Scand. 139:42, 1973 23. Johansson. H., Thor6n, L., Werner, I., Grimelius, L.: Normocalcemic hyperparathyroidism, kidney stones and idiopathic hypercalciuria. Surgery 77:691, 1975 24. Johnson, R.D., Conn, J.W.: Hyperparathyroidism with a prolonged period of normocalcemia. J.A.M.A. 210:2063, 1969 25. Adams, P., Chalmers, T.M., Hill, L.F., Truscot, B.: Idiopathic hypercalcemia and hyperparathyroidism. Br. Med. J. 4:582, 1970 26. Muldowney, F.P., Freaney, R., McMullin, J.P., Towers, R.P., Spillane, A., O'Connor, P., O'Donohoe, P., Moloney, M.: Serum ionized calcium and parathyroid hormone in renal stone disease. Q. J. Med. 14:75, 1976 27. Shimkin, P.M., Powell, D.: Parathyroid hormone levels in thyroid vein blood of patients without abnormalities of calcium metabolism. Ann. Intern. Med. 78:714, 1973 28. Almqvist, S., Hjern, B., W~isthed, B.: The diagnostic value of a radioimmunoassay for parathyroid hormone in human serum. Acta Endocrinol. 78:493, 1975
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29. Hawker, C.D.: Parathyroid hormone: radioimmunoassay and clinical interpretation. Ann. Clin. Lab. Sci. 5:383, 1975 30. Posen, S., Kleerekoper, M., Ingham, J.P., Hirshorn, J.E.: Parathyroid hormone assay in clinical decisionmaking. Br. Med. J. 1:16, 1976 31. de Nutte, N., Debacker, M., Verbeelen, D., Manderlier, T., Six, R., Corvilain, J.: Parathyroid function and urinary cyclic 3'5' adenosine monophosphate. Acta Clin. Belg. 30:91, 1975 32. Shaw, J.W., Oldham, S.B., Rosoff, L., Bethune, J.E., Fickman, M.P.: Urinary cyclic AMP analyzed as a function of the serum calcium and parathyroid hormone in the differential diagnosis of hypercalcemia. J. Clin. Invest. 59:14, 1977 33. Haft, R.C., Ballinger, W.F.: Causes of recurrent hypercalcemia after parathyroidectomy for primary hyperparathyroidism. Ann. Surg. 173:884, 1971 34. Haft, R.C., Armstrong, R.G.: Trends in the current management of primary hyperparathyroidism. Surgery 75:715, 1974 35. Paloyan, E., Lawrence, A.M., Straus, F.H.: Hyperparathyroidism. New York, Grune & Stratton, 1973 36. Paloyan, E., Lawrence, A.M.: The rationale for subtotal parathyroidectomy. In Controversy in Surgery, R.L. Varco and J.P. Delaney, editors. PhiladelphiaLondon-Toronto, W.B. Saunders Co., 1976, p. 41 37. Shannon, W.A., Roth, S.I.: An ultrastructural study of acid phosphatase activity in normal, adenomatous and hyperplastic human parathyroid glands. Am. J. Pathol. 77:493, 1974 38. Paloyan, E., Lawrence, A.M., Baker, W.H., Straus, F.H.: Near-total parathyroidectomy. Surg. Clin. North Am. 49:43, 1969 39. Livesay, J.J., Mulder, D.G.: Recurrent hyperparathyroidism. Arch. Surg. 111:688, 1976 40. Johansson, H., Thoren, L., Werner, I.: Hyperparathyroidism--clinical experiences from 208 cases. Ups. J. Med. Sci. 77:41, 1972 41. Romanus, R., Heimann, P., Nilsson, O., Hansson, G.: Surgical treatment of hyperparathyroidism. Prog. Surg. 12:22, 1973 42. Marsden, P., Day, J.L.: Hyperparathyroidism: the risk of recurrence. Clin. Endocrinol. 2:9, 1973 43. Grimelius, L., Ejerblad, S., Johansson, H., Werner, I.: Parathyroid adenomas and glands in normocalcemic hyperparathyroidism. Am. J. Pathol. 83:475, 1976
9 1977 by the Soci6t6 Internationale de Chirurgie
Hyperparathyroidism with Asymptomatic Hypercalcemia and Symptomatic Normocalcemia LARS THORI~N, M . D .
Department of Surgery, University Hospital, Uppsala, Sweden
Asymptomatic hyperparathyroidism has been found with increasing frequency as serum calcium determinations have become routine. Normocalcemic hyperparathyroidism has been diagnosed in patients who have recurrent urinary tract stones in combination with hypercalciuria. The indications for surgery in asymptomatic hyperparathyroidism are difficult to evaluate. Three treatment options for dealing with verified asymptomatic hyperparathyroidism are discussed. The option of neck exploration is advocated for the purpose of preventing the complications of renal impairment, persistent hypertension, and skeletal disease. The presence of urinary tract stones is the main reason for suspecting normocalcemic hyperparathyroidism. Although various tests can be used, the final diagnosis is often made at neck exploration. The recurrence of urinary tract stones and the possibility of kidney damage are the main reasons for surgery. Further study is needed to evaluate fully the results of parathyroid surgery in normocalcemic hyperparathyroidism.
because of the routine calcium determinations for hospitalized patients and the wider use of health screening programs. So-called normocalcemic hyperparathyroidism is diagnosed mainly in patients who have recurrent urinary tract stones in combination with hypercalciuria. In these cases a thorough evaluation of the type of hypercalciuria is essential before surgical intervention is considered. These types are absorptive hypercalciuria caused by increased uptake of calcium from the intestine; bone resorptive hypercalciuria caused by hyperparathyroidism itsclf; and renal hypercalciuria related to increased renal calcium loss. Recurrent urinary tract stones and hypercalciuria of the absorptive type seem to dominate this syndrome [1-3]. The indications for surgery in asymptomatic hyperparathyroidism and in so-called normocalcemic hyperparathyroidism are difficult to evaluate and will be dealt with in detail.
The diagnosis of hyperparathyroidism is now made much earlier and more frequently in symptomatic patients than it was 10 to 15 years ago. The common use of automated equipment for blood chemistry determinations has increased the detection of hypercalcemia in patients without other symptoms related to the function of the parathyroid glands. As a result, asymptomatic hyperparathyroidism is encountered with increasing frequency
Asymptomatic Hypercaleemic Hyperparathyroidism
In the last decade hyperparathyroidism has been diagnosed with increasing frequency because of growing interest in the disease. The sometimes diffuse symptoms, especially in older age groups, are now considered carefidly. As a result, many patients have had earlier operative treatment for parathyroid disease than would have been truc a decade ago. New diagnostic methods have made it obvious that primary hyperparathyroidism may occur without the symptoms usually attributed to the disease. The per-
Reprint requests: Lars Thor6n, M.D., Department of Surgery, University of Uppsala, Uppsala, Sweden.
739
740
centage of these asymptomatic cases varies from 1% to 74%, depending upon the criteria used [1, 4-9]. Routine measurements of serum calcium have shown that a proportion of the population has hypercalcemia [10]. When other causes of hypercalcemia, such as Cushing's syndrome, Paget's disease, and medication with thiazide drugs, have been excluded, a group of patients with hyperparathyroidism still remains, many of them without clinical symptoms [11, 12]. In the differential diagnosis of patients with hypercalcemia, Edis et al. reported that 20% of patients had primary hyperparathyroidism, 55% had skeletal metastases and myeloma, and 15% had a tumor with ectopic parathyroid hormone-like activity [13]. The remaining 10% included the other diseases mentioned above. The cost-benefit problem in screening hospitalized patients has been discussed [14]. Christensson studied the prevalence of hypercalcemia in a health screening program and reported 95 patients with verified hypercalcemia on repeated measurements (~>11.1 mg/100 ml) among 15,903 subjects (employees aged 20 to 36 years, 0.6%) [15]. The highest prevalence of verified hypercalcemia, 1.3%, was noted in women 60 to 63 years of age. Primary hyperparathyroidism was the most common cause of hypercalcemia in this series, and in 57 of 59 subjects undergoing exploratory neck surgery, parathyroid adenomas (usually single) were found (0.36% of the examined population). The findings of renal calculi, constipation, and mental depression were taken as evidence of symptomatic disease. These symptoms were not found in 48 subjects (71%) defined as having asymptomatic hyperparathyroidism. Approximately 0.3% of the examined population appeared to have asymptomatic hyperparathyroidism, in hypercalcemic subjects the mean systolic and diastolic blood pressures were significantly higher than in matched normocalcemic subjects. The difference was not related to impaired renal function or other factors associated with hypertension. Early diagnosis and treatment may save patients from symptoms and progressive disease. No criteria are available to predict and identify the patients who are to remain asymptomatic or ultimately will require surgical intervention. The few patients who have refused surgery have been followed for several years without signs of progressive disease [16], and most patients with hyperparathyroidism demonstrate long periods with moderate symptoms before turning up for examination and treatment. The prospective study of this problem by Purnell and associates at the Mayo Clinic is of particular interest [5, 17]. In the total series of patients with
World J. Surg. Vol. 1, No. 6, November, 1977
hypercalcemia and a tentative diagnosis of hyperparathyroidism, the patients with asymptomatic and uncomplicated disease and mild hypercalcemia (not above 11 mg/100 ml) were studied prospectively. At the end of the 5-year study, 20% of the original group of 147 had sufficient progression of their disease to require surgical treatment during the first 4 years of the study. However, the study is not complete, since 27 patients were removed from the series during the second 30 months because of inability to cooperate in the follow-up program. Sufficient data are not available concerning these patients to assess any development of complications in this group. Because of different opinions in this field, there are several options for treating verified asymptomatic hyperparathyroidism, as follows: (a) neck exploration on broad indications; (b) observation and thorough follow-up to detect early symptoms or complications; (c) observation of patients with moderate hypercalcemia and neck exploration of patients with serum calcium above a certain level. At our institution we have performed neck exploration (option a) when the patient's status was not clear. We have applied this policy to younger patients as well as older ones. Subtle clinical manifestations may be overlooked, such as the nonspecific symptoms of muscle weakness, muscular fatigability, mental changes, and gastrointestinal problems. The patients may not be aware of their symptoms until they are relieved of them by operation. The relief of unrecognized symptoms is illustrated by the case of a 35-year-old man with a fractured wrist. On x-ray examination a small bone cyst near the elbow was found incidentally. Serum calcium determinations showed moderate hypercalcemia. Otherwise, the patient was fully employed and without symptoms. Neck exploration revealed a parathyroid adenoma, which was removed. The patient became normocalcemic after the operation. A few months later I met him skating. He then mentioned that he had been very fond of that sport up to the age of 25, but was forced to give it up because of weakness in his ankle joints. He thought this was caused by increasing age. After the operation he was able to take up skating again with the same muscle strength as 10 years earlier. This kind of information is difficult to elicit in taking a routine case history. in elderly people many symptoms such as decreased muscle strength, muscular fatigue, and mental disorders are ascribed to the aging per se. Gastrointestinal symptoms and arterial hypertension can be difficult to evaluate. Often these symptoms are discovered by the patient and appreciated by the surgeon after operation when the patient becomes
L. Thor~n: Asymptomatic and Normocalcemic Hyperparathyroidism
aware of the disappearance of symptoms such as muscular weakness, fatigue, and gastrointestinal disturbances. The elderly patient often says, " I feel much stronger now and can get up from an armchair without help." Because of this kind of clinical experience, we follow a policy of surgical exploration of the neck. The Mayo Clinic program reported by Purnell et al. adhered to the third option [5, 17]. However, certain unnecessary difficulties can arise in a program of long-term observation. Asymptomatic patients tend to discount the potential seriousness of their disease and do not cooperate adequately. Some of these patients are at risk for complications such as renal impairment and even hypercalcemic crisis [18]. In the Mayo Clinic study this serious event did not occur during the 5 years of observation. However, we have recently seen a fatal case of hyperparathyroid crisis (pernicious hyperparathyroidism) [19] in an elderly woman about 2 years after her refusal to have a neck exploration which was suggested for hyperparathyroidism with very few symptoms. The metabolic effects of parathyroidectomy in asymptomatic cases have been evaluated objectively [20]. Six patients with asymptomatic hyperparathyroidism on a standardized diet were investigated regarding levels of serum calcium, phosphorous, magnesium, creatinine, cyclic AMP, and parathormone before and after surgery, and were compared to a symptomatic group. The asymptomatic patients were younger than the symptomatic ones. After parathyroidectomy the biochemical evidence of hyperparathyroidism was reversed in both groups. There was no difference between the groups in the morphology of resected parathyroid tissue. There was no x-ray evidence of skeletal disease or excessive bone resorption in the asymptomatic patients, but 4 of 6 had signs of low bone density when measured by 1251photon absorption in the distal third of the radius. Despite lack of symptoms, and with normal routine skeletal x-ray films and normal serum alkaline phosphatase levels, bone disease may be present in asymptomatic patients with so-called biochemical hyperparathyroidism. An appreciable loss of mineral from the skeleton, after hyperparathyroidism has been present for some time, is necessary for detection by ordinary x-ray examination [21]. In summary, neck exploration on rather broad indications is advocated in patients with asymptomatic hyperparathyroidism. This may avoid complications such as renal impairment, persistent hypertension, and skeletal disease, and may relieve symptoms that have been neglected or misinterpreted.
741
Normocalcemic Hyperparathyroidism
The serum calcium level in each individual is stable, but there is a range of variation between individuals. One individual can start at the lower border of the " n o r m a l " range and increase his serum value to the upper border and still be considered to have a normal serum calcium level, taking the albumin level into account. This is the logical background of so-called normocalcemic hyperparathyroidism. The main reason for suspecting the existence of this type of disease is the recurrence of urinary tract stones. The serum calcium values are usually in the upper quartile of the normal distribution curve or occasionally slightly above the upper limit [22, 23]. When patients with stones in the urinary tract are observed over prolonged periods of time, hypercalcemia may supervene [24]. In the diagnostic examination of these patients several tests can be used. Preoperatively, the surgeon needs reasonably satisfactory biochemical evidence in order to suspect primary hyperparathyroidism. In many cases the diagnosis is supported by serial estimations of serum calcium and phosphate, phosphate deprivation combined with thiazide administration [25], determination of ionized calcium [26], parathormone assay [27-30], cAMP in urine [31, 32], a calcium infusion test, a calcium loading test with determination of calcium, cAMP, and creatinine [2], and T R P (tubular reabsorption of phosphate). However, in several instances of normocalcemic hyperparathyroidism, the results of these tests have fallen within the normal range. The final diagnosis is often made at neck exploration. The surgeon must take the responsibility as diagnostician during parathyroid exploration. During the procedure microscopic analysis of material from the parathyroid glands is essential; here the judgment of the surgeon and the pathologist experienced in endocrine pathology is of the utmost importance. All 4 parathyroid glands should be identified. However, all the glands should not be biopsied regardless of the findings at exploration. If one gland is affected, it is removed and a normal gland is biopsied. When 2 glands are enlarged and removed, a third gland is examined. In hyperplasia 3 glands are removed, and a well-vascularlzed portion of the fourth is left tagged with a silk suture or a metallic clip in the adjacent thyroid capsule. The size of the remnant should be approximately 60 to 70 mg. Subtotal parathyroidectomy has been advocated regardless of pathologic findings [33-36] because of the rising incidence of hyperplasia in surgical series, the difficulties in establishing the diagnosis of hyper-
742
plasia at the time of surgery [37], and the published figures of high recurrence rates [33, 38, 39]. We continue to use the approach described above because of the low recurrence rate in our series (2%) [40] and in that of Clark and Goldman (2.2%) [8]. If persistent hyperparathyroidism is excluded, recurrent hyperparathyroidism appears to be unusual [8]. This conclusion is supported by the results of Romanus, et al. [41]. However, in patients with familial hyperparathyroidism, multiple parathyroid adenoma, or a multiple endocrine adenomatosis syndrome, a subtotal parathyroidectomy is advocated regardless of pathology because of the high risk of recurrence [42]. Because preoperative diagnosis is sometimes difficult, the surgeon may find normal parathyroid glands. In our series of 84 patients explored on the provisional diagnosis of normocalcemic hyperparathyroidism [22, 23, 43], we found 26 patients with normal glands, 39 patients with hyperplasia, and 19 with adenomatons diseases. In other studies the incidence of normal findings at neck exploration in patients with normocalcemia and urinary tract stones has been higher [41]. The adenomas did not differ histologically from those causing hypercalcemic hyperparathyroidism. The hyperplasia was of the chief cell type and was slight in most cases [43]. The results following neck exploration in symptomatic normocalcemic hyperparathyroidism, mostly related to urinary tract stones, are relevant to the discussion. In our series the recurrence rate of urinary tract stone disease at follow-up 2 to 5 years postoperatively was about 48% in the group with normal parathyroids at exploration, and 24% in the group with hyperplasia. There were no recurrences in the patients with parathyroid adenoma [23, 43]. However, to be conclusive this series must be followed for a longer period of time. The main reasons for advocating surgery in these cases are the problems of recurrent urinary tract stones and the possibility of concomitant kidney damage. Patients with normocalcemic hyperparathyroidism have developed hypercalcemic crisis [18], but this is exceptional. A prospective randomized series is required to evaluate the results of parathyroid surgery in normocalcemic hyperparathyroidism. R~sum~
Depuis que le dosage de la calcdmie est devenu un examen de routine, de nombreux cas d'hyperparathyroidie asymptomatique ont 6t6 decouverts. Chez des malades atteints de lithiase urinaire recidivante avec hypercalciurie, on a pu diagnostiquer l'hyperparathyroidie normocalcemique.
World J. Surg. Vol. 1, No. 6, November, 1977
I1 est difficile de pr6ciser les indications operatoires de l'hyperparathyroidie asymptomatique. Nous discutons trois options thdrapeutiques et conseillons l'exploration cervicale pour prevenir les complications d'insuffisance rdnale, d'hypertension persistante et d'atteinte osseuse. En presence d'une lithiase renale faisant suspecter une hyperparathyroidie normocalc6mique, on peut utiliser divers tests de diagnostic. Mais, souvent, c'est l'exploration cervicale qui donne la certitude. Ces malades doivent etre operes pour 6viter la lithiase recidivante et le risque de lesion r6nale. A l'heure actuelle, faute d'dtudes completes, il est encore difficile d'6valuer les resultats de la chirurgie des parathyroides pour l'hyperparathyroidie normocalcemique.
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L. Thor6n: Asymptomatic and Normocalcemic Hyperparathyroidism
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