World J. Surg. 1 , 7 0 9 - 7 2 0 , 1977
O
9 1977 by the Soci6l+ lnternationale de Chirurgie
Diagnosis of Primary and Secondary Hyperparathyroidism H.D.
ROEHER,
M.D. and H.
SCHMIDT-GAYK,
M.D.
Departments of Surgery and Internal Medicine, University of Heidelberg, Heidelberg, West Germany
Routine application of multichannel laboratory screening for both inpatients and odtpatients has increased detection of hypercalcemia. With these improved diagnostic tools, it has become possible to distinguish true hyperparathyroidism from nonendocrine disorders of calcium metabolism. Typical features of primary and secondary hyperparathyroidism arc described in relation to their clinical presentation. Diagnosis is based on laboratory findings which include repeated serum calcium and phosphate measurements as the first step, additional specific functional tests for borderline cases, and serum parathyroid hormone (PTH) measurements as pathognomonic proof of excess hormone secretion. Significance and reliability of diagnostic procedures are discussed with regard to routine and selective application.
There has been a tremendous expansion of knowledge regarding how primary hyperparathyroidism affects numerous organic systems and presents clinically with nonspecific symptoms. As a result, hyperparathyroidism can no longer be regarded as a rare disease. In both hospital and outpatient settings, multichannel biochemical screening with routine examination of serum calcium concentration has contributcd greatly to the increased rate of detection of symptomatic and especially asymptomatic disease (Table l) f3-5]. Secondary hyperparathyroidism is a compensatory mechanism for imbalanced calcium metabolism. This imbalance is caused by intestinal malabsorption or, more frequently, by renal insufficiency. In secondary hyperparathyroidism, conservative treatment is usually acceptable. However, long-term maintenance hemodialysis and kidney transplantation leave a certain number of patients with medically intractable secondary hyperparathyroidism, and these have increasingly required surgical ther-
First established as a specific endocrine disorder some 50 years ago, hyperparathyroidism was regarded for several decades as a rare disease. At first, the European approach to diagnosis was dominated by morphological aspects of the disease, and only the typical bone lesions of osteodystrophia fibrosa cystica were considered in diagnosis. In independent work, American researchers paralleled this diagnostic development with physiological and, even better, biochemical approaches to the disease. Coincident with the development of more exact studies of calcium metabolism, other conditions, such as renal disorders, were recognized as an important manifestation of primary hyperparathyroidism [1, 2]. Supported (Schm 400/1).
by
Deutsche
Table 1. Suspected incidence of primary hyperparathy-
roidism following routine serum calcium determination.
Forschungsgemeinschaft
Author
Suspected primary hyperparathyroidism Number of Number of patients patients Percent
Boonstra et N. (1965) (1971) PurneH etal. (1971)
22,847 50,000 1,630
N. London Blood Transfusion Service (1972)
Reprint requests: H.D. Roeher, M.D., Department of Surgery, Ev. Krankenhaus Bethesda, Heerstrasse 219, 4100 Duisburg, West Germany.
709
1,000
67 50 24 4 proven 2
.26 .10 1.40 .25 .20
710
apy. Recently, more sophisticated diagnostic tools have become available to differentiate idiopathic parathyroid diseases from other causes of hypercalcemia [3]. An extensive discussion of the classification of the various forms of hyperparathyroidism is beyond the scope of this article. Such classification would have to consider whether hyperparathyroidism results from autonomous hyperfunction or from regulatory disorders. Hyperfunction of the parathyroids may arise from adenomas or from diffuse primary hyperplasia, or hyperparathyroidism may be a kind of regulatory disorder caused by transitory or permanent and etiologically varying disturbances of calcium metabolism which are followed by individual morphologic reactions of one or all 4 glands. In 1948, Albright aud Reifenstein published 2 definitions which are still acceptable for clinical orientation [6]. They defined primary hyperparathyroidism as a condition in which "more parathyroid hormone is produced than is needed." Secondary hyperparathyroidism is a condition in which "excess parathyroid hormone is secreted for some compensatory purpose." Reiss and Canterbury recently proposed a classification of hyperparathyroidism based on serum calcium levels: hypercalcemic, normocalcemic, and hypocalcemic [7]. They consider these levels to be the best guidelines for determining therapy. Prospective, long-term follow-up studies of mildly symptomatic or asymptomatic patients with normal or slightly elevated serum calcium concentration will have to establish the frequency of treatment. Since there is no proven evidence that secondary hyperparathyroidism can develop into a state of autonomous hyperactivity, no meaningful information is gained in replacing the term "secondary" with the term "tertiary" in instances of apparent autonomous secondary hyperactivity. If differentiation is desirable for therapeutic considerations (either medical or surgical), this can be achieved from laboratory tests which separate suppressible from nonsuppressible secondary hyperparathyroidism.
Diagnosis
The clinical appearance of primary hyerparathyroidism has 3 predominant manifestations: skeletal, urologic, and hypercalcemic. In addition, an undetermined number of individuals have some kind of hidden primary hyperparathyroidism with no subjective complaints or organic involvement whatsoever. Finally, a very few patients are known to appear as medical emergencies with an acute, dramatic illness
World J. Surg. Vol. 1, No. 6, November, 1977
which is generally characterized as an acute hypercalcemic crisis. Osteodystrophia fibrosa cystica is the most common skeletal feature of primary hyperparathyroidism. Because the patient complains of bone pain, arthralgias, or lumbago, this disease is often misdiagnosed as neuritis or rheumatism. Characteristic radiological signs include general osteoporosis and subperiosteal erosions of the middle digital phalanges, the inner aspect of the upper end of the tibia, or the medial surface of the neck of the femur. The skull develops a granular atrophy sometimes described as "ground glass" or "salt and pepper". Solitary or multiple cystic lesions especially in the skull, jaw, and long bones with the impending danger of spontaneous fracture were once considered to be the most frequently found symptoms. Although 30 years ago the skeletal syndrome was present in about 90% of the patients who had a long history and advanced stage of the disease, it is now found in only about 20% of the earlier diagnosed patients. However, milder degrees of bone involvement are seen as accompanying signs of other clinical manifestations of primary hyperparathyroidism. Routine x-ray studies of any patient with proven or suspected primary hyperparathyroidism should include the hands, skull, shoulder joint, and pelvis. Even when specific complaints are given, thorough x-ray examination should be performed (Figs. 1 and 2). In the urologic syndrome, nephrolithiasis is the most frequent and dominating symptom of primary parathyroid disease. Recurrent calculi or the passage of sand or gravel with hematuria and renal colic should always arouse suspicion of parathyroid disease. Between 5 and 10% of patients with repeated renal stone formation, especially those with bilateral formation, are found to have primary hyperparathyroidism as the underlying cause. Nephrocalcinosis, the diffuse parenchymal precipitation of calcium salts, has become a rare finding and is usually linked to a long history of stone diathesis [ I-4]. Two different categories of clinical presentation may be summarized under the hypercalcemic syndrome. The first category includes hypercalcemic patients without any organic manifestation and with such unspecific, seemingly neuropsychiatric symptoms as weakness, fatigue, mild depression, and general irritability. Sometimes hypertension is a concomitant feature. The second group includes patients with gastrointestinal symptoms related to recurrent peptic ulcer which is resistant to conservative treatment and pancreatitis. As long as the specific interdependence of excess parathyroid hormone production and a disposition to ulcers and pancreatitis is not
H. D. Roeher and H. Schmidt-Gayk: Diagnosis of Primary and Secondary Hyperparathyroidism
convincingly established, both should be regarded as consequences of increased serum calcium concentration and a resultant stimulating effect on intestinal hormone activity. In rare instances the clinical appearance of secondary hyperparathyroidism, with varying skeletal involvement, can be related to chronic intestinal realabsorption caused by primary intestinal diseases or pancreatic secretory insufficiency with protracted diarrhea. Of greater frequency and clinical importance is seriously impaired renal glomerular function which consistently stimulates increased parathyroid hormone production. Consequently, renal osteopathy may occur with severe skeletal damage. The clinical picture is governed by general bone pain, multiple cystic lesions in the long bones, and spontaneous fractures. Other manifestations include extraosseous calcification of soft tissue (muscle, arteries, subcutis) and unbearable pruritus. X-ray films show the typical lesions of osteodystrophia fibrosa cystica as found in primary hyperparathyroidism. Additional diagnostic support is gained from bone biopsy which shows pathognomonic changes of fibro-osteoclasis. Biochemical parameters (except for serum PTH measurement) are of little diagnostic value [8].
Laboratory Findings of Primary Hyperparathyroidism
Hypercalcemia and hypophosphatemia are the main diagnostic features of primary hyperparathyroidism. Hypercalciuria is found in only about onehalf of the patients. If the disease is suspected, serum calcium, inorganic phosphate, and urinary calcium should be determined repeatedly, in borderline cases up to 5 times. In addition, serum calcium and protein should be measured simultaneously to exclude hyperproteinemia as a cause of hypercalcemia or hypoproteinemia as a cause of "normocalcemia primary hyperparathyroidism". Of 50 patients with primary hyperparathyroidism only 3 had normal serum calcium levels (Table 2). Only 1 of these 3 patients had a normal calcium level after correction was made for total protein. Serum calcium and phosphate should always be evaluated in relation to renal function. In patients with a history of stone formation, serious reduction of glomerular filtration, as judged by creatinine clearance, is often observed. Because the kidney is responsible for the formation of the active vitamin D metabolite, 1,25-dihydroxy vitamin D, a decrease in renal function will result in less production of this metabolite and, therefore, in less intestinal calcium
Table 2. Laboratory diagnosis of parathyroidism. Value
711
primary
Normal Dimension r a n g e
mEq/1 4.4-5.2 Serum-calcium 2.2-2.6 Serum-phosphate mmol/1 2.5~4.5 Serum-phosphate mg/dl retool/1 0.8-1.5 mEq/day 5-15 Urine-calcium mmol/day 2 . 5 - 7 . 5 ml/min 6-16 Cp % 82-90 TRP Decrease in Cp, above 30 test acc. Kyle % pg/ml 50-400 Serum-PTH pmol/1 5-40 Urinary cyclic AMP/C~. nmol/l GF 2%42
hyper
Pathological above 5.2 above 2.6 below 2.5 below 0.8 above 15 above 7.5 above 16 below 82 below 30 above 400 above 40 above
42
Serum-PTH, selective neck vein catheterization for localization of parathyroid tissue, with venogramm.
absorption; in addition, bone resorption depends on the availability of the active vitamin D metabolite, If one kidney is removed because of prior urologic complications, a serum calcium level above 5.2 mEq/ 1 (2.6 mmol/1) strongly suggests the presence of primary hyperparathyroidism. In addition, serum phosphate, which may have been reduced, will increase into the normal range as renal function decreases. Because serum phosphate depends on circadian rhythm and ingestion of phosphate, blood samples should be taken from the fasting patient between 7 and 9 A.M. In the hypercalcemia of parathyroid overactivity, serum chloride increases and serum phosphate decreases. A normal value of chloride [about 100 mEq/1 (110 mmol/1)] and a normal serum phosphate [about 3.1 mEq/1 (100 mmol/l)] result in a chloride/phosphate ratio of 33. In primary hyperparathyroidism, hypercalcemia is accompanied by an increased chloride/phosphate ratio, whereas other hypercalcemic diseases (bronchial carcinoma, mammary cancer, skeletal metastases) suppress PTH secretion and result in chloride/phosphate ratios below 33. The same rule for serum calcium should be applied to the chloride/phosphate ratio, that is, in cases of poor renal function, the ratio should be interpreted cautiously. For evaluation of phosphate metabolism in borderline cases of hypercalcemia, several parameters of renal phosphate handling may be calculated. For this purpose and for the calculation of the other data (calcium corrected for total protein, creatinine clearance, chloride/phosphate ratio), a desk calculator program can be written and applied. Phosphate
712
World J. Surg. Vol. 1, No. 6, November, 1977
A
Fig. 1. Routine x-ray study of biochemically proven primary hyperparathyroidism. A. Granular atrophy of the skull, "salt and pepper" appearance. B. (see opposite page) Subperiosteal erosions of the radial side of the digital middle phalanges. clearance (Cp) is easily calculated: Cp = U x V/P (normal range 6 to 16 ml/min); however, its use should be restricted to Kyle's calcium infusion test. Cp is dependent mainly on dietal~/ phosphate load, renal function, and parathyroid activity. Distinguishing primary hyperparathyroidism from other disease is aided by calculation of tubular reabsorption of phosphate (TRP) as a percentage of filtered phosphate (normal range 82 to 90%): TRP %
=
(I
-
clearance o f phosphate ~ ~ ' . . ) • 100 clearance o f creatinine
TRP takes renal function into account. The TRP percentage depends mainly on the dietary phosphate load and parathyroid function. In a healthy person on
a normal diet, TRP is 82 to 90%; on a phosphate-rich diet (urinary phosphate per 24 hours, above 1,000 mg), TRP decreases in healthy persons to about 60 to 70%. With increasing use of computers in medicine, a more complex expression of renal phosphate handling (tubular reabsorptive capacity = TrrdGFR) will improve the differentiation of primary hyperparathyroidism from other disorders and prevent misdiagnosing it in healthy persons. On the basis of Cp, patients with primary hyperparathyroidism are well differentiated from controls or those with other diseases (such as absorptive hypercalciuria) by applying Kyle's calcium infusion test [9], which was modified slightly by our group. The test lasts from 7 A.M. on the first day until 10
H. D. Roeher and H. Schmidt-Gayk: Diagnosis of Primary and Secondary Hyperparathyroidism
A.M. on the second day. During the test period, the patient has to drink 3 1of water. During the collection periods, bedrest is indicated. On the first day at 7 A.M., the patient is given 500 ml of water to drink. At 8 A.M. blood is taken for the determination of calcium, phosphate, and creatinine. The bladder should be emptied and urine collected for exactly 120 minutes for determination of phosphate and creatinine. A calcium infusion is given from 9 to 12 A.~., with the patient under supervision. The infusion is 10 mg Ca++/kg bodyweight, given as calcium gluconate dissolved in 250 ml of 5% levulose. On the second morning the exact same procedure is repeated. The
713
timing is of critical importance. The evaluation of the test is shown in Fig. 3. This test is contraindicated in patients with a serum calcium concentration above 6.0 mEq/1 (3.0 mmol/1) because serious hypercalcemia results during infusion. In addition, the patient must not have been taking digitalis for a few days prior to the test. In the normal patients Cp drops by more thau 30% of the control value on the first morning while in primary hyperparathyroidism the decrease, if any, is less than 30%. Urinary creatinine excretion in the first and second collections must be determined to assure accurate collection of the urine. If the urine
714
World J. Surg. Vol. 1, No. 6, November, 1977
Fig. 2. Primary hyperparathyroidism with dominating skeletal symptoms. Typical cystic lesions in the femur are seen.
samples are not comparable in creatinine excretion, the TRP percentage may be calculated in both collection periods. The TRP percentage is independent of completeness of urine collections. As shown in Fig. 3, urinary cyclic AMP is slightly suppressed during calcium infusion in all patients with primary hyperparathyroidism; however, urinary cyclic AMP is not reduced into the control range. PTH increases the activity of the enzyme
adenyl cyclase in the renal cortex, which produces cyclic AMP from ATP. Cyclic AMP is mainly excreted into the urine. After injection of PTH, urinary cyclic AMP increases (50- to 100-fold increase during the Ellsworth-Howard test in healthy persons), whereas in cases of primary hyperparathyroidism, plasma cyclic AMP is not raised. During the Ellsworth-Howard test, plasma cyclic AMP increases up to fivefold. Because the number of tubules capa-
H. D. Roeher and H. Schmidt-Gayk: Diagnosis of Primary and Secondary Hyperparathyroidism
ble of hormonal response is related to the glomerular filtration rate, urinary cyclic AMP should be related to GFR. For diagnostic purposes the clearance of creatinine should be determined. The results in patients with primary hyperparathyroidism are shown in Fig. 4. In all cases urinary cyclic AMP excretion dropped after removal of adenomatous or hyperplastic parathyroids (Fig. 4). Two patients still had elevated urinary cyclic AMP after surgery. In these, low serum calcium documented successful removal of excess parathyroid tissue and indicated " b o n e hunger" for calcium with development of regulatory (secondary) hyperparathyroidism. In one patient with hyperplasia of the parathyroids, 3 ~/2glands were removed and, perhaps because of insufficient blood
715
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Fig. 3. Response of phosphate clearance (top) and urinary cyclic AMP (bottom) to calcium infusion test (Kyle). Black dots indicate patients with proven primary hyperparathyroidism; open diamonds indicate controls.
postop.
Fig. 4. Pre- and postoperative values of urinary cyclic AMP in patients with histologically proven primary hyperparathyroidism.
supply, hypoparathyroidism developed. In the late postoperative period, vitamin D was added to oral calcium to control hypocalcemia. The excretion pattern of serum calcium and urinary cyclic AMP are given in Fig. 5. Patients with primary hyperparathyroidism cannot be differentiated entirely from healthy controls on the basis of cyclic AMP measurements. However, if urinary cyclic AMP is related to serum calcium concentration, as shown in Fig. 6, there is no overlap with the control group. The differentiation is more difficult if urinary cyclic AMP is related to urinary creatinine, or if the total amount of cyclic AMP is calculated. The radioimmunological determination of serum parathyroid hormone (PTH) dates back to 1963 [10]. However, the assay is still not in general use because of the following difficulties: 1. Human P T H is not sufficiently available for immunization of animals to raise antibodies" against PTH. 2. The iodination of PTH produces " d a m a g e " so
716
World J. Surg. Vol. 1, No. 6, November, 1977 pat. A.G.
150-
Ca +2.5g/day U.
C3
~o~
'7
!
0
,6 2 3
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Fig. 6. Interrelationship of serum calcium levels and urinary cyclic AMP excretion for reliable determination of primary hyperparathyroidism.
that iodinated hormone will not bind completely to the antibody, even if excess antibody is incubated with the iodinated hormone. 3. The hormone concentration is usually low in peripheral blood, so the levels cannot be measured by existing assays in normal individuals. 4. Different hormone concentrations are measured by different antibodies. This is related to the fact that various kinds of fragments of P T H circulate for a long time, mainly in the kidney, after inactivation and cleavage of the intact hormone. Most assays use bovine P T H for iodination and antisera against bovine PTH (1-84 peptide), which crossreacts to human PTH. Because normal concen-
Fig. 5. Urinary cyclic AMP and serum calcium levels in patient A.G. with primary hyperparathyroidism caused by diffuse chief cell hyperplasia. After 31/2 glands were removed, hypoparathyroidism resulted and required calcium and vitamin D substitution.
tration of the hormone differs from assay to assay, standardization is urgently needed. Several radioimmunoassays for P T H produce normal ranges which are from 50 to 400 pg/ml, with some up to 1,500 pg/ ml. If a molecular weight of 9,500 is assumed, then 5 to 40 pmol/1 equal 50 to 400 pg/ml. The antisera which recognize the carboxyterminal region of PTH (the region near the amino acid position 84) discriminate best between normal individuals and those with either primary or secondary hyperparathyroidism. Carboxyterminal fragments of PTH accumulate in the circulation, but aminoterminal parts of the hormone are nearly undetectable by current assays. However, in high concentrations near the enlarged parathyroid gland, the intact hormone is most readily recognized by an antiserum directed against the aminoterminal portion of the hormone. For radioimmunoassay of P T H 2 antisera are now in use. One mainly recognizes carboxyterminal fragments and is suitable for the routine diagnosis of primary or secondary hyperparathyroidism. The other antiserum is mainly directed against the aminoterminal fragment for localization of enlarged parathyroid tissue. Our results with these 2 antisera are shown in Fig. 7. As is evident, with either antiserum the control group is not completely distinguished from the group with primary hyperparathyroidism. This small overlap, a technical problem to be overcome, is observed by nearly all authors publishing results on P T H radioimmunoassays [11]. The groups are distinguished more precisely by graphing levels of P T H and serum calcium, as shown in Fig. 8.
Localization of Parathyroid Tumors
Several methods have been used for locating parathyroid tissue. These include angiography and 75-
H. D. Roeher and H. Schmidt-Gayk: Diagnosis o f Primary and Secondary Hyperparathyroidism
selenomethionine scanning of the parathyroid region. However, the results have been disappointing. By measuring parathyroid hormone concentrations in veins draining the parathyroid glands, researchers in recent years have been able to predict the location of a single adenoma or the presence of several hyperplastic glands. However, the method is tedious for the patient and for the radiologist who performs the neck catheterization. The FFH concentrations are very high in veins draining the adenoma. The concentrations are noticeably different from values in other regions when an antiserum directed against the animoterminal portion of the hormone is used (Fig. 9). In some patients, we have observed marked distortion of the neck veins, especially after they have had previous unsuccessful parathyroid exploration. Therefore, whenever this kind of localization is applied, at least one venogram is necessary. The position of the catheter tip must be carefully marked on the venogram each time that blood is drawn for PTH determination. Because of the time and money involved in this procedure, we only perform this kind of parathyroid localization study in patients who have previously had an unsuccessful surgical exploration. Even if this localization procedure indicates a parathyroid tumor on one side of the neck, the surgeon should look at all 4 glands to avoid leaving further hyperplastic glands in situ.
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.
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Fig. 7. Comparison of PTH radioimmunoassays with 2 different antisera.
PTH pmol/I
--
1000
--
Secondary Hyperparathyroidism
What has been stated for the diagnosis of primary hyperparathyroidism does not hold true for the secondary form of the disease. Repeated serum calcium and phosphate determinations are rarely needed because patients with borderline secondary hypeq0arathyroidism, in contrast to those with the primary disease, present no therapeutic problem. Only patients with severe secondary hyperparathyroidism need a thorough diagnostic work-up. Urinary cyclic AMP in these patients is of little help if it is related to creatinine; however, related to GFR, urinary cyclic AMP is invariably elevated. Serum PTH is extremely high in secondary hyperparathyroidism because of renal failure. This not only reflects increased PTH production, but also decreased PTH degradation, which is mainly performed by the kidney. Each laboratory, therefore, must establish its own critical level of PTH concentration in renal secondary hyperparathyroidism. In patients with secondary hyperparathyroidism, apart from laboratory findings, the decision to choose conservative or surgical (parathyroidectomy) therapy is based on clinical criteria. These include
717
AS 211/32 48/48 h incub. 800
600
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Fig. 8. Serum PTH levels in relationship to individual sermn calcium concentration.
the presence of severe skeletal changes, spontaneous fractures, intolerable pruritus, and inefficiency or contraindications to drug treatment [ 12, 13].
718
World J. Surg. Vol. 1, No. 6, November, 1977
I I II
~
290pmol/1 I~ v~thyr-sup -sin. ~ I v, jug. int. sin.
800pmol/1 v. thyr. sup. d e x , ~ J L v, iug. interna dex. ~~'tq \
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Pat. Ruckel, EIke, Parathyroidhormone pmol/1 normalrange 10-40 pmol/1 antiserumBW 211/32 ~ 60% N-terminal ~\ 40 % C- termina~ /~k.'~ sequentialsaturation 48/48h .T-system
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v. azygos]l }/v, hemiazygos Fig. 9. Results of selective venous catheterization and determination of PTH levels in patient E.R., a woman with a functioning adenoma of the right superior parathyroid gland.
Acknowledgments We wish to thank Mrs. Petra Forster for skillful technical assistance and Dr. Karl Freese and Mrs. Renate Voll for evaluation and improvement of the radioimmunoassay of PTH.
R6sum6 L'utilisation en routine du screening de laboratoire par les appareils automatiques multi-canaux, tant pour les malades hospitalis6s que pour les consultants, a accru les possibilit6s de ddtection des hypercalc6mies. Ces m6thodes de diagnostic perfectionn6es permettent de distinguer l'hyperparathyroidie vraie des troubles du m6tabolisme calcique d'origine non endocrinienne. Les car-
act6ristiques de l'hyperparathyroidie primaire et secondaire sont d6crites, ainsi que les tableaux cliniques. Le diagnostic dolt 6tre bas6 sur les investigations biologiques: d ' a b o r d mesures rdp6tdes de la calcdmie et de la phosphor6mie, tests fonctionnels sp6cifiques pour les cas douteux, dosage de la parathormone plasmatique c o m m e preuve de l'hyperproduction hormonale. L a signification et la valeur des moyens de diagnostic sont discutdes, tant pour l'utilisation en routine que dans les cas s61ectionnds.
References 1. Albright, F., Aub, J.C., Bauer, W.: Hyperparathyroidism--a common and polymorphic condition as illustrated by seventeen proved cases from one clinic. J.A.M.A. 102:1276, 1934 2. Cope, O.: The story of hyperparathyroidism at the Massachusetts General Hospital. N. Engl. J. Med. 274:1174, 1966 3. Egdahl, R.H.: Surgery of the parathyroid glands. Surg. Gynecol. Obstet. i30:901, 1970 4. Watson, L.: Primary hyperparathyroidism. Clin. Endocrinol. Metab. 3:215, 1974 5. Boonstra, C.E., Jackson, C.E.: Serum calcium survey for hyperparathyroidism. Results in 50,000 clinic patients. Am. J. Clin. Pathol. 55:523, 1971 6. Albright, F., Reifenstein, E.C.: The Parathyroid Glands and Metabolic Bone Disease. Baltimore, Williams and Wilkins, 1948 7. Reiss, E., Canterbury, J.M.: Genesis of hyperparathyroidism. Am. J. Med, 50:679, 1971 8. Williams, E.D.: Pathology of the parathyroid glands. Clin. Endocrinol. Metab. 3:285, 1974 9. Kyle, L.H., Canary, J.J., Mintz, D.H., DeLeon, A.: Inhibitory effects of induced hypercalcemia on secretion of parathyroid hormone. J. Clin. Endocrinol. Metab. 22:52, 1962 10. Berson, S.A., Yalow, R.S.: Immunochemical heterogeneity of parathyroid hormone. J. Clin. Endocrinol. Metab. 28:1037, 1968 11. Buckle, R.: Disorders of the Parathyroid Glands. London-Philadelphia-Toronto, W.B. Sannders Co., 1974 12. Roeher, H.D., Wahl, R.: Surgical aspects of secondary hyperparathyroidism. Langenbeck's Arch. Chir. 343:23, 1976 13. Goldsmith, R.S., Johnson, W.J., Arnaud, C.D.: The hyperparathyroidism of renal failure: pathophysiology and treatment. Clin. Endocrinol. Metab. 3:305, 1974
O
9 1977 by the Soci6l+ lnternationale de Chirurgie
Diagnosis of Primary and Secondary Hyperparathyroidism H.D.
ROEHER,
M.D. and H.
SCHMIDT-GAYK,
M.D.
Departments of Surgery and Internal Medicine, University of Heidelberg, Heidelberg, West Germany
Routine application of multichannel laboratory screening for both inpatients and odtpatients has increased detection of hypercalcemia. With these improved diagnostic tools, it has become possible to distinguish true hyperparathyroidism from nonendocrine disorders of calcium metabolism. Typical features of primary and secondary hyperparathyroidism arc described in relation to their clinical presentation. Diagnosis is based on laboratory findings which include repeated serum calcium and phosphate measurements as the first step, additional specific functional tests for borderline cases, and serum parathyroid hormone (PTH) measurements as pathognomonic proof of excess hormone secretion. Significance and reliability of diagnostic procedures are discussed with regard to routine and selective application.
There has been a tremendous expansion of knowledge regarding how primary hyperparathyroidism affects numerous organic systems and presents clinically with nonspecific symptoms. As a result, hyperparathyroidism can no longer be regarded as a rare disease. In both hospital and outpatient settings, multichannel biochemical screening with routine examination of serum calcium concentration has contributcd greatly to the increased rate of detection of symptomatic and especially asymptomatic disease (Table l) f3-5]. Secondary hyperparathyroidism is a compensatory mechanism for imbalanced calcium metabolism. This imbalance is caused by intestinal malabsorption or, more frequently, by renal insufficiency. In secondary hyperparathyroidism, conservative treatment is usually acceptable. However, long-term maintenance hemodialysis and kidney transplantation leave a certain number of patients with medically intractable secondary hyperparathyroidism, and these have increasingly required surgical ther-
First established as a specific endocrine disorder some 50 years ago, hyperparathyroidism was regarded for several decades as a rare disease. At first, the European approach to diagnosis was dominated by morphological aspects of the disease, and only the typical bone lesions of osteodystrophia fibrosa cystica were considered in diagnosis. In independent work, American researchers paralleled this diagnostic development with physiological and, even better, biochemical approaches to the disease. Coincident with the development of more exact studies of calcium metabolism, other conditions, such as renal disorders, were recognized as an important manifestation of primary hyperparathyroidism [1, 2]. Supported (Schm 400/1).
by
Deutsche
Table 1. Suspected incidence of primary hyperparathy-
roidism following routine serum calcium determination.
Forschungsgemeinschaft
Author
Suspected primary hyperparathyroidism Number of Number of patients patients Percent
Boonstra et N. (1965) (1971) PurneH etal. (1971)
22,847 50,000 1,630
N. London Blood Transfusion Service (1972)
Reprint requests: H.D. Roeher, M.D., Department of Surgery, Ev. Krankenhaus Bethesda, Heerstrasse 219, 4100 Duisburg, West Germany.
709
1,000
67 50 24 4 proven 2
.26 .10 1.40 .25 .20
710
apy. Recently, more sophisticated diagnostic tools have become available to differentiate idiopathic parathyroid diseases from other causes of hypercalcemia [3]. An extensive discussion of the classification of the various forms of hyperparathyroidism is beyond the scope of this article. Such classification would have to consider whether hyperparathyroidism results from autonomous hyperfunction or from regulatory disorders. Hyperfunction of the parathyroids may arise from adenomas or from diffuse primary hyperplasia, or hyperparathyroidism may be a kind of regulatory disorder caused by transitory or permanent and etiologically varying disturbances of calcium metabolism which are followed by individual morphologic reactions of one or all 4 glands. In 1948, Albright aud Reifenstein published 2 definitions which are still acceptable for clinical orientation [6]. They defined primary hyperparathyroidism as a condition in which "more parathyroid hormone is produced than is needed." Secondary hyperparathyroidism is a condition in which "excess parathyroid hormone is secreted for some compensatory purpose." Reiss and Canterbury recently proposed a classification of hyperparathyroidism based on serum calcium levels: hypercalcemic, normocalcemic, and hypocalcemic [7]. They consider these levels to be the best guidelines for determining therapy. Prospective, long-term follow-up studies of mildly symptomatic or asymptomatic patients with normal or slightly elevated serum calcium concentration will have to establish the frequency of treatment. Since there is no proven evidence that secondary hyperparathyroidism can develop into a state of autonomous hyperactivity, no meaningful information is gained in replacing the term "secondary" with the term "tertiary" in instances of apparent autonomous secondary hyperactivity. If differentiation is desirable for therapeutic considerations (either medical or surgical), this can be achieved from laboratory tests which separate suppressible from nonsuppressible secondary hyperparathyroidism.
Diagnosis
The clinical appearance of primary hyerparathyroidism has 3 predominant manifestations: skeletal, urologic, and hypercalcemic. In addition, an undetermined number of individuals have some kind of hidden primary hyperparathyroidism with no subjective complaints or organic involvement whatsoever. Finally, a very few patients are known to appear as medical emergencies with an acute, dramatic illness
World J. Surg. Vol. 1, No. 6, November, 1977
which is generally characterized as an acute hypercalcemic crisis. Osteodystrophia fibrosa cystica is the most common skeletal feature of primary hyperparathyroidism. Because the patient complains of bone pain, arthralgias, or lumbago, this disease is often misdiagnosed as neuritis or rheumatism. Characteristic radiological signs include general osteoporosis and subperiosteal erosions of the middle digital phalanges, the inner aspect of the upper end of the tibia, or the medial surface of the neck of the femur. The skull develops a granular atrophy sometimes described as "ground glass" or "salt and pepper". Solitary or multiple cystic lesions especially in the skull, jaw, and long bones with the impending danger of spontaneous fracture were once considered to be the most frequently found symptoms. Although 30 years ago the skeletal syndrome was present in about 90% of the patients who had a long history and advanced stage of the disease, it is now found in only about 20% of the earlier diagnosed patients. However, milder degrees of bone involvement are seen as accompanying signs of other clinical manifestations of primary hyperparathyroidism. Routine x-ray studies of any patient with proven or suspected primary hyperparathyroidism should include the hands, skull, shoulder joint, and pelvis. Even when specific complaints are given, thorough x-ray examination should be performed (Figs. 1 and 2). In the urologic syndrome, nephrolithiasis is the most frequent and dominating symptom of primary parathyroid disease. Recurrent calculi or the passage of sand or gravel with hematuria and renal colic should always arouse suspicion of parathyroid disease. Between 5 and 10% of patients with repeated renal stone formation, especially those with bilateral formation, are found to have primary hyperparathyroidism as the underlying cause. Nephrocalcinosis, the diffuse parenchymal precipitation of calcium salts, has become a rare finding and is usually linked to a long history of stone diathesis [ I-4]. Two different categories of clinical presentation may be summarized under the hypercalcemic syndrome. The first category includes hypercalcemic patients without any organic manifestation and with such unspecific, seemingly neuropsychiatric symptoms as weakness, fatigue, mild depression, and general irritability. Sometimes hypertension is a concomitant feature. The second group includes patients with gastrointestinal symptoms related to recurrent peptic ulcer which is resistant to conservative treatment and pancreatitis. As long as the specific interdependence of excess parathyroid hormone production and a disposition to ulcers and pancreatitis is not
H. D. Roeher and H. Schmidt-Gayk: Diagnosis of Primary and Secondary Hyperparathyroidism
convincingly established, both should be regarded as consequences of increased serum calcium concentration and a resultant stimulating effect on intestinal hormone activity. In rare instances the clinical appearance of secondary hyperparathyroidism, with varying skeletal involvement, can be related to chronic intestinal realabsorption caused by primary intestinal diseases or pancreatic secretory insufficiency with protracted diarrhea. Of greater frequency and clinical importance is seriously impaired renal glomerular function which consistently stimulates increased parathyroid hormone production. Consequently, renal osteopathy may occur with severe skeletal damage. The clinical picture is governed by general bone pain, multiple cystic lesions in the long bones, and spontaneous fractures. Other manifestations include extraosseous calcification of soft tissue (muscle, arteries, subcutis) and unbearable pruritus. X-ray films show the typical lesions of osteodystrophia fibrosa cystica as found in primary hyperparathyroidism. Additional diagnostic support is gained from bone biopsy which shows pathognomonic changes of fibro-osteoclasis. Biochemical parameters (except for serum PTH measurement) are of little diagnostic value [8].
Laboratory Findings of Primary Hyperparathyroidism
Hypercalcemia and hypophosphatemia are the main diagnostic features of primary hyperparathyroidism. Hypercalciuria is found in only about onehalf of the patients. If the disease is suspected, serum calcium, inorganic phosphate, and urinary calcium should be determined repeatedly, in borderline cases up to 5 times. In addition, serum calcium and protein should be measured simultaneously to exclude hyperproteinemia as a cause of hypercalcemia or hypoproteinemia as a cause of "normocalcemia primary hyperparathyroidism". Of 50 patients with primary hyperparathyroidism only 3 had normal serum calcium levels (Table 2). Only 1 of these 3 patients had a normal calcium level after correction was made for total protein. Serum calcium and phosphate should always be evaluated in relation to renal function. In patients with a history of stone formation, serious reduction of glomerular filtration, as judged by creatinine clearance, is often observed. Because the kidney is responsible for the formation of the active vitamin D metabolite, 1,25-dihydroxy vitamin D, a decrease in renal function will result in less production of this metabolite and, therefore, in less intestinal calcium
Table 2. Laboratory diagnosis of parathyroidism. Value
711
primary
Normal Dimension r a n g e
mEq/1 4.4-5.2 Serum-calcium 2.2-2.6 Serum-phosphate mmol/1 2.5~4.5 Serum-phosphate mg/dl retool/1 0.8-1.5 mEq/day 5-15 Urine-calcium mmol/day 2 . 5 - 7 . 5 ml/min 6-16 Cp % 82-90 TRP Decrease in Cp, above 30 test acc. Kyle % pg/ml 50-400 Serum-PTH pmol/1 5-40 Urinary cyclic AMP/C~. nmol/l GF 2%42
hyper
Pathological above 5.2 above 2.6 below 2.5 below 0.8 above 15 above 7.5 above 16 below 82 below 30 above 400 above 40 above
42
Serum-PTH, selective neck vein catheterization for localization of parathyroid tissue, with venogramm.
absorption; in addition, bone resorption depends on the availability of the active vitamin D metabolite, If one kidney is removed because of prior urologic complications, a serum calcium level above 5.2 mEq/ 1 (2.6 mmol/1) strongly suggests the presence of primary hyperparathyroidism. In addition, serum phosphate, which may have been reduced, will increase into the normal range as renal function decreases. Because serum phosphate depends on circadian rhythm and ingestion of phosphate, blood samples should be taken from the fasting patient between 7 and 9 A.M. In the hypercalcemia of parathyroid overactivity, serum chloride increases and serum phosphate decreases. A normal value of chloride [about 100 mEq/1 (110 mmol/1)] and a normal serum phosphate [about 3.1 mEq/1 (100 mmol/l)] result in a chloride/phosphate ratio of 33. In primary hyperparathyroidism, hypercalcemia is accompanied by an increased chloride/phosphate ratio, whereas other hypercalcemic diseases (bronchial carcinoma, mammary cancer, skeletal metastases) suppress PTH secretion and result in chloride/phosphate ratios below 33. The same rule for serum calcium should be applied to the chloride/phosphate ratio, that is, in cases of poor renal function, the ratio should be interpreted cautiously. For evaluation of phosphate metabolism in borderline cases of hypercalcemia, several parameters of renal phosphate handling may be calculated. For this purpose and for the calculation of the other data (calcium corrected for total protein, creatinine clearance, chloride/phosphate ratio), a desk calculator program can be written and applied. Phosphate
712
World J. Surg. Vol. 1, No. 6, November, 1977
A
Fig. 1. Routine x-ray study of biochemically proven primary hyperparathyroidism. A. Granular atrophy of the skull, "salt and pepper" appearance. B. (see opposite page) Subperiosteal erosions of the radial side of the digital middle phalanges. clearance (Cp) is easily calculated: Cp = U x V/P (normal range 6 to 16 ml/min); however, its use should be restricted to Kyle's calcium infusion test. Cp is dependent mainly on dietal~/ phosphate load, renal function, and parathyroid activity. Distinguishing primary hyperparathyroidism from other disease is aided by calculation of tubular reabsorption of phosphate (TRP) as a percentage of filtered phosphate (normal range 82 to 90%): TRP %
=
(I
-
clearance o f phosphate ~ ~ ' . . ) • 100 clearance o f creatinine
TRP takes renal function into account. The TRP percentage depends mainly on the dietary phosphate load and parathyroid function. In a healthy person on
a normal diet, TRP is 82 to 90%; on a phosphate-rich diet (urinary phosphate per 24 hours, above 1,000 mg), TRP decreases in healthy persons to about 60 to 70%. With increasing use of computers in medicine, a more complex expression of renal phosphate handling (tubular reabsorptive capacity = TrrdGFR) will improve the differentiation of primary hyperparathyroidism from other disorders and prevent misdiagnosing it in healthy persons. On the basis of Cp, patients with primary hyperparathyroidism are well differentiated from controls or those with other diseases (such as absorptive hypercalciuria) by applying Kyle's calcium infusion test [9], which was modified slightly by our group. The test lasts from 7 A.M. on the first day until 10
H. D. Roeher and H. Schmidt-Gayk: Diagnosis of Primary and Secondary Hyperparathyroidism
A.M. on the second day. During the test period, the patient has to drink 3 1of water. During the collection periods, bedrest is indicated. On the first day at 7 A.M., the patient is given 500 ml of water to drink. At 8 A.M. blood is taken for the determination of calcium, phosphate, and creatinine. The bladder should be emptied and urine collected for exactly 120 minutes for determination of phosphate and creatinine. A calcium infusion is given from 9 to 12 A.~., with the patient under supervision. The infusion is 10 mg Ca++/kg bodyweight, given as calcium gluconate dissolved in 250 ml of 5% levulose. On the second morning the exact same procedure is repeated. The
713
timing is of critical importance. The evaluation of the test is shown in Fig. 3. This test is contraindicated in patients with a serum calcium concentration above 6.0 mEq/1 (3.0 mmol/1) because serious hypercalcemia results during infusion. In addition, the patient must not have been taking digitalis for a few days prior to the test. In the normal patients Cp drops by more thau 30% of the control value on the first morning while in primary hyperparathyroidism the decrease, if any, is less than 30%. Urinary creatinine excretion in the first and second collections must be determined to assure accurate collection of the urine. If the urine
714
World J. Surg. Vol. 1, No. 6, November, 1977
Fig. 2. Primary hyperparathyroidism with dominating skeletal symptoms. Typical cystic lesions in the femur are seen.
samples are not comparable in creatinine excretion, the TRP percentage may be calculated in both collection periods. The TRP percentage is independent of completeness of urine collections. As shown in Fig. 3, urinary cyclic AMP is slightly suppressed during calcium infusion in all patients with primary hyperparathyroidism; however, urinary cyclic AMP is not reduced into the control range. PTH increases the activity of the enzyme
adenyl cyclase in the renal cortex, which produces cyclic AMP from ATP. Cyclic AMP is mainly excreted into the urine. After injection of PTH, urinary cyclic AMP increases (50- to 100-fold increase during the Ellsworth-Howard test in healthy persons), whereas in cases of primary hyperparathyroidism, plasma cyclic AMP is not raised. During the Ellsworth-Howard test, plasma cyclic AMP increases up to fivefold. Because the number of tubules capa-
H. D. Roeher and H. Schmidt-Gayk: Diagnosis of Primary and Secondary Hyperparathyroidism
ble of hormonal response is related to the glomerular filtration rate, urinary cyclic AMP should be related to GFR. For diagnostic purposes the clearance of creatinine should be determined. The results in patients with primary hyperparathyroidism are shown in Fig. 4. In all cases urinary cyclic AMP excretion dropped after removal of adenomatous or hyperplastic parathyroids (Fig. 4). Two patients still had elevated urinary cyclic AMP after surgery. In these, low serum calcium documented successful removal of excess parathyroid tissue and indicated " b o n e hunger" for calcium with development of regulatory (secondary) hyperparathyroidism. In one patient with hyperplasia of the parathyroids, 3 ~/2glands were removed and, perhaps because of insufficient blood
715
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postop.
Fig. 4. Pre- and postoperative values of urinary cyclic AMP in patients with histologically proven primary hyperparathyroidism.
supply, hypoparathyroidism developed. In the late postoperative period, vitamin D was added to oral calcium to control hypocalcemia. The excretion pattern of serum calcium and urinary cyclic AMP are given in Fig. 5. Patients with primary hyperparathyroidism cannot be differentiated entirely from healthy controls on the basis of cyclic AMP measurements. However, if urinary cyclic AMP is related to serum calcium concentration, as shown in Fig. 6, there is no overlap with the control group. The differentiation is more difficult if urinary cyclic AMP is related to urinary creatinine, or if the total amount of cyclic AMP is calculated. The radioimmunological determination of serum parathyroid hormone (PTH) dates back to 1963 [10]. However, the assay is still not in general use because of the following difficulties: 1. Human P T H is not sufficiently available for immunization of animals to raise antibodies" against PTH. 2. The iodination of PTH produces " d a m a g e " so
716
World J. Surg. Vol. 1, No. 6, November, 1977 pat. A.G.
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Fig. 6. Interrelationship of serum calcium levels and urinary cyclic AMP excretion for reliable determination of primary hyperparathyroidism.
that iodinated hormone will not bind completely to the antibody, even if excess antibody is incubated with the iodinated hormone. 3. The hormone concentration is usually low in peripheral blood, so the levels cannot be measured by existing assays in normal individuals. 4. Different hormone concentrations are measured by different antibodies. This is related to the fact that various kinds of fragments of P T H circulate for a long time, mainly in the kidney, after inactivation and cleavage of the intact hormone. Most assays use bovine P T H for iodination and antisera against bovine PTH (1-84 peptide), which crossreacts to human PTH. Because normal concen-
Fig. 5. Urinary cyclic AMP and serum calcium levels in patient A.G. with primary hyperparathyroidism caused by diffuse chief cell hyperplasia. After 31/2 glands were removed, hypoparathyroidism resulted and required calcium and vitamin D substitution.
tration of the hormone differs from assay to assay, standardization is urgently needed. Several radioimmunoassays for P T H produce normal ranges which are from 50 to 400 pg/ml, with some up to 1,500 pg/ ml. If a molecular weight of 9,500 is assumed, then 5 to 40 pmol/1 equal 50 to 400 pg/ml. The antisera which recognize the carboxyterminal region of PTH (the region near the amino acid position 84) discriminate best between normal individuals and those with either primary or secondary hyperparathyroidism. Carboxyterminal fragments of PTH accumulate in the circulation, but aminoterminal parts of the hormone are nearly undetectable by current assays. However, in high concentrations near the enlarged parathyroid gland, the intact hormone is most readily recognized by an antiserum directed against the aminoterminal portion of the hormone. For radioimmunoassay of P T H 2 antisera are now in use. One mainly recognizes carboxyterminal fragments and is suitable for the routine diagnosis of primary or secondary hyperparathyroidism. The other antiserum is mainly directed against the aminoterminal fragment for localization of enlarged parathyroid tissue. Our results with these 2 antisera are shown in Fig. 7. As is evident, with either antiserum the control group is not completely distinguished from the group with primary hyperparathyroidism. This small overlap, a technical problem to be overcome, is observed by nearly all authors publishing results on P T H radioimmunoassays [11]. The groups are distinguished more precisely by graphing levels of P T H and serum calcium, as shown in Fig. 8.
Localization of Parathyroid Tumors
Several methods have been used for locating parathyroid tissue. These include angiography and 75-
H. D. Roeher and H. Schmidt-Gayk: Diagnosis o f Primary and Secondary Hyperparathyroidism
selenomethionine scanning of the parathyroid region. However, the results have been disappointing. By measuring parathyroid hormone concentrations in veins draining the parathyroid glands, researchers in recent years have been able to predict the location of a single adenoma or the presence of several hyperplastic glands. However, the method is tedious for the patient and for the radiologist who performs the neck catheterization. The FFH concentrations are very high in veins draining the adenoma. The concentrations are noticeably different from values in other regions when an antiserum directed against the animoterminal portion of the hormone is used (Fig. 9). In some patients, we have observed marked distortion of the neck veins, especially after they have had previous unsuccessful parathyroid exploration. Therefore, whenever this kind of localization is applied, at least one venogram is necessary. The position of the catheter tip must be carefully marked on the venogram each time that blood is drawn for PTH determination. Because of the time and money involved in this procedure, we only perform this kind of parathyroid localization study in patients who have previously had an unsuccessful surgical exploration. Even if this localization procedure indicates a parathyroid tumor on one side of the neck, the surgeon should look at all 4 glands to avoid leaving further hyperplastic glands in situ.
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PTH pmol/I
--
1000
--
Secondary Hyperparathyroidism
What has been stated for the diagnosis of primary hyperparathyroidism does not hold true for the secondary form of the disease. Repeated serum calcium and phosphate determinations are rarely needed because patients with borderline secondary hypeq0arathyroidism, in contrast to those with the primary disease, present no therapeutic problem. Only patients with severe secondary hyperparathyroidism need a thorough diagnostic work-up. Urinary cyclic AMP in these patients is of little help if it is related to creatinine; however, related to GFR, urinary cyclic AMP is invariably elevated. Serum PTH is extremely high in secondary hyperparathyroidism because of renal failure. This not only reflects increased PTH production, but also decreased PTH degradation, which is mainly performed by the kidney. Each laboratory, therefore, must establish its own critical level of PTH concentration in renal secondary hyperparathyroidism. In patients with secondary hyperparathyroidism, apart from laboratory findings, the decision to choose conservative or surgical (parathyroidectomy) therapy is based on clinical criteria. These include
717
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the presence of severe skeletal changes, spontaneous fractures, intolerable pruritus, and inefficiency or contraindications to drug treatment [ 12, 13].
718
World J. Surg. Vol. 1, No. 6, November, 1977
I I II
~
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Pat. Ruckel, EIke, Parathyroidhormone pmol/1 normalrange 10-40 pmol/1 antiserumBW 211/32 ~ 60% N-terminal ~\ 40 % C- termina~ /~k.'~ sequentialsaturation 48/48h .T-system
//\\
v. azygos]l }/v, hemiazygos Fig. 9. Results of selective venous catheterization and determination of PTH levels in patient E.R., a woman with a functioning adenoma of the right superior parathyroid gland.
Acknowledgments We wish to thank Mrs. Petra Forster for skillful technical assistance and Dr. Karl Freese and Mrs. Renate Voll for evaluation and improvement of the radioimmunoassay of PTH.
R6sum6 L'utilisation en routine du screening de laboratoire par les appareils automatiques multi-canaux, tant pour les malades hospitalis6s que pour les consultants, a accru les possibilit6s de ddtection des hypercalc6mies. Ces m6thodes de diagnostic perfectionn6es permettent de distinguer l'hyperparathyroidie vraie des troubles du m6tabolisme calcique d'origine non endocrinienne. Les car-
act6ristiques de l'hyperparathyroidie primaire et secondaire sont d6crites, ainsi que les tableaux cliniques. Le diagnostic dolt 6tre bas6 sur les investigations biologiques: d ' a b o r d mesures rdp6tdes de la calcdmie et de la phosphor6mie, tests fonctionnels sp6cifiques pour les cas douteux, dosage de la parathormone plasmatique c o m m e preuve de l'hyperproduction hormonale. L a signification et la valeur des moyens de diagnostic sont discutdes, tant pour l'utilisation en routine que dans les cas s61ectionnds.
References 1. Albright, F., Aub, J.C., Bauer, W.: Hyperparathyroidism--a common and polymorphic condition as illustrated by seventeen proved cases from one clinic. J.A.M.A. 102:1276, 1934 2. Cope, O.: The story of hyperparathyroidism at the Massachusetts General Hospital. N. Engl. J. Med. 274:1174, 1966 3. Egdahl, R.H.: Surgery of the parathyroid glands. Surg. Gynecol. Obstet. i30:901, 1970 4. Watson, L.: Primary hyperparathyroidism. Clin. Endocrinol. Metab. 3:215, 1974 5. Boonstra, C.E., Jackson, C.E.: Serum calcium survey for hyperparathyroidism. Results in 50,000 clinic patients. Am. J. Clin. Pathol. 55:523, 1971 6. Albright, F., Reifenstein, E.C.: The Parathyroid Glands and Metabolic Bone Disease. Baltimore, Williams and Wilkins, 1948 7. Reiss, E., Canterbury, J.M.: Genesis of hyperparathyroidism. Am. J. Med, 50:679, 1971 8. Williams, E.D.: Pathology of the parathyroid glands. Clin. Endocrinol. Metab. 3:285, 1974 9. Kyle, L.H., Canary, J.J., Mintz, D.H., DeLeon, A.: Inhibitory effects of induced hypercalcemia on secretion of parathyroid hormone. J. Clin. Endocrinol. Metab. 22:52, 1962 10. Berson, S.A., Yalow, R.S.: Immunochemical heterogeneity of parathyroid hormone. J. Clin. Endocrinol. Metab. 28:1037, 1968 11. Buckle, R.: Disorders of the Parathyroid Glands. London-Philadelphia-Toronto, W.B. Sannders Co., 1974 12. Roeher, H.D., Wahl, R.: Surgical aspects of secondary hyperparathyroidism. Langenbeck's Arch. Chir. 343:23, 1976 13. Goldsmith, R.S., Johnson, W.J., Arnaud, C.D.: The hyperparathyroidism of renal failure: pathophysiology and treatment. Clin. Endocrinol. Metab. 3:305, 1974
