thejournal clinical invustigation, vi, no.€¦ · fuller albright and read ellsworth appearance....

STUDIES ONTHEPHYSIOLOGYOF THE PARATHYROIDGLANDS

I. CALCIUM AND PHOSPHORUSSTUDIES ON A CASE OF IDIOPATHICHYPOPARATHYROIDISm

By FULLER ALBRIGHT AND READELLSWORTH

(From the Medical Clinic of the Johns Hopkins Hospital, Baltimore)

(Received for publication December 12, 1928)

INTRODUCTION

In order to determine, if possible, the exact train of events whichlead to a rise in the serum calcium following the injection of a potentparathyroid extract, we undertook the present series of investigations.The subject of this study was an Italian boy on whomthe diagnosisof idiopathic hypoparathyroidism was made. The criteria on whichsuch a diagnosis can be based will be discussed below.

The injection of a potent parathyroid extract results in four well-established changes and any theory as to the action of a parathyroidextract will have to take cognizance of these four cardinal points.They are:

a. Rise in serum calcium (1).b. Rise in urinary calcium excretion (2) (3) (4).c. Fall in serum phosphorus (5).d. Rise in urinary phosphorus excretion (2) (3).Removal of the parathyroid glands results in the converse changes,

i.e.,a. Fall in the serum calcium.b. Fall in the urinary calcium excretion.c. Rise in the serum phosphorus.d. Fall in urinary phosphorus excretion.In addition Albright, Bauer, Ropes, and Aub (3) emphasize the fact

that on administration of parathormone, the increase in urinary phos-phorus excretion tends to precede the increase in calcium excretion.They further point out that the increased phosphorus appearing in

183

THE JOURNALO CLINICAL INVUSTIGATION, VOL. VI, NO. 2

IDIOPATHIC HYPOPARATHYROIDISM

the urine must come partly from phosphorus dissolved in body fluidsand not entirely from the calcium phosphate of the bones. Inasmuchas the calcium and phosphorus changes are probably not simultaneous,it was apparent that, by reducing the metabolism periods to eighthours instead of three days, as in the investigations above (3), wecould follow this sequence of events more accurately (cf. experiment 1below). Later we had occasion to reduce the period to 1 hour (cf.experiment 2). These shorter periods made it necessary for us to dis-regard the fecal excretions. This, however, is justifiable, as it has beenshown that, following the injection of parathormone, there is a con-spicuous alteration in the urinary excretion of calcium and phosphorus,but not in the fecal excretion of these elements (3).

REPORTOF CASE

Wewere fortunate in having the opportunity of studying the effect of para-thormone on a patient suffering from idiopathic hypoparathyroidism. The clini-cal aspects of a case with this rather unique diagnosis are of interest.

The patient, a school-boy of 14 of Italian descent, first entered the MedicalService of the Johns Hopkins Hospital on January 17, 1927 for relief of tetany(J. H. H. No. 9974).

The family history was non-contributory.The past history was uneventful except that he had had measles and cbicken

pox at 5 vears of age.In 1918, at the age of 5, while under treatment for measles in the Harriet Lane

Children's Clinic, it was noted that the patient had markedly hypertrophied ton-sils. Tonsillectomy was performed in 1921. Shortly thereafter he began to betroubled at night with attacks of laryngismus. In August, 1922 he had hisfirst attack of carpo-pedal spasm, precipitated by a gastro-intestinal upset. Asecond attack in January, 1923 was preceded by an upper respiratory infection.Examination at that time at the Harriet Lane Children's Clinic showed carpo-pedal spasm, a bilateral Chvostek sign, and an injected pharnyx. The cathodalopening contraction was 1.0 milliampere. The serum calcium was 4.9 mgm.per 100 cc. and the serum phosphorus 10.4 mgm. The blood sodium chloride was560 mgm. per 100 cc.

Ammonium chloride gave him symptomatic relief. However, the generalcourse of the disease was downhill so that at the time of his first admission to theMedical Service he was having each day about fifteen attacks of carpopedal spasm.The individual attack was as a rule precipitated by some unusual exertion such ascrossing the street or stealing a base in a ball-game. Momentary loss of conscious-ness was frequently associated with the attacks.

Physical examination showed a normally developed Italian boy of healthy

184

FULLER ALBRIGHT AND READ ELLSWORTH

appearance. The teeth were in poor repair. Both epitrochlear glands werepalpable. Chvostek's and Trousseau's signs were positive.

Other examinations showed a red blood cell count of 5,000,000; hemoglobin of90 per cent (Sahli); white blood cell count 6600 with a normal differential count;a negative Wassermann reaction, a basal metabolism of minus six, and an en-tirely normal urine. The plasma calcium was 8.0 mgm. per 100 cc. and the phos-phorus 10.9 mgm. per 100 cc. The whole blood chlorides were 470 mgm. per100 cc. and the CO2combining power 52.4 volumes per cent.

Following the administration of parathormonel there was complete relief. The\serum calcium was raised to 16.2 mgm. and the serum phosphorus was lowered to

4.7 mgm. Symptoms returned, however, in one week after discontinuingparathormone.

The present, the fourth admission to the Medical Service, was on March 21,1928 for relief for tetany. This time his symptoms had again, as frequently be-fore, been aggravated by a pharyngitis. Examination this time showed, inaddition to the signs of tetany, a spleen which was just palpable. Ophthal-moscopic examination revealed a posterior, subcapsular, lenticular opacity andseveral peripheral, radially distributed, lenticular opacities in the right eye. Inthe left eye a few lenticular opacities were noted. The serum phosphorus was10.8 mgm. per 100 cc. and the serum calcium 5.3 mgm. per 100 cc. X-rays of thebones revealed nothing abnormal.

The features of this case which make it possible to group it with those of hypo-parathyoid tetany are:

a. Low serum calcium.b. High serum phosphorus (in direct contradistinction to the infantile type of

tetany where the serum phoshorus is low or normal or only slightly elevated).c. Cataracts, which so commonly occur in post-operative hypoparathyroidism.d. Normal density of bones as shown by X-ray (in contradistinction to instances

of tetany associated with rickets and osteomalacia).e. Aggravation of tetany by exertion. Wehave found this to be characteristic

in several cases of tetany of parathyroid origin.Thus we believe that, just as myxedema is, as a rule, an idiopathic hypothyroid-

ism, so this case represents an idiopathic hypoparathyroidism.A report of a similar case is soon to be published from the Massachusetts General

Hospital (6). Itis, together with our case, presents exactly converse findings tothose of another patient studied at the Massachusetts General Hospital, in whomadiagnosis of idiopathic hyperparathyroidism was made (7).

EXPERIEFNT I

Experimental. This investigation lasted twenty-seven days. Aneffort was made to have all factors as constant as possible. Conse-

1 Preparation of parathyroid extract introduced by Collip (1) and supplied bythe Eli Lilly Company.

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quently the patient was kept in bed and in doors. Each day wasdivided into three eight-hour metabolism periods. The periods be-gaia at 8 a.m., 4 p.m., and 12 midnight. The patient was given thesame meal three times a day at the beginning of each period. Waterwas likewise administered in equal amounts and at the same relativetime in each period. The urine was collected for each period and ana-lyzed for calcium2 and for phosphorus (9). Vena punctures whendone were performed at the beginning of the periods. Fifty units ofparathormone were administered at the beginning of periods 16, 19,22 and 25 (cf. chart 1). The diet was altered at period 43 and severaltimes thereafter as can be noted from table 1. The data for this ex-periment are given in table 1 and chart 1.

Results. One notes in control periods 1 to 15 before the administra-tion of parathormone a constantly high serum phosphorus, a corre-spondingly low serum calcium, and extremely low calcium excretionin the urine, and a phosphorus excretion in the urine comparable withthat observed in normal persons on a similar phosphorus intake. Thisnormal urinary phosphorus excretion is not at variance with the fourcardinal points mentioned abpve or with the lowered phosphorus ex-cretion following parathyroidectomy, demonstrated by Greenwald(10). In our case the patient was in equilibrium at a constant levelof hypoparathyroidism and was not shifting from a normal to ahypoparathyroid state, as in the post-operative cases. On adminis-tration of parathormone the urinary phosphorus excretion rose to itsmaximum, even exceeding the intake, in the first period (period 16),maintained this high level throughout the period of parathormoneadministration, and then fell abruptly following cessation of parathor-mone administration. The serum phosphorus fell coincidently withthe increased phosphorus excretion and rose again when the phos-phorus excretion fell off. The serum calcium rose as the serum phos-phorus fell and vice versa with almost no tendency for one to lagbehind the other. The calcium excretion failed to rise during thefive periods following parathormone administration but then rose veryabruptly.

The calcium excretion fell off following cessation of parathormone

2 Fiske method described by Blackfan and Hamilton (8).

190

FULLER ALBRIGHT AND READ ELLSWORTH 191

administration. It should also be noted that the calcium excretion inthe urine actually fell slightly during the first five periods after thebeginning of parathormone administration. Following cessation of

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CHART 1. GRAPHIc REPRESENTATIONOF DATA IN EXPERIMENT 1

The scale for the serum phosphorus is twice that for the serum calcium. Thisis so chosen because the normal value for serum calcium is about twice that forserum phosphorus, and because, consequently, a change of 2 mgm. of calciumrepresents the same percentage deviation from normal as a change of one mgm.of phosphorus. For convenience in charting, the scale for the urinarv calciumexcretion is five times that for the urinary phosphorus excretion. Since the ratioof calcium to phosphorus in bone is 2.23 a calcium scale one-half that of the phos-phorus would have been more logical, although not practical.

parathormone administration the phosphorus excretion fell below thepreparathormone level of excretion (cf. periods 29 to 35). This isanalogous to the decreased phosphorus excretion following parathy-

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roidectomy (10). It may be significant that of these four variables,the phosphorus excretion alone seemed to depend quantitatively onthe amount of parathormone given. The others seemed to depend onhow long the parathormone was given and perhaps on how long thishigh level of phosphorus excretion was maintained.

In periods 43 to 63 the phosphorus intake was decreased to a mini-mumin order to determine whether the serum phosphorus could thusbe diminished. The result was a decreased phosphorus excretionwith practically no change in the serum phosphorus or in the serumcalcium. Likewise in periods 64 to 75, when the phosphorus intakewas greatly increased by the addition of primary sodium phosphateto the diet, the urinary phosphorus excretion was greatly elevatedwhile there was only a slight tendency for the serum phosphorus torise and for the serum calcium to fall. Periods 76 to 81 will not bediscussed as the changes in the diet were too radical.

Comment. The observations of experiment I suggest certain con-clusions, the interpretation of which may be as follows:

1. A state of hypoparathyroidism is associated with a fairly normalurinary phosphorus excretion, a very high serum phosphorus, a low-serum calcium, and a very low urinary calcium excretion.

2. Administration of parathormone to an individual in a state ofhypoparathyroidism modifies all four of these factors, viz.:

a. The urinary phosphorus excretion immediately rises to its maxi-mum(at least within eight hours).

b. Coincidently the serum phosphorus falls.c. The serum calcium rises.d. The urinary calcium excretion at-first diminishes, and then when

the serum calcium is about 8.5, suddenly increases.3. Cessation of administration of parathormone to an individual

who had been brought from a hypoparathyroid state to the normal,further modifies these factors, as follows:

a. The phosphorus excretion at once falls even below the prepara-thormone level.

b. The serum phosphorus rises.c. The serum calcium falls.d. The calcium excretion falls, but less precipitously than the

phosphorus excretion.

192


4. Whereas the urinary calcium excretion ordinarily varies with theheight of the serum calcium (3), there seems to be a threshold-level atabout 8.5 mgm. of calcium per 100 cc., below which, the calcium ex-cretion in the urine becomes more or less constant and is independentof the serum calcium value.

TABLE 2

Experiment II

Serum' ~ entSeu0al57mm

C59-102230 RemarksSS Q0'

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8-9 250 185 1.4 6.2 0.50 7.39-10 250 230 1.7 6.4 0.69

10-11 250 255 1.6 6.9 0.48 7.5 10.311-12 250 510 3.3 39.5 1.07 75

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cent. Serum NaCi 591 mgm.per 100 cc. Refractive in-dex of serum 1.3532

6-7 8.0 9.31* Blood for Ca and P taken at beginning of period tabulated.

5. The high serum phosphorus, present in hypoparathyroidism,does not appear to be altered materially in a week's time either by avery low phosphorus intake or by a very high one.

EXPERIMENT II

The impression has been prevalent that parathormone is a drugthat acts slowly. Collip (1) points out that when parathormone is in-

193


jected into dogs the peak of the serum calcium curve is reached intwelve to twenty-four hours. In experiment I, we have shown thatthe maximum effect on urinary phosphorus excretion was reached

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CHART2. GRAPHic REPRESENTATIONOF CALCIUM AND PHOSPHORUSDATA IN EXPERIMENT2

The scale for the serum phosphorus is twice that for the serum calcium. Thescale for the phosphorus excretion in the urine is one-half that of the calciumexcretion.

somewhere during the first eight hours. The second experiment_wasplanned to determine whether this increased phosphorus excretionmight occur even earlier than eight hours.

194

FULLER ALBRIGHT AND READ ELLSWORTH1

Experimental. Following a period of 16 days on a low phosphorusdiet (0.345 gram per day), the patient fasted and remained in bed forthe day of the experiment. He received 250 cc. of water at 7 a.m.and the same amount every hour thereafter until 6 p.m. when the in-vestigation ceased. The urine was collected every hour and analyzedfor calcium, phosphorus and chlorine. At 11 a.m. 75 units of para-thormone were administered. The results can be seen in table 2 andchart 2.

Results. It will be noted that the excretion of urinary phosphorusincreased about 500 per cent in the first hour after parathormone ad-ministration and reached its peak by the second hour. In this ex-periment the serum phosphorus seems to have fallen more quicklythan the serum calcium rose. Both of these values had altered withinthree hours of the injection. The calcium excretion was slightlydecreased following the injection (cf. experiment I). The increasedexcretion of water and sodium chloride in the first hour after injec-tion are interesting but will not be discussed here.

Comment. 6. The action of parathormone on the excretion of uri-nary phosphorus is maximal within the first hour after injection. Itfollows from this that future studies must concentrate on the changesoccurring in the first hour after injection if one is to learn the funda-mental mechanism,-not the remote end-results.

EXPERIMENT III

In the latter part of experiment I it was noted that changes in theamount of phosphorus in the diet had little effect on the serum phos-phorus. It was desired to extend this investigation over longerperiods of time because of its important theoretical significance.

Experimental. This experiment started immediately after experi-ment I and lasted forty days. The time was divided into 10 four-daymetabolism periods. During the first six periods the patient was ona high phosphorus diet (1.756 gram per day) and during the remainingfour on a low phosphorus diet (0.345 gram per day). Except for thechange from the high to the low phosphorus diet, the patient receivedthe same food each day. He likewise received the same amount ofwater each day. He was not kept in bed. The urine for each periodwas examined for calcium, phosphorus and nitrogen, and the feces

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ZESENTATION OF PHOSPHORUSMETABOLISM INExPERmzNT3

197

9IDIOPATHIC HYPOPARATHYROIDISM

for calcium and phosphorus.3 Furthermore, after period 1, becauseof certain marked discrepancies which were at once noted, the dayurine (7 a.m. to 7 p.m.) was collected and analyzed separately fromthe night urine. The results are shown in table 3 and chart 3.

Results. Before drawing any conclusions regarding the phosphorusbalance, we might have made allowance for the phosphorus depositedwith the protein in muscle and with the calcium in bones (11). How-ever, examination of the calcium and nitrogen balances shows thatthese factors are smaller than the probable errors of the investigation.Also, it is true that too much reliance cannot be placed upon balancecolumns where very high intakes are involved, because a small per-centage error in the intake would make a considerable error in thebalance. Even so, although the serum phosphorus did rise consider-ably, it is quite apparent from the phosphorus balances (table 3)that, during the first six periods, while on a high phosphorus intake,the patient's kidneys had little difficulty in excreting phosphorus.Furthermore, when the phosphorus intake was suddenly lowered theexcretion of urinary phosphorus fell immediately rather than slowly,as it would, had there been any previous difficulty in excretingphosphorus.

The marked polyuria at night (table 3) was very striking, especiallyduring the first six periods It is also of interest that there was arelative increase in the urinary excretion of calcium, phosphorus, andnitrogen at night proportional to the increased excretion of water.Like the polyuria noted in experiment II in the first hour followingparathormone injection, these will have to remain as isolated observa-tions for the time being. They lead one to suspect some abnormalityin the water balance.

Comment. 7. At any given level of hypoparathyroidism there wasno marked difficulty in excreting phosphorus nor could the bloodchemistry be markedly altered by high and low phosphorus diets.

DISCUSSION

The serum calcium and serum phosphorus curves in experiment Icertainly suggest that one ion rises because the other falls or vice

3 Weare much indebted to Dr. Joseph C. Aub and his associates at the Massa-chusetts General Hospital for having the feces analyzed for us.

198


versa. One cannot escape the idea that this relationship is dependenton the ability of the serum to hold calcium phosphate, and that, inthe presence of normal bones, the blood calcium contains all the cal-cium and phosphorus ions which its physical state will permit. Italso seems almost certain that the increased phosphorus excretion,the increased calcium excretion, the decreased serum phosphorus, andthe increased serum calcium following parathormone administrationare four interrelated facts.

Our work, together with that of Albright, Bauer, Ropes, and Aub(3) suggests the following tentative hypothesis as to the modusoperandi.

When parathormone is administered, the equilibria of the bodyfluids are upset in such a way that an increased phosphorus excretionis a necessary result. Wedo not know the cause of the increasedphosphorus excretion, but as a result of this increased phosphorusexcretion the body fluids become depleted in phosphorus. The fall-ing serum phosphorus is evidence of this. As the phosphorus andconsequently the phosphate ions in the serum fall, there is a tendencyto an unsaturation of the blood with calcium phosphate. This tend-ency is met by a mobilization of calcium phosphate from the bones.Thus a deficit in phosphate ions is being supplied by calcium andphosphate ions. Consequently the serum calcium rises. With arise in the serum calcium, provided the level is not below the thresholdfor calcium excretion, there is a rise in urinary calcium output.

The sequence of events which takes place after parathormoneadministration (chart 1) strongly supports such an hypothesis, exceptthat we have been unable to show consistently that the fall in serumphosphorus precedes, by any detectable interval, the rise in serumcalcium.

It may be that the calcium-phosphorus equilibrium is so finely ad-justed that we have not been able to detect the small initial change, orpossibly we have not yet studied short enough periods..

On the basis of our hypothesis, the question immediately arises asto what causes the increased phosphorus excretion after parathor-mone injection. It seemed at first that there might be a specificimpairment of renal function in hypoparathyroidism whereby phos-phorus excretion was inhibited. However, in experiment III, the

199


high phosphorus excretion during a high phosphorus diet and theimmediate fall to a low phosphorus excretion when the diet waschanged to one low in phosphorus would seem to disprove this. Allthat we can say, therefore, is that some change in the blood equilibriaoccurs as the result of parathormone administration which makesnecessary this increased phosphorus excretion.

SUMMARYAND CONCLUSIONS

1. The clinical aspects of a case of idiopathic hypoparathyroidismare reported.

2. The criteria on which the diagnosis of idiopathic hypoparathy-roidism is made.are:

a. Low serum calcium.b. High serum phosphorus.c. Cataract.d. Normal density of bones by x-ray.e. Aggravation of tetany by exertion.3. Following the injection of an active parathyroid extract, an in-

crease in phosphorus excretion was immediately detectable andreached its maximum within the first two hours. The mechanism ofthis is not apparent from our data.

4. Evidence is educed from study of the metabolism of the patientto show that the increase in serum calcium, the increase in calciumexcretion, and the decrease in serum phosphorus following parathor-mone administration may all be the sequelae of this increase in phos-phorus excretion.

5. An hypothesis is suggested to explain these interrelationships.6. By using high and low phosphorus diets, it seems that there

is no inability to excrete phosphorus in hypoparathyroidism and itfollows, therefore, that the increased excretion of phosphorus follow-ing injection of parathormone is not due to an increase in the excre-tory ability of the kidney for this element.

7. As the serum calcium rose from 5.2 to 11.2 mgm. per 100 cc.following the injection of parathormone there was a critical serumcalcium value of about 8.5, at which point an almost negligible urinarycalcium excretion suddenly changed to a very appreciable one. Whenthe serum calcium was above 8.5 the urinary calcium increased as the

200


serum calcium rose then decreased abruptly as soon as the serum cal-cium fell below 8.5 mgm. per 100 cc. This suggests that there is athreshold for urinary calcium excretion and that this threshold is be-low the normal value for serum calcium.

Wewish to express our gratitude to Miss M. Struve for her assist-ance in arranging diets and superintending the collection of specimens.

BIBLIOGRAPHY

1. Collip, J. P., Medicine, 1926, v, 1. The Parathyroid Glands.2. Greenwald, I., and Gross, J., J. Biol. Chem., 1926, lxviii, 325. The Effect

of Long Continued Administration of Parathyroid Extract upon the Excre-tion of Phosphorus and Calcium.

3. Albright, F., Bauer, W., Ropes, M., and Aub, J. C., J. Clin. Invest. 1929, vii,139. Studies of Calcium and Phosphorus Metabolism. IV. The Effectsof the Parathyioid Hormone.

4. Hunter, Donald, and Aub, J. C., Quart J. Med., 1927, xx, 123. Lead Studies.XV. The Effect of the Parathyroid Hormone on the Excretion of Lead andof Calcium in Patients Suffering from Lead Poisoning.

5. Albright, F., and Bauer, W., The Effect of the Parathyroid Hormone on theRelation of Serum Calcium to Serum Phosphorus. To be published.

6. Bauer, W., Albright, F., Rossmeisl, E., Aub, J. C., Studies of Calcium andPhosphorus Metabolism. T-he Calcium and Phosphorus Metabolism inTetany with Observations on the Therapeutic Action of Thyroid and Am-monium Chloride Medication. To be published.

7. Bauer, W., and Albright, F., Studies of Calciu;m and Phosphorus Metabolism.A Case of Supposed Hyperparathyroidism with Thyroidectomy. To bepublished.

8. Blackfan, K. D., and Hamilton, B., Johns Hopkins Hbsp. Bull., 1927, xli, 322.Study of the Inorganic Constituents of Serum in Children with AcuteNephritis.

9. Benedict, S. R., and Theis, R., J. Biol. Chem., 1924, lxi, 63. A Modificationof the Molybdic Method for the Determination of Inorganic Phosphorus inSerum.

10. Greenwald, I., and Gross, J., J. Biol. Chem., 1925, lxvi, 185. The Effect ofThyroparathyroidectomy in Dogs upon the Excretion of Calcium, Phos-phorus, and Magnesium.

J 11. Bauer, W., Albright, F., and Aub, J. C., J. Clin. Invest., 1929, vii, 75.Studies of Calcium and Phosphorus Metabolism. II. The Calcium Excre-tion of Normal Individuals on a Low Calcium Diet including Data on aCase of Pregnancy.

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