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Original Studies |
Third Department of Internal Medicine (M.Y.) and Department of General Medicine (T.A.), National Defense Medical College, Saitama 359-8513; Self-Defense Force Central Hospital (T.N.), Tokyo 154-8532; and Cancer Institute Hospital (E.O.), Tokyo 170-8455, Japan
Address all correspondence and requests for reprints to: Michiko Yamamoto, M.D., Third Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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It is reported that vitamin D therapy in patients with activating CaR mutations often results in a disproportionate hypercalciuria and may increase the risk of nephrocalcinosis, nephrolithiasis, and eventually renal insufficiency (7, 8, 9). If the risk of hypercalciuria and resultant complications during treatment is higher in patients with CaR mutations than in those with other types of PTH-deficient hypoparathyroidism, detection of such patients would be of great clinical importance. At present, the only way to diagnose patients with CaR mutations accurately is molecular genetic studies. However, it would be too laborious and time-consuming to examine the CaR gene thoroughly in all patients with hypoparathyroidism and conduct functional analysis of the abnormal gene when a novel mutation is found. Therefore, from both scientific and practical viewpoints, it is a focus of interest whether we can distinguish patients with CaR mutations from those with so-called IHP before undertaking molecular studies, in other words, whether there is a way to select patients who are candidates for examination of probable CaR mutations.
One characteristic that may help identify patients with CaR mutations is familial occurrence as an autosomal dominant hypoparathyroidism (5, 6, 7). However, documentation of sporadic forms of CaR mutations (8, 10) made the family history less useful. Another characteristic associated with CaR mutations is the earlier onset of hypocalcemia. Presentation in infancy or early childhood strongly suggests genetic disorders, but there are patients with hypoparathyroidism due to abnormalities in genes other than CaR (1, 2). Furthermore, some patients with CaR mutations may present in adulthood (8, 12). If clinical characteristics alone are not sufficient to suspect CaR mutations in patients with hypoparathyroidism, additional means of potential usefulness must be sought.
As biochemical characteristics, it is stated that hypocalcemia before treatment is milder and hypercalciuria during treatment is more profound in patients with activating CaR mutations than in those with other forms of PTH-deficient hypoparathyroidism (7, 8, 9). In relation to hypercalciuria it is shown that the CaR is expressed in the kidney, most notably in the thick ascending limb of Henle (14, 15), and activation of the CaR inhibits calcium reabsorption. It is assumed, therefore, that correction of hypocalcemia may result in hypercalciuria of greater magnitude in patients with activating CaR mutations than in those with simple PTH deficiency. However, as hypercalciuria is a common finding in patients with any form of PTH-deficient hypoparathyroidism treated with vitamin D analogs with or without calcium supplements (16, 17, 18), it remains to be established that hypercalciuria during treatment is actually more profound in patients with activating CaR mutations than in those with IHP.
In this study we analyzed the data of 85 patients with so-called IHP and 15 patients with proven activating mutations in the CaR to address the following: 1) whether there were significant differences between groups with CaR mutations and IHP in serum calcium concentrations and urinary calcium excretion either before or during treatment, and if so, based on these data 2) whether we could discriminate a subgroup of patients who might have CaR mutations from the rest of population with IHP.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There were 4 groups of patients. Group I comprised 73 patients
with so-called IHP (37 males and 36 females, aged 13–71 yr), whose
data were obtained from a previous nationwide collaborative study of a
PTH infusion test (19). They satisfied the following
criteria: 1) documentation of hypocalcemia, hyperphosphatemia, and
undetectable or inappropriately low levels of serum immunoreactive PTH;
2) no history of thyroidectomy or parathyroidectomy; 3) serum
creatinine or blood urea nitrogen concentrations within normal range;
4) at least 1 measurement of urinary calcium/creatinine ratio (Ca/Cr)
either before or during treatment; and 5) age of 11 yr or older at the
time of examination. The last criterion was added to exclude data of
infants and small children from the analyses because it was reported
that normal range of urinary Ca/Cr varied depending on age
(20). Group II comprised 12 patients with IHP (6 males and
6 females, aged 25–73 yr at the start of examination) treated by
ourselves (Table 1
). Of them, 1 patient
(no. 10) had a niece with hypoparathyroidism. The others had no family
history of hypoparathyroidism. Group III comprised 6 patients (2 males
and 4 females, aged 11–75 yr) from the same kindred in which we
recently identified a novel activating mutation (S820F) in the CaR
(21). Group IV comprised 9 patients with various CaR
mutations, whose data derived from 2 previous studies (7, 12). Criteria for selecting them were essentially the same as
those in group I: age older than 11 yr (ranging from 17–68) and
availability of urinary Ca/Cr data either before or during
treatment.
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Comparison of pretreatment serum calcium concentration and urinary Ca/Cr between patients with IHP and CaR mutations. Serum and urinary data were compared among all 4 groups and between IHP (groups I and II) and CaR mutations (groups III and IV). In addition, to confirm that the small number of patients with CaR mutations studied here was a representative population, we analyzed all of the pretreatment serum calcium data of patients with activating CaR mutations (5, 6, 7, 8, 9, 11, 12, 22) regardless of the age or availability of urinary Ca/Cr. In this analysis, to avoid unequal influence by the size of each kindred on the results, we calculated the mean value of a kindred when it had multiple affected members. When serum calcium concentrations were given as ranges, the midpoints were used for calculation.
Comparison of urinary Ca/Cr before and during treatment as a function of serum calcium concentration between patients with IHP and CaR mutation. For this analysis, 1 set of serum and urinary data per person was obtained from patients in group I (47 datasets before and 40 during treatment), in group III (4 before and 2 during treatment), and in group IV (5 before and 6 during treatment). Urinary Ca/Cr was plotted as a function of the serum calcium concentration reported concurrently, and the scattergram was compared between groups with IHP and CaR mutations. Patients in group II who had multiple data points were not included because their data were analyzed in-depth as described below.
Comparison of the magnitude of hypercalciuria during treatment
between two patients with an activating CaR mutation and seven with
IHP. Two patients with an activating CaR mutation in group III
(43-yr-old mother and 15-yr-old son at the start of examination) had
been treated as IHP before their CaR mutation was identified. From
them, random urine and simultaneous blood samples were obtained at 1-
to 3-month intervals for 4 yr during treatment with 1
-hydroxyvitamin
D3 (1-OHD3). Their data
were compared with those of 7 patients with IHP in group II (no. 6–12
in Table 1
) treated similarly for 4–8 yr. All of the data thus
collected were pooled for each patient, and the mean urinary Ca/Cr was
calculated at each level of serum calcium, in 0.25 mmol/L
increments.
Between-person variation in hypercalciuria during treatment among
patients with IHP. At the beginning of
1-OHD3 therapy, 24-h urine specimens were
collected two or three times a week for 2–5 weeks from seven
hospitalized patients (no. 1–7 in Table 1). Their daily calcium
excretion was expressed as the Ca/Cr ratio instead of millimoles per
day to correct for the difference in body size among patients and was
plotted as a function of fasting serum calcium concentrations measured
on the same day. During out-patient therapy, the magnitude of
hypercalciuria was evaluated occasionally in 24-h urine samples
together with sodium excretion. The renal handling of calcium was
assessed in each patient as follows. Casual urine and serum samples
were obtained from seven patients (no. 6–12 in Table 1) at each
clinical visit. The urinary Ca/Cr was plotted against the serum calcium
concentration, and a regression line correlating the two variables was
drawn. The apparent renal calcium threshold, which was defined as the
serum calcium concentration at which level urine calcium was zero, was
determined as an intercept of the regression line on the abscissa. The
tubular maximum reabsorption rate of calcium/glomerular filtration rate
(TmCa/GFR) was also determined by calculating urinary calcium per 100
mL glomerular filtrate instead of the Ca/Cr ratio
(23).
Measurements and statistics
The data obtained from a previous collaborative study
(19) or from the literature (7, 12) were
analyzed as they were reported, without detailed information about the
assay methods. To express the urinary Ca/Cr ratio in millimoles per
mmol, results given in milligrams per mg were recalculated by
multiplying by 2.828. In patients studied by ourselves, serum levels of
calcium, phosphate, magnesium, and creatinine and urinary
concentrations of calcium, sodium, and creatinine were measured using
standard laboratory techniques. To define hypercalciuria, spot urine
samples were collected from 56 normocalcemic subjects taking no drugs
known to alter renal handling of calcium. Their range of Ca/Cr ratios
was 0.076–0.656 mmol/mmol (0.027-0.232 mg/mg), and the mean ±
SD was 0.331 ± 0.170. Based on these data, overt
hypercalciuria was defined as a urinary Ca/Cr ratio exceeding 0.700
mmol/mmol (
0.250 mg/mg) and the normal reference range as
0.160-0.500.
Results are presented as the mean ± SEM unless otherwise stated. Statistical analyses were performed using the statistical package StatView (Abacus Concepts, Inc., Berkeley, CA) on a Macintosh computer (Apple Computer, Inc., Tokyo, Japan). Differences between group means were tested by one-way ANOVA and Scheffe’s F test. P < 0.05 at a 95% confidence level was considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The mean serum calcium concentration before treatment was not
different between groups I and II with IHP [1.44 ± 0.03 mmol/L
(n = 47) vs. 1.27 ± 0.07 (n = 11)] and
between groups III and IV with CaR mutations [1.79 ± 0.04
(n = 6) vs. 1.75 ± 0.08 (n = 9)]. When the
data were combined for each disorder, the mean serum calcium
concentration was significantly (P < 0.001)
lower in patients with IHP (1.41 ± 0.03; n = 58) than in
those with CaR mutations (1.76 ± 0.05; n = 15). As shown in
Fig. 1, the range of hypocalcemia
overlapped substantially between IHP and CaR mutation groups
(0.90–1.95 vs. 1.25–2.05), but severe hypocalcemia was
rare in the latter. A serum calcium concentration below 1.5 mmol/L was
observed in only 1 of 15 patients (7%) with CaR mutations
vs. 39 of 58 (67%) with IHP. The findings were essentially
the same when the serum calcium concentrations obtained from all
published cases (13 kindreds including 51 patients) were used as the
CaR mutation group (mean, 1.71 ± 0.07 mmol/L; range,
1.20–2.08).
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). The majority of patients with CaR
mutations (8 of 9 = 89%) showed the urinary Ca/Cr ratios within
or above the reference range, whereas only 14% (8 of 57) of patients
with IHP had values within the lower half of the reference range.
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Before treatment (Fig. 3A), there was a
significant positive linear correlation between serum calcium
concentration and urinary Ca/Cr ratio in patients with IHP (n =
47; r = 0.57; P < 0.001), consistent with the
renal physiology that urinary calcium increases as the elevation of
serum calcium. There was no positive correlation but, rather, a
tendency to a negative correlation between the two variables in
patients with activating CaR mutations (n = 9; r = -0.59;
P = 0.095). Urinary Ca/Cr values were generally higher
in patients with CaR mutations than in those with IHP when compared at
similar serum calcium levels although the two groups were not
completely separable.
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). Overt hypercalciuria was more common in the group of CaR
mutations (4 of 8 = 50%) than was IHP (5 of 40 = 12.5%),
although the total number was small. During treatment (Fig. 3B) and
also when the data from before and during treatment were combined (Fig. 3C), there was a highly significant (P < 0.001)
correlation between serum calcium concentration and urinary Ca/Cr in
patients with IHP (n = 40; r = 0.58 and n = 87; r =
0.67). Under both conditions, no correlation was observed in the CaR
mutation group (n = 8; r = 0.28; P = 0.495,
and n = 17; r = 0.24; P = 0.364). As a whole,
the individual data points in a scattergram were not separable between
the two groups. Comparison of the magnitude of hypercalciuria during treatment between seven patients with IHP and two patients with an activating CaR mutation
As shown by individual lines representing the relationships
between serum calcium concentrations and urinary Ca/Cr (Fig. 4), there were considerable
between-person variations among seven patients with IHP. Overt
hypercalciuria was observed in three patients at subnormal serum
calcium concentrations approximately 2.0 mmol/L, whereas three others
did not show hypercalciuria at normal serum calcium levels. The lines
of two patients with the same CaR mutation were different in position
and slope. However, both were located within the variation of patients
with IHP. Although overt hypercalciuria was not observed in either of
them, the slope of the line suggested that one of them would develop
severe hypercalciuria when serum calcium levels were raised slightly
higher.
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-OHD3 therapy in patients with
IHP
After the start of 1-OHD3 therapy, 24-h
urinary calcium excretion increased progressively with the elevation of
fasting serum calcium concentrations. Urinary calcium exceeded the
level of overt hypercalciuria in six of seven patients before they
attained normocalcemia (Fig. 5). As long
as their serum calcium levels were below 2.0 mmol/L, supplemental
calcium did not seem to enhance the magnitude of hypercalciuria.
Earlier appearance of hypercalciuria (patients 1, 4, 5, and 2 in that
order) was not related to the severity of hypocalcemia before treatment
(patients 6, 7, 4, and 1 in that order), although the only patient who
did not show hypercalciuria during treatment (no. 3) had the highest
pretreatment serum calcium concentration.
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When urinary Ca/Cr was plotted as a function of the serum calcium
concentration determined simultaneously during 4–8 yr of treatment,
there was a significant (P < 0.05 to P
< 0.001) linear correlation between the two variables in all patients.
Reflecting the between-person variation in the position and the slope
of regression lines, the intercepts of the lines on the abscissa ranged
from 1.24–1.94 mmol/L (Fig. 6). Similar
between-person variation was observed in the renal calcium threshold
calculated as the TmCa/GFR (Table 2). In
general, a lower renal calcium threshold was associated with more
profound hypercalciuria and a lesser calcium-raising effect by
1-OHD3 therapy (Table 2). Patients 8, 9, and
10, who had the lowest three TmCa/GFR values, remained hypocalcemic
during maintenance therapy and satisfied the widely accepted criteria
of hypercalciuria (calcium excretion of >6.25 mmol/day for women, 7.50
mmol/day for men, and 0.1 mmol/kg·day for both). The amount of
calcium excretion did not correlate with sodium excretion measured on
the same day.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Interestingly, the mean urinary Ca/Cr ratio of patients with CaR mutations without treatment was not only higher than that of patients with IHP but also was comparable to the value in normocalcemic controls. This observation has several implications. First, it indicates that patients with CaR mutations are characterized by inappropriately normal calcium excretion under pretreatment hypocalcemic conditions (relative hypercalciuria), but not by absolute hypercalciuria. Second, urinary Ca/Cr in the normal range, especially in its upper half, could be used as a clue to suspect CaR mutations in untreated hypoparathyroid patients because such a situation was extremely rare for patients with IHP. Third, a normal amount of urinary calcium in patients with CaR mutations may imply that their intestinal calcium absorption is also normal. It is well established that calcium excretion in urine approximates its net absorption from the intestine in the steady state and that calcium excretion is affected largely by vitamin D action (25). Unfortunately, however, we could not find previous literature on the metabolism and action of vitamin D in patients with CaR mutations, except for a few studies reporting baseline serum 1,25-dihydroxyvitamin D concentrations (12, 21).
The difference in urinary Ca/Cr between the two disorders could result from the difference in serum calcium concentrations and/or renal calcium reabsorption. By comparing urinary Ca/Cr as a function of serum calcium concentration, we found that the higher pretreatment urinary Ca/Cr in patients with CaR mutations was not attributable to their milder hypocalcemia compared to those with IHP. Furthermore, we found that the correlation of urinary Ca/Cr to serum calcium concentration was quite different between the two disorders. As expected, patients with IHP exhibited a significant positive linear correlation. In contrast, those with CaR mutations exhibited a tendency to negative correlation. This may be a coincidental finding due to the small number of patients with CaR mutations. An alternative, more tempting interpretation is as follows. If patients with more severe defects in the function of CaR showed lower serum calcium concentrations in association with more urinary calcium loss than those with milder defects, there would be a tendency to a negative correlation rather than a positive one between serum and urinary calcium. In accordance with this concept, Nagano et al. reported a negative correlation between serum concentration and fractional excretion of calcium in a rat model of CaR activation elaborated by infusing a calcimimetic (26).
Previous studies suggested that hypercalciuria was more common in patients with CaR mutations than in those with IHP or other types of hypoparathyroidism during treatment (7, 8). In our study the percentage of patients with overt hypercalciuria was greater in the former than in the latter. However, we had a reservation about concluding that hypercalciuria developed more frequently in patients with CaR mutations. It was unclear whether the urinary data of patients with CaR mutations reported in the literature (7) were the mean of multiple measurements or the one-point data, and in case of the latter, whether they were chosen arbitrarily or selected as representative values for the disorder that was theoretically linked with hypercalciuria. The urinary Ca/Cr values of our two patients, which were the lowest and the second lowest in the group of CaR mutations, were the one-point data determined after 1 month of treatment. Thus, we could not completely rule out the possibility that the published data had some bias toward hypercalciuria. As for the severity of hypercalciuria during treatment, our results did not demonstrate a significant difference between groups with CaR mutations and IHP. The scattergram of urinary Ca/Cr plotted against serum calcium concentration was not separable between the two groups. This finding in the collective study for a relatively large number of patients, but with only one set of data per person, was confirmed by an in-depth study of a limited number of patients with multiple data points.
The seemingly discrepant results between our study and others could be explained by a difference in the age of patients. We excluded patients under 11 yr from the analyses. On the other hand, Pearce et al. (7) documented the most severe hypercalciuria (urinary Ca/Cr, 2.29 mmol/mmol) in a child aged 4 yr. When their patients with CaR mutations were subdivided into two different age groups to match our study, from 11 yr up and below 11 yr, the mean urinary Ca/Cr in the older group (0.76; n = 6) was not so high as in the younger one (1.22; n = 7). It is known that urinary Ca/Cr values in normal children change with age (20) and are distinctly higher in infants below 18 months of age than in older children (27). Thus, the age of the patient should be taken into consideration when interpreting the results of different studies conducted without age-matched comparison of urinary calcium data between groups with CaR mutations and others.
Another difference between our study and some others was the method of
how hypercalciuria was evaluated. Baron et al.
(8) noticed significantly greater daily calcium excretion
in 4 patients with CaR mutations compared with 10 patients with either
postsurgical or autoimmune hypoparathyroidism at serum calcium
concentrations of approximately 2.0 mmol/L. Mancilla et al.
(9) reported hypercalciuria greater than 8.1 mmol/day in
patients with an activating CaR mutation at serum calcium
concentrations ranging from 2.0–2.4 mmol/L, but their data were not
compared with other types of hypoparathyroidism. These patients were
treated with vitamin D analogs and supplemental calcium. On the other
hand, we analyzed urinary Ca/Cr mostly in spot samples, over a wide
range of serum calcium concentrations. Our patients with an activating
CaR mutation were treated with 1-OHD3 alone
without calcium supplementation. It is possible, therefore, that
hypercalciuria evaluated in 24-h urine was more profound in patients
with CaR mutations than in those with other types of hypoparathyroidism
when they were taking supplemental calcium and their serum calcium
concentrations were near normal. Under such conditions, daily calcium
excretion would be affected largely by postprandial increases in
calcium absorption. However, there is no evidence that postprandial
increases in calcium absorption or in the filtered load of calcium
differ between patients with CaR mutations and those with IHP. It is
also unknown whether the influence of calcium supplementation is
different between the two disorders. Our study in patients with IHP
showed that hypercalciuria in 24-h urine became prominent when their
fasting serum calcium concentrations exceeded 2.0 mmol/L during
treatment with 1-OHD3 and supplemental
calcium.
The results of this study do not necessarily contradict the theoretical view that patients with CaR mutations have abnormality in the function of renal tubular CaR, and therefore they are more prone to hypercalciuria. Several explanations are possible for the observation that the magnitude of hypercalciuria during treatment was not different between the groups with CaR mutations and IHP. Studies in the rat have shown that the distribution of the CaR overlaps with that of PTH receptors along the distal nephron (15, 28). Assuming that renal calcium reabsorption is regulated by the interaction between the two receptor systems and the function of the CaR is influenced by PTH action, a potential difference in calcium reabsorption between the two disorders might be masked during treatment when PTH secretion was suppressed. To disclose the intrinsic difference, it would be necessary to compare the two disorders under conditions where PTH effects are present equally, such as during infusion of exogenous PTH.
Another interpretation is that a wide individual variation within each group might have masked certain differences in the calcium excretion between the groups. It has long been recognized that patients with PTH-deficient hypoparathyroidism develop hypercalciuria of various degrees during treatment (16, 17, 18). Their hypercalciuria is considered inevitable to some extent because vitamin D analogs do not substitute for PTH action to stimulate renal calcium reabsorption (18, 29). However, the mechanisms for the between-person variation in the magnitude of hypercalciuria have not been well defined. Findings in our patients with IHP did not support that the severity of pretreatment hypocalcemia or differences in the treatment regimen determined the degree of hypercalciuria in individual patients. Furthermore, we found considerable between-person variations in the renal calcium handling in two patients with the same CaR mutation treated in the same way. These observations indicate that calcium excretion is variable in individual patients, as reported in normocalcemic subjects with or without hypercalciuria (30). The underlying mechanisms for the individual variation are unknown, but cannot be explained by differences in PTH effects or the function of CaR.
Lastly, we could not completely rule out the following possibilities. First, some of the patients classified as IHP might have mutations in the CaR. Although we did not conduct genetic analyses, this is unlikely at least for the patients we studied. All of our patients diagnosed as IHP had symptomatic severe hypocalcemia and very low urinary calcium excretion before treatment, characteristics typical of IHP. Second, some patients with IHP might have abnormalities in yet to be identified CaR-related genes, as hypothesized in patients with autosomal dominant hypoparathyroidism who had no detectable mutations in the CaR (5, 7). If so, it would be a natural consequence that we could not differentiate the two groups based on the severity of hypercalciuria. Third, some patients with IHP might have autoantibodies to the CaR (31). If their antibodies function to activate the CaR, the pathophysiology of hypoparathyroidism in these patients may mimic gain-of-function mutations in the CaR.
The present study, a retrospective analysis of heterogeneous data sources, has methodological limitations. Urinary calcium data of different populations or different decades may preclude accurate comparison. However, except for those with CaR mutations reported previously (7), the subjects including normocalcemic controls are a current Japanese population and therefore are devoid of major differences in race, life style and diet. The collected data of patients with IHP are sufficient in number and the pretreatment serum calcium concentrations were similar to those of 60 cases analyzed by Parfitt (24). For the patients with CaR mutations, the sample size was small because we selected them according to age and availability of urinary Ca/Cr data. However, their mean and the range of pretreatment serum calcium concentrations were similar to those calculated using all the data of previously published cases. Thus, we think the patients studied here are representative of the two disorders, and most of our findings are valid.
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Acknowledgments |
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Received January 5, 2000.
Revised August 15, 2000.
Accepted August 24, 2000.
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References |
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, patients with IHP from group I; 
and 
, activating CaR
mutations from groups III and IV, respectively. The correlation between
the serum calcium concentration and urinary Ca/Cr was r = 0.57;
P < 0.001 in IHP group (n = 47) and r =
-0.59; P = 0.095 in the CaR mutation group (n
= 9). B, During treatment: 
, IHP from group I; 
