IDIOPATHIC HYPERCALCEMIA

Treatment

with

Sodium

Sulfate

By Avinoam Kowarski, M.D.

Department of Pediatrics, Rothschil4 Hadassah University Hospital, Jerusalem, Israel

IDIOPATHIC

HYPERCALCEMIA

533

Pwriucs, September 1958

I

DIOPATHIC HYPERCALCEMIA was first de-scribed by Lightwood in 1952.’ Since then the disease has been extensively

studied, mainly in England, where most of the reported cases have occurred. Though the disease is theoretically well-known to

pediatricians here, the present case is, to the best of our knowledge, the first de-scribed in Israel.

Some controversy still exists as to the causes and pathogenesis of the disease,2 but agreement prevails as to the principle

of treatment, viz.,

to produce

negative

cal-cium balance. This aim can be secured by: (a) decreasing the quantity of calcium

in-gested; (b) decreasing absorption of calcium

in the intestine; and (c) a combination of methods (a) and (b).3

It has been proved possible to obtain

negative calcium balance by the use of cortisone.34 However, in order to obtain this effect, long-term therapy with cortisone in high dosage is required. This form of

treatment produces many undesirable side-effects. Short courses of treatment are of

value in hypercalcemic crises only and

when administration of cortisone is discon-tinued, the concentration of calcium in the serum quickly rebounds to a higher

ievel.

Decreasing the quantity of calcium in the diet has, therefore, been the method more commonly employed with milk rendered calcium-free by passing it through a column

of ion-exchange resins,35 or with synthetic diets low in content of calcium8

(

soya flour milks, meat base feedings, etc.). With this

form of treatment even reversal of some

cardiovascular and renal changes were

(Accepted March 17, 1958; submitted January 3.)

ADDRESS: 16 Saadia Gaon Street, Jerusalem, Israel.

noted by Stapleton, Macdonald and Light-wood3 in a patient with the severe form of the disorder. Because of the difficulties in obtaining sufficient quantities of calcium-free milk, various methods for rendering

the calcium in the milk poorly absorbable or nonabsorbable have been tried, e.g., the addition of disodium

ethylenediaminetetra-acetic acid (E.D.T.A.)4 or sodium phytate

to milk. Treatment with E.D.T.A. failed be-cause of its toxicity in effective doses4 and the results with sodium phytate were un-satisfactory. Synthetic diets are not palat-able and, according to Stapleton et al., the need for distilled water in their preparation

is a disadvantage.

Because calcium-free milk is unobtain-able in Israel, we have tried to decrease the absorption of calcium by addition of an appropriate amount of sodium sulfate to the milk. We believe that we have proved the efficacy of this method of treatment by follow-up of a patient with idiopathic hy-percalcemia so treated for more than 18 months. Should this result be confirmed in other cases, a method which has the ad-vantages of simplicity and practicability would be available.

History

CASE REPORT

The patient is at present 20 months old. The child was born in Beersheba, Israel, of parents of North African extraction. Pregnancy was uneventful and birth was normal. Parents and

the age of 3 months the weight was 3.0 kg (0.5 kg less than the birth weight). He ap-peared to be dehydrated with reduced tissue turgor, sunken eyes and depressed fontanelle. He was active, but muscle tone of the

extnemi-ties was poor. There was pallor but no cyanosis. The heart was not enlarged on percussion and only slightly so on noentgenogram. A harsh

systolic murmur was heard over the precor-dium. Blood pressure measured by the flush method was 100 mm Hg. The edge of the liver was just palpable. A definite coarseness of the hair was noted.

Laboratory Findings and Course

The urine was acid in reaction; albumin, glucose and bile pigments were absent; no cells or casts were found in the sediment. The concentration of hemoglobin and erythrocyte count were within normal limits. Electrocardi-ogram was normal.

Our usual treatment for babies failing to thrive (viz., intragastnic drips, small

transfu-sions of blood, special mothering and occasional intravenous infusions) was tried for 40 days without success. The child did not gain in weight and continued to refuse the feeds,

which consisted, between the periods of

dehy-0 Eledon#{174} is a half-cream acidified powdered

milk prepared by Nestl#{233}Company.

Contents:

Fat 12.0% Lactic acid 4.0%

Proteins 28.5% Starch 10.0%

Lactose 36.5% Water 3.0%

Mineral Salts 6.0%

The content of calcium of the prepared formula

is equal to that of milk, i.e., 1.0 gm/i.

ograms of long bones and vertebrae8 (Fig. 2). These findings together with the acid reaction

of the urine and the normal carbon dioxide

combining power of the serum established the

diagnosis. Concentrations of cholesterol and

phosphatase in the serum, of proteins in the plasma and urea in the blood were all within

normal limits.

Therapy and Later Course

The diet was then changed. Ten milliliters

of a 10% solution of crystalline sodium sulfate

in distilled water were added to each liter of milk. Vitamins A and D were no longer added

to the diet, at any time in the period covered

by this report. As no diarrhea and no other ill-effects were noted, the quantity of sodium

sui-fate solution was gradually increased to 50 mi/i of milk.

As may be seen from Figure 1 favorable re-suits were noted in a few days. The concentra-tion of calcium in the serum was 11.3 mg/100 ml after 7 days and three subsequent determi-nations during 82 days of treatment showed

further decline. During this period of treat-ment a vast improvement in general condition

was noted. Appetite, alertness, and muscle

tone improved and weight rose from 3.50

to 4.45 kg (Fig. 1). At this point “summer

diarrhea” (a common cross-infection in the

hospital) developed and persisted for several

days. The sodium sulfate-treated milk was not

administered during this illness.

After diarrhea stopped, feeding of untreated

milk was continued for 45 days. During that period the concentration of calcium in the

SEr?uM WEK3HT

:4LCSJM IN KG

MGj

i6

15.

14 6

‘3

2 S

II

I0. 4

0

Jo

I

0 O#{176}J I LEGE ND

(\

-.

____

_____

o-so _\I l0SEUM

I

0 I CALCIUM

I-WEIGHT

I

PEPIOD OF

n_ff-/ IEJ TREATMENT

I ‘ . r-iI

9.

3

Fiu. 2. Roentgenograins of upper extremities at the

time of admission demonstrating transverse lines characteristic of hypercaicemia at ends of long

bones.

ao 200 300 400 5c;o 600

DAyS OF HOSPITALISATIQN

FIG. 1. Concentrations of calcium in serum and body weight in relation to dietary

therapy with sodium sulfate.

there was no gain in weight and the general

condition deteriorated. Feeding of sodium

sul-fate-treated milk was resumed and concentra-tions of calcium in the serum promptly

de-creased and stayed within normal limits during the whole second period of treatment (270

days) during which time the weight increased

and reached 7.5 kg.

It was decided to stop treatment once more.

In the 45 days that followed, the concentration of calcium in the serum rose again reaching 12.8 mg/100 ml and again the patient failed

to gain weight. Treatment with the sodium sul-fate-treated milk was resumed and concentra-tions of calcium fell gradually to 10.6 mg/100

ml with a concurrent gain in weight to 8. 1 kg

in 46 days. During the whole period of

obser-vation no change in the intensity or quality of the systolic murmur was noted. Motor and

mental development were slow; at the age of

1% \ears the patient was not sitting up and

did not speak a single word. (Crowing up in

a hospital did not help the mental develop-ment and might well be considered as a con-tributary cause of retardation.)

As body growth advanced during the

normo-calcemic period, the hvpercalcernic

condensa-tions at the ends of the long bones and the

vertebrae, observed at the time of admission,

retreated froni the eII(l of the diaplivsis as new bone of normal density was laid down.

Dun-ing the second hypercalcemic phase a new

hypercaicemic line was formed at end of the diaphysis only to move gradually along the

within normal limits. A harsh systolic

mur-mur, as heard in the patient described here,

has been a frequent finding in severe cases

of idiopathic hypercalcemia.28 While not

ruling out a congenital anomaly of the

heart, we believe, in view of the normal

electrocardiogram and the roentgenograms of the heart, that the harsh systolic murmur

heard in this patient is a manifestation of

idiopathic hypercalcemia.

As studies of calcium balance were not done, the exact way by which administra-tion of sodium sulfate resulted in decrease

of the concentration of calcium in the serum could not be determined. We suggest the following hypothesis for its manner of action:

Sodium sulfate reacts with calcium ions in the

milk:

Ca + Na2SO - CaSO4 + 2Na

The reaction goes to the right according to the law of mass action because of the lower

solubility of gypsum (calcium sulfate) than

of sodium sulfate in the intestinal environ-ment and the lower electrolytic dissociation of the former. (The reaction is completed in

the low pH environment of the stomach where the calcium carbonate portion of the calcium in the milk is decomposed). Be-cause of the very low absorption of the

sulfate ion in the a relatively

high concentration of this ion is maintained

which, through the common ion effect

pre-vents further ionic dissociation of calcium

sulfate and the absorption of calcium. The

Moreover, because of the possible

vania-tions in the content of calcium in milk,

over-dosage and diarrhea was feared.

We believe that it has been demonstrated in this case that the addition of sodium sul-fate to milk is capable of diminishing the absorption of calcium in the intestine to a

degree which results in lowering the

con-centrations of calcium in the serum. Five definite deflections of concentrations of

cal-cium in the serum related to the

commence-ment and the stopping of the sodium sul-fate treatment were observed; the

concen-tration of calcium in the serum began to decrease immediately after treatment with sodium sulfate was started and rose again soon after it was stopped. It would be very unlikely that these deflections were due to chance alone.

While the observations in this case

merely reconfirm the known beneficial

effect of lowering the concentration of

cal-cium in the serum of patients with idio-pathic hypercalcemia, we believe that the

use of milk treated with sodium sulfate may prove to be a simpler and more practical

way of accomplishing this.

In view of the possible roie of vitamin

D in the etiology of idiopathic

hyper-8 the prophylactic

administra-tion of vitamin D2 (in the high dosage which

is still frequently given in Israel), was stopped, at the start of the sodium sulfate

therapy. Vitamin D was not given again

ARTICLES

It is possible that discontinuance of

the

vitamin D supplement contributed in some

measure towards the improvement in the

child’s condition. However, we believe that the main role was played by the sodium sulfate therapy because, when the latter was discontinued, the child’s condition

de-teriorated, despite the fact that vitamin D was no longer being given.

SUMMARY

A case of idiopathic hypercalcemia with

failure to thrive is described. A new form of diet employing milk treated with sodium

sulfate was tried and proved effective. Mechanism of action of sodium sulfate

in lowering the absorption of calcium from the intestine is discussed.

ACKNOWLEDGMENTS

The author acknowledges with gratitude the invaluable help and guidance given to him by Dr. S. E. Berman, Head of the De-partment of Pediatrics, Rothschild

Hadas-sah University Hospital, Jerusalem. Thanks are also due to Dr. V. Cohen, Head of the Department of Pediatrics, Hadassah

Hos-pital, Beersheba, for her co-operation in the

study of this case.

REFERENCES

1. Lightwood, R. : Idiopathic hypercalcaemia with failure to thrive: nephrocalcinosis (abstract). Proc. Roy. Soc. Med., 45:401, 1952.

2. Forfar,

J.

0., Baif, C. L., Maxwell, C. M., and Thomsett, S. L. : Idiopathic hyper-calcaemia of infancy; clinical and met-abolic studies with special reference to the aetiological role of vitamin D. Lan-cet, 1:981, 1956.

3. Stapieton, T., i’ulacdonald, W. B., and

Lightwood, R. : Management of

“idio-pathic” hypercalcaemia in infancy. Lan-cet, 1:932, 1956.

4. Morgan, H. C., Mitchell, R. G., Stowers,

J.

M., and Thomson,

J.

: Metabolic

studies on two infants with idiopathic hypercalcaemia. Lancet, 1 : 925, 1956. 5. Bonham Carter, R. E., Dent, C. E.,

Fow-ler, D. I., and Harper, C. M. : Calcium

metabolism in idiopathic hypercalcae-mia of infancy with failure to thrive. Arch. Dis. Childhood, 30:399, 1955. 6. Dawson, I. M. P., Craig, W. S., and

Per-era, F.

J.

C.: Idiopathic hypercalcaemia in an infant. Arch. Dis. Childhood, 29:

475, 1954.

7. Lowe, K. C., Henderson,

J.

L., Park, W. W., and McGreai, D. A. : The idiopathic hypencalcaemic syndrome of infancy. Lancet, 2:101, 1954.

8. Creery, R. D. C., and Naill, D. W. :

Idio-pathic hypercalcaemia in infants with failure to thrive. Lancet, 2: 110, 1954. 9. Goodman, M. A., and Gilman, A. : The

Pharmacological Basis of Therapeutics, 2nd Ed. New York, Macmillan, 1955, p. 1056.

10. Sollman, T. : A Manual of Pharmacology and Its Application to Therapeutics and Toxicology, 7th Ed. Philadelphia, Saun-dens, 1948, p. 741.

SUMMARIO IN INTERLINGUA

Hypercalcemia

Idiopathic:

Tractamento

Con

Sulfato

De Natrium

Es descnibite le caso de un patiente de 20 menses de etate con hypercaicemia idiopathic.

Non-prosperation esseva le gravamine general.

Un nove forma de dieta-con lacte tractate con

sulfato de natrium-esseva essayate e se provava

efficace.

1958;22;533

Pediatrics

Avinoam Kowarski

IDIOPATHIC HYPERCALCEMIA: Treatment with Sodium Sulfate

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