an abnormality of thyroid hormone secretion

4
AnAbnormalityofThyroidHormone Secretion* ROBERTE .MACK,M .D .,KATHLEENT .HART,PH .D .,DEADRUE'r,M .s .and MARYANNEBAUER,B .S . St .Louis,Missourt risnowwellestablishedthatthyroxineisthe Iprincipallabeledthyroidhormonewhich canberecoveredfromtheserumsofpatients givenradioactiveiodine,evenwhenlargedoses ofradioactivematerialareemployed[1] .The occurrenceofsmallquantitiesoftriiodothyronine inhumanserumwasfirstdescribedbyGrossand Pitt-Rivers[2] .InasimilarstudyBenuaetal .[3] foundthatwhencirculating1131labeledtri- iodothyroninewaspresent,itsconcentration wasgreaterthanthyroxineonlyinthevery earlyperiodfollowing1131therapy . Thepurposeofthiscommunicationistore- porttheunusualfindingoflargequantitiesof triiodothyronineintheserumofapatientwith thyroidcarcinoma .Thiswasdemonstratedfol- lowingtheadministrationofthreesuccessive therapeuticdosesofradioactiveiodine . CASEREPORT Aforty-eightyearoldmanwastransferredtotheSt . LouisVeteransAdministrationHospitalinApril1935 withthediagnosisofatumorofthefourthlumbar vertebra .Onphysicalexaminationasmallnodulewas notedintheisthmusofthethyroidgland .Therewas tendernessoverthespineofthefourthlumbar vertebra .Thebasalmetabolicratewasplus48 . Roentgenographicexaminationofthelumbosacral spinerevealedthepresenceofanosteolyticprocess involvingthebodyandlaminaofthefourthlumbar vertebra .InMay1955alefthemithyroidectomywas performedwiththepathologicdiagnosisofwelldif- ferentiatedcarcinomaofthethyroidgland .Thiswas followedbyatotalthyroidectomy .Postoperatively, radioiodinestudiesrevealedconcentrationofthe radioactivematerialinthelumbarareaandthree 25me .dosesofP31wereadministeredoveraperiodof severalweeks . InNovember1955progressivespasticparalysisof thelowerextremitiesdevelopedinthepatientwhich necessitatedreadmissiontotheSt .LouisVeterans AdministrationHospital .Hisbasalmetabolicrate wasplus72,laterplus38 .Theserumprotein-bound iodinewas3 .4pg .percent .Roentgentherapytothe lowerpartofhisbackaswellas75mc .of1181were administeredwithoutsymptomaticrelief.InJanuary 1956adecompressionlaminectomywasperformed, andthyroidcarcinomawasfoundintheexcised fragments .Postoperativelytheparaplegiaregressed . OnreadmissiontothehospitalinNovember1956, theonlyphysicalfindingwasawastingawayofthe musclesofthelowerextremities .Therewasnoclinical evidenceofhypothyroidism .Theprotein-bound iodinewas4 .1pg .percent .Followingtheadministra- tionofatracerdoseof1131theconversionratiowas82 percent .Ascintigramoftheneckregionfailedto demonstratethepresenceofanyradioactivityinthe thyroidarea .Scanningoverthebackrevealedtwo concentrationsoftheradioactivematerial,oneatthe levelofthesecondthoracicvertebraandanotherover thefourthlumbarvctcbra .Onehundredandfive millicuriesofI131wereadministeredinNovember 1956,bloodwasobtainedforty-eighthourslaterfor thestudyoflabeledthyroidhormonecontent . Thepatientwasagainadmittedtothehospitalin September1957aftersufferingafractureoftheneck ofthelefthumerusinafall .Physicalfindingswere limitedtopainandtendernessinthelumbarareaand alsoatthefracturesite .Aroentgenogramoftheleft shoulderrevealedthepresenceofafractureofthe neckofthehumerus.Therewasnothingtosuggest thatthiswasapathologicfracture.Tracerstudies againdemonstratedtheconcentrationsofradioactive iodineinthesamelocationsasontheprevioushospital admission,butnoneatthefracturesite .InSeptember 1957,130me .ofI"wereadministeredandbloodwas obtainedattwenty-four,forty-eightandseventy-two hourintervalsforanalysisoflabeledhormone . ThemostrecentadmissiontotheSt .LouisVeterans AdministrationHospitalwasinJune1959withthe complaintofprogressivelossofstrengthinthelower extremities .Thesechangeswerenoticedaboutthree monthspriortothisadmission .Thepatienthadnot takenthyroidextractashadbeenrecommendedin "FromtheSt .LouisVeteransAdministrationHospitalandtheDepartmentofInternalMedicine,St .LouisUniversity SchoolofMedicine,St .Louis,Missouri . FERROARS1961 323

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Page 1: An abnormality of thyroid hormone secretion

An Abnormality of Thyroid Hormone

Secretion*

ROBERT E. MACK, M .D ., KATHLEEN T. HART, PH.D., DEA DRUE'r, M .s. andMARY ANNE BAUER, B .S .

St. Louis, Missourt

r is now well established that thyroxine is theI principal labeled thyroid hormone whichcan be recovered from the serums of patientsgiven radioactive iodine, even when large dosesof radioactive material are employed [1] . Theoccurrence of small quantities of triiodothyroninein human serum was first described by Gross andPitt-Rivers [2] . In a similar study Benua et al . [3]found that when circulating 1131 labeled tri-iodothyronine was present, its concentrationwas greater than thyroxine only in the veryearly period following 1131 therapy .

The purpose of this communication is to re-port the unusual finding of large quantities oftriiodothyronine in the serum of a patient withthyroid carcinoma . This was demonstrated fol-lowing the administration of three successivetherapeutic doses of radioactive iodine .

CASE REPORTA forty-eight year old man was transferred to the St .

Louis Veterans Administration Hospital in April 1935with the diagnosis of a tumor of the fourth lumbarvertebra . On physical examination a small nodule wasnoted in the isthmus of the thyroid gland . There wastenderness over the spine of the fourth lumbarvertebra . The basal metabolic rate was plus 48 .Roentgenographic examination of the lumbosacralspine revealed the presence of an osteolytic processinvolving the body and lamina of the fourth lumbarvertebra . In May 1955 a left hemithyroidectomy wasperformed with the pathologic diagnosis of well dif-ferentiated carcinoma of the thyroid gland . This wasfollowed by a total thyroidectomy . Postoperatively,radioiodine studies revealed concentration of theradioactive material in the lumbar area and three25 me. doses of P31 were administered over a period ofseveral weeks .

In November 1955 progressive spastic paralysis ofthe lower extremities developed in the patient whichnecessitated readmission to the St . Louis Veterans

Administration Hospital . His basal metabolic ratewas plus 72, later plus 38 . The serum protein-boundiodine was 3 .4 pg . per cent . Roentgen therapy to thelower part of his back as well as 75 mc . of 1181 wereadministered without symptomatic relief. In January1956 a decompression laminectomy was performed,and thyroid carcinoma was found in the excisedfragments . Postoperatively the paraplegia regressed .

On readmission to the hospital in November 1956,the only physical finding was a wasting away of themuscles of the lower extremities . There was no clinicalevidence of hypothyroidism. The protein-boundiodine was 4 .1 pg . per cent . Following the administra-tion of a tracer dose of 1131 the conversion ratio was 82per cent . A scintigram of the neck region failed todemonstrate the presence of any radioactivity in thethyroid area . Scanning over the back revealed twoconcentrations of the radioactive material, one at thelevel of the second thoracic vertebra and another overthe fourth lumbar vctcbra . One hundred and fivemillicuries of I131 were administered in November1956, blood was obtained forty-eight hours later forthe study of labeled thyroid hormone content .

The patient was again admitted to the hospital inSeptember 1957 after suffering a fracture of the neckof the left humerus in a fall . Physical findings werelimited to pain and tenderness in the lumbar area andalso at the fracture site . A roentgenogram of the leftshoulder revealed the presence of a fracture of theneck of the humerus. There was nothing to suggestthat this was a pathologic fracture. Tracer studiesagain demonstrated the concentrations of radioactiveiodine in the same locations as on the previous hospitaladmission, but none at the fracture site . In September1957, 130 me . of I" were administered and blood wasobtained at twenty-four, forty-eight and seventy-twohour intervals for analysis of labeled hormone .

The most recent admission to the St . Louis VeteransAdministration Hospital was in June 1959 with thecomplaint of progressive loss of strength in the lowerextremities . These changes were noticed about threemonths prior to this admission . The patient had nottaken thyroid extract as had been recommended in

" From the St . Louis Veterans Administration Hospital and the Department of Internal Medicine, St . Louis UniversitySchool of Medicine, St . Louis, Missouri .

FERROARS 1961

323

Page 2: An abnormality of thyroid hormone secretion

324 Abnormality of Thyroid Hormone Secretion-Mack ei al .

FIO. 1 . A radioautograph of the chromatogram ofserum obtained forty-eight hours after 1 11 ther-apy. Tx refers to carrier thyroxine and TIT totriiodothyronine .

September 1957 . Serum protein-bound iodine was4.1 pg. per cent . Following the administration of atracer dose of 1 181 , the conversion ratio at forty-eighthours was 60 per cent . Scanning revealed two areas ofradioactivity in the spine identical in location withthose previously described . A 110 me . dose of 1131 wasadministered, serum being obtained twenty-four,forty-eight and seventy-two hours afterward forchromatographic analysis . Thyroid extract therapywas instituted several days later and the patient wasdischarged with instructions to return for re-evalua-tion in six weeks.

METHODS OF STUDY

For the chromatographic studies carried out duringthe 1956 and 1957 hospital admissions the patient'sserum was precipitated with trichloracetic acid andthe precipitate extracted with butanol . The extractswere concentrated under vacuum and aliquots of eachwere chromatographed by the ascending method onWhatman No . 1 paper cut in tapered form [4] . Thefollowing two solvent systems were employed : (1) bu-tanol-dioxane-ammonia [5], and (2) butanol-aceticacid-water [6] . Radioactivity on the strips was locatedby radioautography on no-screen x-ray film and byscanning with an automatic scintillation counter .

FIG . 2 . Radioautographs of chromatograms of serum ob-tained twenty-four, forty-eight and seventy-two hoursafter the second therapeutic dose of I"' with the positionof carriers indicated .

Thyroxine, triiodothyronine, c iodide and diiodotyro-sine were similarly chromatographed with eachaliquot of plasma extract. Spraying the strips withninhydrin revealed the location of the former two .Iodide and diiodotyrosine were detected by sprayingwith ceric sulfate-arsenious acid reagent .

The serum collected during the most recent hospitaladmission was acidified, extracted with butanol satu-rated with O .IN HC1 and the extract concentratedunder vacuum . Chromatography of filter paper stripswas carried out as before in butanol-dioxane-am-monia. Radioactivity and carrier thyroxine andtriiodothyronine were located as already described .Two-dimensional chromatograms were also obtainedfor each serum sample using butanol-dioxane-am-monia followed by butanol-ammonia [7] . The locationof radioactivity was compared to that of carrierthyroxine and triiodothyronine .

RESULTS

The chromatograms of the patient's serum inthe butanol-acetic acid-water system failed todisclose either mono- or diiodotyrosine . Figure 1depicts the radioautograph of a chromatogramof the patient's serum obtained in November

* The L-thyroxine and L-triiodothyronine used in thisstudy were made available to us through the kindness ofH. A. Klusek of Smith, Kline and French Laboratories,Philadelphia, Pennsylvania .

AMERICAN JOURNAL OF MEDICINE

Page 3: An abnormality of thyroid hormone secretion

FEBRUARY 1961

Abnormality of Thyroid Hormone Secretion-Mack et al .

Fm. 3 . Radioautograph of the patient's serum obtainedafter the most recent therapeutic dose of radioiodine .Most of the radioactivity is associated with thyroxine .

1956, forty-eight hours after radioiodine ther-apy. The location of the carrier thyroxine andtriiodothyronine on the chromatogram is indi-cated by the markers . Although separation is notcomplete, most of the radioactivity is at a levelcorresponding to triiodothyronine . Analysis ofthis chromatogram by means of an automaticscanning counter demonstrated approximately80 per cent of the total radioactivity associatedwith triiodothyronine . In Figure 2 are theradioautographs of chromatograms obtainedfollowing a second therapeutic dose of radio-iodine ten months later . The strips representsamples of blood drawn at twenty-four, forty-eight and seventy-two hours . The concentrationsof radioactivity at the level of thyroxine and oftriiodothyronine appear approximately equal ineach of the strips . In Figure 3 are radioauto-graphs of chromatograms obtained following themost recent therapeutic dose . Two bands ofradioactivity are seen which correspond to thethyroxine and triiodothyronine labels. Thetwo-dimensional chromatogram in Figure 4 clearlydemonstrates thyroxine, triiodothyronine andiodide .

325

to-Fiu . 4. A two-dimensional chromatogram of the patient'sserum forty-eight hours after the last time l"' therapywas given . Triiodothyronine is well separated fromthyroxine .

COMMENTS

This patient is of particular interest in that acuthyroid state has continued more than fouryears following total thyroidectomy . The find-ing of an elevated I 131 conversion ratio on twooccasions is in marked contrast with the normalserum protein-bound iodine determinations .A somewhat analogous situation may he foundin the low serum protein-bound iodine level ofmyxedematous patients maintained in a euthy-roid state by triiodothyronine [8,9] .

Other investigators [10,11] have noted arti-facts with trichloracetic acid precipitated serumand in butanol-containing chromatographicsystems, both of which were employed in thefirst two studies of this patient . Such artifactshave been shown to appear ahead of thyroxine,where one might expect to find triiodothyronine .

The occurrence of a predominant radioactiveserum component corresponding to triiodo-thyronine has been noted in three of nineteenpatients studied in a similar fashion in ourlaboratory . In addition to the case reportedherein, both of the other patients had had atotal thyroidectomy for thyroid carcinoma andwere receiving therapeutic I131 to eradicateresidual thyroid tissue . The infrequent findingof this quantitatively abnormal serum coiiipu-nent in our series of patients argues against itsbeing an artifact . In view of the clear identifica-tion of triiodothyronine on the more recentlyobtained two-dimensional chromatogram, it is

Page 4: An abnormality of thyroid hormone secretion

326 Abnormality of Thyroid Hormone Secretion-Mack et al .

reasonable to conclude that this patient'smetastatic lesions have persistently secretedlarge quantities of triiodothyronine .

The explanation for the abnormal secretionof triiodothyroninc in our patient is obscure .Increased quantities of it have been found inthe serums of hyperthyroid patients and ineuthyroid persons following the administrationof thyroid-stimulating hormone [12,13] . Ruppand his associates [14] have recently noted theoccurrence of triiodothyronine as the only cir-culating thyroid hormone in a patient with anon-toxic goiter . They postulate an intrathy-roidal enzyme defect leading either to the almostexclusive production or secretion of triiodo-thyronine . Since their patient also demonstratedan elevated 1 131 conversion ratio, a qualitativelysimilar enzymatic defect may exist in ourpatient .

Inspection of the one-dimensional chromato-grams demonstrates a progressive decrease intriiodothyronine and a corresponding increaseof thyroxine with the administration of eachtherapeutic dose of 1131 . It is interesting tospeculate that this change may represent aneffect of radiation on the metastatic cells result-ing in an anatomically and functionally moremature lesion .

SUMMARY

A patient with thyroid carcinoma whosemetastatic lesions have been demonstrated tosecrete abnormally large amounts of triiodo-thyronine is described . It is suggested that thisquantitative abnormality may result from anintracellular enzymatic defect in the metastasis .

REFERENCES

1 . ROBBINS, J ., RALL, J. E ., BECKER, D. V. and RAwsoN,R. W. The nature of the serum iodine after largedoses of I's' . J. Clin. Endotrinol ., 12:856,1952 .

2 . GROss, J . and Psrr-RIVERS, R. The identification of3 :5 :3'-l-triiodothyroninc in human plasma . Lancet,262: 439, 1952.

3 . BENUA, R. S., Doavxs, B. M. and NINMER, A . Tri-iodothyronine in the serum of patients treated withradioactive iodine . Tr. Am. Loiter, A ., p. 216,1955 .

4. ALBRIGHT, E. C., LARSON, F . C. and DElss, W. P .Single dimension chromatographic separation ofthyroxin and triiodothyronine . Proc . Soc. Exper .Biol. & Med., 84 : 240, 1953 .

5 . Gauss, J ., LEBLOND, G. P., FRANKLIN, A . E. andQUASTEL, J . H. Presence of iodinated amino acidsin unhydrolyzed thyroid and plasma . Science, 111 :605, 1950 .

6. RocHE, J., JuTaz, M ., LISSITZKV, S . and MICHEL, R .Chromatographie quantitative des asides aminesiod6s radioactifs de la thyroglobuline marquee .Biochim . et biophys . acta, 7 : 257, 1951 .

7. ROCHE, J., LISSITZSKV, S . and MICHEL, R. Character-ization of iodohistidines in iodinated proteins(thyroglobulin and iodoglobulin) . Binchim- etbiophys . acta, 8 : 339, 1952 .

S . ASPER, S . P., JR., SELENKOW, H. A. and PLAMONDON,C. A. A comparison of the metabolic activitiesof 3,5,3'-l-triiodothyronine and 1-thyroxin inmyxcdema. Bull. Job" Hopkins Hasp ., 93: 164,1953 .

9. STARR, P., SNIPES, G . and LIEBIIOLD-SCIIDECK, RBiological effects of triiodothyroninc in human sub-jects . J. Clin . Endocrinol., 15 : 98, 1955 .

10. ACLANn, J . D. Probable nature of an artifact in thepaper chromatograph of thyroxine caused bytrichlor acetic acid . Nature, 176: 694, 1955 .

11 . OWEN, C. A ., JR., McKENZIE, B. F. and ORVIs, A .An artifact in thyroxine chromatography usingdioxane . J. Lab . & Clin . Med., 47 : 145, 1956 .

12 . BENUA, R. S. and DoEVNs, B. M. Iodinated com-pounds in the serum, disappearance of radioactiveiodine from the thyroid and clinical response inpatients treated with radioactive iodine . J. Clin .Endocrinol ., 15 : 118, 1955 .

13. Hvnovrrz, J . D. and ARONS, W . L . Effect of thyro-tropin on the pattern of thyroid hormones inplasma . J. Clin . Endocrinal ., 17 : 1332, 1957 .

14. Run, J. J., CHAVARRIA, C ., PASHKIS, K . E. andCHABLARIAN, E . The occurrence of triiodothyron-ine as the only circulating thyroid hormone . Ann .Int . Med., 51 : 359, 1959 .

AMERICAN JOURNAL OF MEDICINE