J clin Pth, 1975, 28, 94-98 The predictive vlue of histometry of thyroid tissue in nticipting hypothyroidism fter subtotl thyroidectomy for primry thyrotoxicosis R J YOUNG, J SWNSON BECK', ND W MICHIE From the Deprtment ofpthology, University of Dundee nd Division of Surgery, berdeen Royl Infirmry SYNOPSIS Thyroid tissue removed t prtil thyroidectomy from primry thyrotoxicosis ptients, fter preprtion for opertion with crbimzole nd Lugol's iodine, ws studied with the histometric technique In ptients with little or no evidence of utoimmunity before opertion, the chnce of in 2 in those who hd volume per- developing postopertive hypothyroidism ws pproximtely 1 centge of epithelium greter thn 4, but only pproximtely 1 in 1 in those who hd volume percentge of epithelium less thn 4 This pproch my ultimtely prove of predictive vlue in substntil proportion of ptients for nticipting hypothyroidism fter subtotl thyroidectomy for primry thyrotoxicosis It is not known why subtotl thyroidectomy effects Wyne, 1959) nd serum protein-bound iodine permnent cure in substntil proportion of (PB1271) estimtions Dignosis ws confirmed by ptients with primry thyrotoxicosis, nor is it cler rdioctive iodine uptke test, supplemented where which ptients re most likely to benefit from the necessry by the response to triiodothyronine opertion Recent reports of the incidence of (Hobbs, Byliss, nd McLgn, 1963) ll of the hypothyroidism fter prtil thyroidectomy rnge ptients were prepred for opertion with crbimzole nd hd received potssium iodide (5 from 35 % (Hedley, Flemming, Chesters, Michie, nd Crooks, 197) to 48% (Behrs nd Skulsky, minims of Lugol's iodine three times dily) for 1 1968) Previously it hs been shown tht ptients with dys before opertion Postopertive hypothyroidism low remnnt weight (Michie, Pegg, nd Bewsher, ws ssessed by clinicl exmintion bsed on the 1972), high preopertive ntithyroid ntibody titres stndrd dignostic index (Billewicz, Chpmn, (Irvine nd Stewrt, 1967), nd bundnt lymphoid Crooks, Dy, Gossge, Wyne, nd Young, 1969), infiltrtion of the thyroid (Greene, 195; Levitt, on electrocrdiogrphic evidence, nd on seril 1951; Greene, 1953) re predisposed to the development of postopertive hypothyroidism finl rbiter ws therpeutic tril with thyroxine serum PB1271 nd cholesterol estimtions The The present histometric study ws undertken (Werner nd Spooner, 1955) Ptients were exmined to determine whether the structure of the glnds t one, four, nd 12 months fter opertion nd t the time of opertion bore ny reltion to the therefter on yerly bsis until the services of outcome of tretment computer-ssisted register (Hedley, Scott, Weir, nd Crooks, 197) becme vilble Mterils nd Methods t the time of opertion, the size of the thyroid remnnt ws estimted visully (Michie et l, This study ws undertken on 69 femle primry 1972) The weight of the thyroid ws then deduced thyrotoxic ptients for whom subtotl thyroidectomy ws regrded s the tretment of choice weights The resected tissue ws fixed in 4 % neutrl s the sum of the remnnt nd resected specimen The dignosis of thyrotoxicosis ws bsed on the buffered formldehyde; therefter the thyroids were clinicl dignostic index (Crooks, Murry, nd cut into 5 mm slices Blocks were tken from ny res of unusul nked-eye ppernce, in ddition 'Correspondence: Profesr J Swnn Beck, Deprtment of Pthology, Ninewells Hospitl nd Medicl School, Dundee DD2 IUB ech lobe Sections (5,um) were prepred from to minimum of two representtive blocks from Received for publiction 2 October 1974 prffin blocks nd stined with hemtoxylin nd 94 J Clin Pthol: first published s 11136/jcp28294 on 1 Februry 1975 Downloded from http://jcpbmjcom/ on November 218 by guest Protected by
The predictive vlue of histometry of thyroid tissue Hypothesis tht Observtion greter if No ofptients U Sttistic P Condition B Stisfied Stisfying Condition B B %E %L > 1 16 436 NS' Totl E %L > 1 16 462 NS %L Totl L C positive C positive 28 28 379 237 <1 <1 %L Totl L TRC positive TRC positive 19 19 246 379 <11 <1 %E C positive 28 46 NS Totl E C positive 28 479 NS %E TRC positive 19 314 <5 Totl E TRC positive 19 279-5 < 1 Tble I Mnn Whitney rnking tests on reltion ofhistometric nd serologiclfindings INS = not significnt t 5 /% level eosin with stndrdized techniques For histometry, results closely comprble to those obtined from sections were exmined with x 4 objective nd exmintion of severl sections from the sme glnd x 1 focusing eyepiece contining 36-intersection ntithyroglobulin ntibody nd nticytoplsmic grticule The volume percentges of epithelium ntibody (C) were estimted by the tnned-red- (% E), colloid (% C), lymphoid tissue infiltrte cell-hemgglutintion (TRC) (Fulthorpe, Roitt, (% L), nd other tissues (blood vessels nd strom) Donich, nd Couchmn, 1961) nd immunowere mesured with the point-counting technique fluorescence (IF) (Beck, 1971) techniques respec- (ndern nd Dunnill, 1965) by one observer tively For the purpose of nlysis of results, who did not hve prior knowledge of preopertive TRC titre > 1/25 ws regrded s being TRCtretment until the completion of the study From positive nd n IF result of + + or + + + ws the product of these mesurements nd the weights similrly regrded s being C-positive: this of the totl glnd nd the remnnt respectively, the ccords with the system used previously (Hedley, totl epithelil cell volume (totl E), remnnt epith- Ross, Beck, Donld, lbert-recht, Michie, nd elil volume (remnnt E), nd totl glndulr Crooks, 1971) colloid (totl C), remnnt colloid (remnnt C), totl glndulr lymphoid tissue (totl L), nd rem- Results nnt lymphoid tissue (remnnt L) were clculted In preliminry studies, it ws shown (1) tht the Sctter digrms of the %E, %L, nd totl L did stndrd error of the observtions ws less thn 3 % not show ny reltionship between these mesurewhen 2 fields were selected for counting using ments nd the ge of the ptient t the time rndom numbers to define the coordintes of the of opertion or the durtion of preopertive tretvernier scle of the mechnicl stge, nd (2) tht ment with crbimzole Tble I shows the results of exmintion of one section with this method gve Mnn Whitney rnking tests which estblished tht Hypothesis tht Observtion Greter if No of Ptients U Sttistic P Condition B Stisfied Stisjying Condition B B Preopertive Serology Postopertive Thyroid Sttus Remnnt weight Euthyroid 5 318 < 5 Durtion of therpy Hypothyroid 19 218 <5 Durtion of therpy C negtive Hypothyroid 1 117 NS2 Durtion of therpy C positive Hypothyroid 9 34 < 5 Durtion of therpy TRC negtive Hypothyroid 1 154 NS Durtion of therpy TRC positive Hypothyroid 9 11 <-1 Tble II Mnn Whitney rnking tests on reltion of remnnt weight nd durtion ofpreopertive drug therpy to serologicl findings nd postopertive sttus 1 = not relevnt 2NS = not significnt t 5 % level 95 J Clin Pthol: first published s 11136/jcp28294 on 1 Februry 1975 Downloded from http://jcpbmjcom/ on November 218 by guest Protected by
96 z - 7 6 4-1 I I Ito KEY C TITRE L L16 HYPOTHYROID *EUTHYROID go, 7 go 4 2 1 ': c TRC TITRE the lymphoid tissue infiltrte is more bundnt in ptients who hve nticytoplsmic ntibody or ntithyroglobulin ntibody: these findings confirm nd extend the work of Irvine nd Stewrt (1967) Furthermore, percentge E nd totl E re higher in those ptients who hve ntithyroglobulin ntibody, but not in those who hve nticytoplsmic ntibody: this result suggests tht there my be connexion between hyperplsi nd the brekdown of tolernce to thyroglobulin, possibly from incresed colloid spillge There does not pper to be ny reltion between the extent of epithelil hyperplsi (deduced from percentge E nd totl E mesurements) nd the presence or bsence of lymphoid infiltrte In this series of 69 primry thyrotoxicosis ptients treted by prtil thyroidectomy, 5 becme euthyroid nd 19 developed hypothyroidism fter the opertion In n ttempt to determine which of the fctors studied re relted to the occurrence of postopertive hypothyroidism, Mnn Whitney rnking tests hve shown (tble II) tht in ptients who become hypothyroid fter opertion the remnnt weights re smller, thus confirming the findings of Michie et l (1972) Furthermore, in those ptients who hd ntithyroid ntibodies before opertion, postopertive hypothyroidism is scited with longer preopertive drug therpy, but this does not pply to those in whom the utontibody tests were negtive (tble II); Michie et l (1972) filed to ot t 7 6 2 1 & : t r &t R J Young, J Swnn Beck, nd W Michie /o L Fig 1 The volume percentge of epithelium in the fixed thyroids of * 69primry thyrotoxicosisptients, treted by prtil thyroidectomy, distributed ccording to *^ postopertive thyroid sttus (euthyroid *; hypothyroid ) nd the presence or bsence of * ech of three mnifesttions of thyroid utoimmunity C + = IF stining + + or + + +; * TRC + = 1/25; NL + => IO/ + demonstrte ny reltionship between durtion of drug tretment nd postopertive hypothyroidism No scition is found between the remnnt weight nd the incidence of postopertive hypothyroidism in the smller subgroup of ptients with nd without ntithyroid ntibodies Totl thyroid weight, ge t opertion, percentge nd remnnt E, totl E, percentge nd remnnt C, totl C, percentge nd remnnt L, nd totl L, tken individully, re not relted to the incidence of postopertive hypothyroidism The reltion between %E nd the three mnifesttions ofthyroid utoimmunity in the ptients who remined euthyroid fter opertion is contrsted with tht for those who becme hypothyroid in figure 1 The generl distribution suggeststht in those ptients with little or no evidence of thyroid utoimmunity postopertive hypothyroidism is more frequent in those with %E vlue greter thn 4, wheres postopertive euthyroidism is lmost the rule in those with %E vlue less thn 4 This trend is not pprent in ptients with pprecible evidence of thyroid utoimmunity before opertion The vlidity of this rbitrry seprtion of %E bove nd below 4 ws estblished with x2 tests (tble III) For the purpose of further nlysis of the dt, TRC titre > 1/25, C > + +, %L > 1* were ech regrded s distinct mnifesttions of thyroid utoimmunity Figure 2 shows the reltion between %E nd the number of mnifesttions of J Clin Pthol: first published s 11136/jcp28294 on 1 Februry 1975 Downloded from http://jcpbmjcom/ on November 218 by guest Protected by
The predictive vlue of histometry of thyroid tissue Ptknts with Number with Postopertive xi Probbility tht Hypothyroidism Commoner in Ptients with Hypothyroidism Euthyroidism /E > 4 */E > 4 e/e < 4 %E>4 %E < 4O C negtive 7 3 8 23 7 7 < 5 C positive 4 5 8 11-4 NS TRC negtive 9 4 9 31 955 <125 TRC positive 2 4 7 38 24 NS Lymphoid <1% 7 6 12 28 243 NS Lymphoid >1% 4 2 4 6 1-7 NS No evidence of utoimmunity' 5 2 5 19 6 35 < 125 One mnifesttion of utoimmunity' 3 1 5 1 2-25 NS Two mnifesttions of utoimmunity2 2 5 4 5 42 NS None or one mnifesttion of uto- 8 3 1 29 8-26 <-25 immunity' One, two, or three mnifesttions of 6 6 11 15 19 NS utoimmunity' x2 tests on incidence ofpostopertive hypothyroidism compring glnds with > 4% or < 4% epithe- Tble III lium INS = not significnt t 5% level 'For the purpose of this nlysis, mnifesttions of utoimmunity re defined s lymphoid tissue >1I', C > + +, TRC > 1/25 z I- " ono KEY HYPOTHYROID * EUTHYROID I I 1 2 3 MNIFESTTIONS OF UTOIMMUNITY Fig 2 The volume percentge of epithelium in the fixed thyroids of 69 primry thyrotoxicosis ptients, treted by prtil thyroidectomy, distributed ccording to postopertive thyroid sttus (euthyroid ; hypothyroid ) nd the number ofpositive mnifesttions of utoimmunity 11Im utoimmunity in ptients who remined euthyroid or becme hypothyroid fter opertion This grouping of the findings confirms tht, for those ptients with no mnifesttions of utoimmunity t lest, the %E vlue of 4 forms true wtershed since in this group postopertive hypothyroidism developed in two of the 21 ptients (9 5%) with %E < 4, wheres it ws found in five of the 1 ptients (5%) who hd %E > 4 (x2 = 635; df = 1; p < -125) Cumultion of the dt does not increse the predictive vlue of the observtions (tble III) Figure 2 l shows tht in the ptients who remined euthyroid fter opertion the men %E increses with incresing number of mnifesttions of utoimmunity (x2 = 628; df = ; p < -5): n opposite trend is seen in the ptients who becme hypothyroid (X2 = 4-2; df = 3-; p < 15) No reltionship is found between the %C or totl C nd the vrious fctors studied bove Discussion Quntittive histology is more discriminting thn visul observtion in distinguishing differences in microscopic structure The histometric technique hs shown mrked differences, not obvious in conventionl microscopy, in the extent of lymphoid infiltrte in the thyroid of primry thyrotoxicosis ptients prepred for opertion with different drug tretment regimes (Beck, Young, Simpn, Gry, Nicol, Pegg, nd Michie, 1973) With this technique we hve now demonstrted tht the volume percentge of epithelium in the fixed resected glnd specimen is relted to the development of postopertive hypothyroidism 97 J Clin Pthol: first published s 11136/jcp28294 on 1 Februry 1975 Downloded from http://jcpbmjcom/ on November 218 by guest Protected by
98 The overll incidence of hypothyroidism in our series is 28% However, this study hs reveled group of ptients in whom the incidence of postopertive hypothyroidism is substntilly lower These ptients did not hve detectble serologicl evidence of thyroid utoimmunity before opertion nd, t the time of opertion, glndulr epithelium formed less thn 4% of the volume of the fixed thyroid: in this group the hypothyroid rte is 12% Similr hypothyroid rtes re found in the groups with no evidence of lymphoid infiltrte or with none of the three mnifesttions of utoimmunity: this reflects the positive correltion between these prmeters Conversely, in ptients with one or more mnifesttions of utoimmunity, those remining euthyroid postopertively hd significntly greter proportion of epithelium t opertion (fig 2) It therefore seems possible tht histometric mesurement of thyroid epithelium my ply prt, together with serologicl dt nd estimtion of remnnt size, in predicting the occurrence of postopertive hypothyroidism: further work will be required before it is possible to determine whether these pproches cn be used to choose the optimum mnner of tretment of ptient with primry thyrotoxicosis It is probble tht postopertive hypothyroidism results from progressive destructive utoimmunity We (Hedley et l, 1971) hve suggested tht this my be stimulted by relese of thyroid epithelil cell ntigens into the opertive bed tht contins ded nd dying thyroid tissue nd blood clot nd in which orgniztion nd suture grnuloms develop It follows tht the intensity of ntigenic stimultion will be relted to the mount of dmged thyroid epithelium exposed nd hence to the volume percentge of epithelium in the glnd Of those ptients who hd little or no evidence of destructive utoimmunity before opertion, those who developed postopertive hypothyroidism hd lrger men volume percentge of epithelium nd this suggests tht the more intense ntigen stimultion broke down immunologicl tolernce with respect to thyroid ntigens nd strted the process of destructive utoimmunity leding progressively to hypothyroidism By contrst, of those ptients who showed two or more mnifesttions of destructive utoimmunity before opertion, those who becme hypothyroid hd much smller men volume percentge of epithelium nd we suggest tht in these ptients, smller dose of ntigen hs stimulted further destructive utoimmunity We cnnot explin on immunologicl grounds why the R J Young, J Swnn Beck, nd W Michie men volume percentge of epithelium rises with incresing number of mnifesttions of thyroid utoimmunity in those ptients who remined euthyroid fter opertion: perhps it is relted to the regenertive cpcity of the thyroid epithelium This study ws supported by grnt from the Scottish Hospitl Endowment Reserch Trust During prt of this work, RJY ws finnced by student's vction grnt from the University of Dundee References ndern, J, nd Dunnill, M S (1965) Observtions on the estimtion of the quntity of emphysem in the lungs by the point-smpling method Thiorx, 2, 462-466 Behrs, H, nd Skulsky, S B (1968) Surgicl thyroidectomy in the mngement of exophthlmic goiter rch Surg, 96, 512-516 Beck, J S (1971) Immunofluorescence techniques in immunopthology nd histopthology scition of Clinicl Pthologists' Brodsheet 69, London Beck, J S, Young, R J, Simpn, J G, Grv, E S, Nicol, G, Pegg, C S, nd Michie, W (1973) Lymphoid tissue in the thyroid glnd nd thymus of ptients with primry thyrotoxicosis Brit J Surg, 6, 769-771 Billewicz, W Z, Chpmn, R S, Crooks, J, Dy, M E, Gossge, J, Wyne, Sir Edwrd, nd Young, J (1969) Sttisticl methods pplied to the dignosis of hypothyroidism Qurt J Med, 38, 255-266 Crooks, J, Murry, 1 P C, nd Wyne, E J (1959) Sttisticl methods pplied to the clinicl dignosis of thyrotoxicosis Qurt J Med, 28, 211-234 Fulthorpe, J,Roitt,lM,Donich,D, nd Couchmn, K (1961) stble sheep cell preprtion for detecting thyroglobulin uto-ntibodies nd its clinicl pplictions J clin Pth, 14, 654-66 Greene, R (195) The significnce of lymphdenoid chnges in the thyroid glnd J Endocr, 7, 1-6 Greene, R (1953) Lymphdenoid chnge in the thyroid glnd nd its reltion to postopertive hypothyroidism Mem Soc Endocr, 1, 16-2 Hedley, J, Flemming, C J, Chesters, M I, Michie, W, nd Crooks, J (197) Surgicl tretment of thyrotoxicosis Brit ined J, 1, 519-523 Hedley, J, Scott, M, Weir, R D, nd Crooks, J (197) Computer-ssisted follow-up register for the North-Est of Scotlnd Brit mied J, 1, 556-558 Hedley, J, Ross, 1 P, Beck, J S, Donld, D, lbert-recht, F, Michie, W, nd Crooks, J (1971) Recurrent thyrotoxicosis fter subtotl thyroidectomy Brit itoed J, 4, 258-261 Hobbs, J R, Byliss, R 1 S, nd McLgn, N F (1963) The routine use of 132-1 in the dignosis of thyroid disese Lncet, 1, 8-13 Irvine, W J, nd Stewrt, G (1967) Prognostic significnce of thyroid ntibodies in the mngement of thyrotoxicosis In Tlivrotoxicosis, edited by W J Irvine, pp 111-122 Livingstone, Edinburgh nd London Levitt, T (1951) Evolution of the toxic thyroid glnd: clinicl nd pthologicl study bsed on 2114 thyroidectomies Lncet, 2, 957-965 Michie, W, Pegg, C S, nd Bewsher, P D (1972) Prediction of hypothyroidism fter prtil thyroidectomy for thyrotoxicosis Brit mized J, 1, 13-17 Werner, S C, nd Spooner, M (1955) new nd simple test for hyperthyroidism employing I-triiodothyronine nd the 24-hour 1-131 uptke method Bull N Y cd MeuI, 31, 137-145 J Clin Pthol: first published s 11136/jcp28294 on 1 Februry 1975 Downloded from http://jcpbmjcom/ on November 218 by guest Protected by