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Endocrinol. Japon. 1978, 25 (5), 485-492

Bartter s. Syndrome Associated with Graves Disease and

Myasthenia Gravis: Report of a CaseMITSUO INADA1, MITSUSHIGE NISHIKAWAI, MARIKO OISHI2,

SHUNICHIRO KURATA2, HIROYUKI OGAWA1, TAKEHIKO SAKURAMII,TSUYOSHI KONO1 AND HIROO IMURAI

1Second D vi si on Department of I nternal Medi ci ne Kyoto Uni versi tySchool of Medicine, Kyoto, Japan and 2Endocrine Section, Department

of Internal Medicine, Tenri Hospital, Tenri, Nara, Japan

Synopsis

Described here is a 21-year-old man, who had several episodes of generalizedmuscle weakness, blepharoptosis and a diffuse goiter. The results of thyroid functiontests and histological findings of specimen obtained by thyroid biopsy was compatiblewith mild Graves disease. Blepharoptosis was moderately improved immediatelyafter edrophonium injection, thus established the diagnosis of occular type of my-asthenia gravis. In addition, the patient had markedly diminished serum potassiumlevel, in association with markedly elevated plasma renin activity (PRA). Plasmaaldosterone concentration (PAC) and urinary aldosterone excretion (UAE) were alsomoderately increased. The insensitivity to pressor effect of infused synthetic angio-tensin II and hyperplasia of the juxtaglomerular apparatus of the kidney in histologicalexamination substantiated the diagnosis of Bartter s syndrome complicated withGraves disease and myasthenia gravis.

In order to investigate the effect of indomethacin, an inhibitor of prostaglandinbiosynthesis, on the biochemical abnormalities of Bartter s syndrome, indomethacin(75mg/day) was given with spironolactone and potassium treatment. However, thebiochemical abnormalities were not corrected and, moreover, muscle weakness andfurther decrease in potassium level were observed during the treatment with indo-methacin alone. The findings suggest that the abnormalities observed in this patientcould not be explained by the overproduction of renal prostaglandin.

The present case with Bartter s syndrome was characterized by complicating ofGraves disease and myasthenia gravis, both of which have been regarded as auto-immune diseases. Immunological studies, including subpopulation of lymphocytedetermined by surface immunoglobulin bearing cells, rosette formation and blastoidformation, revealed the suppression of B lymphocyte population in the present case.Although these immunological abnormalities were corrected after administration ofazathioprine, an immunosuppressive agent, serum potassium level was not ameliorated.The result suggest that immunological mechanism is not related to the etiology ofBartter s syndrome in the present case.

Since hyperaldosteronism associated withhypokalemic alkalosis, normal blood pressureand juxtaglomerular cell hyperplasia wasdescribed by Bartter et al.(Bar (ter et al.,1962), a number of patients with similarsyndrome, which is now called Bartter ssyndrome, have been reported. Although

the controversy regarding the etiology ofBartter s syndrome has continued, severalinvestigators have shown that indomethacin,an inhibitor of prostaglandin synthesis,could correct all the abnormalities of thisdisorder, and they suggested a possibleimportant role of renal prostaglandin over-production in the pathogenesis of this syn-drome (Verberckmoes et al., 1976; Fichmaneceived March 23, 1978.


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8 INADA et al.Endocrinol. Japon.October 1978

et al., 1976; Gill et al., 1976; Halushkaet al., 1977).

In the present paper, we report a patientwith Bartter s syndrome associated withGraves disease and myasthenia gravis, bothof which have been regarded as autoimmunediseases. Endocrine studies, including theinvestigation on the effect of indomethacin,and immunological studies before and afterthe administration of azathioprine, an im-munosuppressive agent, were made in thepresent case.

Case Report

A 21-year-old man was admitted toTenri Hospital on October 31, 1975, forevaluation of blepharoptosis and episodesof generalized muscle weakness. The patienthad been in good health until March, 1970,when he became aware of palpitation, in-creasing fatigue and perspiration. He wasponted out a diffuse goiter and diagnosedas having Graves disease. Partial thyroid-

ectomy was performed in a hospital, Oki-nawa, Japan, in May, 1970.

In December, 1972, he began to noteblepharoptosis and, therefore, he had beentreated with eye drop of anti-cholinesterase.The first episode of generalized muscleweakness occurred in the summer, 1973,when he woke in the morning to findhimself unable to stand up or to move hisextremities. There was no convulsion, in-continence or respiratory and swallowingdifficulties. He had cleared spontaneouselyfollowing bed rest for 2days. Thereafter,he had several episodes of muscle weakness.Three months before admission, he com-plained of palpitation and perspiration. Hewas pointed out a diffuse goiter, withslightly elevated serum thyroxine (T4) andtri-iodothyronine (T3) levels in outpatientclinic of Tenri Hospital. He received anantithyroid drug for about one month, whichinduced euthyroid state lasting without

maintenance dose of the drug. He deniedboth the habitual usage of laxatives anddiuretics and the frequent occurrence of

nausea, vomiting and diarrhea.Past history was non-contributory. Fami-ly history was negative for muscle weakness,although one of his cousins had Gravesdisease.

Physical examination on admission re-vealed a well-nourished man, 153 cm inheight and 41kg in weight. The blood

pressure was 100/50mmHg in the supineposition, and the pulse was 70/min in rateand regular. Exophthalmos was not present,

but ptosis of the right eyelid was notedand movement of his eyes were slightlylimited in all directions. Although therewas an operation scar in the neck, thediffuse goiter was still noted. It was elasticsoft and not tender with a smooth surface.Chvostek sign and Trousseau s phenomenoncould not be elicited. There was no pittingedema in the extremities. Neurologicalexaminations were non-contributory.

Following the intravenous administration

of 2mg of edrophonium chloride, moderateimprovement in blepharoptosis was noted(Fig. 1). Thus, the diagnosis of oculartype of myasthenia gravis was made.

Roentgengram of the chest was inter-preted as normal, but an electrocardiogramshowed flat T wave and prominent U wave.67Ga scintigraphy showed no evidence ofmediastinal tumor.

Urinary volume varied 1000 to 3300ml/24hr and a routine urinalysis revealed aspecific gravity of 1008 with no proteinnor sugar. Complete blood count showedno anemia, but slight leucocytosis was noted.Serum transaminases and alkaline phos-phatase were almost within normal limits.Circulatory blood volume and plasma volumedetermined by the dilution method usingiodinated serum albumin were 78.6ml/kgbody weight and 46.0ml/kg body weight,respectively. Endogenous creatinine clear-ance was 100ml/min. Serum sodium varied


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INADA et al.Endocrinol. Japon.October 1978

chlorobenzene (DNCB) skin reaction. Sensitizationof DNCB was performed by applying 0.1ml of 2DNCB in acetone to the forearm. Testing wascarried out with 0.1 DNCB in acetone 14 daysafter the sensitization.

Results

Thyroid function tests

T4 and T3 concentrations in serum about

3 months before admisson were 15.3 pgi

100ml and 195ng/100ml, respectively (T4:

5 to 13g/100ml and T3: 85 to 180ng/

100ml in the normals). Twenty-four hour131I thyroid uptake was 56

.7 , which wasnot suppressed after the administration of

75g/day of T3 for 8days. Serum TSH

concentration was under the limit of deter-

mination and did not increase significantly

after the intravenous injection of 500g

of thyrotropin releasing hormone (TRH).

Histologic examination of the specimen

obtained by thyroid needle biopsy showed

an increase in the height of the lining

epithelial cells, pale pink colloid and the

accumulation of lymphoid cells in some

area, all of which were compatible withthe diagnosis of Graves'disease. After anti-thyroid treatment of one month duration,T4 and T3 concentrations in serum werealmost within normal limit even withoutmedication.

Angiotensin II and noradrenalin infusiontests (Fig. 2)

The blood pressure response to theinfusion of synthetic angiotensin II wasstudied when the patient was taking 175mEq/day of sodium. As shown in Fig. 2,the infusion rate of greater than 20ng/kg/

min was required to obtain an increaseover 20mmHg in diastolic pressure, andsystolic pressure only slightly responded toinfused angiotensin II with an infusion rateof as great as 100ng/kg/min. As the in-crease over 20mmHg in systolic and dias-tolic pressure was obtained in infusion rateof 20ng/kg/min of angiotensin II in normalsubject, marked resistance to pressor actionof exogenous angiotensin II was evident inthe present patient. Furthermore, the patient

showed grossly diminished pressor sensitivity

Angiotensin II Noradrenalin

Fig. 2. Blood pressure response to the infusion of angiotensin II and of noradrenalin.


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Vol . 25 No.5 A CASE OF BARTTER S SYNDROME 489

to noradrenalin (Fig. 2). The incrementof systolic pressure was only 10mmHg orless at an infusion rate of as great as500ng/kg/min, whereas the significant in-crease of systolic pressure was observedin infusion rate under 100ng/kg/min ofnoradrenalin in normal subjects.

Effect of 1-sarcosine, 8-isoleucine angio-tensin II on blood pressure, PRA andPAC (Fig. 3)

After the infusion of 600ng/kg/min of1-sarcosine, 8-isoleucine angiotensin II for30min under the condition of daily sodium

intake of 175mEq, blood pressure fell from94/62mmHg to 88/30mmHg. PRA in-creased from 13.5 to 85.0ng/ml/hr, whilePAC decreased from 19.3 to 12.0ng/100ml(Fig. 3).

1-Sar. 8- I l e. Angi otensi n I I

600ng/kg/mn

Fig. 3. Blood pressure response to the infusion ofangiotensin II antagonist (1-sarcosine, 8-isoleucineangiotensin II).PRA: Plasma renin activity.PAC: Plasma aldosterone concentration.

Effect of alterations in dietary sodium onserum potassium concentration, PRA andPAC (Fig 4)

PRA and PAC were markedly increased

(51.5ng/ml/hr and 30.7ng/100ml, respec-tively) in this patient on a daily sodiumintake of about 9mEq for 4days. Whenthe patient s sodium intake was increasedfrom 90 to 175 mEq/day, PRA decreasedfrom 32.5 to 22.7ng/ml/hr, associated witha slight decrease in PAC from 21.0 to19.1ng/100ml. However, serum potassiumconcentration was further decreased, despitethe diminution of PAC (Fig. 4).

Results of histological studiesA specimen of the right kidney obtained

by percutaneous needle biopsy was fixedin Zenker s solution and stained withhematoxylin and eosin, periodic acid-Schiff(PAS) and Bowie s stains. In hematoxylinand eosin stained sections, slightly congested

sodi umntake

Fig. 4. Effect of various sodium intake on serumpotassium level, PRA and PAC.PRA: Plasma renin activity.PAC: Plasma aldosterone concentration.


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glomeruli were seen with extreme hyperplasiaof juxtaglomerular (JG) cells. No remarkablechanges were seen in the tubules, bloodvessels and interstitium. In Bowie's stainedsections JG cells contained little granulationsand a PAS-positive membrane betweenmacula densa cells and glomerular cellswas not seen.

Results of immunological studies (Table 1)

Blood sedimentation rate was 38mm/hr

and serum concentrations of immunoglobulin

G and A were slightly elevated.

The anti-microsome antibody of circula-

tory thyroid antibody was positive (~105),

but another autoantibodies, including anti-

smooth muscle, anti-parietal cell, anti-

striated muscle, anti-nuclear and anti-mito-

chondrium antibodies, were not detectable.

Markedly diminished proportion of surface

immunoglobulin-bearing cells in peripheral

lymphocytes was evident (14 vs 34}7

in the normals). Moreover, rosette-forming

lymphocytes to sheep red cell incubated

with complement (EAC rosette) and of

blastoid-forming lymphocytes to PWM werealso markedly reduced in percentage (EAC

rosette: 0.8 vs 19}13 in the normals

and blastoid formation to PWM: 3 vs

18}6 in the normals), suggesting the

suppression of B-lymphocyte population. In

contrast, rosette-forming lymphocytes to

sheep red cell (E rosette) was almost within

the normal range (61 vs 55}12 in

the normals) and blastoid forming lympho-

cytes to PHA was slightly elevated (82

vs 55}21 in the normals). Moreover,

both Manteau and DNCB skin tests were

positive in the present case. The results

suggested almost the normal ce llular im-

munity in the present patient.

Effect of azathioprine treatment on im-

munological findings and serum potassium

levels (Table 1)

In order to determine or not the ab-

normalities in immunological findings might

Table 1. Immunological findings and effectof Azathioprine therapy.

play a role in pathogenesis of Bartter'ssyndrome, he was treated with 50 to 100mg/day of azathioprine for 3months andthereafter the immunological studies wererepeated. Blood sedimentation rate andsubpopulation of lymphocytes determinedby surface immunoglobulin-bearing cells,rosette formation and blastoid formation

were all improved by the treatment withazathioprine, while serum potassium levelwas not increased at all.

Effects of indomethacin on serum potas-sium and PRA

Although slightly elevation of serumpotassium concentration was observed afterthe administration of potassium and spiro-nolactone, it was still below the normalrange and the reduction of PRA was not

evident.During the treatment with 75mg/day

of indomethacin combined by potassiumand spironolactone for 4weeks, serumpotassium level was not increased and PRAremained high. Furthermore, during thetreatment with 150mg/day of indomethacinalone for 2days, serum potassium levelwas rather decreased and the patient com-plained of muscle weakness.


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Vol.25, No.5 A CASE OF BARTTER S SYNDROME 9

Discussion

Described herein is a patient who hadseveral episodes of generalized muscleweakness, blepharoptosis and a diffusegoiter. Blepharoptosis was moderately im-proved immediately after the injection ofedrophonium, thus established the diagnosisof ocular type of myasthenia gravis.Results of thyroid function tests and his-tological findings of the thyroid are com-patible with mild Graves disease.

In addition to Graves disease and my-

asthenia gravis, it was noticeable that thepatient had several episodes of generalizedmuscle weakness associated with markedlydiminished serum potassium level. Thismuscle weakness was not ascribed to thy-rotoxicosis, because serum potassium levelwas consistently low evea after thyroidfunction returned to normal by the adminis-tration of an anti-thyroid drug. Moreover,he had markedly elevated PRA in associ-ation with increased PAC and UAE.

Furthrmore, the insensitivity to the pressoreffect of infused synthetic angiotensin IIand the hyperplasia of the juxtaglomerularapparatus in histological examination sub-stantiated the diagnosis of Bartter s syndromecomplicated with Graves disease and my-athenia gravis.

Despite numerous studies (Gardner et al.,1972; White, 1972; Tomko et al., 1976;Fujita et al., 1977), the pathogenesis ofBartter s syndrome remains unknown. Bartteret al. had postulated the vascular insensi-tivity to angiotensin II as a basic defectof Bartter s syndrome (Bartter et al., 1962).However, recent studies (Kono et al., 1976;Sasaki et al., 1976) have demonstrated thehypotensive response to 1-sarcosine, 8-iso-leucine angiotensin II, a specific competitiveantagonist of angiotensin II, in Bartter ssyndrome, suggesting that endogenous angio-tensin II might exert its effect on arteriolarsmooth muscle in patients with Bartter s

syndrome.In the present case, the infusion of the

angiotensin II antagonist also producedsignificant hypotensive reaction, increasedPRA and decreased PAC. The results wereconsistent with those in the previous studies.Furthermore, both PRA and PAC weredecreased with an increase of sodium intake.The findings suggest that renin-angiotensin-aldosterone system is still operative in thissyndrome. On the other hand, serum potas-sium concentration was not increased inthis period, suggesting that hypopotassemiaobserved in this patient might be due to

another factor than hyperaldosteronism.However, the possibility that the increaseof exchangeable sodium in tubulus mightplay a role in hypopotassemia by augmentingthe renal loss of potassium could not beexcluded.

Recently, it has been postulated thatthere is an overproduction of renal pros-taglandins in Bartter s syndrome, based onthe observation that biochemical abnormali-ties of the syndrome were corrected, at

least in the short term, by indomethacin,an inhibitor of prostaglandin biosynthesis(Verberckmoes et al., 1976; Fichman et al.,1976; Gill et al., 1976; Halushka et al.,1977). Although concentrations of pro-staglandins in serum or in urine were notdetermined in the present case, addition ofof indomethacin to spironolactone andpotassium treatment for 4weeks did notcorrect the biochemical abnormalities.Moreover, muscle weakness and further

decrease in serum potassium level wereobserved during the treatment with indo-methacin alone. These findings suggestthat the abnormalities observed in thispatient could not be explained by the over-production of renal prostaglandins.

The association of Graves disease andmyasthenia gravis has been frequently noted(Namba and Grob, 1971). To our know-ledge, however, no case report of Bartter ssyndrome associated with Graves disease


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and myasthenia gravis has appeared inliteratures. Since both Graves disease andmyasthenia gravis are considered to be

based on autoimmune mechanism, of specialinterest is the interrelation between Bartter ssyndrome and autoimmune diseases. It hasbeen frequently observed that the sub-population of B lymphocyte is decreasedin patients with myasthenia gravis (Nakataet al., 1974). Therefore, the suppressionof B lymphocyte population, observed inthe present case, is not ascribed to Bartter ssyndrome. Despite the fact that the im-munological abnormalities were corrected

after administration of azathioprine, animmunosuppressive agent, serum potassiumlevel was not ameliorated. This suggeststhat immunological mechanism is not relatedto the etiology of Bartter s syndrome inthe present case. Further studies shouldclarify whether Bartter s syndrome andGraves disease and myasthenia gravis oc-curred independently or interrelated eachother.

Acknowledgements

We are indebted to Dr. Tadao Tamura for theperformance of renal biopsy.

References

Ault, K. A., M. J. Karnovsky and E. R. Unanne(1973). J. Cliii. Invest. 52, 2507.

Bartter, F. C., P. Pronove, J. R. Gill, Jr. and R. C.MacCardle (1962). Am. J. Med. 33, 811.

Fichman, M. P., N. Telfer, P. Zia, P. Spcckhart,M. Golub and R. Rude (1976). ibid. 60, 785.

Fujita, T., H. Sakaguchi, M. Shibagaki, T. Fukui,M. Nomura and S. Sekiguchi (1977). ibid. 63, 467.

Gardner, J. D., A. P. Simopoulos, A. Lapey andS. Shibolet (1972). J. Clin. Invest. 51, 1565.

Gill, J. R., J. C. Frolich, R. E. Bowden, A. A. Taylor,H. R. Keiser, H. W. Seyberth, J. A. Oates andF. C. Bartter (1976). Am. J. Med. 61, 43.

Halushka, P. V., H. Wohltmann, P. J. Privitera, G.

Hurwitz and H. S. Margolius (1977). Ann. Int.Med. 87, 281.Janossy, G. and M. F. Greaves (1971). J. Clin.

Invest. 51, 1565.Kono, T., F. Oseko, S. Shimbo, M. Nanno, F. Ikeda

and J. Endo (1976). J. Clin. Endocrinol. Metab.43, 692.

Mendes, N. F., M. E. A. Tolnal, N. P. A. Silveira,R. B. Gilbertsen and R. S. Metzgar (1973). J.lmmunol. 111, 860.

Naata, Y., S. Tada and S. Arimori (1974). Allergy23, 742.(In Japanese)

Namba, T. and D. Grob (1971). Neurology 21, 377.Paronetto, F., F. Schffner and H. Popper (1967). J.

Lab. and Clin. Med. 69, 979.Sasaki, H., M. Okumura, M. Ikeda, T. Kawasaki

and K. Fukiyama (1976). New Engl. J. Med. 294,611.

Tomko, D. J., B. P. Y. Yen and W. F. Falls (1976).Am. J. Med. 61, 111.

Verberckmoes, R., B. Damme, J. Clement, A. Ameryand P. Michielsen (1976). Kidney International 9,302.

White, M. G.(1972). Arch. Int. Med. 129, 41.

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