Pathophysiology ofRheumatic Fever - Circulationcirc.ahajournals.org/content/circulationaha/16/4/621.full.pdf · Pathophysiology ofRheumaticFever ... The general plan of therapy was

Pathophysiology of Rheumatic FeverAlterations in the Na24 Space and in the Exchangeable Sodium

and Potassium Contents

By JERRY K. AIKAWA, M.D.

Radioisotopic technics were used to explore physiologic aberrations that may characterize in-(lividuals with acute rheumatic fever. No significant changes were noted in serial measurementsof the blood volume or serum sodium and potassium concentrations. _Most of the individuals withsevere disease showed an initial value for radiosodium space of more than 330 ml./Kg. of bodyweight, with no evidence of edema. The exchangeable sodium content of the body correlated wellwith the radiosodium space. These changes are difficult to explain solely on the basis of extra-cellular edema, and are interpreted as suggesting that the intracellular content of sodium or thatin bone is increased during acute rheumatic fever. An intracellular increase in sodium may be (lue

to an alteration in the permeability of cell membrane induced by an immune mechanism.

AT THE present time there is much evidenceto support the hypothesis that rheumatic

fever is a consequence of a hypersensitivityreaction to an antigen or antigens produced bya previous infection with a beta hemolyticstreptococcus.' Although extensive epidemio-logic and bacteriologic studies on the pathogen-esis of rheumatic fever have been made, littlework has been done on the nature of the ab-normal physiologic processes occurring duringthe acute disease state. Data presented in aprevious preliminary note suggested that acuterheumatic fever may be associated with analteration in the permeability of cell mem-branes.2 Such a hypothesis is compatible withthe known effects of experimental in vivoantigen-antibody reactions on the distributionof body fluids and electrolytes.'The purpose of the present, study was to

make further physiologic measurements inrheumatic subjects, following the alterationsin the distribution of electrolytes by means ofradioactive isotopes of sodium and potassium.

MATERIAL AND METHODS

Subjects. Twcnty patients, 14 males and 6 females,with the diagnosis of acute or chronic activc rhcu-

From the I)epartment of Medicine, University ofColorado School of Medicine, Denver.

DIr. Aikawa is an Established Investigator of theAmerican Heart Association.

This stud-y was aided in part by, a grant-in-aid fromthe American Heart Association and in part tinder a

contract with the U. S. Atomic Energy Commission.621

matic fever were studied. Their ages ranged from 5to 41 years, and 16 patients were under 17 years ofage. The diagnosis was made on the basis of thehistory and the physical signs, according to thediagnostic criteria of Jones.3 The cases were dividedinto 3 categories according to the clinical severity ofthe disease, and these groups were further subdi-vided according to the type of treatment given (table1). Group 1: Eleven patients had clinical and labora-tory evidences of carditis, with persistence of rheu-matic activity for longer than a month after the onsetof symptoms; these 11 cases were classified as severe(3+). Group 2: Four patients wvho had evidences ofcarditis recovered within a month after the onsetof the rheumatic process, and their cases wereclassified as moderatelx severe (2+). Group 3: Fivepatients had rheumatic fever with no evidence ofcarditis, and responded very promptly to hospitaliza-tion and therapy; these cases were considered mild(1 +).The general plan of therapy was to administer

acetylsalicylic acid, sodium salicylate, aminopyrine,cortisone, or ACTH until the clinical and laboratoryevidences of rheumatic activity had subsided. Thedosage of the drug was then gradually reduced. Ifsigns of rheumatic activity recurred, an intermediatedosage was continued until all signs of rheumaticactivity had again subsided.

All subjects were given a regular hospital dietcontaining a maximum of 3 to 4 Gm. of sodiumdailv.

Isotopes. Isotopic sodium (Na24) and potassium(K124)* were prepared for injection in the maIn(ner pre-v-iouslN described.4 5

Measurement of Radioactivity. Early in the study,the activity of the urine and serum specimens was

*J{42 and Na'124 mere supplied by the Oak RidgeNational Laboratory, Oak Ridge, Tennessee, on

allocation from the U. S. Atomic Energy Commission.

Circulation, Volume XVI, October 1957

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PATHOPHYSIOLOGY OF RHEUMATIC FEVER

TABLE 1 -Classification of Cases

Clinical severity

3+ (Group 1) ...... ......

2+ (Group 2).1+ (Group 3).Total cases.

Salicylates

2, 3, 9, 11*

1, 4, 5

13, 14, 15, 16

11

Therapy

Aminopyrine ACTH

6, 7 10, 12, 17

2 3 _

* The figure indicates the case number in the text, tables, and figure 1.

determined with a dipping Geiger-Miuller tube anda scaling circuit. Recent measurements have beenmade with a well-type scintillation counter. A totalof 10,000 counts were made on each sample. All de-terminations were corrected for physical decay.

Determination of Serum Sodium and Potassiumi.The sodium and potassium concentrations in theserum or urine were determined early in the course ofthe study with a Beckman flame photometer by thedirect method, and recently with a Baird flame pho-tometer, by the lithium internal standard method.

ProcedureDetermination of Exchangeable Sodium Content

(Nae). Each subject received from a calibratedsyringe 1.5 me. Na24 per Kg. of body weight, con-

tained in a sterile 0.9 per cent solution of sodiumchloride. All urine voided for the next 24 hours was

collected, and the Na24 content of the pooled speci-men was determined. Blood specimens were obtainedat 3 and 24 hours after the injection of Na24, and thespecific activity of sodium in the serum was deter-mined. The following formula was used to calculatethe value for the exchangeable sodium content ofthe body:

Na i24 -Na 24Na _. \Na 524/NVa 23

Na-, = quantity of exchangeable sodium in milli-equivalents (inEq.).

Na-i24 = quantity of radiosodium administered.

Na-u = quantity of radiosodium excreted in thepooled specimen of urine.

Na 24 = concentration of radiosodium in theserum at 24 hours.

Na-s23 = concentration of nonradioactive sodiumin the serum at 24 hours.

Na- 24/Na- 23 = specific activity of the serum at

24 hours.

Preliminary studies in this laboratory revealedthat the Na, measurement was reproducible within5 per cent in edema-free, hospitalized subjects withvarious chronic diseases whose condition was sta-bilized.

Radiosodiumi Space. The volume of dilution of theinjected Na24 at 3 hours was calculated as follows:

Nra24 space in liters

total Na24 activity injectedserum Na24 concentration per liter at 3 hours

The exchangeable potassium content was deter-mined in a manner similar to the determination ofthe exchangeable sodium content and has been pre-

viously described.4' 5

Determination of Blood Volume. The plasma vol-ume was determined by the T-1824 d(ye (Evans blue)method.6 The hematocrit value was determined on

venous blood collected without stasis in bottlescontaining potassium and ammonium oxalate; theWintrobe hematocrit tubes were centrifuged for 30minutes at 3,000 revolutions per minute. The totalblood volume was calculated from the hematocritreading and the plasma volume.

RESULTS

Radiosodium (Na24) Space

Serial measurements of the radiosodiumnspace were available in 17 patients (table 2,fig. 1). The upper range of normal for this valueis considered to be 330 ml./Kg.4

Group 1. Serial Na24 space determinationswere made in 10 of these cases (fig. 1). In 5patients (cases 2, 7, 9, 11, and 12) the initialdetermination was obtained within 10 daysafter the onset of symptoms; with 1 exception(case 7) all initial values were greater than 330

ml./Kg., the highest value being 528

ml./Kg. (case 6). In the remaining 5 patients(cases 3, 6, 8, 10, and 17) the initial measure-

ment was made between 20 and 62 days ofthe onset of the disease, and all values were

above 330 ml./Kg. Thus, in only 1 instance(case 7) was the initial value for Na24 spacelower than 330 ml./Kg. None of these 10 indi-viduals had clinically demonstrable edema at

any time during the period of observation. In

Cortisone

8, 1918

20

4

Total Cases

1145

20

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TABLE 2.-Changes in the Radiosodium Space, Exchangeable Sodium Content, and Serum ElectrolytesDuring Rheumatic Fever Therapy

Case I Age I Sex Severity

1 16 M 2+

2 15 M 3+

3

4

5

6

7

17

41

13

14

26

M

M

F

M

F

3+

2+

2+

3+

3+

8 13 1IM 3+

9 91 F 3+

Days Na24 Naeafter Wt. (Kg.) Space (mEq./onset (ml/Kg.) Kg.)

41017243570

4111832395482

212734

71521

1117

16233037

815222936

62707683

81522364857

246

51.150.249.852.155.951.9

44.144.544.346.445.950.052.4

53.050.950.7

71.871.170.5

49.147.7

35.540.540.040.5

51.651.952.752.752.3

45.544.543.643.2

26.926.327.327.628.227.930.9

368419388337319316

463458325366327292233

543348371

275250245

268239

400380350318

271319301258299

331311332291

500320320300300300280

414144

4142

60

5248

5851514549

48485555

49474842434640

Serum electrolytes(mEq./L.)

Sodium Potas-sium

122 4.1133 4.0115 4.5145 4.4132 4.1

124129137129143129

140121130

140135145

143154

134143142147

149141148147147

142139145149

142138142135136138135

3.63.54.13.84.23.8

3.93.84.2

5.05.45.8

5.05.1

3.93.93.9

5.65.83.84.5

4.43.94.44.8

5.0

ESR(mm./hr.)

3441139100

383426171585

232115

1838

2813

30281824

3238384040

11393232

4923312311106

Therapy

ASA, 3.6 Gm daily, days4-23

ASA, 3.6 Gm. daily, days4-25, 33-46

ASA, 3.6 Gm. daily, days23-34



Aminopyrine, 0.9-1.8 Gm.daily, days 16-34

Aminopyrine, 1.2 Gm. daily,days 9-18; ASA, 3-6 Gm.daily, days 19-44

ASA, 2.4 Gm. daily, days69-77. Cortisone, 200 mg.daily, days 79-97


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TABLE 2.-Continued

Case Age Sex

10

11

12

13

14

11

5

8

7

14

M

M

F

F

M

15 28 F

Severity

3+

3+

3+

1+

1+

1+

16 15 M I 1+

17 14 M 3+

Daysafter Wt. (Kg.)onset

20486277

61320344862

243

71527

101631

714213550

233852

815222936

616875

32.034.338.237.0

17.316.917.317.517.817.718.5

18.218.618.6

31.032.030.4

52.052.752.055.256.8

62.361.162.3

59.558.960.761.562.4

35.135.936.2

Na24Space

(mL/Kg.)

377274284

528345348319302308328

378327326

259250254

311323309303293

215214215

328302306

303292

372322300

Nae(mEq./Kg.)

64473839

59635447454754

595353

383740

4746484846

343535

4847494344

545149

Serum Electrolytes(mEq./L.)

Sodium Potas-sium

148152145141

136138142138136134143

138140148

135134138

135138140141141

137141145

138141139138139

137138140

3.13.14.44.4

4.4

4.03.83.9

4.24.03.73.7

3.93.93.8

4.04.14.0

ESR(mm./hr.)

0113

46

16144

5061

28259

373433127

482840

3271488

000

Therapy

ACTH gel, 65 units daily,days 16-66

ASA, 1 Gm. daily, days 7-50

ASA, 0.5 Gm. daily, days 2-8;ACTH gel, 50 units daily,days 5-30

ASA, 3 Gm. daily days12-41


ASA, 8 Gm. daily, days15-34, 47-59

ASA, 4 Gm. daily, days 3-34

ACTH gel, 80 units daily,days 59-90

ESR = erythrocyte sedimentation rate.ASA = acetylsalicylic acid or sodium salicylate.

all instances except 2 (cases 7 and 8), subse-quent values were at least 50 ml./Kg. lowerthan the initial values, the maximum decreasebeing 230 ml./Kg. (case 2).

Eight of the 10 patients in this group gainedweight (0.4 to 8.3 Kg.) at a time when theabsolute value for the Na24 space was decreas-ing. Two patients (cases 3 and 8) lost weight.In one (case 3) the Na24 space decreased 11

liters as the body weight decreased 2.3 Kg.;in the other subject (case 8) the Na24 spacedropped 2.5 liters as the body weight decreased2.3 Kg.Group 2. Initial Na24 space determinations

were made between 4 and 11 days of the onsetof the disease, and were below 330 ml./Kg. in2 patients (cases 4 and 5) and above this valuein 1 (case 1). In only 1 instance (case 1) did

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SEVRE.E INMALATTACKS

No24SPACE

mI/K

20 30 40 50 60 70 80DAYS OF DISEASE

SEVER RECURRENT

500

400

20020 30 40 SO 60 70 80 243

MILD ATTACKS MODERATELY SEVEREATTACKS

i6e 14

_ 13 24_IS ~~~~~~~200Ci0 20 30_40 SO 60 70 8o 10 20 30 4

FIG. 1. Radiosodium space in rheumatic fever

0

* @0 0

0~~~

*0% 0**0. 0..

@0.0

*-0

0

0

vA'0,V...

5B0 10,000 150 200FIG. 2. Correlation of changes in Na, (ordinate, mEq.) with those in NaO4 space (abscissa, ml.).

the Na24 space/Kg. subsequently decrease more

than 50 ml./Kg. None of the patients hadclinical edema.

One subject (case 1) gained 4.8 Kg. and theother 2 (cases 4 and 5) lost 1.3 and 1.4 Kg. inbody weight; the Na24 space decreased between2 and 3 L. during this time.Group 3. Initial Na24 space values obtained

in 4 patients between 7 and 23 days of onsetranged between 215 and 328 ml./Kg. In none

of these patients did subsequent values de-crease more than 50 ml./Kg. None of these 5patients showed clinical edema.Four of the 5 subjects in this group gained

weight (0.9 to 4.8 Kg.) during the period ofstudy, and 1 (case 15) lost 1.2 Kg. No strikingchanges in the Na24 space were noted in any ofthese subjects.

Exchangeable Sodium Content (Va()Serial measurements of the exchangeable

sodium content were available in 14 patients(table 2). The upper range of normal for thisvalue is considered to be 46.0 mEq./Kg.7Group 1. Serial Nae measurements were

available in 8 patients in this category (cases6-12, and 17). All initial values were higherthan 46.0 mEq./Kg. (range, 48.0 to 64.0

500

400

300 a

200

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TABLE 3.-Changes in the Exchangeable Potassium Content and Serum Electrolytes During RheumaticFever Therapy

Sex

M

M

M

M

M

Severity

2+

3+

2+

3+

1+

Daysafteronset

1521

62707683

122741

64862

1327

Wt. (Kg.)Ke

(mEV.Kg.)

Serum electrolytes(mEq./L.)

Sodium Potassi-umI I~~~~

71.170.5

45.544.543.643.2

89.587.687.3

20.126.728.3

28.529.4

4136

41463839

273240

394343

4643

135145

142139145149

139149149

150149152

149136

5.45.8

4.43.94.44.8

4.74.84.3

4.54.34.6

5.64.6

ESR(mm./Hr.)

38

11393232

31813

3432

80

Therapy

ASA, 2.4 Gm. daily, days 7-20

ASA, 2.4 Gm. daily, days 69-77.Cortisone, 200 mg. daily, days79-97

ASA, 7 Gm. daily, days 11-22;ASA, 5 Gm. daily + cortisone,300 mg. daily, days 23-40

Cortisone,3-60

Cortisone,4-42

135 mg. daily, days

100 mg. daily, days

ESR = erythrocyte sedimentation rate.ASA = acetylsalicylic acid or sodium salicylate.

mEq./Kg.), even though edema was not clin-ically evident. In 7 of the 8 patients (exception,case 8) the Nae/Kg. subsequently decreasedmore than 5 mEq./Kg. (range, -5 to -26mEq./Kg.). In 4 of the cases, the lowest valueobtained remained higher than 46.0 mEq./Kg.Group 2. Serial Nar values were obtained in

cases 4 and 5. In both cases the initial valuesfor Nae/Kg. were 41.0 mEq./Kg. and were notsignificantly altered during the period of ob-servation.Group 3. Serial Nae values were obtained in

cases 13-16. Two of the 4 initial values were

slightly higher than 46.0 mEq./Kg. (47 and 48mEq./Kg. respectively in cases 15 and 16).In case 16, a decrease of 5 mEq./Kg. subse-quently occurred. The other 3 patients showedno significant changes in this value.

There was excellent correlation between thevalues for the Na24 space and the exchangeablesodium content (fig. 2).

Exchangeable Potassium Content (Ke).The reported range for Ke in normal men is

35.6-55.6 mEq./Kg., the mean being 46.3

mEq./Kg. (table 3).5 For normal women therange in one series8 was 25.1-35.0 mEq./Kg.,with a mean of 31.5 mEq./Kg.; in anotherseries7 it was 28.6-47.2 mEq./Kg., with a mean

of 40.7 mEq./Kg. Data of a similar nature fornormal children are not yet available.Group 1. Serial Ke determinations in a pa-

tient (case 19) with severe acute rheumaticfever rose from a low normal of 780 mEq.(39 mEq./Kg.) on the sixth day to 1208 mEq.(43 mEq./Kg.) as the subject gained 8 Kg. inweight while receiving large doses of cortisone.One patient (case 8) with chronic active rheu-matic fever, in whom serial Nae as well as Kedeterminations were performed, showed normalinitial K, values which first increased approxi-mately 200 mEq., and subsequently decreasedto about 200 mEq. below the initial value. Inthis subject a reciprocal relationship betweenthe Nae and the K4. was suggested, since thevalue for NaJ/Kg. increased as that for K4/wt.decreased, and the sum of the K, and theNa4 remained fairly constant at all times.Group 2. K, measurements were available in

2 subjects with moderately severe rheumatic

Case Age

4 41

8

18

19

20

13

25

6

11

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with salicylates, K, decreased by 360 mEq.between 15 and 21 days after onset, but re-mained within the normal range.Group 3. Two K, determinations were made

in 1 patient (case 20) with a mild disease; bothvalues were within the normal range.

Other Values. A serum potassium value ofless than 3.5 mEq./L. was found in only 1patient (case 10), who was receiving ACTH gelat the time of this determination (table 4). Apotassium value higher than 5.5 mEq./L. wasobtained in 3 subjects (cases 4, 8, and 20).A serum sodium concentration of less than

134 mEq./L. was found in 3 patients (cases1, 2, and 3), and a value higher than 150mEq./L. was obtained in 3 patients (cases 5,10, and 19). There was no correlation betweenthe changes in the serum sodium concentrationand the exchangeable sodium content or theradiosodium space.The plasma volume changes showed no con-

sistent trend during the course of therapy. In6 of the 7 patients (cases 1-6) in whom serialhematocrit determinations were made early inthe course of the disease, the values increasedas clinical improvement occurred. In 1 patient(case 7) it decreased before rising. The totalblood volume showed no consistent trendsduring therapy.

TABLE 4.-Changes in the Plasma Volumle, Hem-atocrit, and Total Blood Volume during RheumaticFever Therapy

Daysafter WX t. (Kg.)onset

41017243570

4111832395482

212734

71521

1117

16233037

815222936

62707683

51.150.249.852.155.951.9

44.144.544.346.445.950.052.4

53.050.950.7

71.871.170.5

49.147.7

35.540.540.040.5

51.651.952.752.752.3

45.544.543.643.2

Plasma Hemato-volume crit

(ml./Kg.) (vol. %)

586745

5756

66586944415759

708057

395049

5153

86606358

5557526058

57536257

37.335.939.339.439.139.7

39.140.240.843.142.142.942.2

37.338.541.0

45.749.548.7

34.335.7

33.034.035.038.2

37.434.536.131.436.6

39.439.838.440.1

Total bloodvolume(ml./Kg.)

9310475

9493

129919894

8886828892

948910195

fever (cases 4 and 18). In case 18 the initialvalue for K(,/X-t., obtained 12 days after onsetof the disease, was subnormal and increasedprogressively to a value of 40 mEq./Kg. as therheumatic process subsided by 41 days; thisincrease occurred while the patient was re-

ceiving cortisone and supplemental potassiumchloride. In the other patient,, who was treated

DiscussioN

Factors Influencing the Radiosodium Space.The value for the radiosodium space, as de-termined by the method used, may be influ-enced by several factors:

Interstitial Edema. Previous studies4 haveshown that values for Na24 space greater than330 ml./Kg. are usually associated with clinicalpitting edema as, for example, in congestiveheart failure. The increased Na24 space in rheu-matic fever cannot be explained on this basisalone, since values in excess of 500 ml./Kg.were found in the absence of any pitting edema.Furthermore, if the increased Na24 space were

due primarily to extracellular fluid retention,loss of this fluid by diuresis should result in a

more or less parallel decline in body weight.In most of the rheumatic subjects the bodyweight increased during therapy as the Na24space decreased, and diuresis did not occur. It

Case

1

2

4

5

6

7

8

627AIKAWA



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is difficult, therefore, to account for the ab-normally high values for Na24 space solely onthe basis of interstitial edema.

Intercellular Cement Substance. The rate ofdiffusion of an ion into the extravascular spacefollowing intravascular injection may be influ-enced by the nature and the state of the inter-cellular cement substance-the hyaluroinic acidand chondroitin sulfuric acid systems. Theradiosodium space is increased, for instance,in myxedema, where the excess of colloidalsubstances in the interstitium causes abnormalretention of salt and water. Such an abnormalphysiologic process is manifested clinically bypuffiness and generalized nonpitting edema,and thyroid therapy results in loss of bodyweight and a parallel decrease in the radioso-dium space.9The apparent increase in the 3-hour value

for the Na24 space in rheumatic subjects maybe explained by an increase in the rate of ex-change between the injected radioactive atomsand the native ions in the intercellular cementsystem. That connective tissue changes occurin acute rheumatic fever has been established.Were this the only factor responsible for theapparent increase in Na24 space, however, the24-hour value for exchangeable sodium contentwould not necessarily be elevated. The findingin the present study of a remarkable correlationlvetween the Na24 space and the exchangeablesodium content suggests that the body's storeof sodium is indeed increased during acuterheumatic processes; this excess sodium, how-ever, does not appear to be extracellular in anamount sufficient to induce clinical pittingedema.

Bone Sodium. If the excess exchangeablesodium is not extracellular, there is a possibilitythat it might be adsorbed on bone in excessiveamounts or exchanged with bone sodium at anincreased rate. The nature and regulation ofbone sodium are poorly understood, and it isconceivable that an increase in the exchange-able sodium content or the radiosodium spacemight be due to an abnormality in exchange orstorage in bone. However, such a possibilityis not thought to be as likely as the followingexplanation.

Tissue Cell Mlemnbrane. The data best fit thehypothesis that, in acute orI chronic active

rheumatic fever, the normal relative impermea-bility of the tissue cell membrane to the sodiumion is altered, with a resultant! increase in therate of exchange of sodium between the extra-cellular and intracellular compartments and illthe amount of sodium within cells. Thus, theradiosodium space and the exchangeable so-dium content are increased to an extent whichis out of proportion to the amount of clinicaledema present.

This increase in the intracellular store ofsodium appears to be accompanied by a de-crease in the intracellular content of potassium.While the data on the exchangeable potassiumare meager, they suggest that the exchangeablepotassium content is lowest early in the courseof severe or moderately severe rheumatic fever,when the exchangeable sodium content ishighest. This change in equilibrium betweenthe intracellular and extracellular compart-ments does not appear to be reflected by anyconsistent alterations in the seruim concentra-tions of sodium and potassium.An increase in (apillary permeability usually

results in extracellular edema formation; sinceedema was not evident, in the present study, itis concluded that capillary permeability was notsignificantly altered. Furthermore, no signifi-cant changes were noted in the plasma volumeor total blood volume. These data suggest thatthe greatest physiologic abnormality occurredat the level of the cell membrane and thatchanges in capillary permeability were slight.

Relationship to Immune Mechanism. Recentstudies with isotopes have dispelled the pre-viously accepted view that all of the body'sstore of sodium and chloride is located extra-cellularly. It is now recognized that a muchmore complex situation prevails. The colnceptof cell membranes impermeable to ions hasbeen supplanted by the view that ionic ex-change occurs continuously across a memibranethat may actively participate in the process bymeans of its own enzymes and metabolic proc-esses. It is now believed that concentrationgradients are maintained by enzymatically con-trolled intracellular metabolic processes as wellas by physicochemical processes. Inorganic ionsare known to play a dynamic role as essentialcomponents of enzyme systems. The results ofthe present study suggest that rheumatic fever

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produces some alterations in such a dynamicprocess.

It is apparent that any severe disease process,whether produced by a physical, chemical, orbiologic agent, will result in abnormal physio-logic changes in the body cells. For instance, anincrease in the intracellular content of sodiumhas been reported in such diverse disease statesas infant diarrhea,'0 dietary deficiency of po-tassium,11 simian malaria,'2 Rocky Mountainspotted fever,'3 serum sickness,'4 congestiveheart failure,"5 and experimental burns andtrauma.'6 Thus, an increase in the intracellularcontent of sodium may be a nonspecific re-sponse to injury of any type.The purpose of the present discussion is not

to describe in detail the mechanisms involvedin these various types of cell injury, but simplyto determine whether the physiologic changesobserved in acute rheumatic fever can be satis-factorily explained by the hypothesis thatrheumatic fever is a hypersensitivity reactionto streptococcal infection. It was formerly as-sumed that antigenic substances that were in-jected parenterally remained in the extracel-lular fluid compartment. Recent studies withtagged antigens, however, have shown thatantigenic substances rapidly cross the cell mem-brane'7 and localize in the mitochondria.18 Ithas been suggested that the mitochonidria arethe anatomic site of protein synthesis, andthat antibody production is a modified form ofgamma globulin synthesis. An in vivo intra-cellular union of antigen and antibody mightbe expected to produce disturbances in theorderly function of intracellular enzyme sys-tems and alterations in membrane permeabil-ity.

In the present study, the evidence of analteration in cell membrane permeability, with-out evidence of abnormal capillary permea-bility, suggests that the changes may be due tothe tuberculin or delayed type of hypersensi-tivity reaction,'9 since an increase in capillarypermeability is usually evident in an in vivoanaphylactic type of reaction.

Adrenal cortical hormones, under certainconditions, can suppress antibody formation.2OAlthough the exact mechanism of this suppres-sion is not known, it has been stated that thesesubstances tend to restore the integrity of cell

membranes.2' The mechanism of action bywhich salicylates and aminopyrine suppress therheumatic symptoms and signs is also un-known, but their effect appears to be more thanantipyretic. The increased radiosodium space,for instance, persisted for several weeks afterinitiation of therapy, whereas the fever usuallysubsided within 48 hours. It has been suggestedthat both salicylates22 and aminopyrine23 stim-ulate the adrenal cortical secretion. Whateverthe exact mechanism of action may be, the datasuggest that the abnormal permeability of cellmembranes in acute rheumatic fever can besuppressed by all of the therapeutic agentsused.

It is obvious that further and more extensivestudies of the type reported here are necessaryfor a better understanding of the patho-immu-nophysiology of rheumatic fever.

SUMMARYSerial measurements of the radiosodium

space and the exchangeable sodium and potas-sium contents were made in 20 patients withacute or chronic active rheumatic fever, duringhospitalization and therapy. Ten of 11 patientswith severe disease had an initial value forNa24 space of more than 330 ml./Kg. of bodyweight, with no evidence of edema. Most ofthe subsequent values were lower, at a timewhen body weight had increased. Such changeswere noted infrequently in individuals withmild or moderately severe disease.The exchangeable sodium content of the

body correlated well with the radiosodiumspace. The exchangeable potassium content ofthe body tended to be low when the exchange-able sodium content was high. No strikingchanges were noted in the serum sodium andpotassium concentratiolls.The results have been interpreted as sug-

gesting that the intracellular content of sodiumis increased during acute rheumatic fever, al-though the possibility of an increase in bonesodium has not been excluded, and that thisabnormality may be due to an alteration in thepermeability of cell membranes induced by animmune mechanism.

SUMMARIO IN INTERLINGUAMesurationes serial del spatio de natrium

radioactive e del contento de excambiabile

62(9



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natrium e kalium esseva facite in 20 patientescon acute o chronic febre rheumatic. Omnesesseva hospitalisate e sub tractamento. Decedel 11 patientes con grados sever del morbohabeva un valor initial pro le spatio de Na24

de plus que 330 ml per kg de peso corporee.

Iste patientes habeva nulle signo de edema.Le majoritate de lor valores subsequenteesseva plus basse, e isto a un tempore quandole peso corporee habeva accrescite. Tal altera-tiones esseva notate infrequentemente inindividuos con leve o moderatemente sever

grados del morbo.Le contento de excambiabile natrium in le

corpore esseva ben correlationate con le spatiode natrium radioactive. Le contento de ex-

cambiabile kalium in le corpore monstrava letendentia de esser basse quando le contentode excambiabile natrium esseva alte. Nullefrappante alterationes esseva notate in leconcentrationes seral de natrium e kalium.

Le resultatos pare indicar que le contentointracellular de natrium es augmentate duranteacute febre rheumatic, sed le possibilitate non

pote esser negligite que il occurre un aug-

mento del contento de natrium in le ossos e

que iste anormalitate resulta de un alterationdel permeabilitate del membranas cellularcomo effecto de un mechanismo immunologic.

REFERENCES'AIKAWA, J. K.: Hypersensitivity and rheumatic

fever. Ann. Int. Med. 41: 576, 1954.2 -: The cell membrane defect in acute rheumatic

fever. North Carolina M. J. 13: 330, 1952.3 JONES, T. D.: The diagnosis of rheumatic fever.

J.A.M.A. 126: 481, 1944.4AIKAWA, J. K.: Comparison of the thiocyanate

and radiosodium spaces in disease states. Am.J. M. Sc. 224: 632, 1952.

5 CORSA, L., OLNEY, J. M., JR., STEENBURG, R. W.,

BALL, M. R., AND MOORE, F. D.: The measure-

ment of exchangeable potassium in man byisotope dilution. J. Clin. Invest. 29: 1280, 1950.

6 GIBSON, J. G., AND EVELYN, K. A.: Clinical stud-ies of the blood volume. IV. Adaptation of themethod to the photoelectric microcolorimeter.J. Clin. Invest. 17: 153, 1938.

7 EDELMAN, I. S., OLNEY, J. M., JR., JAMES, A. H.,BROOKs, L., AND MOORE, F. D.: Body compo-sition: Studies in the human being by the dilu-tion principle. Science 115: 447, 1952.

8 AIKAWA, J. K., HARRELL, G. T., AND EISENBERG,

B.: The exchangeable potassium content of nor-mal women. J. Clin. Invest. 31: 367, 1952.

9 -: The nature of myxedema: Alterations in theserum electrolyte concentrations and radioso-dium space and in the exchangeable sodium andpotassium contents. Ann. Int. Med. 44: 30,1956.

10 DARROW, D. C.: The retention of electrolyte dur-ing recovery from severe dehydration due todiarrhea. J. Pediat. 28: 515, 1946.

11 GARDNER, L. I., MACLACHLAN, E. A., AND BER-MAN, H.: Effect of potassium deficiency on car-bon dioxide, cation, and phosphate content ofmuscle. J. Gen. Physiol. 36: 153, 1952.

12 OVERMAN, R. R.: Reversible cellular permeabilityalterations in disease. In vivo studies on sodium,potassium and chloride concentrations inerythrocytes of the malarious monkey. Am.J. Physiol. 152: 113, 1948.

13 AIKAWA, J. K., AND HARRELL, G. T.: Changes inthe tissue radiosodium space associated withexperimental Rocky iMountain spotted fever. J.Infect. Dis. 93: 263, 1953.

14 The immunophysiology of serum sickness.Alterations in the radiosodium space and serumelectrolyte concentrations during the course ofrepeated injections of horse serum into rabbits.J. Allergy 27: 213, 1956.

15 ISERI, L. T., ALEXANDER, L. C., MCCAUGHEY,R. S., BOYLE, A. J., AND MYERS, G. B.: Waterand electrolyte content of cardiac and skeletalmuscle in heart failure and myocardial infare-tion. Am. Heart J. 43: 215, 1952.

16 Fox, C. L., AND BAER, H.: Redistribution of potas-sium, sodium and water in burns and trauma,and its relation to the phenomena of shock. Am.J. Physiol. 151: 155, 1947.

17 COONS, A. H.: Fluorescent antibodies as histo-chemical tools. Fed. Proc. 10: 558, 1951.

18 HAUROWITZ, F., CRAMPTON, C. F., AND SOWINSKI,R.: Immunochemical studies with labelled anti-gens. Fed. Proc. 10: 560, 1951.

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21 GERMUTH, F. G., AND OTTINGER, B.: Effect of 17-hydroxy-1 1-dehydrocorticosterone (CompoundE) and of ACTH on Arthus reaction and anti-body formation in the rabbit. Proc. Soc. Exper.Biol. & MIed. 74: 815, 1950.

21 THORN, G. W., FORSHAM, P. H., FRAWLEY, T. F.,HILL, S. R., JR., ROCHE, MI., STAEHLIN, D., ANDWILSON, D. L.: The clinical usefulness of ACTHand cortisone. New England J. AMed. 242: 783,824, 865, 1950.

22 KELEMEN, E., MAJOROS, AI., IVANYL, J., ANDKOVACs, K.: Salicylates, stress and cortisone.Experientia 6: 1, 1950.

23 FANTUZZI, B.: Pyramidon (Aminopyrine) and thesuprarenal cortex. AMinerva pediat. 6: 333, 1954.

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JERRY K. AIKAWAExchangeable Sodium and Potassium Contents

Pathophysiology of Rheumatic Fever: Alterations in the Na24 Space and in the

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