Pathophysiology ofRheumatic Fever -...
Transcript of Pathophysiology ofRheumatic Fever -...
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
ASA, 2.4 Gm daily, days7-20
ASA, 2.4 Gm. daily, days13-19
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
ASA, 2.0 Gm. daily, days2-44
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PATHOPHYSIOLOGY OF RHEUMATIC FEVER
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, 4.2 Gm daily, days4-49
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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PATHOPHYSIOLOGY OF RHEUMATIC FEVER
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
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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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PATHOPHYSIOLOGY OF RHEUMATIC FEVER
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.
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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-
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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.
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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.
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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.
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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.
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22 KELEMEN, E., MAJOROS, AI., IVANYL, J., ANDKOVACs, K.: Salicylates, stress and cortisone.Experientia 6: 1, 1950.
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JERRY K. AIKAWAExchangeable Sodium and Potassium Contents
Pathophysiology of Rheumatic Fever: Alterations in the Na24 Space and in the
Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1957 American Heart Association, Inc. All rights reserved.
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doi: 10.1161/01.CIR.16.4.6211957;16:621-630Circulation.
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