hypertension and hyperparathyroidism: inverse relation of serum phosphate level and blood pressure

Hypertension and Hyperparathyroidism

Inverse Relation of Serum Phosphate Level and Blood Pressure

JEFFREY DANIELS, M.D.

A. DAVID GOODMAN, M.D.

Albany, New York

In a retrospective study of 120 patients with surgically proved primary hyperparathyroidism, 71 patients who were normotensive and 49 patients (41 percent) who were either hypertensive at the time of parathyroidectomy or had a history of hypertension were compared. The mean serum calcium levels in the normotensive and hypertensive patients were very similar (11.6 f 0.1 [SEMI mg/dl, and 11.8 f O.l), ruling against the hypothesis that hypercalcemia per se is the dominant cause of the hypertension of hyperparathyroidism. The mean serum creatinine levels in the two groups were also very similar (1.02 f 0.05 and 1.09 f 0.05 mg/dl), indicating that the hypertension of hyperparathyroidism is not the consequence of advanced renal parenchymal damage. The hypertensive patients did not have a significantly higher prevalence of uroltthlasis. A review of the data in this and related studies leads to the conclusion that the hypertension of hyperparathyroidism is heterogeneous in origin. The mean serum phosphate level in the hypertensive patients was significantly lower than that in the normotensive patients (2.20 f 0.06 mg/dl versus 2.69 f 0.09 mg/dl, p <0.02), which may be due to a decrease in renal tubular phosphate reabsorption secondary to hypertension.

It seems well established that there is an increased incidence of hypertension in patients with primary hyperparathyroidism [l-4], but the reason for this increase is unclear. Some investigators have at- tributed the high incidence of hypertension to the capacity of hypercalcemia to cause arteriolar constriction [5] and to enhance myocardial contraction [6], whereas others have suggested that the hypertension is due to the renal parenchymal damage that occurs in some patients with hyperparathyroidism [ 21.

From the Division of Endocrinology and Metabo- lism, Department of Medicine, Albany Medical College, Albany, New York. Requests for reprints should be addressed to Dr. A. David Goodman, Albany Medical College, Albany, New York 12208. Manuscript accepted September 9, 1982.

We attempted to gain insight into the pathogenesis of the hypertension observed in patients with hyperparathyroidism through a retrospective comparison of a group of 49 patients who had hyperparathyroidism and associated hypertension with a group of 71 hyperparathyroid patients who were normotensive. In performing this study, we had three specific objectives. First, we compared the mean serum calcium levels in the two groups, for if hypercalcemia is the direct cause of the hypertension of hyperparathyroidism, some correlation between the degree of hypercalcemia and the level of blood pressure would be expected. Second, we examined the hypothesis that renal damage is the dominant cause of the hypertension by comparing the hypertensive and normotensive patients with regard to indexes of renal function and the prevalence of urolithiasis. Third, we studied other clinical and biochemical characteristics of the two

July 1983 The American Journal of Medicine Volume 75 17

HYPERTENSION AND HYPERPARATHYROIDISM-DANIELS and GOODMAN

groups to determine whether there are factors other than hypercalcemia or renal damage that are associated with hypertension in hyperparathyroidism.

In this report we devote particular attention to our

finding that the serum phosphate level was significantly

lower in the hypertensive patients than in the normo-

tensive patients.

PATlENTS AND METHODS

Study Population. We obtained for review the hospital records of 152 patients who underwent parathyroid explo- ration at the Albany Medical Center Hospital, the Veterans Administration Medical Center of Albany, and St. Peter’s Hospital of Albany from 1968 through 1979. Patients were considered acceptable for the study if they were found at operation to have one or more enlarged parathyroid glands and had a serum urea nitrogen level under 50 mg/dl. One hundred twenty patients met these criteria.

Hypertension was considered to be present if the blood pressure on the first morning of hospitalization exceeded 150 mm Hg systolic and 100 mm Hg diastolic, and 20 patients met this criterion (hypertensive group A). An additional 29 patients had a blood pressure of 150/100 or less but had been told previously that they had hypertension (hypertensive group 6). The mean systolic blood pressure in group B was significantly higher than in the remaining 71 normotensive patients (137 f 4 [SEMI versus 123 f 2, p <O.OOl), as was the diastolic blood pressure (82 f 2 versus 75 f 1, p <0.02). Hypertensive groups A and B did not differ from each other significantly with regard to any of the 22 variables studied,

TABLE I Comparison of Hypertensive Groups A and B

other than blood pressure, as shown in Table I. Therefore, we have compared the normotensive group with the combined hypertensive groups, in addition to comparing the normotensive patients with hypertensive groups A and 6 separately. Methods. We used the initial set of laboratory results from each hospital record. These included determinations of serum calcium (normal 8.6 to 10.6 mg/dl), phosphate (normal 2.5 to 4.5 mg/dl), alkaline phosphatase (normal up to 85 Ill/liter), serum urea nitrogen (normal IO to 20 mg/dl), creatinine (normal 0.7 to 1.5 mg/dl), uric acid (normal 3.6 to 8.0 mg/dl in males and 2.6 to 5.6 mg/dl in females), albumin (normal 3.5 to 5.2 g/dl), sodium (normal 135 to 145 mEq/liter), chloride (normal 99 to 106 meq/liter), and bicarbonate levels (normal 21 to 30 meqjliter), as determined by the Technicon SMAC Method. Parathyroid hormone determinations were performed in at least two different commercial laboratories that had different normal ranges, and the laboratory that performed the test was not always identified in the hospital chart. Therefore, we have not included the parathyroid hormone deteminations in our analysis. A patient was recorded as having urolithiasis on the basis of history or radiologic evidence.

A DEC-1 0 computer and the BMDP Program [7] were used for statistical analyses. All mean values are expressed as the mean f standard error of the mean. The statistical methods used here were the nonpaired, two-tailed Student t test and the chi-square test. Since the normal and hypertensive groups were compared with regard to 20 variables other than blood pressure (Table II), there was a substantial chance that they would differ with regard to at least one variable at a p value

Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg)

Age (yr) Sex (percent female) Calcium (mg/dl) Phosphate (mg/dl) Alkaline phosphatase (It-f/liter) Blood urea nitrogen (mg/dl) Creatinine (mg/dl) Creatinine clearance (ml per minute) Urine calcium (mg per day) Urine calcium/urine creatinine (mg/g) CalciumIcreatinine clearance ratio Urine phosphate (mg per day) Phosphate clearance (ml per minute) PhosphateIcreatinine clearance ratio Sodium (meq/liter) Chloride (meqlliter) Carbon dioxide (mM) Uric acid (mg/dl) Urolithiasis Single gland involvement

Group A’ Hypertensive

Group 8t

174&4(20) 137 f 4 (29) 105 f 2 (20) 82 f 2 (29) 55 f 2 (20) 55 f 2 (29)

13120 (65%) 22/29 (76%) 11.7 f 0.2 (20) 11.9 f 0.2 (29) 2.2 f 0.1 (20) 2.2 f 0.1 (29) 104 f 14 (17) 96 f 12(26)

17 f 2 (20) 16 f 1 (29) 1.07 f 0.09 (16) 1 .OO f 0.06 (28)

90f 13(11) 93 f 7 (17) 267 f 47 (11) 281 f 37 (14) 234 f 54 (6) 208 f 34 (11)

0.020 f 0.005 (6) 0.015 f 0.002 (11) 935 f 129 (7) 716 f 82 (14)

32.4 f 5.6 (7) 22.3 f 2.2 (14) 0.52 f 0.16 (4) 0.30 f 0.06 (12) 141 f l(20) 141 f l(2Q) 105 f l(20) 105 f 1 (29)

26.5 f 0.6 (20) 27.0 f 0.6 (29) 6.5 f 0.3 (16) 6.3 f 0.3 (28)

9/20 (45%) 10129 (34%) 16120 (60%) 26129 (90%)

p Value

p <O.OOl p <O.OOl

NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS

Numbers indicate mean f standard error of the mean. Numbers in parentheses indicate the number of patients studied. l Patients in Group A had blood pressure exceeding 150/100. t Patients in Group B had a blood pressure of 150/100 or less, but had a history of hypertension.

18 July 1983 The American Journal of Medicine Volume 75


of -CO.05 through random variation alone. Therefore, for those variables in which the two groups differed by p <0.05, as calculated in the usual manner, we have also calculated a “corrected p value” (p X 20) [8]

RESULTS

Indexes of Calcium and Phosphate Metabolism. The

mean serum calcium levels in the normotensive and combined hypertensive groups did not differ substantially, as seen in Table II (11.6 f 0.01 versus 11.8 f 0.01). Also, there was little difference between the mean serum calcium levels in the normotensive group and in hypertensive groups A and 6 considered separately (Table I). Further, in the total group of 120 hyperparathyroid patients, there was no significant relation between the serum talcum levels of the individual patients and their systolic or diastolic blood pressures. In the patients for whom data on urine calcium excretion were available, the mean urinary calcium excretion in the two groups was very similar, as was the ratio of calcium clearance to creatinine clearance (Table II).

The mean serum phosphate level was lower in the combined hypertensive group (2.20 f 0.06) than in the normotensive group (2.69 f 0.09, p <O.OOl and corrected p <0.02). Also, the mean phosphate levels of hypertensive groups A and B taken separately (Table I) were each significantly lower than that of the normotensive group (group A, p <0.02; group 6, p

<O.OOl). There was considerable overlap between the hypertensive and normotensive patients (Figure l), but it is remarkable that not one of the 49 hypertensive patients had a serum phosphate concentration greater than 2.9, whereas 2 1 of the 7 1 normotensive patients had values exceeding this level. In the group of 120 patients as a whole, there was a significant negative correlation of the serum phosphate level with the systolic blood pressure (r = 0.238, p <O.Ol), but not with the diastolic blood pressure (r = 0.155, p >O. 1).

The decrease in serum phosphate level in the hypertensive patients was probably due to an increase in phosphate clearance rather than to a decrease in phosphate intake or absorption, because the total urinary phosphate excretion was not substantially different in the two groups (Table II). Further, in the hypertensive and normotensive groups taken together, there was a significant inverse relation between phosphate clearance and serum phosphate level (r = 0.660, p <O.OOl). Consistent with these observations, the mean phosphate clearance was 25 percent greater in the combined hypertensive group than in the normotensive group, although this difference was not statistically significant; in hypertensive group A, taken separately, phosphate clearance was 55 percent higher than in the normotensive group (p cO.05).

The lower serum phosphate level in the hypertensive patients cannot be ascribed to the difference in mean

TABLE II Comparison of the Hypertensive Hyperparathyroid Patients (Groups A and B Combined) with the Normotensive Hyperparathyroid Patients

Hypertensive Patients

Normotensive Patients p Value

Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg)

Age (yr) Sex (percent female) Calcium (mg/dl) Phosphate (mg/dl) Alkaline phosphatase (IWliter) Blood urea nitrogen Creatinine (mg/dl) Creatinine clearance (ml per minute) Urine calcium (mg per day) Urine calcium/urine creatinine (mg/g) CalciumIcreatinine clearance ratio Urine phosphate (mg per day) Phosphate clearance (ml per minute) PhosphateIcreatinine clearance ratio Sodium (meq/liter) Chloride (mEq/liter) Carbon dioxide (mu) Uric acid (mg/dl) Urolithiasis

152f4(49) 91 f 2 (49) 56 f 1 (49) 35/49 (71%)

11.8 f 0.1 (49) 2.20 f 0.06 (49) 100 f 9 (45)

16 f 1 (49) 1.02 f 0.05 (46)

92 f 7 (28) 275 f 29 (25) 218 f 29 (19)

0.017 f 0.002 (19) 789 f 62 (21)

25.6 f 2.6 (21) 0.35 f 0.06 (16) 141 f l(49) 105 f 1 (49)

26.8 f 0.5 (49) 6.4 f 0.2 (46)

19/49 (39%) 42149 (86 %)

123 zt 2 (71) 75 f l(71) 48 f 2(71) 43/71 (61%)

11.6 f 0.1 (71) 2.69 f 0.09 (71) 119 f 17 (65)

16 f l(71) 1.09 f 0.05 (69)

92 f 4 (44) 280 f 24 (42) 218 f 19 (35)

0.019 f 0.002 (35) 748 f 68 (24)

20.9 f 2.5 (24) 0.23 f 0.03 (22) 141 f l(70) 105 f l(70)

26.7 f 0.4 (69) 6.0 f 0.2 (87)

16171 (22%) 58171 (82%) Single gland involvement

Numbers are means f standard error of the mean. Numbers in parentheses indicate number of patients. ’ “Corrected p” for urolithiasis >0.2 (see text).

p <O.OOl p <O.OOl p < 0.005

NS NS

p <O.OOl NS NS NS NS NS NS NS NS NS NS NS NS NS NS

p <0.05’ NS



Fi ‘gure 1. Serum phosphate l&vets in the nomwtensive ana hypertensive hyperparathyroidpatients. (The diamonds and brackets indicate the mean f standard error of the mean for each group.)

.

.

.

. : . . . :z: . . .

5: . . . . . . 4::. 5 t :: l .,‘.if:a

: to t . . .:. :.

NORMOTENSjVE HYPERTENSIVE PATIENTS PATIENTS

age between the hypertensive and normotensive patients, for when the serum phosphate level was ana- lyzed as a function of age in both groups taken together, no significant relation was defined (r = 0.083, p >0.3). Moreover, when the hypertensive patients were matched with a group of normotensive hyperparathyroid patients with regard to age and sex, the serum phosphate level was still significantly lower in the hypertensive patients (2.20 f 0.06 versus 2.68 f 0.11, p KO.001). Neither the mean serum phosphate level nor the mean serum calcium level in the hypertensive group appears to have been affected by the antihypertensive medications that were being ingested by some of these patients, since the mean serum calcium and phosphate levels were essentially the same in the 27 untreated hypertensive patients as in the 22 patients taking antihypertensive medication (Table III). Also, the mean serum phosphate level in the untreated hypertensive patients was significantly lower than that in the normotensive patients (2.17 f 0.07 versus 2.69 f 0.09, p <O.OOl). Indexes of Renal Function and Prevalence of Uroli- thiasis. As noted in Table II, the mean serum urea nitrogen levels, as well as the mean serum creatinine levels, were almost identical in the hypertensive and

normotensive groups, as were the creatinine clearance values in the limited number of patients studied; 32 percent of the normotensive patients and 32 percent of the hypertensive patients had mild renal functional impairment (creatinine clearance between 60 and 80 ml per minute), and 10 percent of each group had severe impairment (creatinine clearance less than 60 ml per minute). The groups also did not differ with regard to serum chloride, bicarbonate, or uric acid levels. The prevalence of urolithiasis was not significantly increased in the combined hypertensive groups (corrected p value >0.2), nor in either of the hypertensive groups considered individually.

COMMENTS

In the present study, the mean serum calcium level in the 49 hypertensive, hyperparathyroid patients was almost identical to that in the 71 normotensive patients. Further, in the total group of 120 hyperparathyroid patients, there was no significant correlation between the serum calcium concentration and the systolic or diastolic blood pressure levels, consistent with the previ- ous finding of Christensson et al [ 11. These observations rule against the hypothesis that hypercalcemia is the dominant cause of the hypertension associated with this disease.

In 1959, Hellstrom et al [2] suggested that the hypertension of hyperparathyroidism is due to renal parenchymal damage secondary to hypercalcemia. In their series of hyperparathyroid patients, 48 percent of the hypertensive patients had a substantial decrease in glomerular filtration rate, as compared with only 20 percent of the normotensive patients. In contrast, in our series, there was virtually no difference between the hypertensive and the normotensive groups with regard to mean values for serum creatinine, serum urea nitrogen, and creatinine clearance. Consistent with our observation are data from a study by Rosenthal and Roy [9] in which 11 of 13 hypertens/ve, hyperparathyroid patients had normal renal function. Furthermore, Christensson et al [l] selected a group of 39 patients with hyperparathyroidism who had relatively normal creatinine clearance and observed that the blood pressure tended to be higher in this group than in age- and sex-matched controls. Our data and those of these other investigators suggest that in most hypertensive, hyperparathyroid patients, the hypertension antecedes and cannot be ascribed to the development of advanced renal damage.

Urolithiasis also does not appear to play a significant role in the pathogenesis of the hypertension; in our study, the incidence of urolithiasis was not significantly higher in the hypertensive patients than in the normotensive patients, and in the hyperparathyroid patients of Hellstrom et al [2], the incidence of urolithiasis was


HYPERTENSION AND HYPERPARATHYROIDISM--DANIELS and GOODMAN

TABLE III Serum Calcium and Phosphate Levels In Hypertensive Hyperparathyrold Patlents with and without Antlhypertenslve Medication

Calcium (mg/dl) Phosphate (mg/dl)

All (n = 49)

11.8 f 0.1 2.20 f 0.05’

Hypertensive Patients

Not Taking Diuretics (n = 34)

11.8 f 0.2 2.22 f 0.06’

Not Taking Any Antihypertensive

Medications (n = 27)

12.0 f 0.2 2.17 f 0.07’

Normotensive Patients (n = 71)

11.6 f 0.1 2.69 f 0.09

Figures indicate mean f standard error of the mean. * Differs from the mean of the normotensive group, p <O.Ol.

actually slightly lower in the hypertensive patients than in the normotensive ones. It is relevant that in the studies of Brinton et al [ 101 and Zawada et al [ 111, seven of 12 patients with hypertension in association with primary hyperparathyroidism had an increase in plasma renin activity. However, the latter investigators found that infusion of saralasin, an angiotensin antag- onist, did not reduce the blood pressure in any of their five patients, suggesting that the hypertension probably was not the consequence of increased renin secre- tion.

It should be emphasized that the hypertension observed in the population with primary hyperparathyroidism may be heterogeneous in origin. The mean age at the time of diagnosis of hyperparathyroidism is approximately 50 years [l-13]. In the general population at this age, the prevalence of hypertension, most of which is of the essential type, is approximately 16 percent in whites and even higher in blacks [ 121. Therefore, since the prevalence of hypertension in hyperparathyroidism appears to be approximately 40 percent [ 11, almost half of the patients with hyperparathyroidism and hypertension may have essential hypertension that is causally unrelated to their hyperparathyroidism. Further, although the evidence in this study suggests that hypercalcemia is not the major cause of the hypertension seen in association with hyperparathyroidism, it is of note that hypertension develops in response to short-term infusion of calcium in a minority of patients with normal renal function, as well as in the majority of patients with renal insufficiency [ 10,13,14], and patients have been described in whom chronic hypercalcemia due to disorders other than hyperparathyroidism appeared to cause hypertension that was reversed with correction of the hypercalcemia [ 15,161. Also, we have accumulated data from five studies concerning the effect of the operative correction of hypercalcemia in patients with primary hyperparathyroidism and hypertension [2,9,10,17,18], and we found that the blood pressure returned to normal post- operatively in 23 of 83 patients studied (28 percent). These data suggest that there may be a subgroup of the general population that is prone to the development of

hypertension in response to hypercalcemia, and that a fraction of the hyperparathyroid hypertensive patients may belong to this group and become hypertensive as a direct consequence of hypercalcemia. An additional fraction of patients could become hypertensive as the result of calcific interstitial fibrosis [ 191. We currently favor the conclusion that the hypertension of hyperparathyroidism is heterogeneous in origin.

We are particularly interested in our finding that the mean serum phosphate level in our hypertensive hyperparathyroid group was significantly lower than in the normotensive groups. Parathyroid hormone increases phosphate clearance [20], but it seems unlikely that the hypertensive patients had a more severe degree of hyperparathyroidism, since the mean serum calcium levels in the hypertensive and normotensive groups were almost identical. A second possible explanation of the lower serum phosphate concentration in the hypertensive patients is that hypophosphatemia is a causal factor in the genesis of the hypertension of hyperparathyroidism. This seems unlikely, for although phosphate has a vasodilatory effect [21], there is actually a significant decrease in the mean arterial blood pressure in patients who have severe phosphate de- pletion [22].

Another possible explanation of the observation is that hypertension itself may cause an increase in phosphate clearance. In a study of 2,000 normal men aged 49 to 50 years, a highly significant inverse correlation between the serum phosphate concentration and both the systolic and diastolic blood pressures was noted [23]. Subsequently, McCarron et al [24], in a study of 34 patients with essential hypertension, found that both the serum calcium and phosphate levels were inversely related to the mean arterial pressure and systolic blood pressures. They also noted a statistically significant difference between the mean serum phosphate level in their patients with essential hypertension (3.0 f 0.4 [SD] mg/dl) and a group of normotensive control patients (3.4 f 0.5). However, the hypertensive patients were residents of the Boston area, whereas the control group patients, who were studied at a later date, were from Oregon, so the small difference in serum



phosphate levels between the groups could have been due to differences in diet.

Ljunghall and Hedstrand [23] pointed out that there is an abnormality in the renal handling of sodium in some patients with essential hypertension, and they speculated that since sodium and calcium resorption are linked, hypertensive patients may have impaired tubular reabsorption of calcium and resultant hypercalciuria. They and McCarron et al [24] suggested that the presumed hypercalciuria would lead to secondary hyperparathyroidism and a resultant increase in phosphate clearance and decrease in serum phosphate. McCarron et al [24] suggested that if this hypothesis is correct, the secondary hyperparathyroidism in some patients with essential hypertension might progress to a state of partial parathyroid autonomy and tertiary hyperparathyroidism, which would be indistinguishable clinically from primary hyperparathyroidism [25]. The increased prevalence of hypertension in hyperparathyroid patients could then be due to an increased incidence of autonomous hyperparathyroidism in the hypertensive population, rather than to a hypertensive effect of hyperparathyroidism.

It is not clear whether calcium excretion is increased in hypertension. In the present study, urinary calcium excretion values in the hypertensive and normotensive groups were almost identical, but this might not be the case in a population without hyperparathyroidism. McCarron et al [24] compared the hourly calcium and sodium excretion of their Boston group of essential hypertensive patients, calculated from measurements of 24-hour urinary calcium and sodium excretion, with the hourly calcium and sodium excretion of their Oregon group of normotensive patients, calculated from a

three-hour morning urine collection in the fasting state. They found that the relation of urinary calcium to sodium in the hypertensive patients was significantly increased. However, the differences in the time of collection and geographic locale make it difficult to interpret these results. McCarron et al [24] also noted a small but statistically significant difference in serum parathyroid hormone concentrations between their hypertensive patients from Boston and an age- and sex-matched group of nomotensive subjects from the same area (79 f 3.1 [SEMI @eq/ml versus 67 f 3.3) but both groups were on ad lib diets, and relatively minor differences in calcium or sodium intake might account for the small difference observed.

An alternate explanation of the inverse relation between serum phosphate and blood pressure, which deserves investigation, is that an increase in blood pressure might decrease the tubular reabsorption of phosphate through a mechanism independent of parathyroid hormone. It is of interest in this regard that expansion of the extracellular fluid volume by saline infusion in dogs causes an increase in phosphate clearance that does not depend on an increase in the glomerular filtration rate, and is evident even in para- thyroidectomized animals [26].

ACKNOWLEDGMENT

We wish to thank Dr. Sherman Gates of the U.S. Vet- erans Administration Hospital of Albany, New York, and Dr. George Marthy of St. Peter’s Hospital, Albany, New York, for allowing us to review the records of their patients. We also acknowledge the excellent secretarial help of Mrs. Laura Barton and Miss Mary Anne Four- nier.

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hypertension and hyperparathyroidism: inverse relation of serum phosphate level and blood pressure

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