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Normocalcemic primary hyperparathyroidism
Normocalcemic
Primary
Hyperparathyroidism* MICHAEL
R.
WILLS,
M.D., t CHARLES
Y.
and FREDERIC
C.
PAIL, M.D., WILLIAM
C. BAR.TTER,
G.
H.\MMOND, XI.D.
M.D.
Bethesda, Maryland In recent years it has become recognized that patients with primary hyperparathyroid&m, particularly those with renal stones, may present with serum calcium concentrations that are within the normal range. The three patients described herein all presented with a long history of recurrent renal calculi, normal serum calcium and phosphorus concentrations, and hypercalciuria while taking an unregulated diet. In all three patients, the diagnosis of primary hyperparathyroidism was proved by surgical exploration of the neck and biopsy of all four parathyroid glands. In two, a parathyroid adenoma was found; in the third, parathyroid hyperplasia. The disease in these three patients was classified as normocalcemic primary hyperparathyroidism.
C
fifty-five cases of primary hyperparathyroidism re;iewed by Yendt and Cagne [.5], mean preoperative serum calcium values were within the normal range. In the patient with normocalccmic hyperparathyroidism described by Melvin, Joplin and Fraser [6] repeated serum calcium estimations gave values in the high normal range, although there was a history of an earlier episode of hypercalcemia. These workers also briefly mentioned, without any details, an additional patient in whom a parathyroid adenoma had been removed and in whom the serum calcium level had never been abnorlnal. The importance of detecting these cases of normocalcemic hyperparathyroidism is stressed by the report of Nichols and Flanagan [7] of six patients with this syndrome representing 37 per cent of all the patients in whom they had made a diagnosis of parathyroid hyperfunction in a three year period. In 1965 we reported eight cases of normocalcemic primary hyperparathyroidism among a group of patients with calcareous renal disease [8]. We now report a further three cases of normocalcemic primary hyperparathyroidism, in all of which the patients presented with recurrent renal calculi and excessive urinary calcium excretion. Two had a para-
LASSICALLY, the diagnosis of primary hyperparathyroidism has been based upon the demonstration of high serum calcium and low serum phosphorus concentrations and excessive urinary excretion of calcium. According to the clinical picture patients may be classified in three main groups; those with bone disease, those with kidney stones and those with neither bone disease nor kidney stones. In all groups, the finding of a raised serum calcium concentration is regarded by most investigators as an essential criterion for the diagnosis of primary hyperparathyroidism [I]. In recent years, however, it has become recognized that patients with primary hyperparathyroidism, particularly those with renal stones, may present with serum calcium concentrations that are within the normal range. In 1956 Bogdonoff et al. [2], in a review of twenty-seven cases of primary hyperparathyroidism, reported that serum calcium values were within the normal range in five. In one of the five cases of primary hyperparathyroidism described by Fanconi and Rose [3] the serum total calcium concentration was within the normal range in two preoperative estimations. In one of the fifty cases reviewed by Pyrah, Hodgkinson and Anderson [4], and in five of the
* From the Endocrinology Branch, National Heart Institute and Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014. This investigation was supported in part by a Public Health Service International Postdoctoral Fellowship (F05-TW-1286) granted to one of us (M.R.W.). Requests for reprints should be addressed to Dr. Michael R. Wills. Manuscript received September 18, 1968. t Present address: Department of Chemical Pathology, Royal Free Hospital, Grays Inn Road, England.
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thyroid adenoma and the remaining one had parathyroid hyperplasia, as proved by surgical exploration and biopsy. This represents a total of eleven patients with this syndrome encountered in this Center over the nine year period since 1959. METHODS
All blood specimens from the patients described were drawn in the early morning after overnight fasting, and without venous stasis. Calcium Infusion Test. The technic used has been described in detail previously [9]. The subjects were given a metabolic diet containing each day 400 mg. of calcium and 1 gm. of phosphorus, for a total period of six days. After an initial three day equilibration period during which no specimens were obtained, all urine was collected for the following three days in twenty-four hour pools for the estimation of phosphorus. At 9:00 A.M. on day 2 of the three day test period an infusion of calcium glucoheptonate (15 mg. of calcium per kg. body weight) was given over a four hour period. Urinary phosphorus excretion on day 1 of the test period was used as the control value. A normal response to this test constituted a decrease in urinary phosphorus excretion of 21 per cent or more on the day of the calcium infusion, with a “rebound” rise of 12 per cent or more on the day after the infusion. Prednisone Test. While on a metabolic diet containing each day 400 mg. of calcium and 1 gm. of phosphorus, the subjects were given prednisone orally (20 mg. twice daily) for eight days. A “normal” response to this test in a patient with hypercalciuria not resulting from hyperparathyroidism is a decrease in urinary calcium excretion.
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This patient (B.G., N.I.H. No. 06-75-43), CASE 1. a sixty-three year old man, was first admitted on July 25, 1966, with a twenty-six year history of recurrent renal calculi. He had his first attack of left renal colic in 1940 and was shown roentgenologically to have calculi in the left kidney. Over the next fourteen years he had frequent attacks of left renal colic; in 1954 he had an attack on the right side after which he spontaneously passed a small stone. During the following year intravenous pyelography showed multiple calculi in the left kidney with one at the lower end of the left ureter which was removed later by uretero-lithotomy. The patient then remained asymptomatic until 1961 when, following a severe attack of left renal colic, he was shown to have a calculus impacted at the lower end of the ureter which required removal by uretero-lithotomy. He again was asymptomatic until early 1965 when he began to have attacks of renal colic; he spontaneously passed over 50 stones and a considerable amount of “gravel” during the following year. In May 1966 there was a further episode in which a calculus was impacted at the lower end of the ureter, requiring surgical removal. Analysis of the stones had shown them to consist of calcium oxalate. The patient was referred for evaluation. He gave no history of having taken medications other than analgesics or of symptoms attributable to ulcer. There was a history of renal stones in four of his six brothers, two of his three sisters and among the progeny of his siblings. There was no known history of renal stones in either of his parents. The inheritance pattern was compatible with that of an autosomal dominant. The initial serum biochemical findings on admission were all within the normal range (Table I). Urinary calcium excretion was excessive while he was taking his usual diet; when he was taking a metabolic diet containing
TABLE I BIOCHEMICAL VALUES ON ADMISSION Case 1
Data
Serum* Calcium (mg./lOO ml.)
Phosphorus (mg./lOOml.) Alkaline phosphatase (King-Armstrong units/100 ml.) Sodium (mEq./L.) Potassium (mEq./L.) Chloride (mEq./L.) Carbon dioxide content (mEq./L.) Total protein (gm./lOO ml.) Albumin (gm./lOO ml.) Blood urea nitrogen (mg./lOO ml.)
Creatinine (mg./lOO ml.) Endogenous creatinine clearance Urinary calcium (mg./24 hr.)t Urinary oxalate (mg./24 hr.)
(ml./min.)
caSe2
Case 3
9.9
10.5 2.8
9.5 3.4
9 142 4.6 102 26 6.4 3.3 17 1.1 100 177 8.2
8 144 5.1 106 28 6.6 4.1 17 1.0 70 327
12 139 4.0 98 28 6.4 3.5 13 1.4 93 290 8
2.7
...
Normal
Values
8.8-10.6 2.4-5.0 4-13 135-146 3.5-5.5 97-110 24-32 6.0-8.0 3.1-5.0 S-20 0.7-1.5 PO-125 <200 9-32
* Samples collected without venous stasis after overnight fasting. t Mean of seven twenty-four hour vahres (Case 1) or three twenty-four hour values (Cases 2 and 3) while patient was taking a metabolic diet containing each day 400 mg. of calcium and 1 gm. of phosphorus. VOL.
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each day 400 mg. of calcium and 1 gm. of phosphorus, his mean urinary calcium excretion was 177 mg. per twenty-four hours over a seven day period. Pyelography showed left renal calculi with caliectasis of the collecting system. Roentgenologic bone survey, including views of the lamina dura, gave no evidence of metabolic bone disease. There was no change in urinary phosphorus excretion on the day of the calciiim infusion and only a small subnormal “reI,oLlnrl” rise on the day after infusion (Table II 1.
Jl i‘ll.s it n/
. .
. .
.
,
. . TABLE RESUI. I’S OF IlRINARY
.
AND PHOSPHORUS
Case 2
85
Case 3
607 625 661
1 113 1 191 1 045
921 945 1.146 “14
9
314
353
2 X 100 normal response is a fall * Clay 1. :>a~ Day~---1 1 of 21 per cent or greater.
x loonormal
RM
&
has not had any attacks of renal colic. At present his urinary calcium excretion under the same metabolic regimen as before (400 mg. of calcium and 1 gm. of phosphorus a day) is 96 and 88 mg. per twenty-four hours. Roentgenograms show calculi in the left kidney that have remained unchanged in size and number since his operation.
Lowest urinary calcium
+ (nay.31~~~1)__-
I
BG
Fasting serum calcium values for the six-month period of study prior to operation.
Prednisone Test excretion with steroid therapy (mg. 124 hr.)f
I
FIG. 1.
Calcium Infusion Test
Urinary phosphorus excretion (mg.,‘24 hr.) Day 1 Day 2 Day 3 Per cent fall* Per cent risct
. . . .
STUDIES
Case 1
Data
Normal Range
II
CALCIUM
EKCRE’rION
,
response is a rise
of 12 per cent or greater. 1 Control values on same metabolic steroid therapy, are xi\-en in Table I.
regimen,
no
CASE 2. This patient (R.M., N.I.H. No. 07-70-69) was a fifty-two year old woman who was first admitted on January 1, 1968, with a twenty-nine year history of recurrent renal calculi. She spontaneously passed two renal stones in 1939 but no investigations were undertaken. In 1965 a diagnosis of pyelonephritis and hypertension was madr after she
50 c 4 51
1 he mean serum calcium concentration during the six month period of study prior to operation was 10.07 mg. per 100 ml., with a mean serum phosphorus of 2.68 mg. per 100 ml. On three occasions during that period the serum calcium concentration exceeded tlie upper limit of the normal range (Fig. 1) and on two occasions the serum phosphorus concentration was below the lower limit of the normal range (Fig. 2). The low values for phosphorus did not correspond with the high values for calcium. At operation (February 27, 1967) all four parathyroid glands were identified and biopsied. There was a chief cell adenoma of the right superior parathyroid, which was removed; the other glands had a normal histologic picture. Following operation transient hypocalcemia developed but oral calcium supplements were not required. The serum calcium level had risen to within the normal range by the tenth postoperative day. In the sixteen months since operation the patient
15-
0
-IBG
&
h
FIG. 2. Fasting serum phosphorus values for the sixmonth period of study prior to operation. AMERICAN
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suffered two episodes of urinary tract infection in the preceding twelve months. In January 1966, following an attack of renal colic, three calculi were removed from the right ureter by retrograde extraction. On analysis the stones were shown to consist of calcium phosphate. In June 1967 intravenous pyelography showed bilateral renal calculi and deformed calyces. In view of these findings the patient was referred for evaluation. On admission the initial serum biochemical findings were all within the normal range (Table I). While she was taking her usual diet her urinary calcium excretion was 390 mg. per twentyfour hours. When she took a metabolic diet containing each day 400 mg. of calcium and 1 gm. of phosphorus, her mean urinary calcium excretion was 327 mg. per twenty-four hours. Intravenous pyelography showed multiple, bilateral renal calculi, with some irregularity of the contour of the right kidney, suggesting old inflammatory scarring. A roentgenologic bone survey, including views of the lamina dura, gave no evidence of metabolic bone disease. There was no change in urinary phosphorus excretion on either the day of or the day after the calcium infusion, and there was no diminution in urinary calcium excretion during eight days of treatment with prednisone (Table II). The mean serum calcium concentration during the six month period of study prior to operation was 10.36 mg. per 100 ml., with a mean serum phosphorus of 3.17 mg. per 100 ml. On seven occasions during that six month period the serum calcium concentration exceeded the upper limit of the normal range (Fig. l), and on two occasions the serum phosphorus concentration was below the lower limit of the normal range (Fig. 2). The low values for phosphorus did not correspond with the high values for calcium. At operation (June 27, 1968) all four parathyroid glands were identified and biopsied. There was an oxyphil adenoma of the right lower parathyroid gland, which was removed; the other three glands had a normal histologic picture. Following operation hypocalcemia developed and oral calcium supplements were needed to maintain a normal serum calcium concentration. CASE 3. This patient (G.P., N.I.H. No. 07-67-55), a forty-two year old man, was referred as an outpatient on November 24, 1967, with a history of recurrent renal calculi since childhood. At the ages of eight, ten and twelve he had spontaneously passed stones, shown on analysis to consist of calcium oxalate. There was no history of enuresis or of urinary tract infection. Although repeated x-ray films showed a calculus in the right kidney, he was asymptomatic for the next thirty years until April 1967. At that time he had an attack of right renal colic and was found to have ureteric obstruction requiring ureterolithotomy. In October 1967, after a further attack of right renal colic, he spontaneously passed a calculus from the right ureter into the bladder. One month later, because of recurrent urethral obstruction VOL.
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caused by the calculus in the bladder, he underwent cystoscopy at which it was possible to remove only a part of the calculus. He gave no history of taking any medication other than analgesics, or of symptoms attributable to ulcer. Investigations elsewhere had shown excessive urinary calcium excretion, and he was referred for evaluation. On admission (February 26, 1968) the initial serum biochemical findings were all within the normal range (Table I), as they had been during outpatient investigations. When he was taking his usual diet his urinary calcium excretion was 380 mg. per twenty-four hours. When he was taking a metabolic diet containing each day 400 mg. of calcium and 1 gm. of phosphorus his mean urinary calcium excretion was 290 mg. per twenty-four hours. Intravenous pyelography showed a calculus in the upper pole of the right kidney and stone fragments in the bladder, but the calyceal outlines were otherwise within normal limits. A roentgenologic bone survey, including views of the lamina dura, gave no evidence of metabolic bone disease. On the day of calcium infusion there was no fall in urinary phosphorus excretion; there was a normal “rebound” rise of 24 per cent on the day after the infusion. Urinary calcium excretion was not decreased during eight days of treatment with prednisone; indeed it was increased (Table II). The mean serum calcium concentration during the six month period of study prior to operation was 9.69 mg. per 100 ml., with a mean serum phosphorus level of 3.23 mg. per 100 ml. At no time prior to operation did either the serum calcium or the phosphorus concentration exceed the normal range (Fig. 1 and 2). At operation (June 6, 1968) all four parathyroid glands were identified and biopsied. There was chief cell hyperplasia of the left upper and right lower parathyroid glands, which were removed; the other glands had a normal histologic picture. Following operation hypocalcemia developed, however, oral calcium supplements were required for only three weeks to maintain a normal serum calcium concentration. COMMENTS
The three patients described here presented with a long history of recurrent renal calculi, normal serum calcium and phosphorus concentrations, and hypercalciuria while they were taking an unregulated diet. In two of them the hypercalciuria persisted despite a restricted intake of calcium. In none of them did the urinary phosphorus excretion decrease on the day of a calcium infusion, and in only one (Case 3) was there a normal “rebound” increase on the day after the infusion. In none of the patients given prednisone orally did urinary calcium decrease during the eight days of treatment. In all three patients the mean preoperative serum concentrations of calcium and phosphorus were within
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Normocalcemic
Primary
Hyperpari~thyroldlsnl-Il/i/l.~
the noritial range ov(r a six month period prior to operation. III one patient (Case 3) the serum calriuin concentrations did not exceed the upper lilnit of noriilal at any time before operation. In the other two patients ten of a total of forty-three seruui calcium determinations over the six nionth period prior to operation were above the upper limit of the norinal range. Keating [ 101 regarded a seruni calcium concentration as “borderline” if it fell within the 99 percentile limits of normal (mean f 3 S.11.). ,411 ten of the estimations that exceeded the upper limit of the normal range in our two patients were within the 99 percentile limits of norinal, and could therefore be regarded as “borderline” rather than as significant hypercalcemia. In all three patients the diagnosis of primary hyperparathyroidism was proved by surgical exploration of the neck and identificat ion and biopsy of all four parathyroid glands. In two a parathyroid adenoma was found; in the third, parathyroid hyperplasia. We could classify the disease in these three patients, therefore, as normocalcemic primary hyperparathyroidism. In our experience, in agreement with that of others, the finding of hypercalcemia is the best index in the diagnosis of primary hyperparathyroidism [ 1,3,8,?0, I7-141. However we do not agree with the view that the finding of hypercalcemia is a sine qua non in establishing the diagnosis. Cope [ 7I] in his review of 230 cases considered that a high serum calcium concentration was the most characteristic disturbance of primary hyperparathyroidism. He mentioned briefly, without details, one patient who presented at the arthritis clinic with bizarre aches and pains, and whose serum calcium concentration was normal initially, who was later operated upon successfully for a parathyroid adenoma. Keating [TO] in reviewing 380 cases of hyperparathyroidism was impressed by the “remarkable stability of the hypercalcemia” in some of the patients who had been observed over a long period. Although Keating stated that the degree of hypercalcemia may be trivial, he believed that if hyperparathyroidism occurred with intermittent hypercalcemia, it must be very rare. In his series fifty-two patients had “borderline” serum calcium concentrations before operation, in that one or more values fell within the 99 percentile limits of normal. In twenty-five of these patients one or more of the preoperative values were within the 95 percentile limits of normal, and of these only one patient had a mean preoperative value within those
rt (I/
litnils. All twenty paticxnts whos~~ d:tla w(‘r(‘ ri’liewed by Mieher and his colleagues 1I-7 1and all thirtv-six patients reviewed by, Kyl(* ;111tl his coworkers [ 121 had hyprrcalceiriia ; tx)rh grolips regard this as the iilost irtiportant diagnostic, feature. Dent [I], reviewing the records of eighty patients with proved priinary hyperparathyroidism, stated that one nortnal value for total seruln calcium, obtained with impeccable tec‘llnit, made the diagnosis most unlikely. Of the thirtv-four patients whose data were rcsviewed 1))~ Riddick and Reiss [ 161 all but one had hypercalcemia at some time prior to operation, and this one exception had inoderately advanced renal insufficiency. Of the forty-eight patients whose records were reviewed by Coffey and his colleagues [13] the diagnosis was based principally on the demonstration of a significant elevation of the serum calciuin concentration and the exclusion of all other causes of hypercalcernia. In only one of the fifty cases reviewed by Pyrah and his co-workers [rl] was the mean preoperative serum calcium concentration within the normal range; these investigators cousidcr the diagnosis of primary hyperparathyroidisin most unlikely when the serum calcium conceittration is less that 10.5 mg. per 100 1t11. In recent years cases of primary hyperparathyroidism have been reported with an increasing frequency in which there has been either intermittent activity of the adenoma, as shown by fluctuations in the serum calcium concentration from within the normal range to values well above it, or serum calcium values that are within the normal range (uide infru). It is important to make a distinction between these patients and those rare patients with clinical and/or biochemical evidence of hyperparathyroidism who have undergone a “spontaneous” remission due to infarction of a parathyroid adenoma [ 17,7X ]. In 1953 Mather 1191 published a report which, as far as we are aware, described the first documented case of proved primary hyperparathyroidism in which the patient was norrnocalcemic from the time of initial observation and over the ensuing three month period until neck exploration and removal of the adenoma. The patient was a thirty-nine year old woman who had diffuse aching pains in the lower limbs and back six months before hospitalization and who had developed a “waddling” gait. Four values for serum calcium concentration during the three month period prior to operation were all within the normal range. Skeletal roentgenograms and sternal AMERICAN
JOURNAL
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Normocalcemic
Primary Hyperparathyroidism-Wills
bone biopsy showed evidence of osteitis fibrosa. At operation the patient was found to have a “wasserhelle” cell adenoma. This patient is of considerable interest, not only because of the short duration of symptoms but also because, as far as we are aware, she represents the only reported case of normocalcemic hyperparathyroidism with osteitis fibrosa. In 1956, Bogdonoff et al. [z] reviewed twentyfive cases of primary hyperparathyroidism observed in one hospital over a twenty-five year period; they reported that serum calcium values were within the normal range in five of these. In only one of these five was the diagnosis made during the first twenty-three years of the period under review. In their paper they stated that the normal mean value of serum calcium concentration for their laboratory was 9.2 mg. per 100 ml. with a standard deviation (SD.) of 0.5 mg. per 100 ml. Thus the upper limit of their normal range (mean + 2 S.D.) was 10.2 mg. per 100 ml. In their analysis of their cases, however, they used a serum calcium concentration of 11.5 mg. per 100 ml. for the upper limit of normal. This value was based on a “composite summary of the values listed in several standard textbooks and reference sources.” If their data are reexamined using the upper limit of normal for their own laboratory, in only two of their cases was the value below that limit at some time. In these two cases the values ranged from 8.8 to 11.2 mg. and from 9.2 to 11.0 mg. per 100 ml., respectively; in only the first of them was the diagnosis proved by surgical removal of an adenoma. Whitby [ZO] described a fifty year old woman with a ten year history of recurrent renal calculi. A diagnosis of “intermittent hyperparathyroidism” was made and a parathyroid adenoma was removed. In this patient five values for serum calcium concentration were reported over a three month period of observation before operation. The values were 9.8, 11.4, 12.0, 12.2 and 12.4 mg. per 100 ml. Nineteen days before the one normal value was obtained, the patient had been anuric for five days following pyelolithotomy and partial nephrectomy, and the blood urea concentration reached 141 mg. per 100 ml. In one of the five cases of primary hyperparathyroidism reported by Fanconi and Rose [3] the total plasma calcium concentration was within the normal range on two occasions in the two week period prior to operation. It is of interest that although the total calcium was normal the ionized fraction was VOL.
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increased. In 1959 McGeown and Morrison [27] reviewed a series of fifty-three patients with proved hypcrparathyroidism and noted that serum calcium values “well within the normal range are often observed in patients who are subsequently proved to have hyperparathyroidism.” In their series the serum calcium concentration had never exceeded 11.0 mg. per 100 ml. in one patient; in twelve, the highest value was below 12.0 mg. per 100 ml. McGeown and Morrison also noted fluctuations in the serum calcium concentration in patients observed over a long period and one of their figures depicts values in three patients which fluctuated by 2 mg. per 100 ml. or more over four to fourteen months of observation. Similar fluctuations in serum calcium concentration in patients with hyperparathyroidism were reported by McSwiney and Prunty [22], who found that hypercalcemia could be present on some occasions but not on others. In discussing some thirteen patients with proved hyperparathyroidism they stated that “In half our patients with hyperparathyroidism definite hypercalcemia did not consistently occur and in one patient this was not observed on any occasion.” Their report is also of interest in that this last patient did not have an elevated ionized calcium fraction, in contrast to the earlier report of Fanconi and Rose [3]. The tendency of the serum calcium to fluctuate in primary hyperparathyroidism was stressed by McGeown [23] who stated that “This tendency to fluctuation appears to be characteristic of the hypercalcemia of hyperparathyroidism” ; with hypercalcemia of other causes she stated that “the serum calcium is much more constant.” In the cases reported here fluctuations did occur over the six month preoperative period in each patient, but they were relatively small, and in no case did they exceed 2.0 mg. per 100 ml. In 1967 Nichols and Flanagan [7] described six patients, four of whom had renal stones, who were later proved to have parathyroid adenoma (five patients) or parathyroid hyperplasia. In the only one of their patients in whom serum calcium concentration was observed over a period of time, there had been “hypercalcemia several months before.” Similarly in the case reported by Melvin, Joplin and Fraser [6] (a forty-five year old man with renal stones) there had been two episodes in which the serum calcium concentration was increased over a long period of observation. In their review of fifty-five
39 1
Normocalcernic
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Hyperparathyroidism-Wills
cases of proved primary hyperparathy-roidism, Yendt and Cagne [5] reported that in five, all in women, the mean preoperative serum calriiun concentration was within the normal range. In these five cases only seven of a total of forty-six determinations were above the upper limit of the normal range. When these workers reviewed their normal range for serum calcium concentration, however, they found that it was lower in women than in men; on replotting their data they concluded that the mean preoperative serum calcium concentration was in fact elevated in four of the five patients, all of whom had recurrent renal stones. In the fifth patient, who is noted briefly as having presented with osteoporosis, a total of fourteen estimations of serum calcium were obtained in the preoperative period of which only one (10.2 mg. per 100 ml.) was above the upper limit of their revised normal range. The surgical findings at neck exploration in this patient were not given. In our patients the mean preoperative serum phosphorus concentrations were within the normal range, although the values obtained over the six months of observation before operation tended to be within the lower part of the normal range (Fig. 2). It is generally accepted that even if renal function is normal a low serum phosphorus concentration is by no means a constant diagnostic biochemical feature of primary hyperparathyroidism [ 7,5,70,23,24]. Two of our patients had an abnormal response to calcium infusion; in the third there was an abnormal response on the day of the infusion but a normal “rebound” increase in urinary phosphorus on the day after the infusion. This test is regarded by some [ 7,9] although not all [23] workers to be a useful diagnostic aid in the diagnosis of hyperparathyroidisn~. The findings in our three patients are in agreement with the observations in the eight cases previously reported by one of us [8]. They support the conclusions of Nichols and Flanagan [7] that hyperparathyroidism exists in a significant number of patients who present with recurrent renal calculi, or other complaints suggesting parathyroid hyperfunction, but fail to show the classic criteria for establishing such a diagnosis. Early diagnosis in such patients should prevent the irreversible renal damage associated with hypercalcemia. It has recently been shown by Lloyd [ 741, in a statistical review of 138 cases of that the rnean pririiary hyperparathyroidism,
et nl.
serum calcium concciilratioli ,IIKI t11(.311 LIIIIW weights are significantly lower iii patients with renal stones than in those with ostcitis fibrosa. He proposes that there arc two iliain t>pcs of parathyroid tumor, one rapidly g-rowing and highly acti\re that causes overt bone disease. and the. other slowly growing and of low activity that causes kidney stones. In oiir own cxpericnce of giving parathyroid extract to norinal s~ibjerts over the relatively short period of three days, there is always a brisk increase in urinary calcium excretion into the range of hypercalciuria although it is unusual for the serum calcium concentration to exceed the upper liinit of normal [25]. Thus, with relatively sinall parathyroid tumors of low activity the finding of patients with normocalcemic priiuary- hy.perparathyroidism is not unexpected. ‘I‘hc rcrognition of such patients among those with recurrent renal stones is of prime importance, as the prc\rention of long-term renal damage inay depend upon the definitive test of neck exploration, with identification and biopsy of all foltr parathyroid glands. REFERENCES 1.
DENT, C. E. Some problems of hyperparathyroidism.
Brit. M. J., 2: 1419, 1962. 2. BOGDONOFF, M. D., \$‘OODS, .\. II., LVIIITE, J. E. and ENGEL, F. L. Hyperparathyroidism. Am. J. Med., 21: 583, 1956. 3. FANCONI, A. and ROSE, G. .I. The ionized, complexed, and protein-bound fractions of calcium in plasma. Quart. J. Med., 27: 463, 1958. 4. PYRAH, L. N., HODGKINSON, .I. and ANDERSON, C. K. Primary hyperparathyroidism. review. Brit. J. Surg., 53: 245, 1966.
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5. YENDT, E. R. and CAGNE, R. J. :\. Detrction of primary hyperparathyroidism, with sprcial reference to its occurence in hypercalciuric females with “normal” or borderline serum calcium. Chad. M. A. J., 98: 331, 1968. 6. MELVIN, K. E. W., JOPLIN, G. F. and FRASER, Ii. Normocalcemic hypwparathyroidism. Proc. Rcy. Sot. Med., 61: 87, 1968. 7. NICHOLS, G., JR. and FLANAGAN, B. Normocalccmic hyperparathyroidism. Tr. A. .4?n. P(t.ririans. 80: 314,1967. 8. GEORGE, J. M., RABSON, A. S., KETCIIAM, .I. and BARTTER, F. C. Calcareous hyperparathyroidism. Quart.
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1965. 9. PRONOVE, P. and BARVER, F. C. Diagnosis of hyperparathyroidism. Metabolism, 10: 349, 1961. 10. KEATING, F. R. Diagnosis of primary hyprrparaclinical and laboratory aspects. thyroidism,
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Hyperparathyroidism; diagnosis management. Am. J. Swg., 99: 394, 1960. AMERICAN
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12. KYLE, I,. H., BEISEL, W. R. and CANARY, J. J. Evaluation of the relative value of diagnostic tests in hyperparathyroidism. Ann. Int. Med., 57: 957,1962. 13. COFFEY, R. J., POTTER, J. F. and CANARY, J. J. Diagnosis and surgical control of hyperparathyroidism. Ann. Surg., 161: 732, 1965. 14. LLOYD, II. M. Primary hyperparathyroidism: an analysis of the role of the parathyroid tumor. Medicine, 47: 53, 1968. 15. MIEHER, W. C., THIBAUDEAU, Y. and FRAME, B. Primary hyperparathyroidism. A diagnostic challenge. Arch. Int. Med., 107: 361, 1961. 16. RIDDICK, F. A. and REISS, E. Hyperparathyroidism. Analysis of recent experiences, clinical spectrum and diagnostic tests. Ann. Znt. Med., 56: 183, 1962. 17. HOWARD, J. E., FOLLIS, R. H., YENDT, E. R. and CONNOR, T. B. Hyperparathyroidism, case report illustrating spontaneous remission due to necrosis of the adenoma, and a study of the incidence of necroses in parathyroid adenomas. J. Clin. Endocrinol., 13 : 997, 1953. 18. PEARL, M. A., STERNBERG,W. H. and DINGMAN,
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19. 20. 21. 22.
23.
24.
25.
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J. F. Unusual cases of hyprrparathyroidism. Arch. Znt. Med., 110: 481, 1962. MATHER, H. G. Hyperparathyroidism with normal serum calcium. Bit. M. J., 2: 424, 1953. WHITBY, L. G. Intermittent hyperparathyroidism. Lancet 1: 883, 1958. MCGEOWN, M. G. and MORRISON, E. Hyperparathyroidism. Postgrad. M. J., 35: 330, 1959. MCSWINEY, R. R. and PRUNTY, F. T. G. The diagnosis of minimal hyperparathyroidism determination of theoretical renal phosphorus threshold. Proc. Roy. Sac. Med., 54: 639, 1961. MCGEOWN, M. G. Tests of parathyroid function in the human subject. In: ‘Hormones and the Kidney,’ Memoirs of the Society for Endocrinology, No. 13. Edited by Williams, P. C., New York, 1963. Academic Press, Inc. WILLS, M. R. and MCGOWAN, G. K. Plasma chloride levels in hyperparathyroidism and other hypercalcemic states. Brit. M. J., 1: 1153, 1964. WILLS, M. R., WORTSMAN, J., PAK, C. Y. C. and BARTTER, F. C. The role of parathyroid hormone in the gastrointestinal absorption of calcium. Submitted for publication.
Primary
Hyperparathyroidism* MICHAEL
R.
WILLS,
M.D., t CHARLES
Y.
and FREDERIC
C.
PAIL, M.D., WILLIAM
C. BAR.TTER,
G.
H.\MMOND, XI.D.
M.D.
Bethesda, Maryland In recent years it has become recognized that patients with primary hyperparathyroid&m, particularly those with renal stones, may present with serum calcium concentrations that are within the normal range. The three patients described herein all presented with a long history of recurrent renal calculi, normal serum calcium and phosphorus concentrations, and hypercalciuria while taking an unregulated diet. In all three patients, the diagnosis of primary hyperparathyroidism was proved by surgical exploration of the neck and biopsy of all four parathyroid glands. In two, a parathyroid adenoma was found; in the third, parathyroid hyperplasia. The disease in these three patients was classified as normocalcemic primary hyperparathyroidism.
C
fifty-five cases of primary hyperparathyroidism re;iewed by Yendt and Cagne [.5], mean preoperative serum calcium values were within the normal range. In the patient with normocalccmic hyperparathyroidism described by Melvin, Joplin and Fraser [6] repeated serum calcium estimations gave values in the high normal range, although there was a history of an earlier episode of hypercalcemia. These workers also briefly mentioned, without any details, an additional patient in whom a parathyroid adenoma had been removed and in whom the serum calcium level had never been abnorlnal. The importance of detecting these cases of normocalcemic hyperparathyroidism is stressed by the report of Nichols and Flanagan [7] of six patients with this syndrome representing 37 per cent of all the patients in whom they had made a diagnosis of parathyroid hyperfunction in a three year period. In 1965 we reported eight cases of normocalcemic primary hyperparathyroidism among a group of patients with calcareous renal disease [8]. We now report a further three cases of normocalcemic primary hyperparathyroidism, in all of which the patients presented with recurrent renal calculi and excessive urinary calcium excretion. Two had a para-
LASSICALLY, the diagnosis of primary hyperparathyroidism has been based upon the demonstration of high serum calcium and low serum phosphorus concentrations and excessive urinary excretion of calcium. According to the clinical picture patients may be classified in three main groups; those with bone disease, those with kidney stones and those with neither bone disease nor kidney stones. In all groups, the finding of a raised serum calcium concentration is regarded by most investigators as an essential criterion for the diagnosis of primary hyperparathyroidism [I]. In recent years, however, it has become recognized that patients with primary hyperparathyroidism, particularly those with renal stones, may present with serum calcium concentrations that are within the normal range. In 1956 Bogdonoff et al. [2], in a review of twenty-seven cases of primary hyperparathyroidism, reported that serum calcium values were within the normal range in five. In one of the five cases of primary hyperparathyroidism described by Fanconi and Rose [3] the serum total calcium concentration was within the normal range in two preoperative estimations. In one of the fifty cases reviewed by Pyrah, Hodgkinson and Anderson [4], and in five of the
* From the Endocrinology Branch, National Heart Institute and Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014. This investigation was supported in part by a Public Health Service International Postdoctoral Fellowship (F05-TW-1286) granted to one of us (M.R.W.). Requests for reprints should be addressed to Dr. Michael R. Wills. Manuscript received September 18, 1968. t Present address: Department of Chemical Pathology, Royal Free Hospital, Grays Inn Road, England.
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thyroid adenoma and the remaining one had parathyroid hyperplasia, as proved by surgical exploration and biopsy. This represents a total of eleven patients with this syndrome encountered in this Center over the nine year period since 1959. METHODS
All blood specimens from the patients described were drawn in the early morning after overnight fasting, and without venous stasis. Calcium Infusion Test. The technic used has been described in detail previously [9]. The subjects were given a metabolic diet containing each day 400 mg. of calcium and 1 gm. of phosphorus, for a total period of six days. After an initial three day equilibration period during which no specimens were obtained, all urine was collected for the following three days in twenty-four hour pools for the estimation of phosphorus. At 9:00 A.M. on day 2 of the three day test period an infusion of calcium glucoheptonate (15 mg. of calcium per kg. body weight) was given over a four hour period. Urinary phosphorus excretion on day 1 of the test period was used as the control value. A normal response to this test constituted a decrease in urinary phosphorus excretion of 21 per cent or more on the day of the calcium infusion, with a “rebound” rise of 12 per cent or more on the day after the infusion. Prednisone Test. While on a metabolic diet containing each day 400 mg. of calcium and 1 gm. of phosphorus, the subjects were given prednisone orally (20 mg. twice daily) for eight days. A “normal” response to this test in a patient with hypercalciuria not resulting from hyperparathyroidism is a decrease in urinary calcium excretion.
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This patient (B.G., N.I.H. No. 06-75-43), CASE 1. a sixty-three year old man, was first admitted on July 25, 1966, with a twenty-six year history of recurrent renal calculi. He had his first attack of left renal colic in 1940 and was shown roentgenologically to have calculi in the left kidney. Over the next fourteen years he had frequent attacks of left renal colic; in 1954 he had an attack on the right side after which he spontaneously passed a small stone. During the following year intravenous pyelography showed multiple calculi in the left kidney with one at the lower end of the left ureter which was removed later by uretero-lithotomy. The patient then remained asymptomatic until 1961 when, following a severe attack of left renal colic, he was shown to have a calculus impacted at the lower end of the ureter which required removal by uretero-lithotomy. He again was asymptomatic until early 1965 when he began to have attacks of renal colic; he spontaneously passed over 50 stones and a considerable amount of “gravel” during the following year. In May 1966 there was a further episode in which a calculus was impacted at the lower end of the ureter, requiring surgical removal. Analysis of the stones had shown them to consist of calcium oxalate. The patient was referred for evaluation. He gave no history of having taken medications other than analgesics or of symptoms attributable to ulcer. There was a history of renal stones in four of his six brothers, two of his three sisters and among the progeny of his siblings. There was no known history of renal stones in either of his parents. The inheritance pattern was compatible with that of an autosomal dominant. The initial serum biochemical findings on admission were all within the normal range (Table I). Urinary calcium excretion was excessive while he was taking his usual diet; when he was taking a metabolic diet containing
TABLE I BIOCHEMICAL VALUES ON ADMISSION Case 1
Data
Serum* Calcium (mg./lOO ml.)
Phosphorus (mg./lOOml.) Alkaline phosphatase (King-Armstrong units/100 ml.) Sodium (mEq./L.) Potassium (mEq./L.) Chloride (mEq./L.) Carbon dioxide content (mEq./L.) Total protein (gm./lOO ml.) Albumin (gm./lOO ml.) Blood urea nitrogen (mg./lOO ml.)
Creatinine (mg./lOO ml.) Endogenous creatinine clearance Urinary calcium (mg./24 hr.)t Urinary oxalate (mg./24 hr.)
(ml./min.)
caSe2
Case 3
9.9
10.5 2.8
9.5 3.4
9 142 4.6 102 26 6.4 3.3 17 1.1 100 177 8.2
8 144 5.1 106 28 6.6 4.1 17 1.0 70 327
12 139 4.0 98 28 6.4 3.5 13 1.4 93 290 8
2.7
...
Normal
Values
8.8-10.6 2.4-5.0 4-13 135-146 3.5-5.5 97-110 24-32 6.0-8.0 3.1-5.0 S-20 0.7-1.5 PO-125 <200 9-32
* Samples collected without venous stasis after overnight fasting. t Mean of seven twenty-four hour vahres (Case 1) or three twenty-four hour values (Cases 2 and 3) while patient was taking a metabolic diet containing each day 400 mg. of calcium and 1 gm. of phosphorus. VOL.
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Normocalcemic
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each day 400 mg. of calcium and 1 gm. of phosphorus, his mean urinary calcium excretion was 177 mg. per twenty-four hours over a seven day period. Pyelography showed left renal calculi with caliectasis of the collecting system. Roentgenologic bone survey, including views of the lamina dura, gave no evidence of metabolic bone disease. There was no change in urinary phosphorus excretion on the day of the calciiim infusion and only a small subnormal “reI,oLlnrl” rise on the day after infusion (Table II 1.
Jl i‘ll.s it n/
. .
. .
.
,
. . TABLE RESUI. I’S OF IlRINARY
.
AND PHOSPHORUS
Case 2
85
Case 3
607 625 661
1 113 1 191 1 045
921 945 1.146 “14
9
314
353
2 X 100 normal response is a fall * Clay 1. :>a~ Day~---1 1 of 21 per cent or greater.
x loonormal
RM
&
has not had any attacks of renal colic. At present his urinary calcium excretion under the same metabolic regimen as before (400 mg. of calcium and 1 gm. of phosphorus a day) is 96 and 88 mg. per twenty-four hours. Roentgenograms show calculi in the left kidney that have remained unchanged in size and number since his operation.
Lowest urinary calcium
+ (nay.31~~~1)__-
I
BG
Fasting serum calcium values for the six-month period of study prior to operation.
Prednisone Test excretion with steroid therapy (mg. 124 hr.)f
I
FIG. 1.
Calcium Infusion Test
Urinary phosphorus excretion (mg.,‘24 hr.) Day 1 Day 2 Day 3 Per cent fall* Per cent risct
. . . .
STUDIES
Case 1
Data
Normal Range
II
CALCIUM
EKCRE’rION
,
response is a rise
of 12 per cent or greater. 1 Control values on same metabolic steroid therapy, are xi\-en in Table I.
regimen,
no
CASE 2. This patient (R.M., N.I.H. No. 07-70-69) was a fifty-two year old woman who was first admitted on January 1, 1968, with a twenty-nine year history of recurrent renal calculi. She spontaneously passed two renal stones in 1939 but no investigations were undertaken. In 1965 a diagnosis of pyelonephritis and hypertension was madr after she
50 c 4 51
1 he mean serum calcium concentration during the six month period of study prior to operation was 10.07 mg. per 100 ml., with a mean serum phosphorus of 2.68 mg. per 100 ml. On three occasions during that period the serum calcium concentration exceeded tlie upper limit of the normal range (Fig. 1) and on two occasions the serum phosphorus concentration was below the lower limit of the normal range (Fig. 2). The low values for phosphorus did not correspond with the high values for calcium. At operation (February 27, 1967) all four parathyroid glands were identified and biopsied. There was a chief cell adenoma of the right superior parathyroid, which was removed; the other glands had a normal histologic picture. Following operation transient hypocalcemia developed but oral calcium supplements were not required. The serum calcium level had risen to within the normal range by the tenth postoperative day. In the sixteen months since operation the patient
15-
0
-IBG
&
h
FIG. 2. Fasting serum phosphorus values for the sixmonth period of study prior to operation. AMERICAN
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suffered two episodes of urinary tract infection in the preceding twelve months. In January 1966, following an attack of renal colic, three calculi were removed from the right ureter by retrograde extraction. On analysis the stones were shown to consist of calcium phosphate. In June 1967 intravenous pyelography showed bilateral renal calculi and deformed calyces. In view of these findings the patient was referred for evaluation. On admission the initial serum biochemical findings were all within the normal range (Table I). While she was taking her usual diet her urinary calcium excretion was 390 mg. per twentyfour hours. When she took a metabolic diet containing each day 400 mg. of calcium and 1 gm. of phosphorus, her mean urinary calcium excretion was 327 mg. per twenty-four hours. Intravenous pyelography showed multiple, bilateral renal calculi, with some irregularity of the contour of the right kidney, suggesting old inflammatory scarring. A roentgenologic bone survey, including views of the lamina dura, gave no evidence of metabolic bone disease. There was no change in urinary phosphorus excretion on either the day of or the day after the calcium infusion, and there was no diminution in urinary calcium excretion during eight days of treatment with prednisone (Table II). The mean serum calcium concentration during the six month period of study prior to operation was 10.36 mg. per 100 ml., with a mean serum phosphorus of 3.17 mg. per 100 ml. On seven occasions during that six month period the serum calcium concentration exceeded the upper limit of the normal range (Fig. l), and on two occasions the serum phosphorus concentration was below the lower limit of the normal range (Fig. 2). The low values for phosphorus did not correspond with the high values for calcium. At operation (June 27, 1968) all four parathyroid glands were identified and biopsied. There was an oxyphil adenoma of the right lower parathyroid gland, which was removed; the other three glands had a normal histologic picture. Following operation hypocalcemia developed and oral calcium supplements were needed to maintain a normal serum calcium concentration. CASE 3. This patient (G.P., N.I.H. No. 07-67-55), a forty-two year old man, was referred as an outpatient on November 24, 1967, with a history of recurrent renal calculi since childhood. At the ages of eight, ten and twelve he had spontaneously passed stones, shown on analysis to consist of calcium oxalate. There was no history of enuresis or of urinary tract infection. Although repeated x-ray films showed a calculus in the right kidney, he was asymptomatic for the next thirty years until April 1967. At that time he had an attack of right renal colic and was found to have ureteric obstruction requiring ureterolithotomy. In October 1967, after a further attack of right renal colic, he spontaneously passed a calculus from the right ureter into the bladder. One month later, because of recurrent urethral obstruction VOL.
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caused by the calculus in the bladder, he underwent cystoscopy at which it was possible to remove only a part of the calculus. He gave no history of taking any medication other than analgesics, or of symptoms attributable to ulcer. Investigations elsewhere had shown excessive urinary calcium excretion, and he was referred for evaluation. On admission (February 26, 1968) the initial serum biochemical findings were all within the normal range (Table I), as they had been during outpatient investigations. When he was taking his usual diet his urinary calcium excretion was 380 mg. per twenty-four hours. When he was taking a metabolic diet containing each day 400 mg. of calcium and 1 gm. of phosphorus his mean urinary calcium excretion was 290 mg. per twenty-four hours. Intravenous pyelography showed a calculus in the upper pole of the right kidney and stone fragments in the bladder, but the calyceal outlines were otherwise within normal limits. A roentgenologic bone survey, including views of the lamina dura, gave no evidence of metabolic bone disease. On the day of calcium infusion there was no fall in urinary phosphorus excretion; there was a normal “rebound” rise of 24 per cent on the day after the infusion. Urinary calcium excretion was not decreased during eight days of treatment with prednisone; indeed it was increased (Table II). The mean serum calcium concentration during the six month period of study prior to operation was 9.69 mg. per 100 ml., with a mean serum phosphorus level of 3.23 mg. per 100 ml. At no time prior to operation did either the serum calcium or the phosphorus concentration exceed the normal range (Fig. 1 and 2). At operation (June 6, 1968) all four parathyroid glands were identified and biopsied. There was chief cell hyperplasia of the left upper and right lower parathyroid glands, which were removed; the other glands had a normal histologic picture. Following operation hypocalcemia developed, however, oral calcium supplements were required for only three weeks to maintain a normal serum calcium concentration. COMMENTS
The three patients described here presented with a long history of recurrent renal calculi, normal serum calcium and phosphorus concentrations, and hypercalciuria while they were taking an unregulated diet. In two of them the hypercalciuria persisted despite a restricted intake of calcium. In none of them did the urinary phosphorus excretion decrease on the day of a calcium infusion, and in only one (Case 3) was there a normal “rebound” increase on the day after the infusion. In none of the patients given prednisone orally did urinary calcium decrease during the eight days of treatment. In all three patients the mean preoperative serum concentrations of calcium and phosphorus were within
388
Normocalcemic
Primary
Hyperpari~thyroldlsnl-Il/i/l.~
the noritial range ov(r a six month period prior to operation. III one patient (Case 3) the serum calriuin concentrations did not exceed the upper lilnit of noriilal at any time before operation. In the other two patients ten of a total of forty-three seruui calcium determinations over the six nionth period prior to operation were above the upper limit of the norinal range. Keating [ 101 regarded a seruni calcium concentration as “borderline” if it fell within the 99 percentile limits of normal (mean f 3 S.11.). ,411 ten of the estimations that exceeded the upper limit of the normal range in our two patients were within the 99 percentile limits of norinal, and could therefore be regarded as “borderline” rather than as significant hypercalcemia. In all three patients the diagnosis of primary hyperparathyroidism was proved by surgical exploration of the neck and identificat ion and biopsy of all four parathyroid glands. In two a parathyroid adenoma was found; in the third, parathyroid hyperplasia. We could classify the disease in these three patients, therefore, as normocalcemic primary hyperparathyroidism. In our experience, in agreement with that of others, the finding of hypercalcemia is the best index in the diagnosis of primary hyperparathyroidism [ 1,3,8,?0, I7-141. However we do not agree with the view that the finding of hypercalcemia is a sine qua non in establishing the diagnosis. Cope [ 7I] in his review of 230 cases considered that a high serum calcium concentration was the most characteristic disturbance of primary hyperparathyroidism. He mentioned briefly, without details, one patient who presented at the arthritis clinic with bizarre aches and pains, and whose serum calcium concentration was normal initially, who was later operated upon successfully for a parathyroid adenoma. Keating [TO] in reviewing 380 cases of hyperparathyroidism was impressed by the “remarkable stability of the hypercalcemia” in some of the patients who had been observed over a long period. Although Keating stated that the degree of hypercalcemia may be trivial, he believed that if hyperparathyroidism occurred with intermittent hypercalcemia, it must be very rare. In his series fifty-two patients had “borderline” serum calcium concentrations before operation, in that one or more values fell within the 99 percentile limits of normal. In twenty-five of these patients one or more of the preoperative values were within the 95 percentile limits of normal, and of these only one patient had a mean preoperative value within those
rt (I/
litnils. All twenty paticxnts whos~~ d:tla w(‘r(‘ ri’liewed by Mieher and his colleagues 1I-7 1and all thirtv-six patients reviewed by, Kyl(* ;111tl his coworkers [ 121 had hyprrcalceiriia ; tx)rh grolips regard this as the iilost irtiportant diagnostic, feature. Dent [I], reviewing the records of eighty patients with proved priinary hyperparathyroidism, stated that one nortnal value for total seruln calcium, obtained with impeccable tec‘llnit, made the diagnosis most unlikely. Of the thirtv-four patients whose data were rcsviewed 1))~ Riddick and Reiss [ 161 all but one had hypercalcemia at some time prior to operation, and this one exception had inoderately advanced renal insufficiency. Of the forty-eight patients whose records were reviewed by Coffey and his colleagues [13] the diagnosis was based principally on the demonstration of a significant elevation of the serum calciuin concentration and the exclusion of all other causes of hypercalcernia. In only one of the fifty cases reviewed by Pyrah and his co-workers [rl] was the mean preoperative serum calcium concentration within the normal range; these investigators cousidcr the diagnosis of primary hyperparathyroidisin most unlikely when the serum calcium conceittration is less that 10.5 mg. per 100 1t11. In recent years cases of primary hyperparathyroidism have been reported with an increasing frequency in which there has been either intermittent activity of the adenoma, as shown by fluctuations in the serum calcium concentration from within the normal range to values well above it, or serum calcium values that are within the normal range (uide infru). It is important to make a distinction between these patients and those rare patients with clinical and/or biochemical evidence of hyperparathyroidism who have undergone a “spontaneous” remission due to infarction of a parathyroid adenoma [ 17,7X ]. In 1953 Mather 1191 published a report which, as far as we are aware, described the first documented case of proved primary hyperparathyroidism in which the patient was norrnocalcemic from the time of initial observation and over the ensuing three month period until neck exploration and removal of the adenoma. The patient was a thirty-nine year old woman who had diffuse aching pains in the lower limbs and back six months before hospitalization and who had developed a “waddling” gait. Four values for serum calcium concentration during the three month period prior to operation were all within the normal range. Skeletal roentgenograms and sternal AMERICAN
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bone biopsy showed evidence of osteitis fibrosa. At operation the patient was found to have a “wasserhelle” cell adenoma. This patient is of considerable interest, not only because of the short duration of symptoms but also because, as far as we are aware, she represents the only reported case of normocalcemic hyperparathyroidism with osteitis fibrosa. In 1956, Bogdonoff et al. [z] reviewed twentyfive cases of primary hyperparathyroidism observed in one hospital over a twenty-five year period; they reported that serum calcium values were within the normal range in five of these. In only one of these five was the diagnosis made during the first twenty-three years of the period under review. In their paper they stated that the normal mean value of serum calcium concentration for their laboratory was 9.2 mg. per 100 ml. with a standard deviation (SD.) of 0.5 mg. per 100 ml. Thus the upper limit of their normal range (mean + 2 S.D.) was 10.2 mg. per 100 ml. In their analysis of their cases, however, they used a serum calcium concentration of 11.5 mg. per 100 ml. for the upper limit of normal. This value was based on a “composite summary of the values listed in several standard textbooks and reference sources.” If their data are reexamined using the upper limit of normal for their own laboratory, in only two of their cases was the value below that limit at some time. In these two cases the values ranged from 8.8 to 11.2 mg. and from 9.2 to 11.0 mg. per 100 ml., respectively; in only the first of them was the diagnosis proved by surgical removal of an adenoma. Whitby [ZO] described a fifty year old woman with a ten year history of recurrent renal calculi. A diagnosis of “intermittent hyperparathyroidism” was made and a parathyroid adenoma was removed. In this patient five values for serum calcium concentration were reported over a three month period of observation before operation. The values were 9.8, 11.4, 12.0, 12.2 and 12.4 mg. per 100 ml. Nineteen days before the one normal value was obtained, the patient had been anuric for five days following pyelolithotomy and partial nephrectomy, and the blood urea concentration reached 141 mg. per 100 ml. In one of the five cases of primary hyperparathyroidism reported by Fanconi and Rose [3] the total plasma calcium concentration was within the normal range on two occasions in the two week period prior to operation. It is of interest that although the total calcium was normal the ionized fraction was VOL.
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increased. In 1959 McGeown and Morrison [27] reviewed a series of fifty-three patients with proved hypcrparathyroidism and noted that serum calcium values “well within the normal range are often observed in patients who are subsequently proved to have hyperparathyroidism.” In their series the serum calcium concentration had never exceeded 11.0 mg. per 100 ml. in one patient; in twelve, the highest value was below 12.0 mg. per 100 ml. McGeown and Morrison also noted fluctuations in the serum calcium concentration in patients observed over a long period and one of their figures depicts values in three patients which fluctuated by 2 mg. per 100 ml. or more over four to fourteen months of observation. Similar fluctuations in serum calcium concentration in patients with hyperparathyroidism were reported by McSwiney and Prunty [22], who found that hypercalcemia could be present on some occasions but not on others. In discussing some thirteen patients with proved hyperparathyroidism they stated that “In half our patients with hyperparathyroidism definite hypercalcemia did not consistently occur and in one patient this was not observed on any occasion.” Their report is also of interest in that this last patient did not have an elevated ionized calcium fraction, in contrast to the earlier report of Fanconi and Rose [3]. The tendency of the serum calcium to fluctuate in primary hyperparathyroidism was stressed by McGeown [23] who stated that “This tendency to fluctuation appears to be characteristic of the hypercalcemia of hyperparathyroidism” ; with hypercalcemia of other causes she stated that “the serum calcium is much more constant.” In the cases reported here fluctuations did occur over the six month preoperative period in each patient, but they were relatively small, and in no case did they exceed 2.0 mg. per 100 ml. In 1967 Nichols and Flanagan [7] described six patients, four of whom had renal stones, who were later proved to have parathyroid adenoma (five patients) or parathyroid hyperplasia. In the only one of their patients in whom serum calcium concentration was observed over a period of time, there had been “hypercalcemia several months before.” Similarly in the case reported by Melvin, Joplin and Fraser [6] (a forty-five year old man with renal stones) there had been two episodes in which the serum calcium concentration was increased over a long period of observation. In their review of fifty-five
39 1
Normocalcernic
Primary
Hyperparathyroidism-Wills
cases of proved primary hyperparathy-roidism, Yendt and Cagne [5] reported that in five, all in women, the mean preoperative serum calriiun concentration was within the normal range. In these five cases only seven of a total of forty-six determinations were above the upper limit of the normal range. When these workers reviewed their normal range for serum calcium concentration, however, they found that it was lower in women than in men; on replotting their data they concluded that the mean preoperative serum calcium concentration was in fact elevated in four of the five patients, all of whom had recurrent renal stones. In the fifth patient, who is noted briefly as having presented with osteoporosis, a total of fourteen estimations of serum calcium were obtained in the preoperative period of which only one (10.2 mg. per 100 ml.) was above the upper limit of their revised normal range. The surgical findings at neck exploration in this patient were not given. In our patients the mean preoperative serum phosphorus concentrations were within the normal range, although the values obtained over the six months of observation before operation tended to be within the lower part of the normal range (Fig. 2). It is generally accepted that even if renal function is normal a low serum phosphorus concentration is by no means a constant diagnostic biochemical feature of primary hyperparathyroidism [ 7,5,70,23,24]. Two of our patients had an abnormal response to calcium infusion; in the third there was an abnormal response on the day of the infusion but a normal “rebound” increase in urinary phosphorus on the day after the infusion. This test is regarded by some [ 7,9] although not all [23] workers to be a useful diagnostic aid in the diagnosis of hyperparathyroidisn~. The findings in our three patients are in agreement with the observations in the eight cases previously reported by one of us [8]. They support the conclusions of Nichols and Flanagan [7] that hyperparathyroidism exists in a significant number of patients who present with recurrent renal calculi, or other complaints suggesting parathyroid hyperfunction, but fail to show the classic criteria for establishing such a diagnosis. Early diagnosis in such patients should prevent the irreversible renal damage associated with hypercalcemia. It has recently been shown by Lloyd [ 741, in a statistical review of 138 cases of that the rnean pririiary hyperparathyroidism,
et nl.
serum calcium concciilratioli ,IIKI t11(.311 LIIIIW weights are significantly lower iii patients with renal stones than in those with ostcitis fibrosa. He proposes that there arc two iliain t>pcs of parathyroid tumor, one rapidly g-rowing and highly acti\re that causes overt bone disease. and the. other slowly growing and of low activity that causes kidney stones. In oiir own cxpericnce of giving parathyroid extract to norinal s~ibjerts over the relatively short period of three days, there is always a brisk increase in urinary calcium excretion into the range of hypercalciuria although it is unusual for the serum calcium concentration to exceed the upper liinit of normal [25]. Thus, with relatively sinall parathyroid tumors of low activity the finding of patients with normocalcemic priiuary- hy.perparathyroidism is not unexpected. ‘I‘hc rcrognition of such patients among those with recurrent renal stones is of prime importance, as the prc\rention of long-term renal damage inay depend upon the definitive test of neck exploration, with identification and biopsy of all foltr parathyroid glands. REFERENCES 1.
DENT, C. E. Some problems of hyperparathyroidism.
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.4 critical
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