References1. Benzan\l=c;\on,F., and others: Hemoptysis and Dilation of

Bronchi, Presse m\l=e'\d.32:157-159 (Feb. 20) 1924.2. Findlay, L., and Graham, S.: Bronchiectasis in Child-

hood: Its Symptomatology, Course and Cause, Arch. Dis.Childhood 2:71-96 (April) 1927.

3. Pinchin, A. J. S., and Morlock, H. V.: H\l=ae\morrhagicDry Bronchiectasis, Brit. M. J. 2:315-317 (Aug. 30) 1930.

4. Burrell, L. S. T., and Trail, R. R.: Bronchiectasis:Forme h\l=e'\mopto\l=i"\ques\l=e`\che,Lancet 1:182-183 (Jan. 25)1930.

5. Wall, C., and Hoyle, J. C.: Observations on DryBronchiectasis, Brit. M. J. 1:597-602 (April 8) 1933.

6. Roles, F. C., and Todd, G. S.: Bronchiectasis: Diagno-sis and Prognosis in Relation to Treatment, Brit. M. J.2:639-643 (Oct. 7) 1933.

7. Warner, W. P.: Factors Causing Bronchiectasis: TheirClinical Application to Diagnosis and Treatment, J. A. M. A.105:1666-1670 (Nov. 23) 1935.

8. Farrell, J. T., Jr.: Importance of Early Diagnosis inBronchiectasis: Clinical and Roentgenologic Study of 100Cases, J. A. M. A. 106:92-96 (Jan. 11) 1936.

9. Ogilvie, A. G.: Natural History of Bronchiectasis: Clin-ical, Roentgenologic and Pathologic Study, Arch. Int. Med.68:395-465 (Sept.) 1941.

10. Martin, L. C., and Berridge, F. R.: BronchiectasisWithout Disability: Report on 25 Cases, Lancet 2:327-330(Sept. 19) 1942.

11. Fine, A., and Steinhausen, T. B.: Non-disablingBronchiectasis, Radiology 46:237-243 (March) 1946.

12. Overholt, R. H.: Recognition and Management ofBronchiectasis, Nebraska M. J. 36:315-322 (Oct.) 1951.

13. Wynn-Williams, N.: Bronchiectasis: Study Centeredon Bedford and Its Environs, Brit. M. J. 1:1194-1199 (May30) 1953.

14. Lindskog, G. E., and Hubbell, D. S.: Analysis of 215Cases of Bronchiectasis, Surg. Gynec. & Obst. 100:643-650(June) 1955.

15. Macklin, C. C.: Musculature of Bronchi and Lungs,Physiol. Rev. 9:1-60 (Jan.) 1929.

16. Hilding, A. C.: Ciliary Streaming in Bronchial Treeand Time Element in Carcinogenesis, New England J. Med.256:634-640 (April 4) 1957.

17. Dalhamn, T.: Method for Determination In Vivo ofRate of Ciliary Beat and Mucous Flow in Trachea, Acta.physiol. scandinav. 33:1-5, 1955.

18. Huppler, E. G.; Clagett, O. T.; and Grindlay, J. H.:Elimination and Transport of Mucus in Lung: ExperimentalStudy, J. Thoracic Surg. 32:661-668 (Nov.) 1956.

TREATMENT OF EIGHT CASES OF HYPERTHYROIDISM WITHCOBALTOUS CHLORIDE

Enrique Pimentel-Malaussena, M.D., Marcel Roche, M.D.and

Miguel Layrisse, M.D., Caracas, Venezuela

Eight patients with hyperthyroidism were

treated with cobaltous chloride by mouth.Clinical improvement was manifested byabatement of the tachycardia, reduction ofbasal metabolic rate, and rise in red bloodcell count and blood hemoglobin content infour patients. These four patients also gavestriking evidence of improvement in labora-tory tests with radioiodine and three of themunderwent thyroidectomy without complica-tion after the cobalt therapy alone. The otherfour patients had less favorable results. Oneshowed improvement in her preexisting ane-

mia but suffered recurrence (after temporaryrelief of her symptoms of hyperthyroidismdespite continued cobalt therapy; the otherthree did not respond to the cobalt at all as

regarded their hypothyroidism, although oneshowed marked hematological improvement.The mode of action and indications for theuse of cobalt in hyperthyroidism require fur-ther study.

Kriss, Carnes, and Gross ' reported in 1955 thedevelopment of thyroid hyperplasia in four chil¬dren and one adult receiving cobaltous chloride bymouth in doses ranging from 2.8 to 3.9 mg. perkilogram per day. In three subjects, in whom

Table 1.—Chief Symptoms and SignsDuration

of Loss ofCase Age, Symptoms, weight, Nervous- Exoph-No. Tr. Sex Mo. Kg. ness thalmos Goiter*

1 47 F 8 12 ++ + Dl2 24 F 12 30 ++++ + D33 24 M 24 15 ++++ + D34 50 P 48 ++ ++ + D25 27 F 7 +++ ++++ ++ N36 22 M 3 30 ++++ ++ N27 38 F 1 ++ +++ ++ D38 13 F 7 ++ ++++ + D2

*D=diffuse; N=nodular; l=barely palpable; 2=palpable and visible:3=grossly visible.

radioiodine (1131) studies were done, it was foundthat thyroid 1131 uptake was markedly depressed.Jaimet and Thode 2 have thrown serious doubts onthose findings, since they were unable to demon-

Assistant Professor of Clinical Medicine, Universidad Central (Dr.Pimentel-Malaussena); Director, Instituto de Investigaciones M\l=e'\dicas(Dr. Roche); and Director, Research Department, Banco de SangreMunicipal ( Dr. Layrisse ).

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strate consistent effects of cobalt (in doses up to6 mg. per kilogram per day) on thyroid I 131 uptake,conversion ratios, and saliva radioactivity. Morerecently, however, Roche and Layrisse3 haveshown that cobaltous chloride in doses of 150 mg.

Table 2.—Treatment and Clinical CourseCo¬balt- Ap-ous No. Clin- parent

Chlo- of ieal In- Pulse/ Weight,ride. Days Im- crease Min.* Kg.*

Case Mg./ Giv- prove- in r- *-v-A-No. Day en ment Goiter A B A B1 150

30055 ++++31

0 130 80 53 53

143 88 43 4«300 3 ++++0 1

150 8300 34300 30t ++++ 0 100 80 61300 45300 15 +++ 0 100 80 41

0 1150 117150 54 ++ +++ 130 94 39300 46

Sub¬totalThy-roiti-

,ecto- Othermy Treatment+ Propylthio-

uracil; stopped\y¿ mo. beforecobalt started

+

ODD300

300150300300150300

1046

fi3

3013

40

104 110 61 60

++ 130 104 50 50

130 144 37 37

+ I.ugol's solu¬tion, 20 drops,t.i.d last 25days

... No response tomethimazoleor to perchlo-rate treatment: Anallycontrolled with1« me. of I«i

+ Response tomethimazole

-f Response tomethimazole

* A=before treatment; B= at the end of treatment.t This patient was ambulatory during the first 30 days of treatment

and it was felt that he did not take his medicament properly duringthis time.

per day in 12 nonanemic euthyroid adults led to adistinct fall in thyroid I 1J1 uptake, in most casesafter one week and in all cases after two weeks. In

Fig. 1 (case 2).—Good response to cobalt therapy.Thyroidectomy.

view of these findings, it was deemed worthwhileto try cobaltous chloride therapy as a means ofcontrolling hyperthyroidism.

Eight cases of hyperthyroidism treated with co¬baltous chloride are herein reported. In four of thecases there was marked clinical improvement, and

in three of these a thyroidectomy was performedwithout complication after cobalt therapy alone(cases 1 and 2 have been briefly reported3). Inone case, there was initial response and later"escape," making it necessary to administer Lugol'ssolution before thyroidectomy; in the three re¬

maining cases, there was no response to cobalt.Methods and Material

Thyroid uptakes were determined with a scintilla¬tion counter (Nuclear, model DS-1), saliva radio¬activity,4 and conversion ratios 5 with a well-typescintillation counter (Nuclear, model 3037 B) 24hours after the administration of 50 /¿c of I 13\correction being made if necessary for residualradioactivity. Cobalt was administered by mouthas cobaltous chloride in a 1% solution, in threedivided doses after meals. The pulse was taken inthe morning upon awakening.

ecu

Fig. 2 (case 5).—Initial good response to cobalt therapyand later "escape." The administration of Lugol's solutionin addition to cobalt led to rapid remission of the hyper¬thyroidism. Lugol's solution was continued after operation.

All patients were hospitalized in the HospitalVargas. The chief symptoms and signs are given intable 1 and the treatment indicated in table 2.Histological study was performed on all thyroidglands removed at operation.

ResultsThe clinical course is summarized in table 2 and

the chief laboratory findings before and at the endof treatment in table 3. Intolerance to medicationin the form of epigastric pain, burning, and nauseawas experienced by four patients, generally towardthe start of treatment, while all other patients tol¬erated treatment well.

In one additional patient, treatment with cobaltcould not be continued because of gastric intol¬erance to the drug. In the cases presented here, itwas not necessary to discontinue medication en¬

tirely; in general, it was sufficient to stop cobalt fora day or two and resume therapy at a lower dosage

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level. After a week or two, the dosage could beraised again to its initial level without furthertrouble.

CommentIn five of the eight patients with hyperthyroidism

treated with cobaltous chloride, there was clear-cutremission of symptoms and laboratory evidence ofblocking of thyroid hormone synthesis.

Although it is well recognized that hyperthy¬roidism may subside spontaneously, it is unlikelythat this should occur in five cases out of eight dur¬ing a relatively short period of observation. In theearly reports collected by Sattler,6 spontaneous re¬mission is said to have occurred in from none to50% of mild unoperated cases, with an average of26%; recovery was described as usually occurringseveral years after onset. Since practically all pa¬tients today receive antithyroid treatment, there areno recent figures available on this point.6 Further¬more, we do not believe that a spontaneous remis¬sion would explain the laboratory evidence of blockof thyroid hormone synthesis.

It was possible to perform thyroidectomy on

three of the five patients who responded to cobaltwithout the addition of any other antithyroid medi¬cation. In one of the patients, who objected tooperation (case 4), it was possible to continuecobalt therapy for 117 days without any untowardeffect. After medication was discontinued, therewas no return of symptoms; the patient died twomonths later of a cerebrovascular accident.

Table 3.—Effect of Cobaltous Chloride on Laboratory Tests

Case No.Response1.

Response and "escape"5t.No response

BloodHemoglobin

Level,Gm./100 Ml.*

A

13.311.513.810.4

11.7

13.18.79.1

B

15.015.017.714.0

14.313.09.1

Red BloodCells.

Million/Ml.*

4.23.94.43.5

4.53.03.3

4.74.45.14.3

4.54.23.0

24-Hr. li»iThyroid Uptake, Conversion

BMR, %* %* Ratio, %*

SalivaRadioactivity,1,000 Counts/

Min./SOc.*

+59+22+28+44

+62

+55+31+44

—6+1

+46

+21

6951

5558

170

171

5949

A

70939289

91

899393

9186

A

0.70.20.3

2.11.60.8

56.461.2

125.7

4.48.66.6

* A=before treatment; B—after treatment with cobalt.t This patient "escaped" treatment. The levels reached before escape were BMR, +15; thyroid uptake. 20; conversion ratio, 10; saliva radioactivity,48.9.

The data on one of the patients who respondedto cobalt (case 2) are presented in figure 1. Inthis case, the initial dose was 300 mg. of cobaltouschloride per day. This had to be stopped after threedays because of nausea and epigastric distress.After 24 hours off treatment, cobalt therapy was

resumed, at a dose of 150 mg. per day, withoutdifficulty, so that after a week the initial dosagecould again be started. There was definite clinicalimprovement after three weeks, associated with

evidence of block in thyroid hormone synthesis,and a decrease in basal metabolic rate (BMR) tonormal levels. Thyroidectomy was performed 45days after the beginning of cobalt therapy.

In one patient (case 5) (fig. 2) there was clinicalimprovement at first and evidence of thyroid block.After 30 days of treatment, pulse and nervousness

Tnvroid1131uptake

(%}<* dos«

OPERaTION

DAYS

Fig. 3 (case 7).—No response to cobalt therapy. Goodresponse to methimazole.

began again to increase and there was evidence ofrenewed thyroid activity; the goiter had increasedmarkedly in size, and on the 70th day while cobalttherapy was being continued, Lugol's solution, 20drops three times a day, was added, with resulting

rapid and marked clinical improvement. Thyroidec¬tomy was performed within 30 days of startingtherapy with Lugol's solution. It is interesting thatthis patient had a nodular goiter, in which resist¬ance to therapy is frequently observed.

Finally, in three cases, there was no response totherapy, even though cobalt was given in dosessimilar to those given in the previous four cases.The data on one such patient ( case 7 ) are shown infigure 3. In spite of the administration of cobalt

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for 45 days, there was no change in clinical status,thyroid uptake, conversion ratio, BMR, or salivaradioactivity. Treatment with methimazole (Tapa-zole ) resulted in rapid improvement, and thyroidec¬tomy was performed after the addition of saturatedpotassium iodide solution. One of the three patientswho did not respond to cobalt (case 6) had also a

nodular goiter, and there was no response to drugtherapy with methimazole or with potassiumperchlorate. Hyperthyroidism was finally controlledin this case with 16 inc. of I l:".

In all of the patients who responded to cobalt,blood hemoglobin levels and red blood cell countsrose under therapy ( table 3 ). Of the three patients

Fig. 4.—Top, thyroid tissue from patient in case 2. Thyroidhyperplasia, high epithelium, sparse colloid; in the center,accumulation of lymphocytes (hematoxylin-eosin stain,X 150). Bottom, thyroid tissue from patient in case 1;infolding epithelium; sparse colloid with abundant vacuoles( hematoxylin-eosin stain, X 300).

whose thyroid status did not change with cobalt,only one (case 7) showed a distinct rise in hemo¬globin and red blood cell count, but this could notbe attributed to cobalt, since this patient was givenferrous sulfate therapy simultaneously. The lack ofresponse in the hematological indexes of two pa¬tients (cases 6 and 8) would suggest that, in thesecases at least, cobalt was not properly absorbedand therefore did not reach in sufficient concentra¬tion either the thyroid gland or the bone marrow.

Histological study of the thyroid glands removedat operation (fig. 4) after cobalt treatment aloneshowed marked hyperplasia of follicular tissue witha high columnar, infolded epithelium. The sparsecolloid contained abundant vacuoles. This appear¬ance is not unlike that seen in patients treated withantithyroid drugs of the thiouracil type.

Cobalt appears to be clearly capable of blockingthyroid hormone synthesis in hyperfunctioning thy¬roid glands, as it does in normal thyroid,3 althoughits action is somewhat unpredictable, as witnessedby the three patients who showed no responsewhatever. The reason for this lack of response is atpresent unclear, as is in fact the mechanism of co¬

balt action on the thyroid. We feel, however, that,in view of the good results obtained in several ofthe cases, it might be interesting to submit thisdrug to further therapeutic trial in hyperthyroidism.

SummaryEight patients with hyperthyroidism were treated

with varying doses of cobaltous chloride by mouth.In four of these, there was marked clinical improve¬ment and evidence of block of thyroid hormonesynthesis. In three of these cases a thyroidectomywas performed; the histological appearance was

that of follicular hyperplasia. One of the four pa¬tients who responded was carried for 117 days on

cobalt therapy, with apparent clinical remission.One patient who responded initially later "escaped"the effect of the drug and had to be given Lugol'ssolution before operation. In three cases, there was

no response to the drug; one of these patients didnot respond to methimazole or potassium per-chlorate, and had to be given I 131 therapy.

Apartado 1827 (Dr. Roche).References

1. Kriss, J. P.; Carnes, W. H.; and Gross, R. T.: Hypo-thyroidism and Thyroid Hyperplasia in Patients Treatedwith Cobalt, J. A. M. A. 157:117-121 (Jan. 8) 1955.

2. Jaimet, C. H., and Thode, H. G.: Thyroid FunctionStudies on Children Receiving Cobalt Therapy, J. A. M. A.158:1353-1355 (Aug. 13) 1955.

3. Roche, M., and Layrisse, M.: Effect of Cobalt on

Thyroidal Uptake of I 131, Letters to the Editor, J. Clin.Endocrinol. 16:831-833 (June) 1956.

4. Thode, H. G.; Jaimet, C. H.; and Kirkwood, S.: Studiesand Diagnostic Tests of Salivary-Gland and Thyroid-GlandFunction with Radioiodine, New England J. Med. 251:129\x=req-\134 (July 22) 1954.

5. Sheline, G. E.; Moore, M. C.; Kappas, A.; and Clark,D. E.: Correlation Between Serum Protein-Bound Iodineand Radioiodine Conversion Ratio in Various Thyroid States,J. Clin. Endocrinol. 11:91-97 (Jan.) 1951.

6. Sattler, H.: Die Basedowsche Krankheit, Leipzig, Wil-helm Engelmann, 1909; quoted by Werner, S. C., in TheThyroid: Fundamental and Clinical Text, edited by S. C.Werner, New York, Paul B. Hoeber, Inc., 1955.

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