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T SJ T w di ei b ri n n 10X 14X 1BX 22X 2SX aox y . 12X itx »X MX 2SX 32X Thaeopy tQtlM bmn hat baan raproduotd thankt off: Mmmm Libmy MeQHI Unlvwrity quality la«lbility tha Tha imagaa appaarinfl hara ara tha poaaibia eonaidarlng tha eondMon of tha ordinal eopy and In kaaping fllminfl eontraot apadfflaatlona. Original coplaa in printad papar eovava aia ffUmad haginning with tha ffront oovar and anding on tha laat paga wHh a printad or illuatratad impraa- ■Ion. or tho bade oovar whan ap p roprl a ta. AN othar original ooploa ara fllmad baginnteig on tha firat paga with a printad or illuatratad impraa- alon, and anding an tha laat paga with a printad or iihiatratad impraaaion. Tha laat raeordad fframa on aach mleroHeha ■haH eantain tha aymbol «»> (moaning "CON* TINUED"). or tho aymbol ▼ (moaning "END"), whiohavar appHaa. L'axamplaira flim4 ffut raprodult griaa A la g4n4roait« da: Mtdieii Ubrary lytoQill Univmity Lao imagaa suivantaa ont it* raprodultaa avae la plua grand aain. oompto tonu do la condition at da la nattatA da l'axamplaira fUmA. at an confformHA avae !aa eanditiona du contrat da fHmaga. Laa axamplairaa originaux dent la eouvartura an paplar aat ImprimAa aont HlmAa an eammanpant par la pramiar plat at an tarminant aait par la damMra paga qui eomporta una amprainta dimpraaalon ou dlHuatratlon. aolt par la aaeond plat, aalon la oaa. Toua laa autraa axamplairaa originaux aont ffllmAa an commandant par la pramlAra paga qui eomporta una amprainta dimpraaalon ou dlHuatratlon at an tarminant par la damlAra paga qui comporto uno talla amprainta. Un daa aymboloa auh/anta apparaltra tur la damlAra Imaga da chaqua microficha. salon lo caa: la aymbdo — »> aigniflo "A 8UIVRE", lo aymbolo V tignifflo "FIN". IMapa. plataa. charta, ats., may ba ffHmad at diffffarant raduction ratioa. Thoaa too larga to ba antlraly inchidad in ana axpoaura ara fNmad beginning in tha upper left hand comer, left to right and top to bottom, aa many framea aa required. The foHowHng diagrama illuatrata the method: Lea cartae. planchea, tableaux, etc.. peuvent Atre filmAe A dea taux da rAduotlon diff Arents. Loraqua la document eat trop grand pour Atre reprodult en un aaui clichA. il aat filmA A partir da Tangle aupArleur gauche, do gauche A drolte, et do iMut en baa. an prenant la nombra d'Imagea nAcaaaaira. Laa diagrammea auivanta IHuatrant la mAthoda. 12 3 1 2 3 4 5 6 ■•■»;.- :sf ^^Va^^, <^-W THE DOCTRINE OF THE NTERNAL OECRETORY AcTl VITY OF ULANDS r IN RELATION TO THE Pathological Anatomy of Sundry Morbid Conditions. DIABETES, ADDISON'S DISEASE, MYXOEDEMA, CRETINISM, GRAVES' DISEASE AND ACROMEGALY. BY J.' GEORGE ADAMI, M.A., M.D., Professor of Pathology, McGill Universitv, Montreal. tiBPRINTED FROM THB MONTREAL MBPIcAl JOURNAL, MAY, 1097. OB^ THE DOCTRINE OF THE INTERNAL SECRETORY ACTIVITY GLANDS IN RELATION TO THE PATHOLOGICAL ANATOMY OF SUNDRY MORBID CONDITIONS.' (of diabetes, Addison's and graves' diseases, myxcedema, cretinis;^ and acuomeoaly.) BY J. Gkoroe Adahi, IA.A., M.D. ProfesHor of Pathology, McGlU University, Montreal. To remove an organ and study the effects of the operation is clearly an exercise in experimental pathology and only secondarily and indi- rectly a physiological investigation, while the greater the precision with which the course and symptoms of any morbid condition are studied, the more the study becomes a matter of science, a matter of pathology rather than of medicine. In other words, asked oA a pathologist to enter into this discussion, I find that all other partici- pants have trespassed into pathological territory. This is one of the penalties of sure advance in our common subject : the pathology of yesterday becomes the medicine of to-day, and I might add, the medi- cine of to-day yields place to the surgery of to-morrow. But this being the case, so as not to reiterate, I am impelled to make my con- tribution to this discussion a resume of the results obtained in a branch of pathology which others are not likely to dwell upon. It is in many respects an unsatisfactory branch — a branch capable of testing rather than of originating any theory. I lefer to morbid anatomy. I propose, therefore, during the next few minutes, to lay before you what may be gleaned from the post-mortem room bearing upon this subject of internal secretion. But first it is necessary tocall your attention to the very narrow limits of the information to be gained from a study of the gross and fine anatomy of diseased organs in this connection. Morbid anatomy alone can tell us singularly little concerning alterations in function. The existence of lesions recognisable to the naked eye or under the microscope may support conclusions reached by other means. It can do little more. We know from experiment 1 Being a contribution to the discusHion upon " Internal Secretions," at the Tri ennial Medical Congress, Washington, May 5th, 1807. that three-quarters of the liver, for example, may be removed from the healthy animal with no pronounced disturbance of the bodily functions, that whenever one- fifth or less of the pancreas is left in the dog it may be weeks before diabetes shows itself, that only when fifteen-sixteenths of the thyroid are removed may the dog succumb. In this enormous reserve of material and force may truly be said to lie the secret of the continued existence of living beings. Thus the mere fact that the greater part of an organ is found wanting by the anatomist, or replaced by tissue of another nature, is not in itself absolute evidence that what remains of the organ is functionless or incapable of meeting the needs of the organism. So long as any con- siderable number of what may be termed the specific cells of an organ are to be determined we must proceed very cautiously in our reason- ing ; only when the destruction is absolute or nearly so are we on sure ground. Contrariwise, if the cells of an organ appear very slightly altered, while we are accustomed to argue that there has been but little disturbance of function, it is questionable whether we are justi- fied in this opinion. So also if an organ like the thyroid be markedly hypertrophied, that is not in itself proof positive that there is accom- panying increased activity and increased internal secretion. In the thyroid, for instance, the boundary line between pure hypertrophy and overgrowth of adenomatous nature is peculiarly vague. It may very possibly be that a simple adenoma of a ductless gland continues to supply an internal secretion ; it is diflScult to imagine that gland structure of almost perfect type can be present in the body without affecting the body at large.' Nevertheless we have no conclusive evidence that this is the case ; hence, it is only after most exact and extensive histological study that we can advance any very secure arguments upon the existence of apparent simple hypertrophy, more especially of the ductless glands. The force of this statement will be seen when we come to discuss the bearing of disease of the hypophysis cerebri. Another matter that has to be taken into account, one that has until now received scant attention, is the existence of vicarious activity. Because one organ is seriously 4iseased it does not follow that the organism as a whole exhibits disturbances commensurate with the lesions in that organ ; other parts may vicariously fulfil its functions. We have the well known example of total extirpation of so important an organ as the spleen being succeeded for years by good health. Here, 1 It is noteworthy how frequently in attempting to co-ordinate the anatomical data in the class of diseases now before us we are brought to regard the possibility- nay, probability— that neoplasms are not functionless (as we are too apt to consider them), but afford, it may be an abundant, internal secretion. 8 presumably, the lymph'glandular tissue in general takes over the fnne- tions of the absent organ. There is the compensatory development of the parathyroids in athyrea, and further, the frequent, but not con- stant co<«xistence of atrophic disease of the thyroid and hypertrophy of the pituitaiy to which Boyce and Beadles (1) have more especially called attention. Similarly and curiously we meet with frequent persistence or enlargement of the thymus when either the thyroid or the pituitary body is the seat of disease. Thus not only is it a matter of peculiar difficulty in that class of diseases, which to-day we have specially to discuss, to determine which of the ductless glands is primarily and which secondarily affected, but the added difficulty besets us, that where the vicarious function is perfect and compensa- tion is complete we may, in the apparently unaffected individual, meet with lesions of an organ — the thyroid for instance — of the same nature as, and every whit as extensive as, the lesions in well marked cases of those special forms of general disease which we are inclined to regard as the direct outcome of disease of that organ. Time after time this co-existence of apparently identical lesions in cases of relative health and pronounced disease places us in a quan- dary, time after time we find ourselves groping vainly in a maze of facts which seem to point in all directions of the compass. And when the facts flatly contradict each other one cause of discrepancy must be this vicarious activity. In passing I may suggest that vicarious activity affords a possible explanation of the not unfrequent cases in which we have the eventual co-existence of more than one of the diseases under consideration. If, for example, the thyroid be the seat of atrophic disease the compensatory hyper' ^ophy and over-action of the pituitary may lead to eventual affection of taat organ. Yet another consideration, seriously weighing upon the morbid anatomist, is that two opposite processes may produce a similar symp- tomatology, one that he can recognise, another that he cannot If the glands afford an internal secretion entering the lymph and so event- tually circulating through the system, we know that the ultimate use of the secretion must be to effect a chemical transformation of some substance in some other part or parts of the system. There are thus four possible conditions, (1) production of an insufficient amount of internal secretion of any gland in consequence of disease of that gland, and (2) the assimilation or production of an excess of that substance which normally is acted upon and transformed by the internal secretion in question. In both cases there will be a heaping up in the system of the substance ; in both cases there may be the same train of s^^mptoms. In the one case the gland or glands may show the dearest signs of disease ; in the other they may appear nonuaL The morbid anatomist may in time discover collateral dis- turbances distinguishing these two states ; at present he cannot adequately. In one case of diabetes ho finds the pancreas unaffected, in the next it is extensively diseased. Unaided by experimental pathology he is quite incapable of determining the important rdle played by this organ in regulating the sugar supply of the organism and in the production of diabetes. Similarly there may be an accumulation of the internal secretion, either duo to (3) hypertrophy of a gland or (4) not associated with recognizable glandular change. In short, gentleman, I fear that I stand before you as a kind of reversed contrary Balaam. Summoned to bless — to illumine this dis- cussion — I can only curse (as I take it all my predecessors must have done who have attempted to reconcile the anatomical results in the class of cases now before us) and can but point out to you the dark- ness that is upon the face of the deep. But happily there is this to be said to the credit of the morbid anatomist that the demonstration of this darkness is of the highest value as indicating the lacunae in our knowledge and suggesting the various factors that have to be taken into consideration and carefully studied in order that we may gain a comprehensive knowledge of this intensely interesting and valuable subject of internal secretion and glandular function. It is in itself a step towards higher things to feel acutely our own ignorance. And then, perhaps, things are not quite so black as hero painted. While it may be that I am overbold — it may also be that this darkness but precedes the dawn; that facts which seem so flatly to contradict each other can, in the growing light of experimental pathology, already be seen to range themselves in an orderly manner. Accepting the postulates, first, that the glands of the body afford an internal secretion capable of acting upon and transposing some substance or substances produced or assimilated by other regions of the body, and, second that, proceeding with due caution, we can utilise the results of anatomical and histological studies, then, applying the considerations which I have just urged, we must recognise the possible existence of three orders of conditions, each order being capable of further sub- division into two well, marked groups. It would seem that we have to deal with Chanobh Abbociatid WITH Symptoms or DlBEAHB. Ghanokb Unaccompanied by Symptoms OF Disease. / I, Rblativi Glandular Inadequacy.— Exomh of tub- ' atanoe acted upon by the internul woretion of • gland, without due compensation. (1.) Altered condition of gland leading to diminish- ed activity and dimished internal secretion. (2.) No dlHease or alteration of gland but excessive production or assimilation of the substance acted upon by the internal secretion. II. Relative (Ilandular Over- Activity.— Excess of in- ternal secretion without compensation. (1.) Altered condition of gland leading to increased activity and increased pouring outof internal secretion. (2.) No disease or alteration of gland, but diminish- ed production or assinulatlon of the sub- stance acted upon by the internal secretion • of that gland. III. Compensation.— Lesions of gland or altered systemic condition unaccompanied by symptoms. (1. Altered condition of eland leading to (a) in- crease or (b) diminution of internal secretion, with due compensation. (2.) 1 picture — so complicated that Bircher (20) argues with very considerable force that " cretinic degeneration, as also dwarfism and chondrodystrophia foetalis hypoplastica have no setiological connection with the functions of the thyroid," Bircher, however, fails to recognize that if we accept the existence of an internal secretion, we must also admit the presence of substances upon which that acts, and he cannot see that widely contrasted anatomical conditions may lead to the same train of symptoms. We must, I think, abide by the experimental and clinical evidence that removal of the thyroid in the young leads to a condition undistinguishable from cretinism. This being so, we find that in some few cases of typical cretinism the thyroid is completely absent, in a large number it is small, in a yet smaller number accord- ing to Von Eiselberg (21) and Kocher (22) there is a goitrous condi- tion present, while according to Bircher the goitres may be of all possible forms, from simple hyperplasia through soft (parenchymatous) and cystic to fibroid. The only point clearly to be made out from Bircher's very destructive criticism is that while in several cases the thyroid has been found of normal size, apparently no ca«e exists in which by microscopical observation it has been found of normal struc- ture. Considering the amount of material he brings forward this is rather remarkable. I further gather that his statements as to the frequency of the various forms of goitre are based upon examination of the living and not upon post-mortem or surgical material. This seriously weakens his case. Beyond this I will not venture to travel. Bircher's statements require to be dealt with by one in authority, and I await with interest Dr. Osier's presentation of the matter. EXOPHTHALMIC GOITRE. I will now briefly refer to the condition which presents a series of symptoms so remarkably contrasted with myxoedema — which also 14 anatomically presents an equal contrast There is to be fonnd in exophthalmic goitre, as Greenfield (23) has shown, and as is now generally accepted a characteristic hyperplasia of the thyroid paren- chyma, complicated, it may be in later stages, by increased fibrosis. The one question of immediate concern here, is whether from this we can safely deduce that there is accompanying increased internal secretion. As I have already hinted, I do not think that from anatomical considerations alone we can safely make this deduction. There is, however, an important fact in favour of such deductions, namely, the strong likeness between the primary glandular changes in Oraves' disease and those described by Halsted (24) and others as occurring in the compensatory hyperplasia of the thyroid after removal of large portions of the gland ; and if, together with the anatomical changes, we consider the favourable effects which so often follow removal, destruction, or diminution in the blood supply of portions of the hypertrophied gland in this disease — of operations which must lessen the internal secretion — it is difiicult to arrive at any other conclusion than that in exophthalmic goitre there is in- creased internal secretion, and that this plays a singularly important part in the development of the symptoms. Whether this be primary or secondary to lesions of the central nervous system — of the restiform bodies for example, our present anatomical data are insufficient to decide — as again they are incapable of deciding whether the increased secretion is altered or unaltered in quality. I may here note that as Joffroy and Achard (25) have indicated the symptoms of parenchy- matous and adenomatous goitre are at times curiously allied to those of exophthalmic goitre. Indeed, together with Vanderwelde and le Boeuf, they hold, I think without due cause, that there is nothing anatomical to distinguish the one condition from the other. That the one condition may lead to the other is a matter of clinical experience. As Dr. Shepherd has pointed out to me extirpation of the goitrous nodules or cysts leads to the almost immediate amelioration of the symptoms. The development of exophthalmic goitre without hyperplastic alteration of the thyroid is a matter concerning which there is little anatomical evidence. I find one case recorded by Joffroy and Achard in which the gland was of normal size and, while not normal histo- logically, presenting nevertheless a series of changes wholly distinct from Greenfield's classic description. The vesicles instead of being small and corrugated, were enormously distended, instead of absence there was abundance of colloid material, in place of a columnar and proliferating epithelium, the lining cells were flattened. Not a few th« in bo( 16 believe in the existence of Graves' disease without goitre. Amon^ recent writers Buschan (26) especially holds this view, but save in the above case I cannot find anatomical substantiation for the opinion. Clinically Graves' disease without enlarged thyroid has very fre- quently been noted ; in some cases enlargement supervenes, in others it does not, but there may well be increased activity of the gland without marked enlai^ement. All that can be said at present from this evidence is that apparently the condition docs occur. So also evidence as to the occurrence of marked hyperplasia and presumably increased secretion without symptoms is not so full and precise as could be wished. I can only point out that if adenomatous nodules in the thyroid produce any internal secretion then, while many cases of adenomatous goitre show a train of symptoms somewhat allied to exophthalmic goitre, and while a few cases pass on to undoubted Graves' disease, many on the contrary appear to last for years with- out symptoms. And in autopsies upon those dying from diseases, other than exophthalmic goitre, we find a wide variation in the condi- tion of the thyroid, from atrophy on the one hand to a condition not far removed from what Greenfield and others describe in association with exophthalmic goitre. Altogether, therefore, while not prepared, from general as from anatomical considerations, to state positively that exophthalmic goitre is in all cases primarily due to increased thyroid secretion, I cannot but admit upon the whole that the facts can be best reconciled by assuming the existence of relative increase in glandular activity. THE PITUITARY BODY AND ACROMEGALY. Finally some few words must be said concerning that strange col- lection of symptoms and anatomical changes to which Marie has given the name of acromegaly. Yearly it has become more clearly recog- nized that the term indicates a definite disease although there is a liability towards confusion with gigantism on the one hand, and on the other with the remarkable overgrowth of bone in certain cases of chronic disease (mainly of the lung) which again Marie was the first to group together under the title — voluminous, and in other respects unsatisfactory — of hypertrophic pulmonary osteoarthropathy. Here again the remarkable trio of conditions forces itself upon our notice ; there may be acromegaly with disease of the pituitary, acro- megaly with apparently unaffected pituitary and extensive disease of the pituitary without acromegaly. Where there is acromegaly, there in by far the greater number of cases the glandular portion of the body is diseased. It is true that the condition is rare. Between 1890. 16 and the present time loss thap thirty affected subjects have undergone post-mortem examinations. Leaving aside from lack of time sundry interesting observations upon the state of the thyroid and thymus, I may say that this one gland alone — the pituitary — has been repeat- edly found altered, the alteration being especially in connection with its anterior or glandular portioa Out of ^4 necropsies upon cases stated to be acromegaly, Tamburini (27) the latest collector, finds that in 17 or over 70 per cent, the pituitary has been found diseased. The remaining 7 are subjected by Tamburini to severe criticism- with the result that he rejects 2 on the ground that the condition had only been recognised clinically for a few months and no microscopical examination had been made. He presumes that time had not been sufficient for the development of naked eye changes. Three other cases he holds to have been osteoarthropathy. There remain two which he could not definitely reject and consequently classified as doubtful. So far as I can follow Tamburini he ic strongly of opinion that morbid changes in the hypophysis cerebri are es.sential to acro- megaly. The majority of observers do not accept this extreme view, and with them I am inclined to believe that here as certainly obtains in diabetes and Addison's disease, there may be typical symptoms without recognisable involvement of the pituitary. But granting this much, that in the majority of instances the gland is diseased, it is difficult to advance much further, for there is a curious discord concerning the exact nature of the alterations in the pituitary body. In about one half of the cases hypertrophy of the organ is de.scribed. Stroebe, (28) Tamburini, Boltz (29) and others of later date conclude that the change is adenomatous, Marino (30) Dallemagne (31) and Qauthier (32) describe a peculiar cystic degeneration, Boyce and Beadles a cystadenoma, while in another of Dallcmagne's cases and in Wolf's (33) there was clearly sarcoma, and in Bury's (34) a ' glioma.' What are we to conclude ? Is acromegaly accompanied by an increased pouring out of internal secretion, or the reverse ? Mere hypertrophy and possibly adenomatous overgrowth might lead to increase, but surely degenerative changes and sarcoma can have no such effect. It is difficult to reason by Analogy, and if we attempt this and seek to base any argument upon what occurs in disease of the gland, which anatoDiically is most closely related to the pituitary — namely, the thyroid — we are led rather to the conclusion that acromegaly must be due to arrest of function of the former. That is to say there is a certain correspondence between the changes occurring in the connec- 17 tive tissues in myxoedema and those affecting the bone, and to some extent the subcutaneous connective tissues in acromegaly. On the other hand, the pituitary is nearly always found enlarged and hypertrophicd in general gigantism as distinguished from this localised acromegalic gigantism. It is difficult to reconcile such gen- eral gigantism with diminished activity on the part of the enlarged hypophysis, while again the contrast may be pointed out between gigantism and cretinic dwarfism. Tamburini, and independently Massolongo (35) have attempted to coordinate the contradictory ana- tomical discoveries by suggesting that two stages of the disease may be recognised, a first in which the hypohysis undergoes hypertrophy, and is in over-action, which may give place to a second in which the hypertrophicd tissue either undergoes atrophy or adenomatous or sar- comatous change. The suggestion is seductive, but for the present must be regarded merely as a suggestion. Briefly therefore, our knowledge in this connection is miserably ina- dequate, and experiments have so far been without result. We cannot say whether in acromegaly there is increased or diminished internal secretion. While the change in the pituitary appears often to be primary, we cannot with certainty lay down that this is the case. It has only to be added that if wo admit that lesions of the pituitaiy are associated with acromegaly, we must also admit that compensation can occur, for there is considerably over a score of cases on record of hypertrophy, adenoma and cystadenoma of the organ, all of consid- erable size and presumably of long duration which had developed without signs of the disease in question. Thus to conclude a long discourse, which in justice to the subject I could not well shorten: I have here, gentlemen, followed a single train of thought Some may find it suggestive, to some it may be so simple as to be specious, so wide in its embrace that its very comprehensive- ness is its damnation. I can only point out that which is here written has been already more or less definitely suggested by various writers in this country and elsewhere, in connection with most, if not all, the conditions here discussed, and impress upon you that, if we are pre- pared to accept the results of experimental research and to believe in the existence of internal secretions, then, inevitably, we must be led to some such views as those brought forward in the course of this paper. 18 RBFERBNCBS. # 1. BojTM and BMdiM.— Jl. 9f PatKology, 1. 1808. pp. U8 and SOB. 1 llMMmmnn-ZtUmihr. f. KUn. Mtdmdn, XXVI. 1891. p. 191 . & WIUlMiiMii.~£aiiM<. 189*. I. p. 917. 4. DiMkboft-JWwAr^/V/lir ThUr/Oekr, Leipiig, 1896. & Olteard.— Dm r««ultate ctij*etif» di FexploraHon du /»(« eheM lea diabetiquea. Park, Mmmii, 1890. fl. Tribonlat— ilwiM de ifM., XVI. 1898, p. ^88. 7. SMidmeyer.-Dntfao* Arehiv. /. KUn, Med., L. 1898, p. 881. k VaughMi Hartoy.-ifMUeal ChronicU, N.S., III. 189606. p. 821. 9. Lewliu-CMaHM Annaim, 1886, p. 880, 1808, p. 888. la Oilman Tboupaon.— ilm. Jt, cf Med. Soiencea, C VI . 1860, p. 377. 11. HafeWhlte.-//.q