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41
STUDIES OF CALCIUM AND PHOSPHORUS METABOLISM III. THE EFFECTS OF THE THYROID HORmONE AND THYROID DISEASE1 By JOSEPH C. AUB, WALTER BAUER,2 CLARK HEATH3 AND MARION ROPES (From the Medical Clinic of the Massachusetts General Hospital, Boston) (Received for publication September 14, 1928) INTRODUCTION AND REVIEW OF THE LITERATURE It is known that the internal secretion of the thyroid gland raises the basal rate of combustion of carbohydrate, fat and possibly protein, and consequently appreciably increases the total heat production of the organism, but its effect on calcium and phosphorus metabolism has not been definitely determined. Studies of the effect of thyroid secretion on the calcium metabolism have been reported.in the literature, but they are inconclusive because unsatisfactory methods were employed and because the data obtained were scanty and contradictory. A short summary of these observations, however, is of interest in this discussion as a background for our experiments on the relation of the thyroid gland to calcium and phosphorus metabolism. As early as 1892, Koeppen (1) reported that there appeared to be a connection between exoph- thalmic goiter and osteomalacia and other bone diseases. Pierallini (2) in 1906 investigated the possibility of an intimate relation between thyroid function and the metabolism of calcium and phosphorus. In his experiments urinary calcium only was determined; the calcium in- take was unknown and unrestricted because he assumed that the uri- nary content is an index of endogenous calcium metabolism. These assumptions are now known to be incorrect so that his results are of limited value. His figures showed the calcium and phosphorus ex- 1 The expenses of this investigation were defrayed in part from the Lead Fund of Harvard University. 2 Medical Resident, Massachusetts General Hospital. 3 Medical Interne, Massachusetts General Hospital. 97 THE JOURNAL OF CLINICAL INVESTIGATION, VOL. VII, NO. 1

Transcript of AND HEATH3dm5migu4zj3pb.cloudfront.net › manuscripts › 100000 › ... · J. C. AUB, W. BAUER,...

Page 1: AND HEATH3dm5migu4zj3pb.cloudfront.net › manuscripts › 100000 › ... · J. C. AUB, W. BAUER, C. HEATH AND M. ROPES tration of thyroid affected the calcium metabolism. The report

STUDIES OF CALCIUM AND PHOSPHORUSMETABOLISM

III. THE EFFECTSOF THE THYROIDHORmONEANDTHYROIDDISEASE1

By JOSEPHC. AUB, WALTERBAUER,2 CLARKHEATH3ANDMARIONROPES(From the Medical Clinic of the Massachusetts General Hospital, Boston)

(Received for publication September 14, 1928)

INTRODUCTIONAND REVIEW OF THE LITERATURE

It is known that the internal secretion of the thyroid gland raisesthe basal rate of combustion of carbohydrate, fat and possibly protein,and consequently appreciably increases the total heat production ofthe organism, but its effect on calcium and phosphorus metabolismhas not been definitely determined.

Studies of the effect of thyroid secretion on the calcium metabolismhave been reported.in the literature, but they are inconclusivebecause unsatisfactory methods were employed and because thedata obtained were scanty and contradictory. A short summaryof these observations, however, is of interest in this discussion as abackground for our experiments on the relation of the thyroid glandto calcium and phosphorus metabolism. As early as 1892, Koeppen(1) reported that there appeared to be a connection between exoph-thalmic goiter and osteomalacia and other bone diseases. Pierallini(2) in 1906 investigated the possibility of an intimate relation betweenthyroid function and the metabolism of calcium and phosphorus. Inhis experiments urinary calcium only was determined; the calcium in-take was unknown and unrestricted because he assumed that the uri-nary content is an index of endogenous calcium metabolism. Theseassumptions are now known to be incorrect so that his results are oflimited value. His figures showed the calcium and phosphorus ex-

1 The expenses of this investigation were defrayed in part from the Lead Fundof Harvard University.

2 Medical Resident, Massachusetts General Hospital.3 Medical Interne, Massachusetts General Hospital.

97

THE JOURNALOF CLINICAL INVESTIGATION, VOL. VII, NO. 1

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CALCIUM AND PHOSPHORUSMETABOLISM. III

cretions to be normal in Basedow's disease. Another article publishedin the same year by Scholz (3) gave the results of careful studies of themetabolism of cretins before and after thyroid therapy. The un-treated cretin was found to retain phosphorus and to excrete an abnor-mally large quantity of alkaline earths. Administration of thyroidpreparations exerted no marked influence on the phosphorus metabo-lism, but reduced the urinary excretion of the alkaline earths, partic-ularly that of calcium. The fecal calcium, however, was increased.A year later, Silvestri and Tosatti (4) reported the effect of administra-tion of thyroid extract on the calcium exchange in various diseases.They found that daily ingestion of "one tablet" of thyroid favored re-tention of calcium. The calcium output was determined in one-dayperiods during the first six days of thyroid medication, so that theirresults can probably be explained by insufficient dosage of thyroidand inadequate duration of observation. In referring to work donewith Bolaffio and Tedesco, Falta (5) in 1909 mentioned experimentsin which administration of thyroid increased the ratio of nitrogen tophosphoric acid in the urine and increased the phosphate in the stools,and concluded that there must be an increase in the fecal excretion ofcalcium to account for the augmented phosphorus output in the stools.Another series of observations on the effect of thyroid feeding on cal-cium excretion was made by Parhon (6) in 1912. In this very inter-esting study the calcium exchange of nine rabbits was determinedboth before and after administration of thyroid. The first group ofanimals received 0.05 gram of thyroid daily and suffered a net loss of0.007 gram of calcium per kilo per week; the second group of three,all of which died within seventeen days, received 0.10 gram of thyroiddaily and lost 0.228 gram (average figures) of calcium per week; thelast three, which died within five days after the beginning of medica-tion, received 0.3 gram of thyroid daily and lost on the average0.662 gram of calcium per kilogram per week. These experimentsindicate that the thyroid does exert a stimulating influence on calciumexcretion. Kojima (7) in 1917 approached the problem from a dif-ferent angle. He removed the thyroid gland and the parathyroid fromrats and then replaced the latter. He then determined the nitrogenand calcium excretions and found that both had been diminished. Hecould not, however, demonstrate in these experiments that adminis-

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J. C. AUB, W. BAUER, C. HEATHAND M. ROPES

tration of thyroid affected the calcium metabolism. The report in-cluded no data concerning the adequate functioning of the parathy-roid transplants and therefore the reduced calcium excretion afterthyroidectomy might be explained by parathyroid deficiency.

Kummer (8) in the same year published data obtained from obser-vation for thirteen days of a patient with exophthalmic goiter. Twoand one half liters of milk were given daily, which meant that thecalcium intake was approximately 5 grams per day. No determina-tions were made of the basal metabolic rate and control calciumfigures apparently were taken from the literature. The author con-cluded that the mineral excretion was high but very irregular, boththe calcium and phosphorus losses being especially great. Becausethe quantity of calcium in the urine was normal and that in the feceswas large, he attributed the high fecal calcium in Basedow's diseaseto a difficulty in absorption rather than an abnormal excretion.

Vines (9) stated, without data, in his book on the relation of theparathyroid glands to disease, that calcium is lost from the body dur-ing diabetes mellitus and Graves' disease and retained by myxedema-tous individuals.

In view of the undoubted importance of the thyroid secretion oncalcium metabolism and the disagreement in the findings of previousauthors, it seemed desirable to reinvestigate this subject.

EXPERIMENTS

Wehave studied the calcium, phosphorus and nitrogen excretion in aseries of patients with various thyroid diseases. The calcium excretedby an individual while on a diet adequate in all respects except incalcium should represent chiefly the endogenous calcium metabolism.Our results demonstrate conclusively that increased thyroid secretioncaused a striking accentuation of the calcium excretion and likewiseincreased phosphorus and nitrogen elimination.

The methods used have been described in a previous communica-tion (10). The daily diets were practically identical for each indi-vidual and except for their very low calcium content were well balancedand adequate. There was, however, a temporary negative nitrogenbalance in the patients very toxic from exophthalmic goiter. The lowcalcium diet has a twofold value for it not only permits a more ac-

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CALCIUM AND PHOSPHORUSMETABOLISM. I1I

curate evaluation of the endogenous calcium metabolism, but it alsolargely eliminates the unknown factor of unabsorbed calcium foundin the feces.

RESULTS

Serum calcium

In this series of 14 cases it was found that the serum calcium andphosphorus values remained within the accepted normal limits, thougha few cases suggested a slight fall in these values during the period ofobservation. The serum findings gave no indication of the rate ofcalcium metabolism, as may be seen when the data on calcium andphosphorus excretion are examined.

Calcium excretion

1. In exophthalmic goiter. Our normal standards for calcium ex-cretion have been obtained from thirteen normal individuals who weremaintained upon a similar diet inadequate in calcium. These dataare to be found in Paper II of this series.

The most obvious conclusions which can be drawn from our dataare the marked increase of calcium excretion in exophthalmic goiterand hyperfunctioning adenomata of the thyroid, and the striking de-crease found in myxedema. (See table 4 and chart 1.) This increase isout of proportion to the increase in the basal metabolic rate, for thoughthe latter averages only 55 per cent above the normal in our six casesof exophthalmic goiter, the average calcium excretion is 170 per centabove our average control figures. These results are even more strik-ing than they appear, for the average normal calcium excretion of0.79 gram per three day period is based on the total excretion of menof average weight of 62 kgm., while the thyroid patients were thinindividuals, some of them women, with an average weight of 50 kgm.Whencalculated for three day periods, the average calcium excretion forthe normal individual becomes 12.7 mgm. per kilogram of bodyweight, and for the patients with exophthalmic goiter 42.0 mgm. perkilogram of body weight, which is an iiicrease of 231 per cent abovenorrhal. This increase in calcium excretion is shown most strikinglyin the case of Norman G. (chart 4), where 4.6 grams of calcium were

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J. C. AUB, W. BAUER, C. HEATHAND M. ROPES

excreted in 3 days instead of 0.79 grams, the average found in thenormal persons. Expressed in milligrams per kilogram of body weight,he excreted 96.4 mgm., which is 8 times the average excreted by ournormal individuals on the same intake. This was out of all propor-tion to the change in his metabolic rate which was approximately

ADOciJon. t2 20 1 r4m LS 88 9 rT F"W. a 3 toXW al TOPlwI 20

CHART 1. A GRAPHIc REPRESENTATIONOF THE CALCIUM METABOLISmDATAGIVEN IN TABLE 4, IN THE CASES OF NORMANG., CHRISTINE B., AND

HERBERTF.The double cross hatching represents the calcium intake, the single cross hatch-

ing up to the heavy dark line represents the urinary calcium excretion, the singlecross hatching above the heavy black line represents the fecal calcium excretion.

twice normal. As his basal metabolic rate returned towards normal,the calcium excretion also approached normal. This was found to betrue in all our other cases also. The calcium excretion in the urinealone was far higher than the total excretion found in our controlcases. The increased calcium excretion in both urine and feces inthyrotoxic patients was about proportional. Because of the inade-

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CALCIUM AND PHOSPHORUSMETABOLISM. III

quate calcium intake on our routine diet, this increased calcium excre-tion must represent largely calcium loss from the body.

2. In toxic adenomata. Added evidence of the effect of thyroidon calcium metabolism was furnished by two typical cases with hyper-functioning thyroid adenomata in which the basal metabolic rateswere not as high as in those suffering from exophthalmic goiter. The

16 Apr26 1 oy 10 15 26foi Apr 10 20 2.6Por Aprl0

CHART 2. A GRAPIc REPRESENTATIONOF THE CALCIUM METABOLISMDATASHOWNIN TABLES 5 AND 7

The calcium intake, urinary calcium excretion and fecal calcium excretion are

represented in the same manner as shown in chart 1.

calcium, phosphorus and nitrogen excretions were likewise less ele-vated than in the series of patients with Graves' disease. (Seetable 5.) With this small number, however, it is impossible to saythat there is any fundamental difference in the calcium excretion inthe two diseases. The calcium excretion in these two cases was abovenormal and fell definitely after the adenomata were removed (chart 2).

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J. C. AUB, W. BAUER, C. HEATHAND M. ROPES 103

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104 CALCIUM AND PHOSPHORUSMETABOLISM. III

3. During thyroid medication. The foregoing observations were cor-roborated by the feeding of thyroid extract to two normal individuals.

Cxophtholmic Adenomo of Notmol Myxedemo ThrothyroidGoiter Thyroid Controls Tetony

CHART4. A COMPOSITECHARTSHOWINGTHE AVERAGECALCIUM METABOLISMIN 6 CASES OF EXOPHTHALMIc GOITER, 2 CASES OF ADENOMATAOF THETHYROID, 15 NORMALINDIVIDUALS, 6 CASES OF MYXEDEMAAND 2 PA-TIENTS SUFFERINGFROMPARATHYROIDTETANY

The calcium intake is represented by double cross hatching, the urinary calciumexcretion by the single cross hatching below the heavy line, and the fecal cal-cium excretion by the single cross hatching above the heavy black line.

Their calcium excretion was first determined for two control periodson a low calcium diet and then thyroxin and thyroid extract weregiven in doses sufficient to raise their basal metabolism and produce

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J. C. AUB, W. BAUER, C. HEATHAND M. ROPES

some of the symptoms of thyrotoxicosis. (One of them (Clark H.)complained of fever, malaise, rapid pulse and nervousness for two days.)The administration of thyroid raised definitely their calcium excretion(chart 2 and table 7), although prolonged observations on patientswith tetany indicate that these two control experiments were not con-tinued sufficiently long to observe the maximum effect of thyroid oncalcium metabolism. This observation does not agree with the find-ings of Boothby and his co-workers (11) who found no increase incalcium excretion after a single dose of 7 mgm. of thyroxin, but this

TABLE 1

Patients with thyroid disease

u\i thMetabolic balances

0 o 0~~~~~~

cm. kgm. Per grams grams grams grams gramscent

HazelW.,myxedema, 9 ..... 23 164 52.8 -32 2,400-0.27-0.01 +1.4 12.2Eliz. B., exophthalmic goiter,

Q*................ . 27 163 49.5 +704,330 -1.39 -1.60 -19.3 42.8Eliz. B., exophthalmic goiter,Qt. .... +40 7,850 -1.36 -1.01 -1.4 24.3

Chris. B., exophthalmic goiter,Q *................. . 22 140.5 42.9 +54 7,530'- 1.81 -0.37 -1.2 33.5

* Periods II and III during which no medication was given.t Periods Vand VI in which Lugol's solution was being taken.

discrepancy is probably due to the smaller thyroid dosage given inBoothby's case.

4. In myxedema. If the thyroid secretion increases calcium ex-cretion, then myxedema may be expected to be associated with a di-minished calcium output. This was clearly established in our sixcases, for their average excretion was 40 per cent below the normalaverage. With an average weight of 66.3 kgm. they excreted 7.2 mgm.per kilogram of body weight-as compared to 12.7 mgm. in our normalcontrols. Without any change in their dietary intake, feeding thy-roid to these patients resulted in an increase both in metabolism andin calcium excretion. (See table 6 and chart 3.) This demonstrates

105

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J. C. AUB, W. BAUTER, C. HEATHAND M. ROPES

again that thyroid increases the endogenous calcium metabolism, forthe extra elimination must come from the tissues, and presumablymostly from the bones. Similarly, two cases of parathyroid tetanywith very low calcium levels in both their blood and excreta re-sponded to thyroid therapy by a distinct elevation not only of theircalcium excretion but also of their serum calcium level. This effectwas prolonged and greatly benefited their general condition (12).

It is thus definitely established that increased thyroid secretion aug-ments the excretion of calcium. This effect of thyroid secretion oncalcium excretion is greater than its effect upon total metabolism.Thus the percentage variations from the normal controls, as shown inchart 4, indicate this marked difference, although the limits of varia-tion of calcium metabolism are not as definitely established as thosefor the basal metabolic rate. The differences, however, exceed greatlythe limits of variation in our normal series.

The marked effect of thyroid activity in three women can well becompared (Elizabeth B. and Christine B., who had Graves' disease,and Hazel W. who had myxedema). They were all young, and Eliz-abeth B. and Hazel W. were remarkably similar in age, height andweight. The thyroid effects are obvious from table 1.

5. In other states of increased basal metabolism. Is the high calciumexcretion of hyperthyroidism dependent on the increased thyroid se-cretion, or is it merely an accompaniment of an increased metabolism?This question could only be answered by determining the calcium ex-cretion in cases with a high metabolism due to factors other than thethyroid, such as prolonged fever and leukemia. Three such cases-two suffering from subacute bacterial endocarditis, and one fromlymphatic leukemia-showed a normal calcium excretion on our routinediet. A fourth case (M. G. B.), suffering from myelogenous leuke-mia, showed an elevated calcium excretion approaching that foundin hyperthyroidism. Three of the four cases, therefore, demonstratednormal calcium excretion in spite of an elevation of general metabo-lism. The basal metabolic rates in these four cases varied from plus21 to plus 41 per cent. Wemay conclude therefore that an increasedcalcium excretion is not necessarily a function of an elevated meta-bolic rate alone.

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CALCIUM AND PHOSPHORUSMETABOLISM. III

X-rays of bones in exophthalmic goiterIt is not to be expected that all cases of hyperthyroidism would show

osteoporosis of the bones because of this increased calcium elimina-

__~~~K

FIG. 1. SINGLE X-RAY OF THE, HANDsOF THREEWOMENOF SimsnAR AGE, SIZEAND WEIGHT

C is a normal control; E is the hand of a patient who is known to have hadexophthalmic goiter for seventeen years; M is the hand of a case of severemyxedema.

tion, which could probably be compensated for by a diet containingan adequate amount of calcium. In some cases of long duration, how-ever, this increased calcium loss from the bones may be apparent inx-ray pictures. This is obvious in the x-ray pictured in figure 1, where

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J. C. AUB, W. BAUER, C. HEATHAND M. ROPES

the hands of a patient with exophthalmic goiter of 17 years' duration,a case of myxedema, and a normal control are all shown in the sameexposure. These individuals (all women) were approximately thesame as regards age, weight and the shape of the hands. The marked

CHART5. A GRAPImcREPRESENTATIONOFTHE PHOSPHORUSMETABOLISmDATAGIVEN IN TABLE 4 IN 3 CASES OF EXOPHTHALMCGOITER

The phosphorus intake is represented by a cross, the heavy black line dividesthe fecal and urinary phosphorus excretions, the part of the column below beingthe urinary phosphorus excretion, and the part above being the fecal phosphorusexcretion. The nitrogen balance is represented by o------ 0; that above thezero line represents a negative nitrogen balance, and that below, a positive nitro-gen balance.

loss of calcium in this case of hyperthyroidism is very striking. Wehave seen one similar case, although less marked. This observationof osteoporosis in thyroid disease has recently been confirmed byPlummer (13).

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CALCIUM AND PHOSPHORUSMETABOLISM. III

Phosphorus metabolism

Phosphorus metabolism determinations were made in connectionwith those of calcium in all of these experiments. This gave us anopportunity to find out whether the calcium loss from the body as aresult of thyrotoxicosis represents calcium phosphate withdrawn fromthe bones. If that were the case there should be a ratio such thatthe calcium loss to the phosphorus loss would equal that of calciumto phosphorus in tertiary calcium phosphate (Ca/P = 1.93). In ad-dition a correction should be introduced for the phosphorus liberated

- ZjIII I1111ZZ III I"' Z11ZE IMGene. T 1wI T 1Q M. Jo1 hn I 1

!1T~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~1CHART6. A GRAPHIc REPRESENTATIONOFTHE PHOSPHORUSMETABOLISMDATA

GIVEN IN TABLE 6 ON FOURCASES OF MYXEDEMA

The phosphorus intake, urinary phosphorus excretion and fecal phosphorusexcretion are represented as in chart 5.

in protein metabolism (N/P = 17.4). In table 3 there is includedthe actual phosphorus balance and the theoretical phosphorus balancecalculated from the calcium and nitrogen balances as above described.In general the actual and theoretical balances agree as closely as couldbe expected. This supports the supposition that the increased cal-cium excretion represents, for the most part at any rate, calcium phos-phate withdrawn from the bones. That some of this calcium mayrepresent calcium carbonate withdrawn from the bones as suggestedby Goto (14) is of course possible.

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J. C. AUB, W. BAUER, C. HEATHAND M. ROPES

TABLE 3

Phosphorus excretion

Phosphorus Phosphorus 9excretion calculated from

Periroaedeou eos ' RemarksAculCakcu- Endo- Endo- v

Actual__|_ ltdcalcium nitrogen 3 _ __

Exophthalmic goiter

IIIII

IVV

VIVII

grams

-4.99-4.52

-3.92-3.10-2.50-0.60

grams

-5.37-4.39

-3.81-3.01-2.40-1.88

grams

-2.37-2.08

-1.88-1.52-1.34-1.24

VIII -3.55 -2.12-1.19IX -0.06 -1.21 -0.58

grams

-3.00-2.31

-1.93-1.49-1.06-0.64

-1.53-0.63

percent

+86+76

+79+52+56+41

+44

X 1+1.21 1+0.191-1.111+1.301 +19

XI

XII

XIII

XIV

XV

+0.2851-1.031-1.43

+1.667+1.925+2.180

-0.351-1.02

+0.571 -0.68

+0.40

+0.67+1.27+1.25

II -0.61 -1.20-0.73-0.47III -2.59 -2.40-0.651-1.75

IVV

VIVII

VIII

IX

X

XI

XII

XIII

XIV

XV

-1.15-1.13-0.95-0.71-0.06

+0.16-1.16+0.01+1.06+1.32+0.69+0.45

-1.28-0.59-0.94-0.88+0.07

+0.30-0.71-0.36+0.22+0.67+0.15+0.39

-0.40-0.59-0.77-0.57-0.33

-0.30-0.29-0.30-0.32-0.12-0.43-0.42

-0.880

-0.17-0.31+0.40

+0.60-0.42-0.06+0.54+0.79+0.58+0.81

+18

kgm.

56.3

48.348.348.2

46.0

48.0

+701 49.0

+40+43

46.745.5

+161 46.5

+71 43.9

+81 53.4

Lugol's solutionstarted

Subtotal thyroid-ectomy

Lugol's solution dis-continued

House diet for 3weeks

Tonsillectomy.House diet, for 1week

Lugol's solutionstarted

Subtotal thyroid-ectomy

Norman, G.Age 29(see Table 4)

Elizabeth, B.Age 27(see Table 4)

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CALCIUM AND PHOSPHORUSMETABOLISM.

TABLE 3-Continued

Phosphorus Phosphorus NU

excretion calculated fromPeriod

Ai ~~~~~~~~~Remarksnumb.er Endo- Epdo- 'oActual lated g |fnou s

calcium nitrogen ~__

Normal controls

groms grams grams grams p kgm.

I -1.69 -1.08-0.30-0.78 0II -0.04 -0.36-0.27-0.09

Clark H. III -1.13 -0.80 -0.34 -0.46 -6 ThyroidstartedAge 25 IV -1.83 -0.89-0.27-0.62(see Table 7) V -1.08 -2.00 -0.54 -1.46 +16 Thyroid stopped

VI -0.85 -1.19-0.51-0.68VII -4.03 -1.46-0.55-0.91 +48

I -0.11 -0.43-0.12-0.31 -15II -0.57 -0.60-0.27-0.33 -12

Clement I. K. III -0.85 -0.62-0.22-0.40 -7 Thyroid startedAge 27 IV -1.13 -0.66-0.18-0.48(see Table 7) V -0.80 -0.81 -0.33 -0.48 +8 Thyroid stopped

VI -1.34 -1.88 -0.36 -1.52VII -0.68 -0.94-0.29-0.65 +2

Myxedema

I +0.18 +0.09-0.10 +0.19 -38 52.3

Hazel B. W.' II +0.19 -0.20-0.17-0.03 -25 Thyroid, grs. VIAg 23 dailyAsee 23le6 III -0.75 -0.52 -0.30 -0.22 -16 50.6(see Table 6)l| IIIV -1.12 -136 -0.36 -100 - 7

V -0.40 -0.931-0.351-0.58 -9 50.7

DISCUSSION

Thyroid secretion has been shown to increase markedly calcium ex-cretion. The cause of this is as yet undetermined. There are sev-eral possibilities:

1. A stimulating effect on the parathyroid glands directly or throughtheir sympathetic innervation. The absence of any marked rise in theserum calcium is very much against this, although Hunter and Aub(15) reported a case in which the administration of Couip's parathy-roid extract increased the calcium excretion without appreciably rais-

12 HII

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J. C. AUB, W. BAUER, C. HEATHAND M. ROPES

ing the serum calcium level. Work now in progress will probablydetermine this possible relationship.

2. A method of neutralizing the acid products of an increased metab-olism. The neutralization of the phosphorus set free as a result of theincreased protein metabolism might account for the increased calciumexcretion. Such an explanation would be analogous to the increasedcalcium output following the injection of phosphates found byGreenwald (16). However, unpublished observations (14) from thislaboratory, on normal people following the administration of largeamounts of acid phosphate, showed that a large part of this neutrali-zation was accomplished by ammonia. The increased calcium excre-tion in these cases was not as marked as was observed in our cases ofexophthalmic goiter. The other acid products resulting from an in-creased protein metabolism might call upon the calcium deposits in asimilar manner. Studies on the total acid-base metabolism in hyper-thyroidism and myxedema are now being made and should help decidethis point.

3. The remaining explanation, namely a direct stimulating cataboliceffect on the calcium deposits in the bones, seems the most likely one,and this would be in agreement with the general action of thyroid onother body tissues. It remains, however, for future work to estab-lish thii.

CONCLUSIONS

1. The calcium excretion in patients with exophthalmic goiter andin those with hyperfunctioning thyroid adenomata is increased mark-edly above the normal. This increase (231 per cent) is far greaterthan the increase in basal metabolic rate (55 per cent).

2. The ingestion of thyroid by normal individuals likewise increasesthe calcium elimination.

3. The calcium excretion in myxedema is markedly diminished be-low that found in normal individuals.

4. A marked increase in phosphorus excretion was also found. Thisincrease was quantitatively such as to suggest that most of the calciumexcreted came from tertiary calcium phosphate in the bones.

5. This high rate of calcium elimination is not obvious in the blood,

113

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CALCIUM AND PHOSPHORUSMETABOLISM. III

for essentially normal values for calcium and phosphorus are foundin the serum.

6. X-ray evidence is presented which indicates that marked osteo-porosis may develop in the bones from prolonged hyperthyroidism.

7. The increased calcium excretion is not dependent upon the ele-vated metabolism alone, for three out of four cases with high metab-olism due to leukemia or fever had normal calcium eliminations.

PROTOCOLS

Norman G. No. 273649. Age 29 years, white, male, married. Admitted:December 17, 1925. Discharged: February 28, 1926.

History. One brother had a goiter with hyperthyroidism. Patient has beenmarried nine years. He has three children. One child died at age of 2 months.Nine months previous to entry patient noticed nervousness, palpitation, andtremor of extremities. Dyspnea and headache were present on exertion. Therewas a gradual progression of symptoms until four months previous to entrywhen swelling of neck and prominence of eyes was noticed with slightly increasedsweating. One month previous to entry he had a sense of constriction in histhroat and slight constipation. He has had nocturia for five or six months.

Physical examination. He was a nervous, restless, sweating, flushed young manwith slight prominence of the eyes. There was slight lid lag. There was a finetremor of fingers and tongue. Tonsils were very large and cryptic. Thyroidwas symmetrically enlarged, firm and smooth, with definite bruit. Heart showedno enlargement. There was a systolic murmur over the preCordium. There wasa palpable thrill at the apex. Skin was warm and moist.

Laboratory findings. Urine was examined five times-there were a few redblood cells on three occasions and sugar was slightly positive on three occasions;otherwise urine was negative. Blood-red count was 4,450,000; white count7100; hemoglobin 80 per cent. Differential count showed polymorphonuclears45 per cent, small lymphocytes 48 per cent, large lymphocytes 6 per cent, and mastcells 1 per cent. Wassermann was negative. Non-protein nitrogen was 34 mgm.per 100 cc. Phthalein excretion was 35 per cent. Basal metabolic rate on De-cember 19, 1925 was plus 99 per cent with a weight of 48.3 kgm.

Treatment and progress. He had complete rest in bed and after ten days,Lugol's solution was started. On January 8, 1926, he had a sub-total thyroidec-tomy with uneventful recovery. On January 26, 1926, he had an attack of acutetonsillitis with a fever of 104.5 degrees F. which lasted ten days. On February 3,1926, he had a tonsillectomy and adenoidectomy performed.

Impression. This was a most severe case of exophthalmic goiter, greatly im-proved but not cured by operation. This condition was complicated by severelyinfected tonsils.

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J. C. AUB, W. BAUER, C. HEATHAND M. ROPES

George R. A. No. 275358. Age 24 years, white, male, married, truck driver.Admitted: March 24, 1926. Discharged: April 29, 1926.

History. For years he has had frequent frontal headaches. For three yearshe has had shortness of breath and severe palpitation on exertion which has grad-ually become more intense. He also has had an occasional, non-radiating, stab-bing, precordial pain. For one year he has noticed an increasing weakness,emotional instability, and a feeling of heat with marked sweating. He had amarkedly increased appetite but good digestion and regular bowels. His neckwas growing larger.

Physical examination. He was well developed and nourished. Skin wasmoist. There was tremor of the hands. There were visible pulsations in hisneck. Thyroid was enlarged with marked bruit. There were no eye signs.There was a diastolic murmur heard at the left border of the sternum. Bloodpressure was 210/75. There was a capillary and corrigan pulse. Heart rate was130.

Laboratoryfindings. Urine and blood were normal.Treatment and progress. He had complete rest in bed and after two weeks

Lugol's solution was started. On April 17, 1926, a sub-total thyroidectomy wasdone. He had an uneventful recovery. Pathological report showed follicularhyperplasia.

Impression. This was a case of aortic regurgitation with a very mild Graves'disease. Operaton was advised largely because of the heart lesion and it pro-duced a marked general improvement.

Herbert B. E. No. 275575. Age 34 years, married, white, male, mail carrier.Admitted: April 5, 1926. Discharged: May 23, 1926.

History. He has been married ten years and has three children. One childdied at 5j months from lobar pneumonia. His wife has liver enlargement andsome cardiac decompensation. He had a Neisserian infection fifteen years ago.For a year he has noticed prominence of his eyes. Gradually he noted definitenervousness and irritability, excessive perspiration with a voracious appetitebut loss of strength and 22 pounds in weight. For two weeks he has noticed amuch enlarged thyroid with increased tremor of his hands, palpitation, anddyspnea on exertion. He has had three transient attacks of precordial painin the past month.

Physical examination. He was fairly well developed and nourished and in nodistress. He was very nervous. Skin was moist and warm, with tan pigmenta-tion. There was marked bilateral exophthalmos and lid lag. Thyroid wassymmetrically enlarged. There was lumbar lordosis. Heart showed a forcefulapex impulse but was not enlarged. Sounds were rapid and regular. Bloodpressure was 175/75. There was a fine tremor of the hands.

Laboratoryfindings. Urine was normal. Blood showed a red count of 4,680,000;white count 8,150, and hemoglobin of 75 per cent. Differential count showedpolymorphonuclears 61 per cent, small lymphocytes 12 per cent, large lympho-

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CALCIUM AND PHOSPHORUSMETABOLISM. III

cytes 25 per cent, and eosinophiles 2 per cent. Non-protein nitrogen was 29mgm. per 100 cc. Wassermann was strongly positive on two examinations. Basalmetabolism on April 7, 1926 was plus 48 per cent.

Treatment and progress. He had complete rest in bed and Lugol's solution wasstarted after two weeks. On April 29, 1926 a sub-total thyroidectomy was done.Pathological report showed follicular hyperplasia. Following operation he hadtypical lobar pneumonia of the left lower lobe with a crisis on the eighth day.Basal metabolic rate on May 20, 1926 was minus 18 per cent.

Impression: Exophthalmic goiter; tertiary syphilis.

Rose Lee K. No. 275699. Age 63 years, female, white, married, housewife.Admitted: April 12, 1926. Discharged: May 23, 1926.

History. Patient has had fourteen children of whomseven died from obstetricaloperations and three died in infancy. She has had no miscarriages. She has hadrecurrent tonsillitis. She also has had pleuritis and pneumonia. She had hermenopause at 53 years of age.

Present illness. She was always a hard worker. For the past year she hadnoticed increasing fatigue, nervousness, palpitation, and trembling of hands.Swelling in her neck was noticed ten months previous to entry. Appetite becamepoor and she had epigastric distress relieved by food, and difficulty in swallowing.For six months she has had shortness of breath and orthopnea. She was easilyirritated and perspired easily. She has lost 57 pounds in weight.

Physical examination. Patient was poorly developed and nourished, appre-hensive, and nervous. There was slight exophthalmos, blepharitis, and slightlycongested -pharynx. Her thyroid was asymmetrically enlarged, nodular, andvery firm. There was local glandular enlargement. Heart was enlarged to theleft. Rate was rapid and regular. Liver edge was palpable. Blood pressurewas 180/70.

Laboratory findings. Urine was normal. Blood showed red count of 5,200,000;white count 15,000; and hemoglobin 70 per cent. Differential count showedpolymorphonuclears 63 per cent, small lymphocytes 29 per cent, large lympho-cytes 7 per cent, and mast cells 1 per cent. Non-protein nitrogen was 26 mgm.per 100 cc. Wassermann was negative. Basal metabolic rate on April 15, 1926was plus 87 per cent.

Treatment and progress. She had complete rest in bed and after eleven daysLugol's solution was started. On May 6, 1926, a sub-total thyroidectomy wasperformed. Pathological report showed follicular hyperplasia. Basal metabolicrate on discharge was plus 27 per cent.

Impression. Exophthalmic goiter.

Christine B. No. 274688. Age 22 years, female, white, married, hospitalward maid. Admitted: February 15, 1926. Discharged: April 3, 1926.

History. She was separated from her husband. She had had no pregnancies.She was strong and well up to present illness. She noticed a goiter one year

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J. C. AUB, W. BAUER, C. HEATHAND M. ROPES

previous to entry and had been easily upset emotionally with crying and nervousspells. For one month she had noticed palpitation, slight prominence of her eyes,increitsed sweating, and slight difficulty in swallowing.

Physical examination. She was a well developed and nourished, very shortyoung woman who felt hot. There was definite exophthalmos. There was afine tremor of hands and tongue. Thyroid was symmetrically enlarged, firm,with bruit. Heart was rapid and regular with no enlargement.

Laboratory findings. Urine was negative. Blood showed red count 5,656,000;white count 8,000, and hemoglobin 80 per cent. Smear showed polymorphonu-clears 78 per cent, small lymphocytes 20 per cent, and large lymphocytes 2 percent. Non-protein nitrogen was 32 mgm. per 100 cc. Wassermann was negative.Basal metabolic rate on February 17, 1926 was plus 76 per cent, pulse 116, andweight 43.8 kgm.

Treatment and progress. Patient had complete rest in bed and Lugol's solutionwas started at the end of two weeks. On March 12, 1926, a subtotal thyroidec-tomy was done. Her basal metabolic rate at time of discharge was minus 7per cent. Patient was apparently cured by the operation.

Impression. Severe exophthalmic goiter.

Elizabeth B. No. 274040. Age 27, female, white, single, stenographer.Admitted: January 9, 1926. , Discharged: March 3, 1926.

History. Rheumatic fever at eight years for six months. She had two attacksof tonsillitis. Catamenia was somewhat irregular. For ten years she had beennervous, marked by very easy excitability, crying and insomnia. She had grownworse in the last three months and had lost 15 pounds in spite of an increasedappetite. She had a feeling of warmth, fatigue, and palpitation. For ten daysshe had noticed swelling in her neck. She felt quite tired.

Physical examination. Patient was nervous and twitchy. She was well devel-oped but slightly thin with moist skin. Throat and tonsils were slightly red.There were no definite eye signs. Thyroid showed moderate, smooth, diffuse en-largement greater on the right with a marked bruit. Heart was enlarged. A dias-tolic murmur was heard by one examiner only. Blood pressure was 144/80.

Laboratory findings. Urine showed a few white cells, otherwise negative onfive examinations. Blood: red count 4,300,000; white count 8,000; hemoglobin70 per cent. Diiferential count showed polymorphonuclears 50 per cent, smalllymphocytes 40 per cent and large lymphocytes 10 per cent. Wassermann wasnegative. Non-protein nitrogen was 29 mgm. per 100 cc. Basal metabolism onJanuary 11, 1926, was plus 79 per cent.

Treatment and progress. Patient had complete rest in bed and Lugol's solutionwas started at the end of eleven days. During her stay in the hospital she had sev-eral attacks of severe pain in her joints accompanied by slight fever and a rise in herwhite blood count. Joints were all slightly swollen, warm, tender, but not red.She was relieved by salicylates. February 13, 1926, a subtotal thyroidectomy wasdone. Pathological report showed follicular hyperplasia.

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10 CALCIUM AND PHOSPHORUSMETABOLISM. III

Treatment and progress. She was greatly improved by the operation and leftthe hospital apparently well. Basal metabolism on February 23, 1926 was plus7 per cent.

Impression. Moderately severe exophthalmic goiter-complicated by a mildattack of rheumatic fever.

Sophia J. K. No. 277495. Age 58 years, married, white, female. Admitted:July 15, 1926. Discharged: August 8, 1926.

History. Patient was in good health until three years ago when she first noticeda lump in the right side of her neck which had gradually increased in size. Shethen became nervous and "fidgety." This increased so that two years ago herhands began to tremble, enough to bother her in writing. She also has noticedsome palpitation and shortness of breath on the slightest exertion. There hasbeen no increased perspiration. For the past three years she has had occasionalstabbing pains in the lumbar region. During the past seven months she has hada vaginal discharge which is watery, at times bloody, and at other times purulentand bloody, no odor. She had measles and whooping cough as a child and rheu-matism twenty years ago. Thirty years ago she was treated for metritis. Elevenyears ago she had two uterine tumors removed.

Physical examination. She was a nervous woman with marked coarse tremorof hands but no exophthalmos. There was a smaU round hard mass in the rightlobe of the thyroid. There was a blowing systolic murmur at apex. Heart wasnormal in size. Blood pressure was 150/70. She had a moderate cystocele and amarked bloody discharge from the uterus.

Treatment and progress. Operation was performed with excision of adenoma.Dilatation and curettage was done; the curettings showing tuberculosis.

Impression. Toxic adenoma of thyroid; tuberculous endometritis.

Margaret D. No. 269527. Age 48 years, white, married, female. Admitted:April 8, 1926. Discharged: May, 13, 1926.

History. She has been married twice. First husband divorced. She hasone child living and well. Menopause occurred at 44 years. Patient entered thehospital one year previous to present entry complaining of nervousness of 8 monthsduration, some dizziness and dyspnea, increased perspiration, dislike of warmplaces, slight palpitation for one month, with a tight feeling in her throat. Shehad noticed enlargement of the thyroid for some time. She refused operationat that time. Two treatments by x-ray were without benefit and she feels shehas grown worse since her first entrance. Dyspnea and weakness are increased.She is emotionally unstable and she has noticed an increase in the size of her neckwith some difficulty in swallowing.

Physical examination. She was a well developed and fairly well nourishedwoman with considerable brownish pigmented areas of the skin. There 'wasmoderate exophthalmos and some tremor of fingers. The right lobe of the

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thyroid had a solid, nodular enlargement, approximately 5 by 5 cm. with a leftlobe not appreciably enlarged. Heart showed no enlargement. There was asystolic murmur at the aortic area. Blood pressure was 124/80.

Laboratory findings. Urine was negative. Blood was negative. Wassermannwas negative. May 10, 1926, non-protein nitrogen was 26 mgm. per 100 cc.

Treatment and progress. She had complete rest in bed and Lugol's solutionwas started after seven days. April 28, 1926 a lobectomy was performed.Pathological report: "Probably comes within limits of normal thyroid except forfew miliary adenomata." She made an uneventful recovery. Patient was veryquiet and calm when discharged. Basal metabolic rate on discharge was plus5 per cent.

Impression. Adenoma of thyroid with mild toxicity.

John Francis W. No. 277489. Age 63 years, widower. Admitted: July 15,1926. Discharged: August 14, 1926.

History. He dated his present pallor back twenty years. He said it came onfollowing a "drinking bout" and had been present ever since. He thought his skinwas more dry, coarse, and yellow than formerly. Several years later he noticedhis body hair (eyebrows, chest, axillary and pubic) began to fall out. Forthe past three years he had noticed he could not stand cold weather. He had hadincreasing weakness and inability to endure exercise. He was drowsy most of thetime and said his memory was very poor for recent events. He had noticed in-creased constipation for the past few years. Appetite was fair. He had had puffyeyes of late. He could not obtain work as a collector because of his appearance.There had been no increase in weight.

Physical examination. He was a very obese man of 63 with a marked pallor ofhis mucous membranes. Skin had a yellow tint, was coarse, dry and appearededematous-did not pit on pressure. His eyebrows were almost absent, as wasthe hair of his axillae, chest and pubic region. His tongue was thick. Speech wasslow and sluggish. There was a perforation of the nasal septum. Lungs showedchronic bronchitis. Heart was negative. Blood pressure was 160/74. Vesselsshowed moderate sclerosis.

Laboratory findings. Urine, blood and Wassermann were all negative. Non-protein nitrogen on July 15, 1926 was 30 mgm. per 100 cc.

Progress and treatment. Patient was studied for 14 days before therapy wasstarted. On July 31, 1926 he was started on thyroid extract grains 6 per day.On thyroid therapy he was greatly improved. Basal metabolic rate on August8, 1926 was minus 14 per cent.

Impression. Myxedema; arteriosclerosis; emphysema and chronic bronchitis.

Hazel B. WV. No. 277422. Age 23 years, single, white, female. Admitted:July 12, 1926. Discharged: August 12, 1926.

History. For years patient had suffered from backache which was relieved byrest. For the past eight months she had had increasing general weakness often

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CALCIUM AND PHOSPHORUSMETABOLiSM. III

accompanied by shortness of breath requiring rest after she had walked a fewhundred yards. For the past six months she had been sensitive to cold, in factshe felt cold most of the time. She also had noticed she perspired very little andthat her skin was dry and much coarser than previously. During this same periodher memory had become poor. At times her tongue had felt swollen and tender.With the above symptoms she had increased gradually in weight so that at thetime of entry she weighed 130 as compared with her best previous weight of 102.Appetite was poor. She had been constipated for years. Catamenia had beenabsent for the past 2j years.

Physical examination. She was a young womanof 23, well developed and nour-ished. She appeared drowsy and apathetic. Face had a puffy appearance espe-cially about the eyes. Skin was coarse and dry. Hair was coarse. She had adefinite pallor. Blood pressure was 80/60.

Laboratory findings. X-rays showed an enlarged sella turcica and sacroiliacarthritis. Electrocardiogram showed the T2 to be 1 mm. with small complexesand a rate of 85. Wassermann was negative. Blood-red count was 3,720,000,white count 7,500, hemoglobin 80 per cent. Non-protein nitrogen was 26 mgm.per 100 cc. Phthalein excretion was 5 per cent.

Follow-up notes. September 11, 1926. She did not mind the cold. Herstrength seemed to have returned. Appetite was better. She talked much faster.Her skin was softer. She weighed 108 pounds. She was taking thyroid grains6 daily. Basal metabolic rate was plus 35 per cent. Thyroid was cut down tograins 2 per day because of the high basal metabolic rate.

November 16, 1926. Menses returned last month, lasted seven days, requiredthree to four napkins per day. It was non-painful. Her basal metabolic rate wasplus 1 per cent but she had some symptoms of myxedema returning. Thyroidwas increased to grains 41 per day.

Impression. Myxedema.

Elizabeth M. D. No. 276291. Age 52 years, white, married, female. Firstadmisssion: May 13, 1926. Discharged: May 20, 1926. Second admission:June 2,1926. Discharged: July 2,1926.

History. She had her menopause seven years ago. She felt well until oneyear ago. At that time numbness and a cold feeling in her hands began. Shegained 28 pounds in one year. She had minded the cold especially during the pastwinter. Her skin always had been dry and she had not perspired much. Herhands had become broad and puffy in the past two years. She was not excitableand her memory had become poor. There had been very little loss of hair. Herappetite was good. She had no dyspnea and no palpitation. She had recentlystumbled over curbstones and for six months she had had difficulty in climbingstairs because of stiffness of the legs.

Physical examination. She was a well developed and nourished, obese woman-dull and apathetic. Skin was coarse and dry. Hair was rather coarse. Heart

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was not enlarged. The sounds were distant. There was a soft systolic murmurat the base. Abdomen was protuberant with diastasis recti. Extremities showedvaricose veins and slight edema of both ankles.

Laboratory findings. Urine was negative except for occasional white bloodcells and epithelial cells on four examinations. Blood-red count was 4,300,000.White count was 6,400. Hemoglobin was 60 per cent. Differential count showedpolymorphonuclears 64 per cent, small lymphocytes 30 per cent and large lympho-cytes 6 per cent. Non-protein nitrogen was 38 mgm. per 100 cc. Wassermannwas negative. Basal metabolic rate was minus 34 per cent. Weight was 73.5kgm.

Treatment and progress. She had complete rest in bed and during this timemetabolic studies were made. She was discharged on May 20th because of deathin her family. No treatment was started.

She returned, June 2, 1926. She was put on a low calcium diet and calciummetabolism studies were made before and during thyroid therapy.

Impression. Myxedema.

Mable H. M. No. 274766. Age 34 years, white, married, female. Firstadmission: February 19,1926. Discharged: February 25, 1926. Second admis-sion: April 6,1926. Discharged: April 28, 1926.

History. She had been married eight years. She had one child. She had hadno miscarriages. For ten years she had been troubled with a dull ache in her lowerback on bending forward and had felt tired. For five years this weakness andfatigue had become increasingly more severe. She noticed slowing of her mentalreaction and a feeling of coldness. Catamenia was always irregular and painful.She was nervous, irritable, and slept poorly. Three and a half years ago her basalmetabolic rate at the Homeopathic Hospital was minus 15 per cent and minus18 per cent. For two years she had noticed thickness of her tongue and lips withdifficulty in her speech. "Thyroid extract" at first resulted in headaches and pal-pitation but gave her relief.

Physical examination. She was well developed and nourished, with thick lipsand tongue. The skin of her face was slightly yellowish. Expression was slightlyapathetic. She had external hemorrhoids.

Laboratory findings. Urine was negative. Red blood count was 4,384,000;white count 8,600, hemoglobin 80 per cent. Differential count was normal.Non-protein nitrogen was 35 mgm. per 100 cc. Wassermann was negative. Basalmetabolic rate on February 20, 1926, was minus 17 per cent. Basal metabolicrate on April 8, 1926, was minus 29 per cent. Fundi were negative. X-rayshowed a large deep sella turcica.

Progreds. This patient was very much improved by thyroid therapy but wasstill nervous and easily upset emotionally. She tired very easily and had fre-quent frontal headaches.

Impression. Mild myxedema; question of pituitary tumor; sacro-iliac arthritis.

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Jennie W. No. 270359. Age 46 years, white, single, female. History ofprevious entry-June, 1925.

History. 'Iwo years ago she came to the Out Patient Department complainingof weakness, lack of ambition, loss of appetite and coldness of extremities. Ihesesymptoms had come on gradually over two years. Her speech was dull and list-less and she looked pale with pouches under her eyes. Menopause occurred sixyears ago. Basal metabolic rate on July 3, 1924, was minus 26 per cent. Basalmetabolic rate on July 22, 1924, was minus 32 per cent. She was given thyroidextract-grains 11 three times a day. Basal metabolic rate on August 11, 1924was minus 13 percent. Thyroidwas increased to 7igrains a day. Basal metabolicrate on September 5, 1924, was minus 1 per cent and patient felt better. Basalmetabolic rate on January 26,1925, was minus 24 per cent. Thyroid was reduced.Basal metabolic rate on April 10, 1925, was minus 13 per cent. She then enteredthe Hospital (June, 1925) and her condition was studied. Discharged: July 4,1925.

Second admission was on April 30, 1926. She returned because of recurrenceof symptoms. After discharge she was taking 7i grains of thyroid daily buther supply gave out about one month ago and symptoms slowly recurred.Basal metabolic rate on April 27, 1926, was minus 33 per cent.

Physical examination. She was well developed and nourished with slightpuffiness under her eyes. There was moderate pallor of her skin with very slightdryness.

Laboratory findings. Urine was negative. Blood shdwed a red count of4,216,000; white count 5,700, and a hemoglobin of 65 per cent. Differentialcount showed polymorphonuclears 38 per cent, small lymphocytes 47 per cent,large lymphocytes 4 per cent, mast cells 9 per cent and eosinophiles 2 per cent.Non-protein nitrogen was 23 mgm. per 100 cc. Basal metabolic rate was minus34 per cent. Wassermann was negative.

Treatment and progress. She had complete rest in bed. On May 14,1926,she developed a definite psychosis with delusions of persecution. She wanted toleave the hospital. She was given thyroxin, 10 mgm. intramuscularly. On May16, 1926, her psychosis was much improved, 48 hours after 10 mgm. of thyroxinintramuscularly, yet she retained certain ideas of persecution. The basal meta-bolic rate rose to plus 13 per cent on thyroid extract.

Impression. Myxedema complicated by mild psychosis.

Susan B. F. No. 265471. Age 48 years, white, married, female. Admitted:June 1,1926. Discharged: July 15, 1926.

In 1924 she was in the Massachusetts General Hospital with the diagnosis of:(1) strangulated internal hernia, (2) myxedema, (3) chronic cystitis. A lapa-rotomy for intestinal obstruction was done.

History. She was born and had lived in Halifax, N.S., until 7 years ago. Shehad nine children and no miscarriages. Her periods stopped when her last child

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J. C. AUB, W. BAUER, C. HEATHAND M. ROPES

was born 17 years ago. She had not felt well since then. At that time she suf-fered from weakness and shortness of breath and often had to rest. She noticedsome paleness and bloating of her skin with considerable drowsiness. After twoyears of these symptoms treatment with "pills and medicine" relieved her and sheremained fairly well until 1918 when she had influenza, after which she becameweaker and more short of breath on exertion. No other symptoms occurred untiltwo or three years ago when a new group appeared. Her face became morebloated, lid fissures narrowed, at times her eyes almost closed and she had swellingof her hands and ankles. Her skin was rough, pale, dry and flaked readily and in-creased thickness was especially noticeable over the extremities. Her hair fell out,was coarser and more brittle. Her feet have been cold during the past three orfour years. At times she had tingling and numbness of her fingers and toes.Her speech was more indistinct, slower and her tongue felt thick. Her memorywas bad; she remembered past events better than present. She had frequentdizzy spells. Her appetite was poor. She had been constipated for years.Occasionally she had short transient pains over precordium accompanied bysmothering and choking spells. All symptoms had grown progressively worseso that she needed a three to four day rest in bed every week. Apparently shehad not taken the thyroid extract which had been prescribed for her.

Physical examination. She was a pale, sluggish woman with well markededema about the eyes. Her skin was dry. Her hair was coarse and brittle.Tongue was large. Mucosae were pale. Heart was slightly enlarged to the left.Sounds were feeble and distant. There was a moderate amount of pitting edemaover the vertebral column from first lumbar vertebra down. Klnee jerks wereextremely sluggish. There was a reddish brown scar of an old varicose ulcer, overthe middle anterior surface of the left tibia.

Laboratory findings. Urine was negative except for occasional white blood cellsand hyaline casts on three examinations. Blood showed a red count of 3,088,000;white count 3,160; hemoglobin 45 per cent. Differential count showed poly-morphonuclears 44 per cent, small lymphocytes 46 per cent, large lymphocytes1 per cent, mast cells 4 per cent, basophiles 2 per cent, and eosinophiles 3 percent. Platelets were increased. Non-protein nitrogen was 38 mgm. per 100 cc.Basal metabolic rate was minus 35 per cent, weight 60.4 kgm.

Treatment and progress. She had complete rest in bed.June 7, 1926. Patient was very weak. She complained of weakness, pains in

elbows and knees. She seemed semi-stuporous at times. She had nausea andvomiting. Patient was given 10 mgm. thyroxin at 10:15 p.m.

June 10, 1926. Patient had sore throat with fever. Thyroxin 10 mgm. given.June 13, 1926. Patient had very low caloric intake and continued fever.

She complained of pain in the muscles of arms and legs. Thyroxin 10 mgm. againgiven.

June 22, 1926. She was weaker and very nauseated. She ate nothing andrefused to cooperate.

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136 CALCIUM AND PHOSPHORUSMETABOLISM. III

June 26, 1926. She seemed disoriented and irrational at times. Non-proteinnitrogen 80 mgm. per 100 cc. Serum phosphorus 8.8 mgm. per 100 cc. Whiteblood count was 4100. She was given 20 cc. of CaCl2 intravenously.

June 28, 1926. She was given 20 cc. CaCl2 again and 500 cc. 5 per cent dex-trose intravenously. Non-protein nitrogen today was 110 mgm. per 100 cc. Attimes she was irrational, at other times semi-comatose.

July 14, 1926. She was much improved, was eating again, and did not vomither food. She looked thin. The signs of myxedema had disappeared.

Impression. The most marked type of myxedema.

BIBLIOGRAPHY

1. Koeppen, H., Neurologisches Centralblatt, 1892, xi, 219. Ueber Knochener-krankungen bei Morbus Basedowii.

2. Pierallini, G., Lo Sperimentale (Archivio di Biologia normale e patoligica).1906, lx, 59. Sull eliminazione della calce e della magnesia in rapporto adalcune forme cliniche.

3. Scholz W., Ztschr. f. exper. Path. u. Therapie, 1905, ii, 271. Ueber den Stof-fwechsel der cretinen.

4. Silvestri, T. and Tossati, C., Gaz. degli Ospedali, 1907, xxviii, 1067. Di unafunzione della glandola tiroide non ancora ben studiata.

5. Falta, W., Wien. klin. Wochnschr., 1909, xxii, 1059. Weitere Mitteilungenuber die Wechselwirkung der Driisen mit innerer Sekretion.

6. Parhon, M., Memoires de la Societe de Biologie 1912, lxxii, 620. L'influencede la thyroide sur le metabolisme du calcium.

7. Kojima, M., Quart. J. Exper. Physiol., 1917, xi, 351. Studies on the Endo-crine Glands; V. Effects on Metabolism of Castration, of Thyroidectomy,of Parathyroidectomy and of Thyroid and Parathyroid Feeding.

8. Kummer, R. H., Rev. med. de la Suisse Romande, 1917, xxxvii, 439. Re-cherches sur le metabolisme mineral dans la maladie de Basedow.

9. Vines, H. W. C., The Parathyroid Glands in Relation to Disease. London,1924, E. Arnold and Co.

10. Bauer, W. and Aub, J. C., J. Am. Diet. Assoc., 1927, IlI, 106. Studies ofInorganic Salt Metabolism. I. The Ward Routine and Methods.

11. Deuel, H. J., Jr., Sandiford, I., Sandiford, K., and Boothby, W. M., J. Biol.Chem., 1928, lxxvi, 407. The Effect of Thyroxin on the Respiratory andNitrogen Metabolism on a Normal Subject Following Prolonged Nitrogen-free Diet.

12. Bauer, W., Albright, F., Rossmeisl, E., and Aub, J. C., Studies of Calcium andPhosphorous Metabolism. VI. In Parathyroid Tetany. To be published.

13. Plummer, W. A., and Dunlap, H. F., Proc. Staff Meetings of Mayo Clinic,1928, iii, 119. Cases Showing Osteoporosis due to Decalcification inExophthalmic Goiter.

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J. C. AUB, W. BAUER, C. HEATHAND M. ROPES 137

14. Goto, K., J. Biol. Chem., 1918, xxxvi, 355. Mineral Metabolism in Experi-mental Acidosis.

15. Hunter, D., and Aub, J. C., Quart. J. Med., 1927, xx, 123. Lead Studies.XV. The Effect of the Parathyroid Hormone on the Excretion of Lead and

of Calcium in Patients Suffering from Lead Poisoning.16. Greenwald, I., J. Biol. Chem., 1926, lxvii, 1. The Effect of the Administra-

tion of Calcium Salts and of Sodium Phosphate upon the Calcium and Phos-phorus Metabolism of Thyro-Parathyroidectomized Dogs, with a Con-siderdtion of the Nature of Calcium Compound of the Blood and theirRelation to the Pathogenesis of Tetany.

17. Farquharson, R., Salter, W., and Aub, J. C. To be published.