Metabolic Effects of Parathyroidectomy in Asymptomatic Primary Hyperparathyroidism ROY A. KAPLAN, WILLIAM H. SNYDER, ALAN STEWART, AND CHARLES Y. C. PAK Mineral Metabolism Section, Department of Internal Medicine, Southwestern Medical School, the University of Texas Health Science Center at Dallas, Dallas, Texas 75235 fasting urinary Ca greater than 0.2 mg/mg creatinine for a night-time sample after a 6-hour fast), and decreased renal function (creatinine clearance of less than 65 ml/min). Following parathyroidectomy, most of these deleterious effects were reversed commensurate with the return of immunoreactive serum PTH, serum Ca, and urinary cyclic AMP toward normal. These quantitative non-invasive techniques may be useful for the initial evaluation and follow-up of patients with asymptomatic primary hyperparathyroidism. (/ Clin Endocrinol Metab 42: 415, 1976)
ABSTRACT. Effects of parathyroidectomy on parathyroid function and calcium (Ca) metabolism were carefully evaluated in 6 patients with primary hyperparathyroidism without symptoms normally attributed to the disease and in 7 with bone disease or nephrolithiasis. Before parathyroidectomy, both groups of patients demonstrated evidence of the sequelae of parathyroid hormone (PTH) excess, since they presented one or more of the following features: low bone density by m I-photon absorption, hypercalciuria (urinary Ca greater than 200 mg/day on an intake of 400 mg/day), negative Ca balance (absorbed Ca less than urinary Ca), elevated
P
RIMARY hyperparathyroidism is now being diagnosed with increasing frequency, probably because of growing awareness of the disease, increased use of multiphasic biochemical screening and availability of sophisticated diagnostic methods. The incidence of primary hyperparathyroidism has been reported to be as high as 0.12 per cent (1). With this trend, there has been a marked increase in the percentage of those with biochemical evidence of primary hyperparathyroidism who present no clear symptoms of the disease. Although the need for parathyroidectomy in advanced, severe hyperparathyroidism is well recognized, the efficacy of parathyroidectomy in the "asymptomatic" form of this disease have not yet been established. In previous studies, we devised a reliable protocol for a rapid assessment of parathyroid function and quantitative assessment of Ca metabolism, based on a constant liquid synthetic diet (2). In the present study, six Received April 2, 1975. Supported by grants from USPHS 1-RO1-AM-16061 and 1-MO1-RR-00633. Dr. Kaplan is a post-doctoral fellow supported by USPHS grant 5-TO1-AM-05028. Requests for reprints should be addressed to Dr. Pak.
patients with asymptomatic primary hyperparathyroidism and seven with symptomatic disease were evaluated according to this protocol before and after parathyroidectomy. This objective evaluation has provided a better assessment of the efficacy of parathyroidectomy in the asymptomatic cases. Materials and Methods Clinical data. Thirteen patients referred for evaluation of hypercalcemia were hospitalized in our General Clinical Research Center. All patients had a thorough diagnostic evaluation to exclude other causes of hypercalcemia. The diagnosis of primary hyperparathyroidism was made on the basis of an elevated concentration of serum immunoreactive parathyroid hormone (iPTH) and/or high renal excretion of cyclic AMP (cAMP). Six patients (cases 1-6) were classified as "asymptomatic" since they had a) no symptoms referrable to hypercalcemia, such as weakness, mental or gastrointestinal disturbances, polyuria, or polydipsia, b) no symptoms of bone disease and no evidence of radiolucency, subperiosteal resorption, or osteitis fibrosa on skeletal roentgenologic examination, c) no past history of nephrolithiasis or renal colic, and no stones visualized on abdominal roentgenogram, and d) no history or symptoms of peptic ulcer disease or pancreatitis. They were all women, from 35 to
415
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416
KAPLAN, SNYDER, STEWART AND PAK
58 years old (mean of 48 years). Seven patients (Cases 7-13) were classified as "symptomatic" because of symptomatic bone disease alone in 3 cases, nephrolithiasis alone in 2 cases and both bone disease and nephrolithiasis in 2 cases. Among 3 patients who suffered from only bone disease, one was a 65-year-old black woman with vertebral compression fractures, and another was a 41-year-old white man with a compression fracture of 11th thoracic vertebra and subperiosteal resorption in phalanges of both hands (on routine roentgenologic examination). The third was a 55-year-old white postmenopausal woman. Although her vertebral compression fractures could be accounted for by osteoporosis of estrogen-lack, she had subperiosteal resorption in phalanges of both hands as well. This group consisted of 5 women and 2 men from 49 to 65 years of age (mean 60 years). All patients underwent parathyroid exploration 1 week to 14 months after evaluation. During surgical exploration, all 4 parathyroid glands were identified. In each case, one grossly enlarged gland was resected, and identified histologically as a parathyroid adenoma. The remaining glands were grossly normal. Selected glands were biopsied and found to be normal by light microscopy. At least one gland was left intact in each case. All patients were then reevaluated 3 to 13 months postoperatively. Case 1 was restudied both 3 and 7 months postoperatively. Protocol of study. All patients were evaluated under the following protocol before and following parathyroid exploration. This protocol, reported in detail elsewhere (2), will be briefly described here. All patients were placed on a constant liquid synthetic diet1 for 3 days. The daily composition of the diet included 400 mg Ca, 800 mg phosphorus (P), and 100 meq sodium. Urine specimens were collected under refrigeration in 24-hour pools beginning at 9 AM each morning. These specimens were analyzed for Ca, P, magnesium (Mg), creatinine (Cr), and cAMP. The day before the synthetic diet began, a 7-hour fasting urine sample (from midnight to 7 AM) was collected after at least 6 hours of fast and analyzed for Ca and Cr. Venous blood was obtained without stasis while the patients were in 1
The synthetic diet may be obtained from Doyle Pharmaceutical Co., Highway 100 at West 23rd Street, Minneapolis, Minnesota 55416.
JCE & M . 1976 Vol 42 • No 3
a supine position at 9 AM daily for Ca, P, Cr, and alkaline phosphatase, and on day 2 of the diet for iPTH. On day 2 or 3,47Ca, mixed in 250 cc of the synthetic diet (containing 100 mg Ca), was given orally for the measurement of fractional Ca absorption (a) from the intestinal tract. "Bone density" of the distal third of the radius of the non-dominant forearm was measured in vivo. All patients were asked not to ingest dairy products and to avoid excess salt in their food for at least one week before the study. Analytic procedures and other methods. Ca and Mg were determined by atomic absorption spectrophotometry. Urinary cAMP was analyzed by the protein-binding assay of Gilman (3). Phosphorus was determined by the method of Fiske and SubbaRow (4). Creatinine and total serum alkaline phosphatase were determined by autoanalyzer. The radioimmunoassay of PTH in serum was performed according to the procedure of Arnaud (5) using CH 14M as antiserum. This antiserum measures predominantly the NH2-terminal portion of the PTH molecule. Radioiodination of purified bovine PTH (a gift of Dr. B. Brewer) was accomplished as described (5). The culture medium of human parathyroid gland was utilized for standard PTH (2). Serum concentrations of PTH were expressed in terms of equivalent protein contained in the culture medium used for standard PTH. An expression of "\ f*g eq/ml" indicates that one milliliter of serum sample contains the same amount of protein in \ micrograms protein equivalent of the medium. Samples were assayed in duplicate at 3 different dilutions and the results were accepted only if the mean of duplicate values at 3 dilutions agreed within 10%. Fractional Ca absorption was measured preoperatively in all but patient 7, and in all patients postoperatively. One to 2 /xCi of 47Ca (as the chloride, Amersham/Searle Corporation, Arlington Heights, Illinois) was mixed in one meal of synthetic diet (containing 100 mg Ca) and given orally. Fractional Ca absorption was obtained from the recovery of fecal radioactivity according to the procedure previously described (6). The product of a and dietary Ca intake of 400 mg per day gave CaA, the absorbed calcium. The CaA correlates highly with net Ca absorption (7) and approximates closely the true calcium absorption determined from 47Ca kinetic analysis after an
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METABOLIC EFFECTS OF PARATHYROIDECTOMY intravenous administration of the isotope (unpublished data). It therefore represents unidirectional uptake of calcium from the gastrointestinal tract, exclusive of intestinal secretion. If certain assumptions are made regarding the extent of endogenous fecal Ca, the difference between CaA and 24-hour urinary Ca excretion (Cauv) gives an estimate of the state of Ca balance. If CaA is less than Ca uv , the Ca balance is negative. The bone density was determined from the absorption of 125I-photon by bone with a NorlandCameron Bone Mineral Analyzer (8). Bone density was expressed as the ratio of bone mineral content and bone width (BM/BW) in grams/cm2.
417
The reproducibility of measurement in the same patient was within 3%. Results Serum Ca (Table 1, Fig. 1). Before parathyroidectomy (PTX), serum Ca was elevated (greater than 10.6 mg/100 ml) in all asymptomatic patients with a mean of 11.86 ± 0.54 SD mg/100 ml. This was significantly higher than the value in the symptomatic group of 10.96 ± 0.65 mg/100 ml (P < 0.05). Three of the symptomatic cases were normocalcemic during study, although they were hyper-
TABLE 1. Summary of biochemical measurements in asymptomatic and symptomatic primary hyperparathyroidism before and after parathyroidectomy
Post-PTX
Pre-PTX Combined group
Asymptomatic group
Symptomatic group
Combined group
Asymptomatic group
Symptomatic group
Cas (mg/100 ml)
11.37 ±0.74
11.86 ±0.54
10.96 ±0.65
9.40 ± 0.45$
9.52 ± 0.53f
9.29 ± 0.37$
Ps (mg/100 ml)
2.79 ±0.34
2.58 ±0.26
2.97 ±0.32
3.32
± 0.46t
3.51 ± 0.511
3.16 ±0.37
Alk 0 (IU) Serum PTH (fig eq/ml) Urinary Ca (Cauv) (mg/day)
99 ±40 1.929 ± 1.630
283 ±99
93 ± 18 2.483 ± 2.031 274 ± 93
105 ±22 1.459 ± 1.143 290 ± 111
71 ±22 0.487 ± 0.3491
95 ±60$
69 ±24 0.699 ± 0.384 80
±65f
73 ± 22 0.306 ± 0.196 109
Fasting urinary Ca/Cr (mg/mg/Cr)
0.30 ±0.10
0.28 ±0.11
0.33 ±0.08
0.11 ±0.09$ .
0.09 ± 0.10*
Urinary cAMP (/xmoles/gm/Cr)
7.16 ±2.97
8.42 ±3.72
6.08 ± 1.77
4.02 ± 1.20t
4.18 ± 0.59*
±58f 0.13 ± 0.09t 3.90 ± 1.60f
a
0.71 ±0.11
0.71 ±0.11
0.69 ±0.13
0.60 ±0.12
0.62 ±0.18
0.59 ±0.12
CaA-Cauv (mg/day)
-11 ±95
+ 13 ±68
-35 ± 117
Urinary P (mg/day)
721 ±215
690 ±209
748 ±232
126 ±37 85 ±19
123 ±30
128 ±33
83 ±18
81 ±19
Urinary Mg (mg/day) Cr clearance (ml/min)
+ 152 ±73$ 563 ±110*
+ 184 ±86f
93 ±27 88 ±22
90 ±24
+ 126 ± 53* 582 ± 147 95 ±31
101 ±30
89 ±22
540 ±47
In each group, results are represented as mean ± SD of values from individual cases. The significant difference between corresponding groups pre- and post-PTX is indicated by * P < 0.05, \ P < 0.01, and $ P < 0.001. Abbreviations: Ca^ serum calcium; Ps, serum phosphorus, alk , serum alkaline phosphatase; and a, fractional calcium absorption.
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418
KAPLAN, SNYDER, STEWART AND PAK
JCE & M • 1976 Vol 42 • No 3
SYMPTOMATIC
ASYMPTOMATIC
13
13 •PreoPost-PTX I ***P
ABSTRACT. Effects of parathyroidectomy on parathyroid function and calcium (Ca) metabolism were carefully evaluated in 6 patients with primary hyperparathyroidism without symptoms normally attributed to the disease and in 7 with bone disease or nephrolithiasis. Before parathyroidectomy, both groups of patients demonstrated evidence of the sequelae of parathyroid hormone (PTH) excess, since they presented one or more of the following features: low bone density by m I-photon absorption, hypercalciuria (urinary Ca greater than 200 mg/day on an intake of 400 mg/day), negative Ca balance (absorbed Ca less than urinary Ca), elevated
P
RIMARY hyperparathyroidism is now being diagnosed with increasing frequency, probably because of growing awareness of the disease, increased use of multiphasic biochemical screening and availability of sophisticated diagnostic methods. The incidence of primary hyperparathyroidism has been reported to be as high as 0.12 per cent (1). With this trend, there has been a marked increase in the percentage of those with biochemical evidence of primary hyperparathyroidism who present no clear symptoms of the disease. Although the need for parathyroidectomy in advanced, severe hyperparathyroidism is well recognized, the efficacy of parathyroidectomy in the "asymptomatic" form of this disease have not yet been established. In previous studies, we devised a reliable protocol for a rapid assessment of parathyroid function and quantitative assessment of Ca metabolism, based on a constant liquid synthetic diet (2). In the present study, six Received April 2, 1975. Supported by grants from USPHS 1-RO1-AM-16061 and 1-MO1-RR-00633. Dr. Kaplan is a post-doctoral fellow supported by USPHS grant 5-TO1-AM-05028. Requests for reprints should be addressed to Dr. Pak.
patients with asymptomatic primary hyperparathyroidism and seven with symptomatic disease were evaluated according to this protocol before and after parathyroidectomy. This objective evaluation has provided a better assessment of the efficacy of parathyroidectomy in the asymptomatic cases. Materials and Methods Clinical data. Thirteen patients referred for evaluation of hypercalcemia were hospitalized in our General Clinical Research Center. All patients had a thorough diagnostic evaluation to exclude other causes of hypercalcemia. The diagnosis of primary hyperparathyroidism was made on the basis of an elevated concentration of serum immunoreactive parathyroid hormone (iPTH) and/or high renal excretion of cyclic AMP (cAMP). Six patients (cases 1-6) were classified as "asymptomatic" since they had a) no symptoms referrable to hypercalcemia, such as weakness, mental or gastrointestinal disturbances, polyuria, or polydipsia, b) no symptoms of bone disease and no evidence of radiolucency, subperiosteal resorption, or osteitis fibrosa on skeletal roentgenologic examination, c) no past history of nephrolithiasis or renal colic, and no stones visualized on abdominal roentgenogram, and d) no history or symptoms of peptic ulcer disease or pancreatitis. They were all women, from 35 to
415
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416
KAPLAN, SNYDER, STEWART AND PAK
58 years old (mean of 48 years). Seven patients (Cases 7-13) were classified as "symptomatic" because of symptomatic bone disease alone in 3 cases, nephrolithiasis alone in 2 cases and both bone disease and nephrolithiasis in 2 cases. Among 3 patients who suffered from only bone disease, one was a 65-year-old black woman with vertebral compression fractures, and another was a 41-year-old white man with a compression fracture of 11th thoracic vertebra and subperiosteal resorption in phalanges of both hands (on routine roentgenologic examination). The third was a 55-year-old white postmenopausal woman. Although her vertebral compression fractures could be accounted for by osteoporosis of estrogen-lack, she had subperiosteal resorption in phalanges of both hands as well. This group consisted of 5 women and 2 men from 49 to 65 years of age (mean 60 years). All patients underwent parathyroid exploration 1 week to 14 months after evaluation. During surgical exploration, all 4 parathyroid glands were identified. In each case, one grossly enlarged gland was resected, and identified histologically as a parathyroid adenoma. The remaining glands were grossly normal. Selected glands were biopsied and found to be normal by light microscopy. At least one gland was left intact in each case. All patients were then reevaluated 3 to 13 months postoperatively. Case 1 was restudied both 3 and 7 months postoperatively. Protocol of study. All patients were evaluated under the following protocol before and following parathyroid exploration. This protocol, reported in detail elsewhere (2), will be briefly described here. All patients were placed on a constant liquid synthetic diet1 for 3 days. The daily composition of the diet included 400 mg Ca, 800 mg phosphorus (P), and 100 meq sodium. Urine specimens were collected under refrigeration in 24-hour pools beginning at 9 AM each morning. These specimens were analyzed for Ca, P, magnesium (Mg), creatinine (Cr), and cAMP. The day before the synthetic diet began, a 7-hour fasting urine sample (from midnight to 7 AM) was collected after at least 6 hours of fast and analyzed for Ca and Cr. Venous blood was obtained without stasis while the patients were in 1
The synthetic diet may be obtained from Doyle Pharmaceutical Co., Highway 100 at West 23rd Street, Minneapolis, Minnesota 55416.
JCE & M . 1976 Vol 42 • No 3
a supine position at 9 AM daily for Ca, P, Cr, and alkaline phosphatase, and on day 2 of the diet for iPTH. On day 2 or 3,47Ca, mixed in 250 cc of the synthetic diet (containing 100 mg Ca), was given orally for the measurement of fractional Ca absorption (a) from the intestinal tract. "Bone density" of the distal third of the radius of the non-dominant forearm was measured in vivo. All patients were asked not to ingest dairy products and to avoid excess salt in their food for at least one week before the study. Analytic procedures and other methods. Ca and Mg were determined by atomic absorption spectrophotometry. Urinary cAMP was analyzed by the protein-binding assay of Gilman (3). Phosphorus was determined by the method of Fiske and SubbaRow (4). Creatinine and total serum alkaline phosphatase were determined by autoanalyzer. The radioimmunoassay of PTH in serum was performed according to the procedure of Arnaud (5) using CH 14M as antiserum. This antiserum measures predominantly the NH2-terminal portion of the PTH molecule. Radioiodination of purified bovine PTH (a gift of Dr. B. Brewer) was accomplished as described (5). The culture medium of human parathyroid gland was utilized for standard PTH (2). Serum concentrations of PTH were expressed in terms of equivalent protein contained in the culture medium used for standard PTH. An expression of "\ f*g eq/ml" indicates that one milliliter of serum sample contains the same amount of protein in \ micrograms protein equivalent of the medium. Samples were assayed in duplicate at 3 different dilutions and the results were accepted only if the mean of duplicate values at 3 dilutions agreed within 10%. Fractional Ca absorption was measured preoperatively in all but patient 7, and in all patients postoperatively. One to 2 /xCi of 47Ca (as the chloride, Amersham/Searle Corporation, Arlington Heights, Illinois) was mixed in one meal of synthetic diet (containing 100 mg Ca) and given orally. Fractional Ca absorption was obtained from the recovery of fecal radioactivity according to the procedure previously described (6). The product of a and dietary Ca intake of 400 mg per day gave CaA, the absorbed calcium. The CaA correlates highly with net Ca absorption (7) and approximates closely the true calcium absorption determined from 47Ca kinetic analysis after an
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 07 July 2015. at 03:35 For personal use only. No other uses without permission. . All rights reserved.
METABOLIC EFFECTS OF PARATHYROIDECTOMY intravenous administration of the isotope (unpublished data). It therefore represents unidirectional uptake of calcium from the gastrointestinal tract, exclusive of intestinal secretion. If certain assumptions are made regarding the extent of endogenous fecal Ca, the difference between CaA and 24-hour urinary Ca excretion (Cauv) gives an estimate of the state of Ca balance. If CaA is less than Ca uv , the Ca balance is negative. The bone density was determined from the absorption of 125I-photon by bone with a NorlandCameron Bone Mineral Analyzer (8). Bone density was expressed as the ratio of bone mineral content and bone width (BM/BW) in grams/cm2.
417
The reproducibility of measurement in the same patient was within 3%. Results Serum Ca (Table 1, Fig. 1). Before parathyroidectomy (PTX), serum Ca was elevated (greater than 10.6 mg/100 ml) in all asymptomatic patients with a mean of 11.86 ± 0.54 SD mg/100 ml. This was significantly higher than the value in the symptomatic group of 10.96 ± 0.65 mg/100 ml (P < 0.05). Three of the symptomatic cases were normocalcemic during study, although they were hyper-
TABLE 1. Summary of biochemical measurements in asymptomatic and symptomatic primary hyperparathyroidism before and after parathyroidectomy
Post-PTX
Pre-PTX Combined group
Asymptomatic group
Symptomatic group
Combined group
Asymptomatic group
Symptomatic group
Cas (mg/100 ml)
11.37 ±0.74
11.86 ±0.54
10.96 ±0.65
9.40 ± 0.45$
9.52 ± 0.53f
9.29 ± 0.37$
Ps (mg/100 ml)
2.79 ±0.34
2.58 ±0.26
2.97 ±0.32
3.32
± 0.46t
3.51 ± 0.511
3.16 ±0.37
Alk 0 (IU) Serum PTH (fig eq/ml) Urinary Ca (Cauv) (mg/day)
99 ±40 1.929 ± 1.630
283 ±99
93 ± 18 2.483 ± 2.031 274 ± 93
105 ±22 1.459 ± 1.143 290 ± 111
71 ±22 0.487 ± 0.3491
95 ±60$
69 ±24 0.699 ± 0.384 80
±65f
73 ± 22 0.306 ± 0.196 109
Fasting urinary Ca/Cr (mg/mg/Cr)
0.30 ±0.10
0.28 ±0.11
0.33 ±0.08
0.11 ±0.09$ .
0.09 ± 0.10*
Urinary cAMP (/xmoles/gm/Cr)
7.16 ±2.97
8.42 ±3.72
6.08 ± 1.77
4.02 ± 1.20t
4.18 ± 0.59*
±58f 0.13 ± 0.09t 3.90 ± 1.60f
a
0.71 ±0.11
0.71 ±0.11
0.69 ±0.13
0.60 ±0.12
0.62 ±0.18
0.59 ±0.12
CaA-Cauv (mg/day)
-11 ±95
+ 13 ±68
-35 ± 117
Urinary P (mg/day)
721 ±215
690 ±209
748 ±232
126 ±37 85 ±19
123 ±30
128 ±33
83 ±18
81 ±19
Urinary Mg (mg/day) Cr clearance (ml/min)
+ 152 ±73$ 563 ±110*
+ 184 ±86f
93 ±27 88 ±22
90 ±24
+ 126 ± 53* 582 ± 147 95 ±31
101 ±30
89 ±22
540 ±47
In each group, results are represented as mean ± SD of values from individual cases. The significant difference between corresponding groups pre- and post-PTX is indicated by * P < 0.05, \ P < 0.01, and $ P < 0.001. Abbreviations: Ca^ serum calcium; Ps, serum phosphorus, alk , serum alkaline phosphatase; and a, fractional calcium absorption.
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418
KAPLAN, SNYDER, STEWART AND PAK
JCE & M • 1976 Vol 42 • No 3
SYMPTOMATIC
ASYMPTOMATIC
13
13 •PreoPost-PTX I ***P
