BODY WATER AND SODIUM IN PATIENTS WITH

Transcription

1 BODY WTER ND SODUM N PTENTS WTH CROMEGLY'- By DENS KKOS, ROLF LUFT, ND BJORN SJOGREN (From the Division of Endocrinology of the Deprtment of nternl Medicine, Serfimerlsrettet, Stockholm, Sweden) (Submitted for publiction December 1, 1953; ccepted Mrch 2, 1954) The cromeglic stte often is ccompnied by n enlrgement of the soft tissues of the body. The purpose of the present work ws to determine whether these tissue chnges re ccompnied by chnges in the content nd distribution of wter nd electrolytes in the body. n this connection the dministrtion of growth hormone ws shown to induce n increse in the totl body wter of norml (1-4) nd hypophysectomized (5) rts, nd of norml dogs nd cts (3). Similrly, growth hormone cused retention of sodium nd potssium in norml (6) nd dibetic (7) rts, nd retention of sodium, potssium, nd chloride in drenlectomized rts (8). The thiocynte spce in norml nd hypophysectomized rts (9) nd the plsm volume in dogs (10) incresed fter injection of growth hormone. The present pper gives the results of mesurements of the totl body wter, the extrcellulr wter nd the exchngeble sodium in 18 cromeglic ptients. MTERL ND METHODS Totl body wter ws clculted from the volume of distribution of ntipyrine (11). Totl exchngeble sodium ws clculted from the pprent volume of distribution of the rdioctive sodium isotope N' (12). The extrcellulr wter ws clculted from the volumes of distribution of inulin (13) or thiosulfte (14). n six cses, both of these methods were used to estimte the volume of extrcellulr wter. n six cses, no mesurement of the extrcellulr fluid ws mde. ll experiments strted t 8.m. The ptients were not llowed to et fter 8 p.m. the dy before the test. Urine ws collected the preceding dy for the determintion of the blnk excretion of inulin. The ntipyrine ws given from clibrted burette, nd venous blood smples were drwn fter two, three, four, nd five hours. mmeditely fter the injection of ntipyrine the constnt infusion of inulin ws strted. The infusion of inulin ws continued for 6 to 7 hours. When simultneous 1 These studies were ided by grnts from the Medicl Reserch Council of Sweden nd from Knut nd lice Wllenberg's Foundtion. mesurements of the thiosulfte nd inulin spces were performed, thiosulfte ws injected immeditely fter the inulin test ws completed. f the thiosulfte spce only ws used for the mesurement of the extrcellulr wter, the test ws performed the dy fter the determintion of totl body wter, since thiosulfte interferes with the chemicl nlysis of ntipyrine in plsm. Rdioctive sodium, Nn, ws injected intrvenously, immeditely fter the determintion of the extrcellulr wter ws completed. Urine ws collected for the following 18 hours, nd blood smples were tken t the end of the urine collection period. ntipyrine in plsm ws nlyzed ccording to Brodie, xelrod, Sobermn, nd Levy (15). n our hnds the time necessry for the completion of the rection between ntipyrine nd sodium nitrite ws different from dy to dy. Repeted redings, therefore, were tken every five to ten minutes fter the ddition of sodium nitrite. The mximl extinctions obtined were plotted on semilogrithmic pper, nd the extinction t zero time ws obtined by extrpoltion. The volume of distribution of ntipyrine ws clculted by dividing the given mount of ntipyrine by its zero time plsm concentrtion. The inulin in plsm ws nlyzed by Roe's resorcinol method, s modified by Schreiner (16). The inulin spce ws obtined by dividing the totl mount of inulin excreted fter discontinution of the infusion by the inulin concentrtion in plsm t equilibrium. The thiosulfte in plsm ws nlyzed by the indirect iodometricmcromethod of Newmn, Gilmn, nd Philips (17). The thiosulfte concentrtion t zero time ws obtined by extrpoltion, nd the volume of distribution clculted from this vlue nd the mount of thiosulfte given. The concentrtion of'sodium in plsm ws mesured by Beckmn flme photometer. The conversion of the ntipyrine, inulin, nd thiosulfte spces to totl body wter nd extrcellulr wter, respectively, ws mde by multiplying the vlues obtined by The concentrtion of sodium in plsm wter ws clculted from the corresponding vlue in plsm, using the sme figure, The plsm wter content of the cromeglic ptients ws tken s norml. The surfce re of the body ws derived from the nomogrm of DuBois, lthough the uthors re wre of the fct tht the pplicbility in cromegly of the Du- Bois surfce re tbles hs not been proved. ntrcellulr wter ws tken s the difference between totl body wter nd extrcellulr wter. Totl ex- 989

2 990 DENS KKOS, ROLF LUFT, ND BJORN SJOGREN TBLE Cse mril Durtion Surfce Of Soft Cse ge Height Weight re disese tissue no. Ptient yers Sex CM. Kg. m2 yers swelling 1 S. K. 36 M M.H. 53 F D. P. 35 F C. B. 40 M E. E. 23 F F F. 42 M J.. 60 M L. H. 23 M E. J. 40 F M. M. 42 F C. L. 20 M S.. 49 F H. W. 51 M K. L. 52 M M. S. 32 F B. 30 M F. O. 38 M * These vlues were observed during the whole period of observtion. Plsm phosphorus, mg. % t the Highest Lowest present vlue vlue study observed* observed* chngeble sodium (meq.) ws clculted from the p- (liters). ntrcellulr sodium ws clculted s the difprent volume of distribution of rdio-sodium N" ference between totl body sodium nd extrcellulr so- (liters) nd the concentrtion of sodium in the plsm dium. The pprent men intrcellulr sodium concenwter (meq. per liter). Extrcellulr sodium ws cl- trtion (meq. per liter) ws clculted by dividing the culted s the product of plsm wter sodium concen- intrcellulr sodium by, the intrcellulr wter volume. trtion (meq. per liter) nd extrcellulr wter volume The mteril of the present study consisted of 18 cses TBLE Totl body wter nd totl exchngeble sodium in ptients with cromegly Totl body wter Totl exchngeble sodium Sodium 70 of L./m meq./l. meq./kg. meg./m' meq./l. Cse body surfce plsm body surfce totl body no. L. weight re wter meq. weight re wter , , , , , , , , S S5 3, , l15 3, , , , S5 4, , , , , , , , S5 5, , S , , S3 4, S , , , , , , , , verge , Stndrd error of men S Helthy subjects: vrerge , Stndrd error of men 0.9 O.S Significnce of difference: P-vlue <0.01 <0.001 <0.001 <0.001 <0.001

3 BODY WTER ND SODUM N PTENTS WTH CROMEGLY o0-4 oooouwoto; o0000 U) -pt % i i. Ni lo. -3- oz el4i lep N j ou t-oc4mc4%t-m=)%o -4P! el n co co so W) t.. NO X 'u g 04 o" c; ci d- '0 U t-z ('4 ('4i) 4o )o so40u)4 " )"Oi)if) V & Le _ 'o w4oz t..t-t. *0 * * *.. 0Z0U)U% W; 00 4 ('4 U) MP "4 i) qd4 if) m ********~V-.-CN,.4.Z.~ 0 U) ) 000% 00 1' U) if 0N qw 0' r000% o U) U) W) (' 4('40% RV if i ('40i) (4 ; -.k 9; -.t W. fil..2 ; 21 bw " Ps C bi m -4 4ti H P* 164.U.%b E i r '% 94 e, z gi.z1.1; -- 0 C;1 nd to4 143:e 4g d _d _) N roin 0d,Ui)'0 4'c. (inf) U) 00'4-U001W)% m k- U ' 0 ' - 0% N04'- O1' t- ' %ln!' (4Ck if '4 ('4- (' l4o m m Qo m m qd U) 4' %'0-4 C4" '0 '0 U) C '44'0i) -' f)4.0 *6 *. w* *i.. 6 4" 4'. ' px 4-.9 ' :4) P*- *4 *l? 3 w :D 8 L ou *C43 --i fso o c o ; ' C 4.4 '4400U)00if4'.0..). %o 00' U 06 C 0% - --W o v - ; le 4-1*.2 94.' 3 > u e,0 0Col. if m if0 '4 ('4if"if. * *444 if). ('4." ('4; W * V ) Es 34, %S -j., " 0 e 4-b g" t ll.. 4.0,.. :.., 4& x ('---- lc44 i) '-. 4'-Z 0 C4 " if)" if)q ;i 9 U) U) 00-U -0 --l; i

4 992 DENS KKOS, ROLF LUFT, ND BJORN SJOGREN of cromegly (Tble ). n none of the ptients thyrotoxicosis, dibetes ewlitus, testiculr trophy or drenl corticl insufficiency could be demonstrted. Signs of congestive hert filure were not present in ny of the cses. No instnces of cromeglic gigntism ppered in these ptients. The cses were unselected with respect to the ctivity of the disese; cses Nos. 6, 11, nd 15 were therefore included despite the fct tht they were considered lmost "cured." The tble gives clinicl nd lbortory dt, describing the sttus of the ptients t the time of the present study. RESULTS n the cromeglics (Tble ) the verge totl body wter ws found to be 55.8 per cent of the body weight or 23.2 liters per squre meter of body surfce. The corresponding figures for the norml group of nine helthy subjects (18) were 49.7 per cent nd 18.6 liters, respectively. The differences between the figures of the two groups were sttisticlly significnt. The mount of totl exchngeble sodium in the cromeglics corresponded to 52.8 meq. per Kg. body weight-or 2174 meq. per squre meter of surfce re or 94.8 meq. per liter of totl body wter. These figures were significntly higher thn the corresponding ones in the group of helthy subjects. The distribution of body wter between the intr- nd extrcellulr phses, using the inulin or thiosulfte spces in the clcultion of the mount of extrcellulr wter, is presented in Tbles nd V, respectively. n Tbles nd V is lso presented the distribution of exchngeble sodium between the intr- nd extrcellulr spces using inulin or thiosulfte. The men vlues of the results presented in Tbles nd V re given in Tble V together with the corresponding figures obtined by similr mesurements in the group of helthy subjects (18). Tble V shows tht extrcellulr wter expressed s liters per squre meter of surfce re or s percentge of body weight ws significntly incresed in the cromeglics, whether the clcultions were mde from the inulin or thiosulfte spces. However, when expressed s percentge of totl body wter, the extrcellulr wter ws significntly higher, only when the thiosulfte spce ws used. The mount of intrcellulr wter expressed s per cent of body weight ws of the sme mgnitude in the cromeglics nd in the helthy subjects. Expressed s liters per squre meter of surfce re it ws different (higher) in the cromeglics, only when clculted from the inulin spce. When expressed s per cent of totl body wter it ws significntly higher in the cromeglics, only when clculted from the thiosulfte spce. The distribution of exchngeble sodium between the intr- nd extrcellulr fluid comprtments in the cromeglics did not differ from tht in the helthy subjects. However, the "pprent" men intrcellulr sodium concentrtion TBLE V comprison of the distribution of wter nd exchngebk sodium in helthy subjects nd cromeglics Body wter Exchngeble sodium (N.) Extrcellulr (ECW) ntrcellulr (CW) E Ct)ellulr ntrceclulr % Of % Of % of L./m' totl % of L./m' totl % of % Of body surfce body body surfce body Rtio totl totl meq./l. Rtio weight re wter weight re wter CW:ECW N. N. CW C:EC Extrcellulr wter clculted from the inulin spce Normls (9 subjects) verge S.E.* co ngly (7 subjects) verge 19.S P-vlue <0.01 <0.01 <0.01 <0.001 Extrcelklr wter clculted from the thiosulfte spce Normls (9 subjects) verge S.E.* cromegly (11 subjects) verge S.E.* P-vlue <0.001 <0.001 <0.001 <0.001 <0.001 <0.01 * Stndrd error of men.

5 BODY WTER ND SODUM N PTENTS WTH CROMEGLY ws significntly higher in the cromeglic ptients. DSCUSSON The question my be rised, whether, with the methods used, it is possible to obtin exct mesurements of the totl body wter nd extrcellulr wter. The ntipyrine spce in helthy subjects hs been found to be 2 to 5 per cent smller thn the deuterium or tritium spce (11, 19, 20). The sme reltion ws obtined in some disesed sttes (21) except in the presence of edem (22). This constncy shows tht the ntipyrine spce represents t lest constnt frction of the totl body wter if not the true volume. n edemtous ptients the ntipyrine spce hs been found to be bout 15 per cent smller thn the deuterium spce (22). No comprison hs been mde between the ntipyrine nd deuterium spces in cromegly. Whether the rtio of the ntipyrine spce to the deuterium spce in cromeglics is smller, s in edemtous ptients, or of the sme mgnitude s in helthy subjects, the significnce of the differences found in the present work will still hold true. t is very much discussed, whether the inulin nd thiosulfte volumes of distribution represent the whole extrcellulr comprtment. However, it hs been shown tht they mesure reproducible spce, which is believed to be the functionl extrcellulr fluid volume (23). Consequently, we hve used the chnges in the inulin nd thiosulfte spces s indices of chnges in the extrcellulr comprtment. "Extrcellulr wter" in the present work therefore represents the portion of the true extrcellulr wter, which is included in the inulin nd thiosulfte spce. From this it is obvious tht the clculted "intrcellulr wter" in the present work might be somewht overestimted. better reference for the fluid comprtments would perhps be the correltion to the len body mss. However, we did not consider the formuls developed for the clcultion of the len body mts priori pplicble to cses of cromegly, where nothing is known bout the men wter content of the len body mss or the cell mss. n view of the bnorml body build in cromegly we hve correlted our results to body weight, surfce re, nd in the cse of extrcellulr nd 993 intrcellulr wter nd exchngeble sodium lso to totl body wter. The finding of n incresed totl body wter content in cromeglics is of interest in the light of the results obtined in the niml experiments mentioned in the introduction, s n bnorml secretion of growth hormone is generlly believed to be, if not the only, t lest the principl fctor in the production of the clinicl picture of cromegly. The increse in extrcellulr wter in the cromeglics, when expressed s percentge of body weight or s liters per squre meter of surfce re, obtined with inulin s well s with thiosulfte, two substnces so different in mny respects, fvors the view tht the observed chnge in the extrcellulr wter volume ws true increse nd not due to ltertions of the permebility of the cell membrnes. lthough the ltter possibility cnnot be excluded, the lrge increse in exchngeble sodium strongly fvors the view tht the extrcellulr spce ws incresed. The extrcellulr wter represented lrger prt of the totl body wter in the cromeglic thn in the helthy subjects, but the difference ws sttisticlly significnt with thiosulfte only. n three (Nos. 1, 11, nd 15) of the seven ptients studied with inulin the inulin spce formed n entirely norml percentge of the totl body wter. Two of these cses (Nos. 11 nd 15) hd been treted for long time nd were considered lmost "cured." Our results fvor the hypothesis tht in cromegly the extrcellulr wter is incresed disproportionlly to the intrcellulr wter. The increse in totl exchngeble sodium observed in cromegly ws concomitnt with the increse in the extrcellulr spce. s to the observed increse in the "pprent" men intrcellulr sodium concentrtion this finding does not prove n ctul increse in the sodium content of the cells. t is known tht bout fifty per cent of the body sodium is to be found in the skeleton nd tht only bout hlf of it exchnges with rdiosodium in helthy subjects (24). n increse in the percentge of the bone sodium exchnged or disproportionl increse in the bone mss over the soft tissue would give n incresed "men intrcellulr sodium concentrtion." The significnce of the chnges observed in the cromeglics, i.e., the increse in totl body wter nd in totl exchngeble sodium nd the prob-

6 994 bly disproportionl increse in the mount of extrcellulr wter, cnnot be decided t present. However, these differences between the cromeglic nd helthy subjects re similr to those observed between infnts nd dults (19, 25, 26). SUMMRY The mount of totl body wter (ntipyrine spce) per Kg. of body weight nd per squre meter of body surfce, ws significntly incresed in group of 18 cromeglic ptients. The mount of totl exchngeble sodium in meq. per Kg. of body weight, per squre meter of surfce re or per liter of totl body wter ws lso incresed in the sme ptients. The mount of extrcellulr wter (inulin or thiosulfte spces) per Kg. of body weight or per squre meter of surfce re ws higher in the cromeglic ptients. The pprent men intrcellulr sodium concentrtion ws higher in the cromeglic subjects. REFERENCES DENS KKOS, ROLF LUFT, ND BJORN SJOGREN 1. Bierring, E., nd Nielsen, E., The composition of the tissues of lbino rts treted with lkline nterior pituitry extrcts. Biochem. J., 1932, 26, Lee, M. O., nd Schffer, N. K., nterior pituitry growth hormone nd the composition of growth. J. Nutrition, 1934, 7, Young, F. G., Growth nd dibetes in norml nimls treted with pituitry (nterior lobe) dibetogenic extrct. Biochem. J., 1945, 39, Li, C. H., Simpson, M. E., nd Evns, H. M., The gigntism produced in norml rts by injection of the pituitry growth hormone;. Min chemicl components of the body. Growth, 1948, 12, Li, C. H., Simpson, M. E., nd Evns, H. M., nfluence of growth nd drenocorticotropic hormones on the body composition of hypophysectomized rts. Endocrinology, 1949, 44, Whitney, J. E., Bennett, L. L., nd Li, C. H., Reduction of urinry sodium nd potssium produced by hypophysel growth hormone in norml femle rts. Proc. Soc. Exper. Biol. & Med., 1952, 79, Glfkides, C. M., nd Bennett, L. L., Reduction of urinry sodium nd potssium of dibetic rts produced by hypophysel growth hormone. Proc. Soc. Exper. Biol. & Med., 1951, 77, Stein, J. D., Jr., Bennett, L. L., Btts,.., nd Li, C. H., Sodium, potssium nd chloride retention produced by growth hormone in the bsence of the drenls. m. J. Physiol., 1952, 171, Btts,.., nd Bennett, L. L., Effect of hypophysel growth hormone (GH) on the thiocynte spce nd muscle electrolytes. J. Clin. Endocrinol., 1951, 11, Cmpbell, J., Husler, H. R., Munroe, J. S., nd Dvidson,. W. F., Effects of growth hormone in dogs. Endocrinology, 1953, 53, Sobermn, R., Brodie, B. B., Levy, B. B., xelrod, J., Hollnder, V., nd Steele, J. M., The use of ntipyrine in the mesurement of totl body wter in mn. J. Biol. Chem., 1949, 179, Forbes, G. B., nd Perley,., Estimtion of totl body sodium by isotopic dilution.. Studies on young dults. J. Clin. nvest., 1951, 30, Gudino, M., Schwrtz,. L., nd Levitt, M. F., nulin volume of distribution s mesure of extrcellulr fluid in dog nd mn. Proc. Soc. Exper. Biol. & Med., 1948, 68, Crdozo, R. H., nd Edelmn,. S., The volume of distribution of sodium thiosulfte s mesure of the extrcellulr fluid spce. J. Clin. nvest., 1952, 31, Brodie, B. B., xelrod, J., Sobermn, R., nd Levy, B. B., The estimtion of ntipyrine in biologicl mterils. J. Biol. Chem., 1949, 179, Schreiner, G. E., Determintion of inulin by mens of resorcinol. Proc. Soc. Exper. Biol. & Med., 1950, 74, Newmn, E. V., Gilmn,., nd Philips, F. S., The renl clernce of thiosulfte in mn. Bull. Johns Hopkins Hosp., 1946, 79, kkos, D., Luft, R., nd Sj6gren, B., The distribution of fluid nd sodium in helthy dults. Metbolism, n press. 19. Friis-Hnsen, B. J., Holidy, M., Stpleton, T., nd Wllce, W. M., Totl body wter in children. Peditrics, 1951, 7, Prentice, T. C., Siri, W., Berlin, N.., Hyde, G. M., Prsons, R. J., Joiner, E. E., nd Lwrence, J. H., Studies of totl body wter with tritium. J. Clin. nvest., 1952, 31, kkos, D., Ljunggren, H., Luft, R., nd Sjogren, B n preprtion. 22. Hurst, W. W., Schemm, F. R., nd Vogel, W. C., Simultneous determintion of totl body wter by ntipyrine nd deuterium oxide; evlution of the methods on edemtous subjects. J. Lb. & Clin. Med., 1952, 39, Nichols, G., Jr., Nichols, N., Weil, W. B., nd Wllce, W. M., The direct mesurement of the extrcellulr phse of tissues. J. Clin. nvest., 1953, 32, Edelmn,. S., Jmes,. H., nd Moore, F. D., Penetrtion of sodium nd wter into bone s mesured with rdiosodium nd D20. Federtion Proc., 1952, 11, Fellers, F. X., Bmett, H. L., Hre, K., nd Mc- Nmr, H., Chnge in thiocynte nd sodium spces during growth. Peditrics, 1949, 3, Ktcher,. L., Levitt, M. F., Sweet,. Y., nd Hodes, H. L., ltertions of fluid nd electrolyte distribution nd renl function in dirrhe of infncy. J. Clin. nvest., 1953, 32, 1013.