journal of Internal Medicine 1992 : 232 : 42 1 4 2 5
Increasing parathyroid hormone concentrations in untreated primary hyperparathyroidism M. KUDNICKI & I. TRANSBQL From the Mineral Metabolic Research Group. Copenhagen. and Division oJ Endocrinology. Department lnternal Medicine. Hvidovre Hospital. University OJ Copenhagen. Denmark
OJ
Abstract. Kudnicki M, Transbd I (Mineral Metabolic Research Group, Copenhagen, and Division of Endocrinology, Department of Internal Medicine, Hvidovre Hospital, University of Copenhagen, Denmark). Increasing parathyroid hormone concentrations in untreated primary hyperparathyroidism. Journal of Internal Medicine 1992 : 232 : 42 1 4 2 5. Twenty-four patients with mild to moderate primary hyperparathyroidism were followed for an average of 2.45 years with serial determinations of serum ionized calcium and intact parathyroid hormone (PTH). For the entire group serum ionized calcium remained stable, whereas serum PTH increased significantly. Eleven patients (group 1 ) demonstrated a significant increase in PTH with time. The remaining 1 3 patients formed group 2. Comparison of the changes (%) in each subgroup showed a small but significant increase in serum ionized calcium of 2.6% with time in group I , while serum PTH increased by 78%. In group 2 serum ionized calcium remained stable whereas PTH increased modestly by 22 %. Serum concentrations of creatinine were stable throughout the follow-up period in both groups. Despite the greater precision of serum ionized calcium, measurements of intact PTH are evidently more sensitive than measurements of serum ionized calcium for the detection of progression in primary hyperparathyroidism.
Keywords: follow-up studies, ionized calcium, parathyroid hormone, primary hyperparathyroidism.
Introduction Introduction of the multichannel analysers two decades ago considerably improved the recognition of mild to moderate primary hyperparathyroidism C1-41. Most of the patients turned out to be elderly females, many of them being asymptomatic [ 1-31. The choice of treatment of such patients became a matter of dispute. Some authors believed that most patients with primary hyperparathyroidism should be treated surgically to avoid the risk of acute hypercalcaemia and progressive osteopenia [5-81. Others suggested that asymptomatic patients should be treated conservatively [9, 101. The finding of stable levels of serum calcium over long periods of follow-up was considered indicative of stable parathyroid function, and favoured the conservative attitude to treatment [9]. Surprisingly, the natural
history of mild to moderate primary hyperparathyroidism lacks information about the course of parathyroid function. A stable serum calcium level does not necessarily indicate stable parathyroid function. Conditions associated with old age, such as poor vitamin D intake and impaired vitamin D synthesis [ll,121, are responsible for impairments in dietary calcium absorption [13], which in turn may lead to compensatory hyper-secretion of parathyroid hormone (PTH). To shed light on parathyroid function in mild to moderate primary hyperparathyroidism we have studied the relative time-related changes in ionized calcium and PTH. using sensitive and precise measurements by the calcium ion electrode and an assay detecting the intact PTH molecule.
421
422
M. KUDNICKI & I. 'I'KANSBQI,
Patients and methods
Table 1 . Data on patients with primary hyperparathyroidisni treated surgically or conservatively
Study population
Our study group comprised 24 patients with mild to moderate primary hyperparathyroidism, diagnosed by raised concentrations of serum ionized calcium and inappropriate high levels of PTH. After the diagnosis was made 11 women experienced clinical deterioration, most often an osteoporotic fracture, and seven of them underwent surgical treatment because of this. Only measurements taken prior to the operation were included in the study. In the remaining 1 7 patients surgical treatment was refused in two patients while several patients had relative contraindications such as advanced age ( n = 7) and symptomatic heart or lung diseases ( n = 2). Others had a mild and asymptomatic disease which did not justify surgical intervention ( n = 6). Table 1 presents data for patients who underwent surgical treatment and those who followed conservative treatment. All patients were female (average age 68.9 years, range 32-89 years). The time spent on the actual study averaged 2.45 years (range 1.0-4.25 years). They were seen in our out-patient clinic approximately every third month for clinical and biochemical evaluation including measurements of serum ionized calcium, intact PTH, phosphate and creatinine.
Methods Biochemical analyses were performed when specimens were collected. Intact PTH was measured using a commercial immunoradiometric assay [ 141. The intra-assay coefficient of variation was 5%. The interassay coefficient of variation was estimated four times a year and was 7.5% on average (range 4-12%) using a pool of serum with a PTH concentration of 3.0 pmol I-'. Normal range was 1.14.8 pmol I-'. The detection limit was 0.30 pmol I-'. No systematic time-related change was observed in the measurements of intact PTH. Ionized calcium was measured on an ICA 1 calcium-ion electrode at pH 7.4 (Radiometer, Copenhagen, Denmark). The intra-assay coefficient of variation was 1 %. The intra-assay coefficient of variation was estimated every month during the study period (mean 1.16%. range 0.80-1.64%). Normal range was 1.15-1.31 mmol I-'. There was no systematic change with time in the measurements of ionized calcium.
Surgically treated 11 = 7 Mean SI) Age (years) Observation period (years) Ionized calcium (mmol 1-l) Phosphate (mmol I-]) Magnesium (mmol I-') PTH (pmol I-') 25-OHD:,(nmolI-') 1,25(OH),D, (pmol I-') Creatinine (prnol I-])
67.3 2.43 1.48 0.82 0.81 7.2 57 215 89
Conservatively treated rt = 17 Mean SD
69.7 (8.2) (0.45) 2.45 (0.12) 1.41 (0.15) 0.89 0.85 (0.07) (4.0) 6.6 56 (10) ( 1 57) 188 83 (25)
(17.1) (0.35) (0.07) ( 0 .13) (0.09) (3.5) (26) (76) (21)
Table 2. Mean levels of ionixed calcium (Ca") and parathyroid hormone (PTH) in 24 patients with primary hyperparathyroidism. Patients were grouped according to whether they had a signilicantly increased I'TH with time (group 1) or without (group 2). SD is shown in brackets
Patient no. n
1 2
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 rt
16 6 9 4 11 19 9 7 9 7 10 12 9 9 10 6 9 11 10 14 7 9 5 10
PI'H (pmol 1-l)
Ca'+ (rnmol 1-l)
13.0(3.38) 11.5 (4.98) 8.7 (1.48) 7.8 (0.60) 7.3 (0.85) 6.2 (1.50) 5.8 (1.48) 5.5 (0.70) 4.9 (0.78) 3.0 (0.61) 3.0 (0.67) 12.7 (3.90) 11.4 (2.29) 9.0(1.58) 7.7 (1.55) 7.1 (1.61) 6.5 (0.51) 5.9(1.32) 5.6(1.36) 5.2 (0.50) 3.7 (1.28) 3.3 (0.82) 3.3 (0.19) 2.7(0.50)
1.56(0.10) l.50(0.14) 1.42 (0.03) 1.36 (0.02) 1.56 (0.03) 1.53 (0.10) 1.48 (0.04) 1.43 (0.04) 1.37(0.02) 1.40 (0.03) 1.43 (0.06) 1.52 (0.04) 1.43 (0.05) 1.33 (0.05) 1.40 (0.02) 1.37(0.02) 1.42 (0.04) 1.39(0.03) 1.34(0.04) 1.38 (0.01) 1.44 (0.03) 1.34 (0.02) 1.34 (0.02) 1.39 (0.03)
I'TH CaZ+ vs. time w. time Regression coefficients
(r) 0.89$ 0.95' 0.887 0.9Xt 0.95t 0.88$
0.89$ 0.92t 0.8AS 0.80' 0.70' 0.02 0.66 0.18 0.62 0.59 -0.03 0.51 0.66 0.35 0.68 0.27 0.33 0.30
(4 -0.50 -0.61 0.19 0.18 -0.62 0.10 0.30 0.62 0.38 0.46 0.48 0.07 0.05 -0.18
0.22 -0.13 0.49 0.07 0.14 -0.67 0.60 0.09
-0.26 -0.23
*
denotes the number of measurements in each patient. I' < 0.01 : I' < 0.001.
' P < 0.05: t
Serum concentrations of phosphate and creatinine were measured on a multichannel autoanalyser (Technicon SMAC 3, Tarrytown, NY, USA). Normal
Pl’H I N PKIMARY HYPEKPARATHYROIDISM
a-”
v
E
423
50 1
- 400
.-
0
I
2
3
0
4
I
2
3
4
Years
Years
Fig. 1 . ‘I’hc relative changes in PTH (TI)during follow-up in patients with untreated primary hyperparathyroidism. who had a significant increase in I T H levels with time (a), or without (b).
ranges were 0.79-1.51 mmol I-’ and 491 2 1 pmol I-’. respectively. Serum 2 5-hydroxyvitamin D, (2 5-OHD,) was measured by a competitive protein binding assay after extraction and chromatography 1151. The coefficientof variation (interassay) was 10%.Normal range was 38.8-93.3 nmol I-’. The active vitamin D metabolite, 1.2 5-dihydroxyvitamin D:, (1,25(OH),D,) was measured by purification on Sephadex LH-20 column followed by high-pressure liquid chromatography. Assay was performed as previously described [ 161. lnterassay coefficient of variation was 14%. Normal range was 24-158 pmol I-’. Serum 25-OHD,, and 1,25(OH),D, was measured only once when the diagnosis of primary hyperparathyroidism was established. All parameters are presented as mean and SD. Serum concentrations of PTH were logarithmically transformed to achieve a normal distribution. Student’s t-test was used to compare serum levels of selected variables. Kegression analysis was applied to evaluate relationships between selected variables using the least-squares method. To improve the sensitivity of the evaluation of time-related changes and their comparison within groups, the first obser-
vation in each patient was ascribed the value of 100% and all the following measurements are expressed as a percentage relative to the initial value. A P-value less than 0.05 was considered as statistically significant.
Results On average the level of ionized calcium remained stable during the follow-up period: at start 1.41k0.08 (mean and SD) versus 1.44f0.08 (NS) at the end of the study period: whereas the level of PTH increased from a n average of 5.4 k 3.2 pmol I-’ to 7.8k4.1 pmol I-’ ( P < 0.01). There were no changes in ionized calcium with time when each patient was studied separately, whereas there was a significant increase of serum PTH concentrations in 11 patients, with a regression coefficient ranging from 0.70 to 0.98 (group 1,Table 2). The remaining 13 patients (group 2 ) did not demonstrate significant time-related changes of serum PTH, with a regression coefficient ranging from -0.03 to 0.68. The followup period was about the same in the two groups, on average 2.50 years versus 2 . 3 5 years. Figures 1 and 2 present the relative time-related changes in
424
M. RUDNICKI & I. TRANSB0L
u)
m
5 8
120
0)
2 -mal
a:
110 I00
0
2
I
3
4
I
I
1
I
I
0
I
2
3
4
Years
Years
Fig. 2. The relative change in Cay+(%) during follow-up in patients with untreated primary hyperparathyroidism. who had a significant increase in PTH concentrations with time (a). or without (b).
Table 3. Biochemical measurements in patients with significant (group 1 ) or no increase (group 2 ) of parathyroid hormone (PTH) with time Croup 1 r1=
11
Mean Ionized Calcium (mmol I-') Phosphate (mmol I-') Magnesium (mmol I-') P1'H (pmol I-') 25-OHD, (nmol I-') 1,25(OH),D, (pmol I-') Creatinine (pmol 1-l)
t
SD
Croup 2 ) I = 13 Mean SI>
1 47 (0 09) 1 40 ( 0 0 6 ) $ 086(015) 089(013) 0 83 (0 09) 0 84 (0 08) 7 0 (38) 6 7 (36) 58 8 ( 2 0 6 ) 5 4 0 ( 1 0 1 ) 262 (132) 145 (71)t 82 ( 1 7) 89 (17)
P < 0 0 1 $ P
Increasing parathyroid hormone concentrations in untreated primary hyperparathyroidism M. KUDNICKI & I. TRANSBQL From the Mineral Metabolic Research Group. Copenhagen. and Division oJ Endocrinology. Department lnternal Medicine. Hvidovre Hospital. University OJ Copenhagen. Denmark
OJ
Abstract. Kudnicki M, Transbd I (Mineral Metabolic Research Group, Copenhagen, and Division of Endocrinology, Department of Internal Medicine, Hvidovre Hospital, University of Copenhagen, Denmark). Increasing parathyroid hormone concentrations in untreated primary hyperparathyroidism. Journal of Internal Medicine 1992 : 232 : 42 1 4 2 5. Twenty-four patients with mild to moderate primary hyperparathyroidism were followed for an average of 2.45 years with serial determinations of serum ionized calcium and intact parathyroid hormone (PTH). For the entire group serum ionized calcium remained stable, whereas serum PTH increased significantly. Eleven patients (group 1 ) demonstrated a significant increase in PTH with time. The remaining 1 3 patients formed group 2. Comparison of the changes (%) in each subgroup showed a small but significant increase in serum ionized calcium of 2.6% with time in group I , while serum PTH increased by 78%. In group 2 serum ionized calcium remained stable whereas PTH increased modestly by 22 %. Serum concentrations of creatinine were stable throughout the follow-up period in both groups. Despite the greater precision of serum ionized calcium, measurements of intact PTH are evidently more sensitive than measurements of serum ionized calcium for the detection of progression in primary hyperparathyroidism.
Keywords: follow-up studies, ionized calcium, parathyroid hormone, primary hyperparathyroidism.
Introduction Introduction of the multichannel analysers two decades ago considerably improved the recognition of mild to moderate primary hyperparathyroidism C1-41. Most of the patients turned out to be elderly females, many of them being asymptomatic [ 1-31. The choice of treatment of such patients became a matter of dispute. Some authors believed that most patients with primary hyperparathyroidism should be treated surgically to avoid the risk of acute hypercalcaemia and progressive osteopenia [5-81. Others suggested that asymptomatic patients should be treated conservatively [9, 101. The finding of stable levels of serum calcium over long periods of follow-up was considered indicative of stable parathyroid function, and favoured the conservative attitude to treatment [9]. Surprisingly, the natural
history of mild to moderate primary hyperparathyroidism lacks information about the course of parathyroid function. A stable serum calcium level does not necessarily indicate stable parathyroid function. Conditions associated with old age, such as poor vitamin D intake and impaired vitamin D synthesis [ll,121, are responsible for impairments in dietary calcium absorption [13], which in turn may lead to compensatory hyper-secretion of parathyroid hormone (PTH). To shed light on parathyroid function in mild to moderate primary hyperparathyroidism we have studied the relative time-related changes in ionized calcium and PTH. using sensitive and precise measurements by the calcium ion electrode and an assay detecting the intact PTH molecule.
421
422
M. KUDNICKI & I. 'I'KANSBQI,
Patients and methods
Table 1 . Data on patients with primary hyperparathyroidisni treated surgically or conservatively
Study population
Our study group comprised 24 patients with mild to moderate primary hyperparathyroidism, diagnosed by raised concentrations of serum ionized calcium and inappropriate high levels of PTH. After the diagnosis was made 11 women experienced clinical deterioration, most often an osteoporotic fracture, and seven of them underwent surgical treatment because of this. Only measurements taken prior to the operation were included in the study. In the remaining 1 7 patients surgical treatment was refused in two patients while several patients had relative contraindications such as advanced age ( n = 7) and symptomatic heart or lung diseases ( n = 2). Others had a mild and asymptomatic disease which did not justify surgical intervention ( n = 6). Table 1 presents data for patients who underwent surgical treatment and those who followed conservative treatment. All patients were female (average age 68.9 years, range 32-89 years). The time spent on the actual study averaged 2.45 years (range 1.0-4.25 years). They were seen in our out-patient clinic approximately every third month for clinical and biochemical evaluation including measurements of serum ionized calcium, intact PTH, phosphate and creatinine.
Methods Biochemical analyses were performed when specimens were collected. Intact PTH was measured using a commercial immunoradiometric assay [ 141. The intra-assay coefficient of variation was 5%. The interassay coefficient of variation was estimated four times a year and was 7.5% on average (range 4-12%) using a pool of serum with a PTH concentration of 3.0 pmol I-'. Normal range was 1.14.8 pmol I-'. The detection limit was 0.30 pmol I-'. No systematic time-related change was observed in the measurements of intact PTH. Ionized calcium was measured on an ICA 1 calcium-ion electrode at pH 7.4 (Radiometer, Copenhagen, Denmark). The intra-assay coefficient of variation was 1 %. The intra-assay coefficient of variation was estimated every month during the study period (mean 1.16%. range 0.80-1.64%). Normal range was 1.15-1.31 mmol I-'. There was no systematic change with time in the measurements of ionized calcium.
Surgically treated 11 = 7 Mean SI) Age (years) Observation period (years) Ionized calcium (mmol 1-l) Phosphate (mmol I-]) Magnesium (mmol I-') PTH (pmol I-') 25-OHD:,(nmolI-') 1,25(OH),D, (pmol I-') Creatinine (prnol I-])
67.3 2.43 1.48 0.82 0.81 7.2 57 215 89
Conservatively treated rt = 17 Mean SD
69.7 (8.2) (0.45) 2.45 (0.12) 1.41 (0.15) 0.89 0.85 (0.07) (4.0) 6.6 56 (10) ( 1 57) 188 83 (25)
(17.1) (0.35) (0.07) ( 0 .13) (0.09) (3.5) (26) (76) (21)
Table 2. Mean levels of ionixed calcium (Ca") and parathyroid hormone (PTH) in 24 patients with primary hyperparathyroidism. Patients were grouped according to whether they had a signilicantly increased I'TH with time (group 1) or without (group 2). SD is shown in brackets
Patient no. n
1 2
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 rt
16 6 9 4 11 19 9 7 9 7 10 12 9 9 10 6 9 11 10 14 7 9 5 10
PI'H (pmol 1-l)
Ca'+ (rnmol 1-l)
13.0(3.38) 11.5 (4.98) 8.7 (1.48) 7.8 (0.60) 7.3 (0.85) 6.2 (1.50) 5.8 (1.48) 5.5 (0.70) 4.9 (0.78) 3.0 (0.61) 3.0 (0.67) 12.7 (3.90) 11.4 (2.29) 9.0(1.58) 7.7 (1.55) 7.1 (1.61) 6.5 (0.51) 5.9(1.32) 5.6(1.36) 5.2 (0.50) 3.7 (1.28) 3.3 (0.82) 3.3 (0.19) 2.7(0.50)
1.56(0.10) l.50(0.14) 1.42 (0.03) 1.36 (0.02) 1.56 (0.03) 1.53 (0.10) 1.48 (0.04) 1.43 (0.04) 1.37(0.02) 1.40 (0.03) 1.43 (0.06) 1.52 (0.04) 1.43 (0.05) 1.33 (0.05) 1.40 (0.02) 1.37(0.02) 1.42 (0.04) 1.39(0.03) 1.34(0.04) 1.38 (0.01) 1.44 (0.03) 1.34 (0.02) 1.34 (0.02) 1.39 (0.03)
I'TH CaZ+ vs. time w. time Regression coefficients
(r) 0.89$ 0.95' 0.887 0.9Xt 0.95t 0.88$
0.89$ 0.92t 0.8AS 0.80' 0.70' 0.02 0.66 0.18 0.62 0.59 -0.03 0.51 0.66 0.35 0.68 0.27 0.33 0.30
(4 -0.50 -0.61 0.19 0.18 -0.62 0.10 0.30 0.62 0.38 0.46 0.48 0.07 0.05 -0.18
0.22 -0.13 0.49 0.07 0.14 -0.67 0.60 0.09
-0.26 -0.23
*
denotes the number of measurements in each patient. I' < 0.01 : I' < 0.001.
' P < 0.05: t
Serum concentrations of phosphate and creatinine were measured on a multichannel autoanalyser (Technicon SMAC 3, Tarrytown, NY, USA). Normal
Pl’H I N PKIMARY HYPEKPARATHYROIDISM
a-”
v
E
423
50 1
- 400
.-
0
I
2
3
0
4
I
2
3
4
Years
Years
Fig. 1 . ‘I’hc relative changes in PTH (TI)during follow-up in patients with untreated primary hyperparathyroidism. who had a significant increase in I T H levels with time (a), or without (b).
ranges were 0.79-1.51 mmol I-’ and 491 2 1 pmol I-’. respectively. Serum 2 5-hydroxyvitamin D, (2 5-OHD,) was measured by a competitive protein binding assay after extraction and chromatography 1151. The coefficientof variation (interassay) was 10%.Normal range was 38.8-93.3 nmol I-’. The active vitamin D metabolite, 1.2 5-dihydroxyvitamin D:, (1,25(OH),D,) was measured by purification on Sephadex LH-20 column followed by high-pressure liquid chromatography. Assay was performed as previously described [ 161. lnterassay coefficient of variation was 14%. Normal range was 24-158 pmol I-’. Serum 25-OHD,, and 1,25(OH),D, was measured only once when the diagnosis of primary hyperparathyroidism was established. All parameters are presented as mean and SD. Serum concentrations of PTH were logarithmically transformed to achieve a normal distribution. Student’s t-test was used to compare serum levels of selected variables. Kegression analysis was applied to evaluate relationships between selected variables using the least-squares method. To improve the sensitivity of the evaluation of time-related changes and their comparison within groups, the first obser-
vation in each patient was ascribed the value of 100% and all the following measurements are expressed as a percentage relative to the initial value. A P-value less than 0.05 was considered as statistically significant.
Results On average the level of ionized calcium remained stable during the follow-up period: at start 1.41k0.08 (mean and SD) versus 1.44f0.08 (NS) at the end of the study period: whereas the level of PTH increased from a n average of 5.4 k 3.2 pmol I-’ to 7.8k4.1 pmol I-’ ( P < 0.01). There were no changes in ionized calcium with time when each patient was studied separately, whereas there was a significant increase of serum PTH concentrations in 11 patients, with a regression coefficient ranging from 0.70 to 0.98 (group 1,Table 2). The remaining 13 patients (group 2 ) did not demonstrate significant time-related changes of serum PTH, with a regression coefficient ranging from -0.03 to 0.68. The followup period was about the same in the two groups, on average 2.50 years versus 2 . 3 5 years. Figures 1 and 2 present the relative time-related changes in
424
M. RUDNICKI & I. TRANSB0L
u)
m
5 8
120
0)
2 -mal
a:
110 I00
0
2
I
3
4
I
I
1
I
I
0
I
2
3
4
Years
Years
Fig. 2. The relative change in Cay+(%) during follow-up in patients with untreated primary hyperparathyroidism. who had a significant increase in PTH concentrations with time (a). or without (b).
Table 3. Biochemical measurements in patients with significant (group 1 ) or no increase (group 2 ) of parathyroid hormone (PTH) with time Croup 1 r1=
11
Mean Ionized Calcium (mmol I-') Phosphate (mmol I-') Magnesium (mmol I-') P1'H (pmol I-') 25-OHD, (nmol I-') 1,25(OH),D, (pmol I-') Creatinine (pmol 1-l)
t
SD
Croup 2 ) I = 13 Mean SI>
1 47 (0 09) 1 40 ( 0 0 6 ) $ 086(015) 089(013) 0 83 (0 09) 0 84 (0 08) 7 0 (38) 6 7 (36) 58 8 ( 2 0 6 ) 5 4 0 ( 1 0 1 ) 262 (132) 145 (71)t 82 ( 1 7) 89 (17)
P < 0 0 1 $ P
