Metabolism Clinical and Experimental VOL.

XXVII,

FEBRUARY

NO. 2

1978

Selective Effects of Thiazide on Intestinal Absorption of Calcium in Absorptive and Renal Hypercalciurias D. E. Barilla,

R. Tolentino,

R. A. Kaplan,

The effect of long-term thiazide therapy on the intestinal Ca absorption was measured in 10 well-defined cases of absorptive hypercalciuria with intestinal hyperabsorption of Co and 8 with renal hypercalciuria (“renal leak’ of Ca), many of whom had hyperabsorption of Ca. In most cases of absorptive hypercalciuria, the intestinal hyperabsorption of Ca persisted during treatment, despite restoration of normal urinary Ca. In contrast, the in-

and C. Y. C. Pak

testinal Ca absorption decreased significantly during thiazide therapy in 7 of 8 patients with renal hypercalciuria commensurate with the “correction” of the renal leak of Ca and secondary hyperparathyroidism. The results support the hypothesis that the intestinal hyperabsorption of Ca in absorptive hypercalciuria may be primary, whereas that in renal hypercalciuria may be associated with the hyperparathyroid state.

A

BSORPTIVE HYPERCALCIURIA (AH)lm3 and renal hypercalciuria (RH)4 probably represent two major subtypes of idiopathic hypercalciuria.’ The hypercalciuria in AH is believed to result from an enhanced intestinal absorption of Ca, whereas that in RH is thought to be the consequence of a primary defect in the renal tubular reabsorption (renal leak) of Ca. Parathyroid function in AH is normal or suppressed, unlike in RH, where it is stimulated. The intestinal Ca absorption, which is invariably high in AH,’ may also be increased in RH.396 It has been postulated that the cause for the increased Ca absorption in RH is the promotion of the renal synthesis of la,25-dihydroxycholecalciferol (1,25-DHCC) associated with secondary hyperparathyroidism.‘** Coe et al. have shown that the hypercalciuria and the secondary hyperparaFrom the Section on Mineral Metabolism, Department of Internal Medicine. University of Texas Health Science Center at Dallas, Southwestern Medical School, Dallas, Tex. Received for publication October 21, 1976. Supported by USPHS Grants ROI-AM 16061. MOI-RROO633, and POI-HLl1662. Reprint requests should be addressed to D. E. Barilla. M.D., Department of Internal Medicine. University of Texas Health Science Center at Dallas, 5323 Harry Hines Blvd.. Dallas, Tex. 75235. 0 1978 by Grune & Stratton, Inc. W260495/78/2702-0001$01.00/0 Metabolism, Vol. 27, No. 2 (February), 1978

125

126

BARILLA

ET Al.

thyroidism of RH may be corrected or ameliorated by treatment with thiazide.4 It is therefore possible that this therapy may restore normal intestinal Ca absorption in RH. In contrast, thiazide may not significantly alter the intestinal absorption of Ca in AH, in which there is no parathyroid stimulation. In this study, the preceding hypothesis was tested by a careful measurement of intestinal Ca absorption in well-defined cases of AH and RH. MATERIALS

AND METHODS

Clinical Data Eighteen adult patients. Clinical

Research

Center.

IO with AH

consent. As shown previously,’

or ~1 > 0.61),

(iPTH)

and

CAMP

fasting

state (~0.1 I mg/mg

of 1 g Ca (>0.20

mg/mg

normal

(~5.4 Cr),

aration.

type 1, and 5 had AH

urinary

urinary

with RH

stimulatiq;

was above the normal

tients. However,

urinary

Ca

(frac-

hormone during

following

type II, urinary

the

oral

load

Ca on a constant

whereas it was high in AH

range.

antiserum

of Arnaud,’

characteristics: Ca/Cr

of Ca

and high

hypercalciuria.

following

normal

an oral

in the

Ca

the assay of serum iPTH

21 l-32 or 21 l-41.

All patients

patients.

During

Ca, urinary in all the pa-

by the technique

et al..* or the procedure

had endogenous

Ca 24-hr

had to be modi-

was utilized

in fasting serum were found of Kaplan

The

by absorbed

no single assay procedure

prep-

fractional

load.’

remaining

Unfortunately,

the method

dietary

here had an increased

not compensated

Thus,

high serum

after an adequate

was probably

elevated values of iPTH

antiserum

Wellcome

normal

mg/day).

who were evaluated

renal excretion

tied during the course of the study. CH14M

(~200

fasting urinary

was high in four patients

the fast, when parathyroid CAMP

parathyroid

Ca excretion

type 11.9 In AH

was normal

and elevated

and an exaggerated

CAMP

[Cr]),

written

Ca absorption

immunoreactive

urinary

was made from the following

CAMP,

Most of the patients

absorption

gave informed

intestinal

features were the same.

The diagnosis of RH and/or

creatinine

and an exaggerated

diet of 400 mg Ca and 100 meq Na/day

iPTH

had elevated

or suppressed

rmoles/g

in this study at the General

all patients

Cr13

Five patients had AH type I. Otherwise

participated

of the study.

the patients with AH

tional Ca absorption urinary

and 8 with RH,

Prior to the initiation

utilizing

using Burroughs-

creatinine

clearance

greater

than 80 ml/min.

Outline of Protocol All patients throughout initially

underwent

modification synthetic

were maintained

the period

on

of study,

of a previously

described

Doyle

refrigeration

least and

I

yr

of

avoidance

preceding

parathyroid were

Minn.),

pools and were analyzed

daily without

a venous stasis before a 12-hr fast, a 2-hr

for Ca and Cr. On day 2, IL2 PCi of 47Ca mixed

Urine for

Ca,

breakfast

fasting

urine

in 250 ml of the

daily

specimens Cr,

synthetic

liquid 400

mg

were col-

P. and

meal for Ca, sample

They

to a slight

on a constant

containing

l-3).

products

treatment.

according

maintained

days (days

of dairy

thiazide

function,

Minneapolis,

for 3 consecutive

of day 4, following

consisting

They

method.’

daily in 24-hr

Venous blood was obtained

diet.

at

Pharmaceutical,

Ca, 800 mg P, and 100 meq Na,

Cr. On the morning

for

studies of Ca metabolism

diet (Calcitest,

lected under

a low-Ca and

CAMP. P. and

was obtained

diet

containing

100 mg Ca was given orally to measure a. After with AH

the initial evaluation,

all patients

was given chlorthalidone.

were begun on diuretic

50 mg orally each day. Others

50 mg twice a day orally.

All patients

and reevaluated according

to the same protocol

was conducted

HCTZ

was withheld

received

3 mo after

as in the initial

after 6, 12, 18, and 24 mo of therapy

In some patients, studied again.

were readmitted

(HCTZ)

18-24

One patient

hydrochlorothiaride.

the initiation

evaluation.

in those in whom

for 3 mo after

therapy.

of treatment

Similar

treatment

mo of treatment;

evaluation

was continued. they were then

Ip

< 0.001.

tp < 0.01.

*Significant

Abbreviations:

as mean

HCTZ,

9.86

zt 0.34

* 0.03$

* 1.12 & 1.70

zk 0.46

0.589

0.719

Cr;3 24-hr

from control

period,

Co,

obtained

by paired

zt 0.037

zt 0.67

* 0.68

patients.

0.552

0.699

134

Co absorption.

t test, p < 0.05.

01, fractional

-

f f

1.58 1.16*

f 0.069

0.772

In normal

4.02

0.0597 CAMP,

i

+ 0.085

114+201

0.486 urinary

zk 0.021

* 0.02

* 0.87 i 0.40*

f 0.12

f 0.32

18

149+31*

0.03

0.07

4.49 4.00

9.83

9.67

far a is 0.61.’

subjects:

f 0.064’

control

0.560

0.669

111 + 40t

limit of normal

in normal

* 0.50 f 0.27

139 l 40*

0.07

3.45 3.85

9.70

9.40

Months of HCTZ Treatment 12

The upper

Values

zk 0.103

127 zt 58*

0.06

0.04

3.41 6.71

108 & 42 (SD) mg/day.’

or chlorthalidone;

urinary

different

* 0.108*

* 0.059

92 zt 32i

9.85 10.01

6

Effectsof Thiazide in Absorptive and Renal Hypercalciurios

117 * 56*

0.04

0.06

3.49 5.69

9.65

3

+ SD of mean values from

0.104

zt 0.064

i

hydrochlorothiazide

(SD) mg/mg

difference

=t 0.027

Values are presented

0.695

0.701

AH

248 f 66

RH

204 + 57

* 0.07

+ 0.02

+ 0.76 f- 1.53

RH

Co, 0.057

a

* 0.45

+ 0.41

AH

Urinary

0.21

3.21 5.54

0.08

Co (mg/day)

9.53

9.76

RH

Cl)

Cr)

ml)

AH

Ca (mg/mg

Fasting urinary

AH RI-I

Urinary CAMP @male/g

RH

Serum Ca (mg/lOO AH

Control

Table 1.

9.79

0.725

subjects,

257

0.031

o.os7t

(Y is reproducible

(SD) pmoles/g

i

f 0.107

83 k 321

0.499 -I: 0.70

f

zt 0.03

+z 1.33 f 0.777

0.14

zt 0.29 f

149 f

0.06

0.06

4.20 3.50

9.74

24

Cr;’

f

0.21

f

f 0.046

19

0

to within

fasting

5%.

urinary

0.6 13 + 0.059

0.733

240 f

0.04

z!.z0.38 + 3.23

230 f

0.18

0.07

3.14 6.43

9.5 f 0.28

9.65

Off

E ID z 0 P

2

z ;;I

g

2 6 E Fi

2

BARILLA

128

ET

AL.

Analytical Procedures Ca was determined

by atomic

by the protein-binding

absorption

assay of Gilman.”

spectrophotometry. Cr was analyzed

sured from the fecal recovery of orally administered

Urinary

CAMP

by,;utoanalyzer,

was measured

and a was mea-

radiocalcium.

RESULTS

Serum Ca and Urinary CAMP (Table 1 I In both AH and RH, serum concentration of Ca was normal initially and did not change significantly during treatment with HCTZ. Before treatment, urinary CAMP was significantly higher in RH than in AH (p < 0.05). In RH, urinary CAMP decreased during later periods of treatment and returned toward pretreatment levels when therapy was stopped. In AH, urinary CAMP levels remained in the normal range throughout the treatment period. Fasting Urinary Ca/Cr (Figs. 1 and 2 and Table 1 I Fasting urinary Ca was normal (co.1 1 mg/mg Cr), both in the control period and during HCTZ treatment phase in all patients with AH in whom it was measured. In contrast, fasting urinary Ca was high initially in every case of RH. It decreased to the normal range during treatment, and returned to the high pretreatment range when therapy was stopped. 030 FASTING

0.20

URINARY

cam

w/w

0.10

:.---

t

OL 400 r 300 URINARY CO

mq/day

t 200 t

1.0 r 0.8 -

FRACTIONAL CO

Q6-

ABSORPTION

0.4 -

0.2 0 L

, 0 +-MONTHS

,

6

OF

12

I8

HCTZ

THERAPY+

I

24 OFF

Fig. 1. Effect of HCTZ on fasting urinary Cct. 24-hr urinary Ca, and fractional Co absorption in absorptive hypercalciuria. Each line represents a study in a separate patient.

EFFECTS

OF THIAZIDE

ON INTESTINAL

129

ABSORPTION

FASTING

020

URINARY

corn

w/w

0.10

0

URINARY CO

200

mq/day 100

FRACTIONAL

0.6 -

Co ABSORPTION

0.4 -

0.2 -

Fig. 2. Effect of HCTZ in renal hypercalciurio. Origin of horizontal broken line indicates the time when HCTZ was discontinued.

0-

0 k-MONTHS

6

12 OF HCTZ

I8 THERAPY+

24 OFF

24-hr Urinary Ca (Figs. 1 and 2) Before treatment, hypercalciuria was found in both AH and RH. During treatment with HCTZ, urinary Ca decreased significantly in virtually every patient in both groups. When treatment was stopped, urinary Ca returned toward control values. These changes were also significant when urinary Ca was calculated for the whole group (Table 1). Fractional Ca Absorption (Figs. 1 and 2) Fractional Ca absorption was high or high normal initially in both AH and RH patients. The mean values for both groups were significantly elevated (p < 0.001). In patients with AH, (Yremained high both during and following treatment with HCTZ, except in one in whom it was high normal after 24 mo of treatment. Values for the whole group did not change significantly during HCTZ treatment, and remained elevated (Table 1). In contrast, seven of eight patients with RH had a fall in (Y during HCTZ treatment. In six patients who had high Q initially, cy decreased to the normal range in every case. In one patient, however, CYdid not decrease during treatment, but remained high normal. The mean value for (Yfor the whole group of RH patients decreased significantly to normal during HCTZ treatment; it returned toward pretreatment values when therapy was stopped.

BARILLA

130

ET Al.

DISCUSSION

Thiazide diuretic was effective in ameliorating hypercalciuria in both AH and RH. In RH, it corrected the renal leak of Ca and probably restored normal parathyroid function.4 Thus, fasting urinary Ca and urinary CAMP decreased during treatment. The effect of thiazide on intestinal Ca absorption was distinct in the two conditions. In RH, thiazide typically reduced the fractional Ca absorption, commensurate with the “correction” of renal leak of Ca and secondary hyperparathyroidism. It is recognized that PTH may play an important role in the with potent action regulation of the synthesis of 1,25-DHCC,8S’37’4 a metabolite on intestinal Ca transport. The results therefore suggest that the increased intestinal Ca absorption in RH may be secondary to an enhanced synthesis of 1,25-DHCC associated with the hyperparathyroid state.’ The reduction in intestinal Ca absorption during thiazide therapy may then be explained by the reduced synthesis of the vitamin D metabolite consequent to restoration of normal parathyroid function. In contrast, thiazide did not correct the intestinal hyperabsorption of Ca in AH, even though it caused a fall in total renal Ca excretion. The results support the primacy of intestinal hyperabsorption of Ca in AH. Assessment of thiazide response by a direct analysis of circulating concentration of I ,25-DHCC and of iPTH may provide further clarification. Other workers have reported varying effects of thiazide on intestinal Ca absorption in patients with idiopathic hypercalciuria.‘5.‘6 However, they did not segregate the group into AH and RH. REFERENCES I. Pak CYC. Ohata M. Lawrence EC, et al: The hypercalciurias: Causes, parathyroid functions and diagnostic criteria. J Clin Invest 54: 387-400, 1974 2. Nordin BEC, Peacock M, Wilkinson R: Hypercalciuria and calcium stone disease, in McIntyre I (ed): Clinics in Endocrinology and Metabolism, vol I. Philadelphia, Saunders, 1972. pp 169~ml83 3. Pak CYC, Kaplan R, Bone H. et al: A simple test for the diagnosis of absorptive, resorptive and renal hypercalciurias. N Engl J Med 292:497 500, 1975 4. Coe FL. Canterbury JM. Firpo JJ, et al: Evidence for secondary hyperparathyroidism in idiopathic hypercalciuria. J Clin Invest 52: I34142. 1973 5. Henneman PH. Benedict et al: idiopathic hypercalciuria. 259:8022807, 1958

PH. Forbes AP, N Engl J Med

6. Pak CYC, Barilla D, Bone H. et al: Medical management of renal calculi, in Rose (ed): Symposium on Advances in Endocrinology and Metabolism. New York, Grune & Stratton, 1977, pp 97-106

7. Pak CYC, Kaplan R. Bone H. et al: A simple test for hypercalciuria? N Engl J Med 292:1134~1136, 1975 8. Kaplan RA, Haussler MR, Deftos LJ. et al: The role of In.25dihydroxyvitamin D in the mediation of intestinal hyperabsorption of calcium in primary hyperparathyroidism and absorptive hypercalciuria. J Clin Invest 59: 756 760. 1977 9. Pak CYC. Holt K: Nucleation and growth of brushite and calcium oxalate in urine of stone-formers. Metabolism 25:665 673. 1976 IO. Pak CYC: Idiopathic hypercalciuria, in Massry S. Ritz E (eds): Phosphate Metabolism. New York, Plenum, 1977, pp 3099317 I I. Gilman AC: A protein binding assay for adenosine 3’5’-cyclic monophosphate. Proc Natl Acad Sci USA 67:3055312. 1970 12. Pak CYC. East DA, Sanzenbacher LJ, et al: Gastrointestinal calcium absorption in nephrolithiasis. J Clin Endocrinol Metab 35: 261-270, 1972 13. Garabedian M, Holick MF. DeLuca HF, et al: Control of 25-hydroxycholecalciferol metabolism by parathyroid glands. Proc Natl Acad Sci USA 69:167331676, 1972

EFFECTS

OF THIAZIDE

ON INTESTINAL

ABSORPTION

14. Haussler MR. Bursac KM, Bone H, et al: Increased circulating la,25dihydroxy vitamin Ds in patients with primary hyperparathyroidism. Clin Res 23:322A, 1975

IS. Ehrig U, Harrison feet of long-term thiazide

JE, Wilson DR: Eftherapy on intestinal

131

calcium absorption in patients with recurrent renal calculi. Metabolism 23:139-147, 1974 16. Curse1 E: Effects of diuretics on renal and intestinal handling of calcium. NY State J Med 70:399-405, 1970