Presidential address: Normocalcemic hyperparathyroidism

Volume 118

Number 6

SURGERY DECEMBER

1995

American Association of Endocrine Surgeons Presidential address: Normocalcemic hyperparathyroidism John M. Monchik, MD, Providence, R~L

From the Department of Surgery, Rhode Island Hospital and Brown University School of Medicine, Providence, R.I.

IT ISA PRIVILEGEto have the h o n o r of serving as president of the American Association of Endocrine Surgeons. I am grateful for the opportunity to have associated with each of you a n d for the privilege of this forum, which allows me to express my gratitude. I have benefited a n d b e e n influenced greatly by my association with the members of this society. I am particularly pleased to have witnessed the growth of this organizauon a n d the enthusiasm that this meeting has generated in the United States a n d t h r o u g h o u t the world. I have chosen a controversial topic, normocalcemic hyperparathyroidism, for my presidential address. This topic has played an important role in my development as an endocrine surgeon. My interest in e n d o c r i n e surgery started as a third-year residen! at Massachusetts General Hospital on Dr. Oliver Cope's service. As a residenl o n his service I attended the medical e n d o c r i n e conferences and was fascinated to learn about the development of the radioimmunoassay, which permitted direct m e a s u r e m e n t of h o r m o n e s a n d revolutionized the diagnostic a n d dynamic studies of endocrine function. O n completion of my residency I spent a year working with Dr. J o h n Potts, who was then chief of endocrinology at Massachusetts General Hospital. I was Presented at the SixteenthAnnual Meetingof the AmericanAssociation of Endocrine Surgeons.Philadelphia,Pa., April 23-25. 1995. Reprint requests:J. M. Monchik.MD. 154 WatermanSt.. Providence. RI 02906. SURGERY1995:118:917-23 Copyright @1995 by Mosby-YearBook. Inc. 0039-6060/95/$5.00 + 0 11/6/66963

part of a group of people working on the development of the radioimmunoassay for parathyroid h o r m o n e . These were exciting times; at almost any h o u r of the day or night someone was working in the laboratory o n the development of this assay. The following year I j o i n e d the surgical staff in the office of Drs. Cope a n d Wang a n d c o n t i n u e d clinical studies using the then developed radioimmunoassay for parathyroid hormone. I am grateful for the experience a n d associations that I had d u r i n g those 2 years because they have had a lifelong influence o n my career. The following 2 years were spent fulfilling my military commitment, a n d I was privileged to be assigned to Walter Reed Army Hospital to do e n d o c r i n e surgery and to set up the radioimmunoassay for parathyroid horm o n e in the Endocrine U n i t at the Walter Reed Army Institute of Research. It was here that normocalcemic hyperparathyroidism first came to my attention. James Low, an endocrinologist at Walter Reed. occupied the laboratory next to m i n e and was involved in working with an electrode to measure ionized calcium. During the course of his studies he f o u n d several patients with recurrent renal calculi who had minimal or n o elevation of the total serum calcium. He was c o n c e r n e d that these patients had hyperparathyroidism and should be considered for parathyroid surgery. I consulted with several experts a r o u n d the country who believed that the techn i q u e for measuring ionized calcium level was n o t reliable. I was reluctant to operate o n these patients, but I was intrigued by the possibility of using ionized calcium as a means to identify patients with normocalcemic hyperparathyroidism with nephrolithiasis. SURGERY 917

918

Monchik

TOTAL C A L C I U M ( m g

Surgery December 1995

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TOTAL CALCIUM (mg/dl)

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IONIZED

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CALCIUM

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IONIZED CALCIUM (mg/dl)

PATIENTS

Fig. 1. Concurrentvaluesfor ionized and total calcium in five patients with primary hyperparathyroidism and intermittent elevation of total calcium level. (From MonchikJM, Martin HF. Ionized calcium in the diagnosis of primary hyperparathyroidism. SURGERY1980;82:185-92.)

7.0

DD 0

6.0

0

5.0

O n completing my military obligation, Dr. H e n r y Randall appointed me to the staff at Rhode Island Hospital a n d Brown University School of Medicine. It was here in collaboration with Dr. Horace Martin that we initiated studies on the role of ionized calcium in the diagnosis of normocalcemic hyperparathyroidism. Dr. Martin was the head of clinical chemistry at the Rhode Island Hospital and a n o t e d authority o n the developm e n t of n o r m a l laboratory values for biochemical tests. Without his expertise the proper establishment of normal values a n d laboratory controls wouid n o t have b e e n possible. Hypercalcemia as manifested by an elevated total calcium level has traditionally b e e n the most important parameter in the diagnosis of hyperparathyroidism. Early experience stressed the remarkably constant elevation of the total serum calcium in this disorder. The possibility of intermittent or n o elevation of the total ser u m calcium was considered to rarely, if ever, occur. 13 Mather 4 in 1953 was the first to d o c u m e n t the existence of normocalcemic hyperparathyroidism in a 33-year-old woman with skeletal symptoms a n d osteitis fibrosa cys-

4.0

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Fig. 2. Concurrent measurements of total calcium, ultrafiltrable calcium, and ionized calcium in six patients with primary hyperparathyroidism and intermittent elevation of total calcium level. (From ForsterJ, MonchikJM, Martin HF. A comparative study of serum ultrafiltrable, ionized, and total calcium in the diagnosis of primary hyperparathyroidism in patients with intermittent or no elevations in total calcium. SURGERY1988;104:113%42.)

tica. Surgical removal of a parathyroid a d e n o m a resulted in relief of her symptoms. Subsequent reports identified a group of patients with primary hyperparathyroidism with minimal, intermittent, or n o elevation of the total serum calcium. 5, 6 Normocalcemic hyperparathyroidism defined as completely n o r m a l total serum calcium values is a definite b u t rare entity that must be searched for in patients with symptoms or corn-

Surgery Volume 118, Number 6

Monchik

919

1"RMA PTH Percent of Baseline)

TOTAL CALCIUM (mg %)

11-

9-

'~176 l

Normal Range

IONIZED CALCIUM (mg %)

2

:

:. 9

" 7

7

."

t

I

I

BASELINE

30

60

I 120

TIME (Minutes)

4 1

2

3

4

5

6

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PATIENTS

Fig. 3. Concurrent measurements of ionized and total calcium in eight patients with normocalcemic hyperparathyroidism.

plications of hyperparathyroidism. W h e n definite intermittent hypercalcemia as d e t e r m i n e d by the total serum calcium is f o u n d c o m b i n e d with an elevated parathyroid h o r m o n e level, the diagnosis of hyperparathyroidism is established. Minimal o r no elevation of the total calcium level, however, presents a diagnostic challenge. Most patients with normocalcemic hyperparathyroidism are identified because o f a renal calculus, a n d m a n y of these padents have hypercalciuria. 7 Most patients with renal calculi a n d hypercalciuria, however, have idiopathic hypercalciuria, a condition also associated with n o r m o c a l c e m i a as d e t e r m i n e d by the total serum calcium. 8 Since the original description of idiopathic hypercalciuria by Albright et al.9 in 1953, several hypotheses have b e e n advanced to explain this entity. Increased intestinal absorption, diminished tubular resorption o f calcium resulting in a renal calcium leak, a primary urinary p h o s p h a t e leak, and, lastly, normocalcemic hyperparathyroidisnl have b e e n postulated. 1~12 In practice the classification of idiopathic hypercalciuria into subgroups o t h e r than normocalcemic hyperparathyroidism is n o t reproducible a n d does n o t a p p e a r to influence the o u t c o m e o f treatment./3 The identifi-

Fig. 4. Response of intact parathyroid hormone to 1000 mg oral calcium load in six patients with renal calculi and primary hyperparathyroidism who have intermittent or no elevation of total calcium level. (From MonchikJM, Lamberton RP, Roth U. Role of the oral calcium-loading test with measurement of intact parathyroid hormone in the diagnosis of symptomatic subtle primary hyperparathyroidism. SURGERY1992;112:1103lO.)

cation o f n o r m o c a l c e m i c hyperparathyroidism, however, is of p r i m e i m p o r t a n c e because of the success of parathyroid surgery in preventing further stone formation in these patients. 14 A failure to separate the rare patient with normocalcemic hyperparathyroidism from the o t h e r subgroups of idiopathic hypercalciuria has led to i n a p p r o p r i a t e neck exploration. Parathyroid surgery in patients with idiopathic hypercalciuria has resulted in finding no a b n o r m a l parathyroid pathologic condition a n d c o n t i n u e d stone formation in most patients. 7, 15 Ionized calcium appears to have a major role in separating patients with n o r m o c a l c e m i c hyperparathyroidism with renal calculi from kidney s t o n e - f o r m i n g patients with idiopathic hypercalciuria a n d in identifying patients with primary hyperparathyroidism who have minimal or no elevation o f the total calcium level. 1618 O u r initial study with ionized calcium identified five patients each o f whom h a d at least one renal calculus a n d a m i n i m u m of 50% o f their preoperative total calcium values within the n o r m a l range (Fig, 1) .16 In two of these patients (patient n u m b e r s 1 a n d 9) 10 o f 12 p r e o p e r a tive calcium values were within n o r m a l limits. O n the basis of m e a n values obtained, these five patients may be referred to as normocalcemic in the statistical sense but also in the i m p o r t a n t practical sense that a clinician

920

Monchik

Surgery December 1995

IRMA PTH (Percent of Baseline)

TRMA PTH (Percent of Baseline)

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TIME (Minutes)

Fig. 5. Response of intact parathyroid hormone to 1000 mg oral calcium load in 18 normal controls. (From MonchikJM, Lamberton RP, Roth U. Role of the oral calcium-loading test with measurement of intact parathyroid hormone in the diagnosis of symptomatic subtle primary hyperparathyroidism. SURGERY1992;112:1103-10.)

would be unlikely to d o further studies to identify hyperparathyroidism in a patient with n o r m a l total ser u m calcium values. T h e elevated value for ionized calcium raised the suspicion ofhyperparathyroidism, which was established by subsequent studies a n d corrected by surgery. A previous study by Muldowney et at.19 showed the value o f ionized calcium in identifying primary hyperparathyroidism in a p o p u l a t i o n of patients considered to have idiopathic hypercalciuria. These patients h a d at least one renal calculus a n d minimal or no elevation o f the total calcium. A persistently elevated serum ionized calcium led to further investigation in 10 patients. These patients h a d elevated serum parathyroid h o r m o n e values a n d r e d u c e d suppressibility o f parathyroid horm o n e d u r i n g an intravenous calcium infusion study. At operation a parathyroid a d e n o m a was f o u n d in nine o f these patients, with r e t u r n to n o r m a l of the serum ionized calcium a n d parathyroid h o r m o n e values subseq u e n t to the surgery. T h e initial R h o d e Island Hospital patients with r e n a l calculi diagnosed with n o r m o c a l c e m i c or subtle hyperparathyroidism on the basis of an elevated ionized calcium level h a d the diagnosis o f hyperparathyroidism confirmed by elevated parathyroid h o r m o n e levels a n d a b n o r m a l suppression o f n e p h r o g e n o u s cyclic adenosine m o n o p h o s p h a t e (cAMP) with oral calcium loading. A previous study h a d shown a clear separation o f

Fig. 6. Mean intact parathyroid hormone values during oral calcium loading expressed as percent of baseline in preoperative patients with hyperparathyroidism (n = 10), postoperative patients with hyperparathyroidism (n= 5), and normal control subjects (n = 18). p < 0.05 when preoperative patients with hyperparathyroidism are compared with control subjects. No significant difference exists when control subjects are compared with postoperative patients with hyperparathyroidism. (From MonchikJM, Lamberton RP, Roth U. Role of the oral calcium-loading test with measurement of intact parathyroid hormone in the diagnosis of symptomatic subtle primary hyperparathyroidism. SURGERY1992;112:1103-10.)

n o r m a l patients from patients with hyperparathyroidism with m e a s u r e m e n t of n e p h r o g e n o u s cAMP after oral calcium loading. 2~ As we gained m o r e experience with the ionized calcium, the combination of persistently elevated ionized calcium values in a patient with nephrolithiasis a n d an elevated parathyroid h o r m o n e level was considered satisfactory for the diagnosis o f hyperparathyroidism. T h e initial instrumentation that we used for measuring ionized calcium level was expensive a n d r e q u i r e d f r e q u e n t r e p l a c e m e n t o f the calcium sensor electrode in addition to f r e q u e n t servicing of the instrument. The electrode r e q u i r e d a skilled technician to assure uniformity of results. 16 These problems led us to p e r f o r m a comparative study of serum ultrafiltrable, ionized, a n d total calcium in the diagnosis o f subtle hyperparathyroidism. 18 Calcium in serum is present in three distinct fractions in equilibrium. T h e ionized a n d c o m p l e x e d calcium tog e t h e r comprise the ultratiltrable fraction. Ultrafiltrable calcium represents a b o u t 50% o f the total serum calcium with ionized calcium accounting for 90% o f the ultrafiltrable calcium a n d a b o u t 45% of the total serum calcium. 21 T h e m e a s u r e m e n t of ultrafiltrable calcium would, therefore, provide an indirect measure o f the

Surgery Volume 118, Number 6

serum ionized calcium. Ultrafiltrable calcium was det e r m i n e d by passing the serum t h r o u g h a filter that separated the ultrafiltrate a n d then measuring the calcium in the ultratiltrate by atomic absorption spectroscopy, thereby eliminating the n e e d for the m o r e complicated ionized calcium determination. A graph of serum ultrafiltrable calcium versus that o f ionized calcium showed a highly significant linear regression analysis. Six symptomatic patients with primary hyperparathyroidism who had intermittent o r n o elevation o f the total calcium level were studied. Two of these patients h a d renal calculi; the r e m a i n i n g four h a d b o n e or j o i n t symptoms. C o n c u r r e n t daily values for total calcium, ultraliltrable calcium, a n d ionized calcium were o b t a i n e d in this g r o u p of patients (Fig. 2). Ionized calcium was the best indicator of hyperparathyroidism in this g r o u p o f patients with intermittent, minimal, or no elevation of the serum total calcium. Ultrafiltrable calcium app e a r e d to be a m o r e sensitive indicator o f hypercalcemia than total calcium b u t did n o t reach statistical significance in this small study. The results o f this study a n d further r e f i n e m e n t in the flow-through electrode technique for measuring ionized calcium m a d e us r e t u r n to the ionized calcium measurements for further studies in patients with minimal, intermittent, or no elevation of the total calcium level, is Subsequent studies at the Rhode Island Hospital with ionized calcium identified eight patients with at least one renal calculus who h a d Completely n o r m a l total ser u m calcium levels. T h e c o n c u r r e n t ionized calcium levels in these patients were almost always elevated (Fig. 3). These patients all h a d elevated intact or C-terminal parathyroid h o r m o n e values. At o p e r a t i o n a parathyroid a d e n o m a was f o u n d in each of these patients with correction of the ionized calcium a n d parathyroid horm o n e values. 1618' 29 O n e can justifiably question why the total serum calcium is n o t increased in all patients with primary hyperparathyroidism assuming the patient has n o r m a l serum albumin level a n d does n o t have vitamin D deficiency, pancreatitis, increased p h o s p h a t e intake, o r hypomagnesemia, factors known to cause a decrease in the serum total calcium level. Some authors have attributed a n o r m a l total calcium level in patients with normocalcemic hyperparathyroidism to an increased ratio o f ionized a n d ultrafiltrable calcium to total calcium in these patients c o m p a r e d w i t h normalindividuals. 16 ' 19 ' 93" Others, however, have r e p o r t e d that the ratios of ultrafiltrable o r ionized calcium to total calcium were identical in n o r m a l subjects a n d patients with hyperparathyroidism.24, 25 Resistance to the parathyroid h o r m o n e effect to increase tubular resorption o f calcium resulting in increased calcium excretion has also b e e n postulated. 26 T h e d e v e l o p m e n t of the i m m u n o r a d i o m e t r i c assay

Monchik

INTACT

921

HORMONE

PARATHYROID

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NORMAL I0

. . . . .

"I . . . . .

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"I

TOTAL CALCIUM %)

(mg

10"4 1

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9

9

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NORMAL

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RANGE

IONIZED CALCIUM (mg %) o

4.8~

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9

NORMAL

RANGE

4.2 I I

I 2

I 3

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I 5

Doys Fig. 7. Total calcium, ionized calcium, and intact parathyroid hormone in patient with recurrent renal calculi and all normal total calcium and intact parathyroid hormone values but elevated values for ionized calcium. (From MonchikJM, Lamberton RP, Roth U. Role of the oral calcium-loading test with measurement of intact parathyroid hormone in the diagnosis of symptomatic subtle primary hyperparathyroidism. SURCERY1992;112:1103-10.) p e r m i t t e d the m e a s u r e m e n t of intact parathyroid horm o n e , which is the p r e d o m i n a n t form o f circulating biologically active h o r m o n e 3 7 This resulted in increased specificity c o m p a r e d with the previous polyvalent assays, a n d it also provided a m e t h o d n o t previously available to directly measure rapid change of biologically active parathyroid h o r m o n e that is n e e d e d for dynamic studies. Although patients with subtle hyperparathyroidism may only occasionally have elevated total calcium levels, they usually exhibit a constant hyperparathyroidism when challenged with dynamic studies. Previous oral a n d intravenous calcium loading studies have shown significantly less suppression of n e p h r o g e n o u s cAMP in patients with subtle hyperparathyroidism c o m p a r e d with n o r m a l individuals or patients with idiopathic hypercalciuria.11, 20 T h e oral calcium loading study with m e a s u r e m e n t of intact parathyroid h o r m o n e can easily be d o n e in an office setting as o p p o s e d to requiring a metabolic unit.

922

Monchik

A n office based study u s i n g the intact p a r a t h y r o i d h o r m o n e assay after a 1000 m g oral c a l c i u m l o a d was carried o u t to c o n f i r m the use o f this p r o c e d u r e in 10 patients w h o h a d m i n i m a l o r n o elevation o f the total s e r u m c a l c i u m a n d / o r intact p a r a t h y r o i d h o r m o n e level. E i g h t e e n n o r m a l individuals were also s t u d i e d with the oral c a l c i m n l o a d i n g study. Five o f these patients h a d all n o r m a l total c a l c i u m values, a n d o n e p a t i e n t h a d only o n e value o f 10.5 m g / d l above t h e upp e r limit o f n o r m a l , w h i c h is 10.4 m g / d l . T h e s e six patients w e r e c o n s i d e r e d to have n o r m o c a l c e m i c hyperparathyroidism. Five o f these six patients h a d at least o n e r e n a l calculus. Eighty-five p e r c e n t o f the c o n c u r r e n t i o n i z e d c a l c i u m values in these six patients w e r e elevated. Fig. 4 shows that five o f these six patients with n o r m o c a l c e m i c h y p e r p a r a t h y r o i d i s m did n o t suppress below 70% o f the baseline intact p a r a t h y r o i d h o r m o n e level at 60 minutes. Sixteen o f the 18 n o r m a l individuals d i d suppress b e l o w 70% o f the baseline intact p a r a t h y r o i d h o r m o n e value at 60 m i n u t e s (Fig. 5). S u b s e q u e n t u n p u b l i s h e d data f r o m the R h o d e Island H o s p i t a l have s h o w n that an occasional p a t i e n t w i t h subtle h y p e r p a r a t h y r o i d i s m will have c o m p l e t e l y normal suppression o f t h e intact p a r a t h y r o i d h o r m o n e , ind i c a t i n g that n o single test can reliably identify all patients with n o r m o c a l c e m i c h y p e r p a r a t h y r o i d i s m . 22 Fig. 6 illustrates the characteristic findings in the oral c a l c i u m l o a d i n g study in patients with p r i m a r y hyperp a r a t h y r o i d i s m c o m p a r e d with n o r m a l controls a n d patients w h o have h a d h y p e r p a r a t h y r o i d i s m surgically c o r r e c t e d . N o significant d i f f e r e n c e was n o t e d b e t w e e n the n o r m a l controls a n d patients w h o have h a d hyperp a r a t h y r o i d i s m surgically c o r r e c t e d . 22 T h e oral calcium l o a d i n g study a p p e a r s to have a place in the diagnosis o f p r i m a r y h y p e r p a r a t h y r o i d i s m w h e n the intact p a r a t h y r o i d h o r m o n e level is m i n i m a l l y o r n o t elevated in a p a t i e n t w h o has elevated i o n i z e d c a l c i u m a n d n o r m a l total c a l c i u m levels. Fig. 7 illustrates this type o f a patient. This p a t i e n t h a d r e c u r r e n t r e n a l calculi, a n d an oral c a l c i u m l o a d i n g study s h o w e d minimal s u p p r e s s i o n o f intact p a r a t h y r o i d h o r m o n e strongly suggesting h y p e r p a r a t h y r o i d i s m . At o p e r a t i o n a parathyroid a d e n o m a was f o u n d with c o r r e c t i o n o f the serum ionized calcium and abnormal calcium tolerance study. I o n i z e d c a l c i u m appears to have an i m p o r t a n t r o l e in identifying h y p e r p a r a t h y r o i d patients with renal calculi w h o have m i n i m a l , i n t e r m i t t e n t , o r n o elevation o f the total c a l c i u m level. It a p p e a r s to be the least e x p e n s i v e a n d least c u m b e r s o m e test to identify these patients. A c o m b i n a t i o n o f elevated i o n i z e d c a l c i u m level a n d intact s e r u m p a r a t h y r o i d h o r m o n e level is diagnostic o f p r i m a r y , h y p e r p a r a t h y r o i d i s m a n d w o u l d e l i m i n a t e the n e e d for the oral c a l c i u m l o a d i n g study. In those patients with n o r m o c a l c e m i c o r subtle

Surgery December 1995

h y p e r p a r a t h y r o i d i s m in w h o m the c o m b i n a t i o n o f total calcium, i o n i z e d calcium, a n d intact p a r a t h y r o i d horm o n e levels c a n n o t p r o v i d e a definitive diagnosis, the oral c a l c i u m l o a d i n g study may c o n f i r m the diagnosis o f h y p e r p a r a t h y r o i d i s m by identifying the characteristic d e c r e a s e d suppressibility o f p a r a t h y r o i d h o r m o n e activity c o m p a r e d with n o r m a l individuals o r patien!s with i d i o p a t h i c hypercalciuria. A l t h o u g h t h e studies d e s c r i b e d in this r e p o r t u s e d i o n i z e d c a l c i u m a n d oral c a l c i u m l o a d i n g to identify patients with n o r m o c a l c e m i c h y p e r p a r a t h y r o i d i s m with r e n a l calculi, these studies may also p r o v e h e l p f u l in identifying patients with n o r m o c a l c e m i c hyperparathyr o i d i s m w h o p r e s e n t with o t h e r n o n s p e c i f i c symptoms, b o n e o r j o i n t p a i n o r d e c r e a s e d b o n e density. REFERENCES

1. Dent CE. Some problems of hyperparathyroidism. BMJ 1962; 2:1495-500. 2. Keating FR. Diagnosis of primary hypeFparathyroidism, clinical and laboratory aspects. JAMA 1961;178:547-55. 3. Cope O. Hyperparathyroidism; diagnosis and management. Am J Surg 1960;99:394403. 4. Mather HG. Hyperparathyroidism with normal serum calcium. BMJ 1953;2:424-5. 5. Bogdonoff MD, Woods AH, White JE, et al. Hyperparathyroidism. AmJ Med 1956;21:583-95. 6. Wills MR, PAK CYC, Hammond WG, et al. Normocalcemic primary hyperparathyroidism. Am J Med 1969;47:384-91. 7. Johannson H, Thoren L, Werner L, et al. Normocalcemic hyperparathyroidism, kidney stones, and idiopathic hypercalciuria. SUaCERY1975;77:691-6. 8. Hodgkinson A, Pyrah LN. The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stones of renal origin. BrJ Surg 1958;46:10-8. 9. Albright F, Henneman P, Benedict PH, Forbes AP. Idiopathic hypercalciuria (a preliminary report). Pro Roy Soc Med 1953; 46:1077-81. 10. Bordier P, Ryckewart A, Gueris J, et al. On the pathogenesis of so called idiopathic hypercalciuria. Am J Med 1977;63:398409. 11. Broadus AE, Dominguez M, Bartter FC. Pathophysiological studies in idiopathic hypercalciuria; use of an oral calcium tolerance test to characterize distinctive hypercalciuric subgroups. J Clin Endocrinol Metab 1978;47:751-60. 12. Pak CYC,Kaplan R, Bone H, et al. A simple test for the diagnosis of absorbtive, resorbtive, and renal hypercalciurias. N EnglJ Med 1975;292:49%500. 13. Peacock M. The mechanisms of hypercalciuria are unnecessary for treatment of recurrent renal calcium stone formers. Contrib Nephrol 1982;33:152-62. 14. Parks J, Coe F, Fauvus M. Hyperparathyroidism in nephrolithiasis. Arch Intern Med 1980;140:1479-81. 15. Poole GV, Albertson DA, Myers RT. Normocalcemic hyperparathyroidism revisited. Am Surg 1983;49:668-71. 16. MonchikJM, Martin HF. Ionized calcium in the diagnosis of primary hyperparathyroidism. SUROERY1980;82:185-92. 17. McLeod MK, MonchikJM, Martin HF. The role of ionized calcium in the diagnosis of subtle hypercalcemia in symptomatic primary hyperparathyroidism. Surgery 1984;95:66%73. 18. ForsterJ, MonchikJM, Martin HF. A comparative study of serum ultrafilu'able, ionized, and total calcium in the diagnosis of primary hyperparathyroidism in patients with intermittent or no elevations in total calcium. SURGERY1988;104:1137-42.

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Monchik

19. Muldowney FP, Freaney R, McMullinJP, et al. Serum ionized calcium and parathyroid holanone in renal stone disease. QJ Med 1976;45:75-86. 20. Broadus AE, Horst RL, Littledike ET, et al. Primm3~ hyperparathyroidism with intermittent hypercalcemia: serial observation and simple diagnosis by means of an oral calcium tolerance test. Clin Endocrlnol 1980;12:225-35. 21. Neer R, Berman M, Fisher L, et al. Mnlticompartmental analysis of calcium kinetics in norulal adult males.J Clin Invest 1967;46: 1364-79. 22. MonchikJM, Lamberton RP, Roth U. Role of the oral calciumloading test with measurement of intact parathyroid hormone in the diagnosis of symptomatic subtle primary hyperparathyrnidism. SURGERY1992;112:1103-10. 23. Yendt ER, Gagne RJA. Detection of primary hyperparathyroidism

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