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EXCHANGEABLE POTASSIUM IN STATES OF ADRENOCORTICAL DYSFUNCTION AND IN INDUCED HYPERCORTISONISM B. LIBERMAN, B. L. WAJCHENBERG and E. F. MOHRER PUBLICAÇÃO lea N.«244 Julho 1971 INSTITUTO DE ENERGIA ATÔMICA Caixa Postal (Pinheiros) CIDADE UNIVERSITARIA ARMANDO DE SALLES OLIVEIRA SÃO PAULO BRASIL EXCHANGEABLE POTASSIUM IN STATES OF ADRENOCORTICAL DYSFUÎ^ICTION AND IN INDUCED IIYPERCORTISONISî'î* B. Liberman, B.L. Wajchenberg and E.F. Mohrer Divisão de Radiobiologia Instituto de Energia Atômica são Paulo Brasil Publicação lea N9 244 Julho Reprinted from European Journal of Clinical and Biological Research 1971 , Flammarion Médecine-Sciences 20, rue de Vaugirard, Paris-é^, France, Short Communication, Issue 3 - Volume XVI - Pages 255-2él. Comissão Nacional de Energia Muclear Presidente: Prof.Dr. Hervásio Guimarães de Carvalho Universidade de São Paulo Reitor: Prof.Dr. Miguel Reale Instituto de Energia Atômica Diretor: Prof.Dr. Rômulo Ribeiro Pieroni Conselho Técnico-Científico do lea Prof.Dr. José Moura Gonçalves ) Prof.Dr. José Augusto Martins ) pela USP Prof.Dr. Rui Ribeiro Franco ) Prof.Dr. Theodoreto H.I. de Arruda Souto ) pela CNEN Divisões Didático-Científicas Divisão de Física Nuclear - Chefe: Prof.Dr. José Goldenberg Divisão de Radioquímica - Chefe: Prof.Dr. Fausto Walter de Lima Divisão de Radiobiologia - Chefe: Prof.Dr. Rômulo Ribeiro Pieroni Divisão de Metalurgia Nuclear - Chefe: Prof.Dr. Tharcísio D.S. Santos Divisão de Engenharia Química - Chefe: Lic. Alcídio Abrão Divisão de Engenharia Nuclear - Chefe: Eng9 Pedro Bento de Camargo Divisão de Operação e Manutenção de Reatores Chefe; Eng? Azor Camargo Penteado Filho Divisão de Física de Reatores - Chefe: Prof.Dr. Paulo Saraiva de Toledo Divisão de Ensino e Formação - Chefe: Prof.Dr. Rui Ribeiro Franco Divisão de Física do Estado Sólido - Chefe: Prof.Dr. Shigueo Watanabe EXCHANGEABLE POTASSITM IN STATES OF ADRENnCQRTICAL DYSFUNCTION AND IN INDUCED UYPERCORTISONIS!Í B. Liberman, B.L. Wajchenberg and E.F. Hohrer^ SUMMARY Exchangeable potassium (Ke) was determined in patients with primary and secondary adrenal insufficiency before and after replacement therapy and the induction of a state of hypercortisonism. Ke was also measured in 4 patients with Cushing's syndrome and in 3 of them after therapeutically induced remission, The effect of large doses of prednisone for? weeks on Ke in one normal subject was determined. The results suggest that the changes in body potassium content must represent a composite of increases or decreases in body fat and potassium rich lean tissue from non-specific nutritional effects and the specific action of glucocorticoids on the distribution of potassium between intra- and extracellular compartments and or the renal transport of potassium. There is little information regarding the measurement of exchangeable potassium in states of adrenocortical dysfunction. It was the purpose of this study to investigate in human beings the relationship of adrenal steroids to body potassium composition by the measurement of Ke before and after the administration of prednisone and in conditions of hyper and hypofunction of the ad renal cortex, before and after correction of the abnormal state. PATIENTS AND METHODS Eleven healthy normal subjects, 5 males and 6 females, aged 18 to 42 years, were studied to determine the normal values for exchangeable potassium. Eight patients with adrenocortical iia sufficiency, 5 secondary to pituitary post-partum necrosis(sheehan's disease) and 3 with Addison's disease were studied. The 5 patients \/ Diabetes and Adrenal Unit, 1st. Medical Clinics and Radiobiology Section, Instituto de Energia Atómica, Hospital das Clinicas, São Paulo, Brazil. . 2. V7ith Sheehan's disease were studied after the induction of o state of hypercortisonism with prednisone, 40 mp daily for.3 v.'ecks. The dia.cjnosis of Sheehan's disease was established from 131 the low urinary gonadotropin excretion, lov; FBI and I uptake and lov; urinary excretion of hydroxycorticosteroids x.'it!\ a propre sive increased excretion of these steroids during intravenous administration of ACTII for two consecutive days. The Addison's disease did not shov.' response to ACTrl. patients with Four patients with Cushing's syndrome, one with bilater^ al adrenal hyperplasia, of a moderate degree, other with unilate al adenoma, also of a moderate degree and both without detecable muscular wasting or osteoporosis and two patients adrenal carcinoma, both with a severe form of the disease, clinical with were studied. Three of these patients were also studied after treatment of the disease. One normal subject V7as also studied after the long-term administration of prednisone, 40 m.g/day for 50 days, with 4 studies during steroid treatment. Exchangeable potassium (Ke) was determined by isotope dilution folloiv'ing the intravenous administration of 0.3 nci of K. The specific activity of potassium was measured in urine after an equilibration time of 24 hours. 4 nl aliquots of two urines samples, obtained after the equilibration time, were used for meas_ urements of radioactivity, each sample of urine v/as counted in du plicate in a well-type scintillation counter. Ke was determined dividing the amount of radioactivity rem.aining in the body after the injection of K (i.e., injected radioactivity minus 24-bour excretion of radioactivity in the u- rine) by the mean of the specific activities of the two urine sam pies. . 3. Ye = injected - '^^K excreted (urine) urine ^^Yjurine ^^K ^^K losses in the stools were not measured as its excr tion is negligible (our patients did not have unusual fecal loss es), In many patients each Ke value was based on two isotope dilution studies performed within a 7 to 10 day period, the average value given. The error of a single Ke determination based on 20 paired Ke determinations was ± 5 per cent. Statistical analysis \jas made using standard procedures, the difference of the means being considered significant at 0.05 and highly significant at 0.001, RESULTS Table I summarizes the data obtained from the normal subjects. The mean values for total exchangeable potassium were significantly greater in males than in females (t=a.47, p 0.001) as well as when expressed in terms of body weight (t=2.930, 0.05). These data are in complete agreement with those reviewed by Edelman and Leibman^^^ and Moore et al.^^^\ The Ke obtained in 5 patients with Sheehan's disease he fore and after the induction of acute hypercortisonism with prednisone (40 mg daily for 21 days) are given in table II. The patients, before treatment, showed the Ke within the normal female range the results being expressed either as absolute values (t= 1.521) or as the Ke/Kg ratio (t = 1.860). After steroid trea_t ment, there was a highly significant increase in Ke indicated by its absolute values (t = 8,745) but still within the normal range. However, no significant changes were observed in the ratio Ke/Kg Table I - Exchangeable potassium (Ke) in normal subjects Males Females Age (years) Height (cm) Body weight (kg) Ke (meq) Ke/kg Patient Age (years) Height (cm) Body weight (kg) Ke (meq) Ke/kg éo M.M Y.L l M.F I5I M.S l A.B D.O. 168O idence interval for single values Table II - Exchangeable potassium (Ke) in patients with Sheehan's disease* before after prednisone treatment (40 mg/da.y-21 days) and Weight (kg) Exchangeable potassium Patient and age (years) Height (cm) Before prednisone After prednisone Before prednisone After prednisone meq meq/kg meq meq/kg S.E., 30 y H.K., 35 y é M.R., 37 y W.A., 40 y él.o el O.B., 41 y Mean S.D * All patients on tri-iodothyronine therapy (50 or 75 meg/day). (t = 1.860) with prednisone treatment. Serum potassium, in the normal range before (from 3.7 to 4.3 meq/1) did not change alter steroid therapy. The results in Addison's disease, before and after replacement tlierapy, with cortisone 37.5 mg daily, are shown, in ta ble III. Refore treatment, tv7o of the patients (''.G..and M. ' .) v;ho were in excellent clinical condition and with normal scrum potassium, had the Ke/Kg ratios within the 95% confidence li.nit.s of the normal values in table T. In patient R. M., studied in acute adrenal crisis (serum sodium: 122 meq/1 and serum potassium: 6.4 raeq/1), the Ke was below the confidence limits for nor-mal absolute values but not when expressed by the Ke/Kg ratio.after onft month of cortisone replacement therapy, both the Ke and Ke/vg v.tere lower th.-în before treatment, particularly in patient N. n. in whkh 6. Table III - Exchangeable potassium (Ke) in patients with Addison's disease and after replacement treatment (cortisone 37.5 mg/day-l month) Patient, sex and age (years) Height (cm) Weight (kg) Before cortisone After cortisone Serum potassium (meq/l) Before cortisone After cortisone Exchangeable potassium Before cortisone After cortisone meq meq/kg meq meq/kg M.G.,5,3ly N.D.,QT40y R.M.,of42y * * I876* * * After 5 weeks on cortisone + DOCA 5 mg I-M. every other day, on the last 5 days. Ke fell from 3076 to 2459 meq, without significant changes being noticed in serum potassium, except in patient R.M. In that patient a decrease of 338 meq in Ke was accompanied by a fall in serum K from 6.4 to 5.8 meq/1, still in hyperkdlemic range. At this time the patient's clinical status was not completely improved as he still was weak, anorectic and had postural hypotension. When DOCA was added, without additional salt intake, there was a dramatic return of a sense of well-being, disappearance of anorexia and a rise in blood pressure within 24 hours. Five days after giving DOCA, the patient hat put on 1.1 kg, his serum potassium was 4.5 meq/1, with pratically no change in the previous values for exchangeable potassium. The results in Cushing's syndrome are given in table 17. the two young women with moderately severe disease (M.R.S. and M.J.) had normal serum K levels but Ke and Ke/Kg ratios slightly below the 95% confidence limits for normal single adult female values. Since in females, as well as in males, the total exchan geable notassium, as a function of body weight, decreases with advancing age^^^^ the low values are even more significant. The . 7 Table IV - Exchangeable potassium (Ke) in patients with Gushing's- syndrome before and after treatment Patient, sex and Weight (kg) age (aetiology) Before After treatment Serum potassium (meq/1) Before After treatment Exchangeable potassium Before 1.reatment meq meq/kg After ti eatment meq meq/kg M.R.S., 2, 15 y (bilateral adrenal hyperplasia) * ** 33-2 S.J.,2, 43 y (left adrenal carcinoma) *** M.J-,2, 13 y (left adrenal adenoma) **** 32.2 F.C., (TT 12 y (left adrenal carcinoma) months after bilateral total adrenalectomy on oral prednisone (10 mg/day). 3 months after bilateral total adrenalectomy on 50 mg cortisol/day (l.m.) and in acute adrenal insufficiency . 3 1/2 months after surgery on Cortisol (50 mg) and d-aldosterone 1 mg, I.M., daily. 1 month after adrenalectomy and maintained on oral prednisone 2.5 mg/day. 1 month after left adrenalectomy and maintained on oral prednisone 10 mg/day. tv7o Other patients, with the severe form of the disease and low serum potassium (S.J. and F.C.), showed a lower Ke and Ke/Kg. The patient with bilateral adrenal hyperplasia (M.R.S.), was studied 2 and 3 months after bilateral total adrenalectomy, at the time that she was deeply pigmented, suggesting either the development of a pituitary tumour (later shovm not to be the case) or that the amount of replacement therapy v/as not sufficient,.^t both studies, Ke and Ke/Kg increased in relation to the pre-opera . 8. tive values. The 2nd measurement, when the patient was on I. M. Cortisol, 50 mg daily, she was hypotensive with the clinical signs of an adrenal crisis. Only after the addition of I. M. d-aldost rone, she was well maintained and 15 days afterwards there was a great decrease in Ke, from 182A to 1269 meq, and in the Ke/Kg ratio, from 33.2 to 22.6, still lower that the preoperative valua Afterwards, the patient was maintained on 75 mg daily of oral cortisone, and the body pigmentation was significantly reduced. Patient M. J., with an adrenal adenoma, studied 1 month after adrenalectomy and maintained on prednisone (2.5 rag/day) showed a significant increase in both Ke and Ke/Kg without change in serum potassium levels. Of the two patients with adrenal carcinoma who had the lowest exchangeable and serum potassium values, one of them(f.c.) was studied again 1 month after adrenalectomy and kept on prednisone, 10 mg daily. This patient showed a large increase in Ke and Ke/Kg and serum K which more than doubled, coincident with the marked improvement after treatment. The effects of induced hypercortisonism is shown in t ble V. Exchangeable potassium, expressed as its absolute value and as the Ke/Kg ratio, was determined repeatedly before and after the treatment of a normal female volunteer, with a pharmacological dose of prednisone for 7 weeks, that caused severe muscle atropty. Her exchangeable potassium decreased progressively to very low levels without change in serum potassium values. The last detemu nation showed an increase in exchangeable potassium in relation to the previous one, but still greatly reduced in comparison to the mean control value. In the first two weeks of prednisone treatment a compa ison between the change in exchangeable potassium and the external , 9 Table V - Exchangeable potassium (Ke) in a normal subject before and after induction of hypercortisonism with prednisone (40mg/day) D.O.,0, 41 years, Height : l60 cm. - Wt : 44.5 kg Duration of treatment (Weeks) Weight (kg) Serum potassium (meq/1) Exchang cable potass ium meq meq/kg Control * * Mean of 4 studies (range 36.0 to 40.2) balance of potassium (diet, urine and fecal potassium measurements) was made. The change in Ke was meq and in external balance \-jas meq (almost exclusively accounted for by urinary losses), the difference of body measurement from external balance being therefore of meq. No further balance studies were pe formed. DISCUSSION As noted in previous publications 4,10 there is a wide range of normal values for Ke and Ke/Kg (table I) to a great extent related to individual differences in the electrolyte-free ad^ ipose tissue of the body. This factor of relative body contents of adipose tissue and lean body mass must be kept in mind in inter^ preting the values of exchangeable body potassium per Kg in patients with adrenocortical dysfunction. On the other hand, it is conceivable that any increase in body potassium in adrenocortical . 10. insufficiency (Sheehan's and Addison's disease), to be expected from the experimental data ^ ^' ' ^^^ tends to be masked by its change in opposite direction which characterizes many chronic within normal limits. It is felt that the lower Ke and Ke/Kg values after 1 month of replacement therapy in patients M. G. and N. D.(tablein) were mainly a reflection of the renal losses of potassium due the steroid treatment as we have seen in Addison's balance disease potassium becoming positive during cortisone withdrawal and subsequently negative on steroid resumption, until the patient potassium equilibrium after several days of therapy, disease states: that is, body potassium stores would tend to fall as muscle mass decreases and concomitantly the extracellular space tends (9) to expand absolutely and body sodium content increases. This is probably the situation in the patients with Sheehan's kept on triiodothyronine disease replacement treatment whose control val^ ues for Ke and Ke/Kg are in the lower limits of the confidence in terval for single normal values. In both Addisonian patients, in good health, there was normal pre-treatment values forkeand Ke/Kg (patients M. G. and N.D., table III). Similar results were obtain (2) ed by Brown et al., in two patients with Addison's the patient R. M. in acute adrenal insufficiency we found,similar to Arons et al.^'''^ in their acutely ill patient the Ke/Kg was vjell enters without si nificant changes in serum potassium levels (unpublished data). In patient R. M., examined during an crisis, the serum potassium concentration, abnormally high before treatment,fell but not to normal during the initial treatment period with cortisone. However, when mineralocorticoid deficit was corrected producing a normal serum potassium without a significant change in Ke (table III), the fall in serum potassium levels was probably the result of internal redistribution of potassium between fluid compartments . 11. of the body and/or hemodilution following the increase of plasma volume due to sodium retention; the latter is suggested by a serum sodium concentration of meq/1 at the time when the po^ tassium level became normal and the patient had gained 1.1 kg since DOCA was started. The evidence is insufficient to show which of these factors were predominant in the fall of serum potassium. The obese and protein depleted Cushing's syndrome patients had low levels of Ke and Ke/Kg (table IV) particularly in those with the greatest reduction of lean tissue manifested as muscular wasting and osteoporosis, developed most rapidly in ma^ lignant disease with decrease in servm potassium (patients S. J. and F. C, table IV). In those patients with hypercortisonism (Cushing's syndrome) studied after therapeutically induced remission, there was an increase in Ke, as previously reported by Ernest^^^, without a change in serum potassium in those cases normal values before treatment. In patient F. C, with low serum potassium, the increase in Ke was associated with normal concentration in the serum. The effect of large doses of prednisone, on a short-term basis, in patients with Sheehan's disease and for a longer period in a normal female subject, caused the opposite results: a decrease in Ke and Ke/Kg in the normal subject (table V) with a decrease in body weight and a significant increase in Ke in all pa^ tients with Sheehan's disease with a gain in body weight in half of them (table II). The increase in Ke is interpreted as a refle tion of an increase in body cell mass and indicating an improvement of the disease with the subsequent increase in food intake (8) and body weight. In animals, the amount of dietary calories and protein can modify the nitrogen balance during cortisone treat ment and that an initial negative balance may improve during pro .12. longed treatment. Kyle et al. have shown that dietary intake are of decisive importance for the body composition in patients with Cushing's syndrome. Finally, Lindholm has shown that patients with bronchial asthma under synthetic Cortisol analogues treatment for more than two years, in a daily dose corresponding to mg of cortisone, did not show a decrease in Ke and some showed increase in of body composition during which their diet was adequate due to improvement of their asthma. The increase in Ke and Ke/Kg in all patients with Sheehan's disease after the treatment with prednisone, suggests the patient's gain in potassium-rich lean body mass as the Ke/Kg ratio change was not significant. The opposite effect observed in the normal control, was certainly related to her low dietary intake with loss of body weight. In this patient the discrepancy between potassium balance and exchangeable potassium in the first 2 weeks of steroid treatment, suggests that previously non-exchangeable depots of potassium may have become exchangeable during the period of hormone ad_ ministration. However, the difference observed between the balance and Ke was not sufficiently large to rule out inherent errors of determining the balance. Arons et al. have also noticed instances of significant discrepancies between potassium balance and body potassium measurements and have postulated similar expl nations. and Sagild In favor of this concept is the study reported by Rundo (12) that the v
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