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M^BBBBBBB^lBBlBSaaBHB^^HBaBBai^^Ba^BflB 
 
m^ 
 
TABLE OF CONTENTS. 
 
 The Internal Secretory Activity of Glands in Rela- 
 tion TO THE Patiiologicai. Anatomy of Sundry Mor- 
 bid Conditions; Paper dy J. George Adami, M.A., 
 
 M.D 
 
 On the narrow limitations of deductions to be drawn 
 
 from the anatomical changes in a given organ 103 
 
 Limitations due to reserve material and reserve force. . 104 
 Limitations due to vicarious activity and compensation 105 
 Limitations due to variations in amount of internal 
 secretion and of substances acted upon by the internal 
 
 secretion respectively 106 
 
 Table of conditions which may be present in connection 
 
 with gland affording an internal secretion 107 
 
 The pancreas and diabetes 108 
 
 The suprarenal bodies and Addison's disease in 
 
 The thyroid and myxcEdema 113 
 
 The thyroid and cretinism 116 
 
 The thyroid and exophthalmic goitre 116 
 
 The pituitary body and acromegaly 1 18 
 
 P«(je 
 
 103— 121 
 
INTERNAL SECRETIONS; 
 
 CONSIDSRSD IN THBIR 
 
 Physiological, Pathological and Clinical Aspects. 
 
 The Internal Secretory Activity of Glands in Relation to the Pathologi- 
 cal Anatomy of Sundry Morbid Conditions— Diabetes, Addison's 
 Disease, Myxoedema, Cretinism, Graves' Disease and Acromegaly. 
 
 BV 
 
 J. GEORGE ADAM!, M.A., M.D. 
 
 Rbprinteu fkom Vol. IV 
 TRANSACTIONS OK THE CONGRESS OK AMERICAN PHYSICIANS AND 
 
 SURGEONS 
 1897 
 
 I 
 
 7/ 
 
I 
 
 
 'Qo 
 
 INTERNAL SECRETIONS CONSIDERED IN THEIR 
 
 PIIYSIOLOGR^VL, PATIIOLOUICAL AND 
 
 CLINICAL ASPECTS. 
 
 Thb Iktebnal SECBETonv Activity of Glands is Rei.atiox to tiu; Patiioloqical 
 Anatomy of Sunihiy Monniii CoNniTioN.s— Diaheths, Audison's Disease, 
 Myxu-jdemji, Chetinism, Gbaves' Disease and Ackomeoai.y. 
 
 by j. qkoroe adami, m.a., m.d. 
 
 ProfeHsor of l'atholi>aUy McGlll Vnivermltt/, 
 
 To remove an organ and study the effects of the operation is 
 olearly an exercise in experimental pathology and only spcondarilv 
 and indirectly a physiological investigation, whi the greater uie 
 precision 'v ch which the course and symptoms of any mc ')id condi- 
 tion are studied, the more the study becomes a matter oi science, 
 a matter of pathology rather than of medicine. In other words, 
 asked as a pathologist to enter into this discussion, I fin J that all 
 other participants have trespassed into pathological territory. Thi? 
 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 medicine 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 contribution 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 refer 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 to call 
 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 recog'iizable to 
 
 t 
 
104 
 
 PATHOLOGICAL ANATOMY OF OKRTAIN GLANDS 
 
 the naked eye or under tlic microscope may support conclusions 
 reached by other means. It can do Uttle more. We know from 
 experiment that three-quarters of the hver, for example, may be 
 removed from the healthy animal with no pronounced Hsturbance 
 of the bodily functions, that whenever one-fifih or less of the 
 pancreas is left in tlic 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 anatomists, 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 considerable number of 
 what may be termed the specific cells of an organ are to be 
 determined, we must proceed very cautiously in our reasoning; only 
 when the destruction is .ubsolute or nearly so are we on sure ground. 
 Contrariwise, if tlie cells of an organ appear very slightly altered, 
 while ^\ e are acustomcd to argue that there has been but little dis- 
 turbance of function, it is (|uestionable whether we are justified in 
 this opinion. So also if an organ like the thyroid be markedly 
 hypertrophied, that is not in itself proof positive that there is 
 accompanying increased activity and increased internal secretion. 
 In the thyroid, for instance, the boundar)- line between pure hyper- 
 trophy 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 sectelion; it is dillicult to imagine 
 that gland structure of almost perfect t}pe can be present in the 
 body without affecting the body at 'arge.* Nevertheless we have 
 no conclusive evidence that this is the case; hence, it is only after 
 most exact and extensive histological sttidy 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 
 
 *It is noteworth)' how frequently, in attempting to co-ordinate the anatomical 
 data in the class of disease now before us, we are brought to regard the possi- 
 bilit)' — nay, probabilitj — that neoplasms are ujt functionless (as we are too apt 
 to consider them), but afford, it may be, an abundant, internal .secretion. 
 
 •I 
 
WITH INTERNAL SECRETIONS, 
 
 105 
 
 •i 
 
 [ 
 
 l^^ 
 
 activity. Because one organ is seriously diseased it does not follow 
 ^hat 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, presumably, the lymph-glandular tissue in 
 general takes over the functions of the absent organ. There is the 
 compensatory development of the parathyroids in athyrea, and 
 further, the frequent, but not constant co-existence of atrophic 
 disease of the thyroid and hypertrophy of the pituitary to which 
 Boyce and Beadles (i) have more especially called attention. 
 Similarly and curiously we meet with frequent persistence or 
 enlargement of the tliynuts 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, for the anatomist to determine which of the ductless 
 glands is primarily and which secondarily atifccted, but the added 
 difficulty besets us, and where die vicarious function is perfect and 
 compensation is complete we n^ay, 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 pronciiuced 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 appear flatly to contradict each other one cause of 
 discrepancy nuist be this vicarious activity. 
 
 Yet another consideration, seriously weighing upon the morbid 
 anatomist, is that two opposite processes may produce a similar 
 symptomatology, one that he can recognize, another that he cannot. 
 If the glands afford an internal secretion entering the lymph and 
 so eventually circuiting through the system, we know that the 
 ultimate use of the secretion must be to effect a chemical trans- 
 formation of some substance or substances in some other part or 
 parts of the system. There are thus four possible conditions: (i) 
 produ'-tion of an insudicient amount of internal secretion of any 
 gland in consequence of disease of that gland, and (2) the assimi- 
 
lOA 
 
 PATHOLOGICAL ANATOMY OF OKHTAIN GLANDS 
 
 the naked eye or under the microscope may support conclusions 
 reached by other means. It can do Uttle more. We know from 
 experiment that three-quarters of the hver, for example, may be 
 removed from the healthy animal with no pronounced Hsturbance 
 of the bodily functions, that whenever one-tifth 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. ]n tliis enormous reserve of material and 
 force may truly be said to lie the secret of the continued existence 
 of living beings. Thus tlie mere fact that the greater part of an 
 organ is found wanting by the anatomists, or replaced by tissue 
 of another nature, is not in itself absolute evidence that what 
 remains of the organ is fnnctionless or incapable of meeting the 
 needs of the organism. So long as any considerable number of 
 what may be termed the specific cells of an organ are to i)e 
 determined, we must proceed very cautiously in our reasoning; only 
 when the destruction is rabsolute or ncarl}- so are we on sure ground. 
 Contrariwise, if the cells of an organ appear very slightly altered, 
 while we are acustomcd to argue that there has been but little dis- 
 turbance of function, it is questionable whether we are justified in 
 this opinion. So also if an organ like the thyroid be markedly 
 hyi>ertrop!iied, that is not in itself proof positive that there is 
 accompanying increased activity and increased internal secretion. 
 In the thyroid, for instance, the boundary line between pure hvper- 
 trophy 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 sectelion; it is dilllcult to imagine 
 that gland structure of almost perfect type can be present in the 
 body without affecting the body at 'arge.* 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 
 
 *It is noteworthy how frequently, in attempting to co-ordinate the anatomical 
 data in the class of disease now before us, we are brought to regard the possi- 
 bility — nay, probability— that neoplasms are ujt functionless (as we are too apt 
 to consider them), but afford, it may be, an abundant, internal secretion. 
 
onclusions 
 
 <now from 
 
 e, may be 
 
 Hsturbance 
 
 ess of the 
 
 etes shows 
 
 e removed 
 
 aterial and 
 
 1 existence 
 
 part of an 
 
 by tissue j 
 
 that what 
 
 eeting the 
 
 number of 
 
 are to be 
 
 ning; only 
 
 re ground. 
 
 tly altered, 
 
 t little dis- 
 
 ustified in 
 
 markedly 
 
 t there is 
 
 secretion. 
 
 ure hyper- 
 
 irly vague. 
 
 tless gland 
 
 o imagine 
 
 ent in the 
 
 s we have 
 
 only after 
 
 n advance 
 
 ent simple 
 
 le force of 
 
 bearing of 
 
 e that has f 
 
 vicarious • 
 
 anatomical 
 
 d the possi- 
 
 are too apt 
 
 tion. 
 
 WITH INTERNAL SECRETIONS. 
 
 106 
 
 activity. Because one organ is seriously diseased it does not follow 
 *-hat 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, presumably, the lymph-glandular tissue in 
 general takes over the functions of the absent organ. There is the 
 compensatory development of the parathyroids in athyrea, and 
 further, the frequent, but not constant co-existence of atrophic 
 disease of the thyroid and hypertrophy of the pituitary to which 
 Boyce and Beadles (i) have more especially called attention. 
 Similarly and curiously we meet with frequent persistence or 
 enlargement of the thynuis when either the thyroid or the pituitary 
 body is the scat 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, for the anatomist to determine which of the ductless 
 glands is primarily and which secondarily atifected, but the added 
 diiTiculty besets us, and where die vicarious function is perfect and 
 compensation 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 appear flatly to contradict each other one cause of 
 discrepancy must be this vicarious activity. 
 
 Yet another consideration, seriously weighing upon the morbid 
 anatomist, is that two opposite processes may produce a similar 
 symptomatology, one that he can recognize, another that he cannot. 
 If the glands afford an internal secretion entering the lytnph and 
 so eventually circuk^ing through the system, we know that the 
 ultimate use of the secretion must be to effect a chemical trans- 
 formation of some substance or substances in some other part or 
 parts of the system. There are thus four possible conditions: (i) 
 produ'-tion of an insuflicient amount of internal secretion of any 
 gland in consequence of disease of that gland, and (2) the assimi- 
 
106 
 
 PATHOLOGICAL ANATOMY OF CERTAIN GLANDS 
 
 lation or production of an excess of that substance which normally 
 is acted upon and transformed by tlie internal secretion in question. 
 In both of these first two cases there will be a heaping up in the 
 system of the substance; in both there may be the same train of 
 symptoms. In the one the gland or glands may show the clearest 
 signs of disease ; in the otiier they may appear normal. The morbid 
 anatomist may in time discover collateral disturbances distinguish- 
 ing these two states; at present he cannot adequately. In one case 
 of diabetes he finds the pancreas unaffected, in the next it is 
 extensively diseased. Unaided by experimental pathology, he is 
 quit? incapable of determining the important role played by this 
 organ in regulating the sugar supply of the organism and in the 
 production of diabetes. Similarly there mav be an accumulation 
 of the internal secretion, either due to (3) hypertrophy of a gland, or 
 (4) not associated with recognizable glandular change. 
 
 In short, gentleman, I fear that I stand before vou as a kind of 
 reversed, contrary Balaam. Summoned to bless— to illumine this 
 discussion— I can only curse and can but point out to you the 
 darkness that is upon the face 01 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 lacunc-e 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. 
 
 And then, perhaps, things are not quite so black as here painted. 
 While it may be that I am overbold, it may also be tliat this dark- 
 ness but precedes tlie 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 utilize the results of anatomical and histological studies,' 
 then, applying tlie considerations which I have just urged, we must 
 recognize the possible existence of three orders of conditions, each 
 order being capable of further subdivision into two well marked 
 groups. 
 
NDS 
 
 WITH INTERNAL SECRETIONS. 
 
 107 
 
 /Iiich normally 
 on in question, 
 jing up in the 
 same train of 
 )w the clearest 
 . The morbid 
 es distinguish- 
 In one case 
 he next it is 
 thology, he is 
 )layed by this 
 ;ni and in the 
 accumulation 
 of a gland, or 
 
 .1 as a kind of 
 ) illumine this 
 It to you the 
 ippily there is 
 nist, that the 
 ; as indicating 
 us factors that 
 died, in order 
 this intensely 
 and glandular 
 
 here painted, 
 hat this dark- 
 1 so flatly to 
 
 experimental 
 ti an orderly 
 is of the body 
 d transposing 
 ted by other 
 t due caution, 
 gical studies, 
 ged, we must 
 iditions, each 
 
 well marked 
 
 It would seem that we have to deal with : 
 
 Changes 
 associatep 
 
 WITH 
 
 Symptoms 
 
 OF 
 
 Disease. 
 
 Changes 
 Unaccompanied 
 
 EY 
 
 Symptoms 
 
 OF 
 
 Disease. 
 
 I. Glandular Inadequacy.— Excess of siibst.incc acted 
 upon by the internal secretion of a gland, without 
 due compensation. 
 
 (i.) Absolute. Altered condition of gland lead- 
 ing to diminished activity and diminished 
 internal secretion. 
 
 (2.) Rklativk. Nodiseaseor alteration of gland, 
 but excessive production or assimilation 
 of the substance acted upon by the inter- 
 nal secretion. 
 
 II, Glandular Over-Activity.— Excess of internal se- 
 
 cretion without compei\sation. 
 
 (i.) Absolute. .Mteved condition of gland lead- 
 ing to increased activity .and increased 
 pouring out of internal secretion. 
 
 (2.) Relative. No disease or alteration of gland, 
 but diminished production or assimilation 
 of the substance acted upon by the inter- 
 nal secretion of that gland. 
 
 III. Compensation. — 
 
 (i.) Altered condition of gland leading to M in- 
 crease or (/') diminution of internal secre- 
 tion, with due compensation. 
 
 (2.) {ti) Increased or (/') diminished production or 
 assimilation of substance acted upon by 
 internal secretions, with due compensa- 
 tion. 
 
 Let me here emphasize the fact that I do not pretend that this 
 table includes every possible condition leading to local or general 
 disturbance of these glands affording an internal secretion, and 
 leading to the symptoms most often associated with disease of these 
 glands. For example, we know from experiments with phloridzin 
 that glycosuria may, among other things, be the result, not so much 
 of increased production of sugar as of increased lemoval of this^ 
 body through the kidneys. Such cases are not embraced in this 
 table. Again, what I may term compound cases, as, for instance, of 
 glandular inadequacy, in part from disease, in part from increased 
 production of the substance acted upon bv the secretions, are pre- 
 sented only by implication. All I urge is, that this table, cc ■form- 
 ing with what experiment has shown may occur, may very possibly 
 be utilized to explain the a: ;>!;ently contradictory revelations of the 
 post-mortem room. Can it be so utilized? While I will not say 
 that in connection with every gland we shall find evidence of the 
 existence of each of the three main orders of the above table, I 
 must acknowledge that the acceptance of the considerations here 
 
108 PATHOLOGICAL ANATOMY OF CERTAIN GLANDS 
 
 brous-lit forward aids wonderfully in explaining facts otherwise 
 inexi)licablf and chaotic. 
 
 I would now proceed rapidly to review those conditions, local 
 and general, concerning which we liave already a modicum of 
 knowledge and which fall within the scope of to-day's discussion. 
 
 'riiic I'.wtkKAs AM) ()i.\I!I-:ti:s. 
 
 Let nic in the first ])!ace take into consideration lesions of the 
 pancreas and their relationshii) to diabetes. Aluch more than a 
 century has passed since attention was first called to the pronounced 
 changes to be seen in the pancreas in some cases of diabetes. We 
 all know that not until 1889, when Von Mering and Minkowski in 
 Germany, and de Dominicis in Italy, published the results of their 
 researches, did the belief in the existence of a pancreatic diabetes 
 begin to become generalized. i)nt even at the present moment the 
 fact that two cases, closely resembling each other clinically, may 
 post-mortem show, the one extensive pancreatic disturbance, the 
 other an ai)parently healthy pancreas, creates great confusion. 
 
 \\ hat tlien can In- gathered so far as to the relative frequency 
 and the nature of the lesions of the pancreas which may be associ- 
 ated with diabetes? 
 
 We have at least three careful studies upon this subject, those of 
 IJanscmann {2), Williamson (3) and Dieckhofif (4), and all demon- 
 strate that three conditions may be distinguished: (i) very exten- 
 sive pancreatic disease with associated diabetes;. (2) very exten- 
 sive pancreatic disease without diabetes; (3) diabetes unassociated 
 with recognizal)le pancreatic disease, llansemann, from a careful 
 investigation of the records of the I'athological Institute and the 
 Augusta Hospital at Berlin, found that the first condition (of pan- 
 creatic disease with diabetes) is more common than the two others 
 • combined, it may be said that in Berlin tlie consumption of much 
 beer predisposes to the pancreatic form of the disease; it may be 
 that the material upon which Hansemann worked was imperfect to 
 this extent, that full care was not taken to distinguish between 
 extensive and extrenie destruction of the pancreatic tissue; Imt it 
 will, I think, be the experience here, as it was that of Williamson 
 in England, and Dieckhofif in Rostock, that advanced pancreatic 
 disease, associated and unassociated with diabetes, are to be 
 encountered the one but little more frequently than the other. 
 
 This nmch, however, stands out very prominently, that where in 
 diabetes the pancreas is found affected, the morbid process within 
 
ts otherwise 
 
 litions, local 
 modicuin of 
 s discussion. 
 
 sions of the 
 nore than a 
 pronounced 
 abctcs. We 
 [inkowski in 
 ults of their 
 itic diabetes 
 moniont the 
 nically. may 
 irbancc. the 
 fusion, 
 e frequency 
 y be associ- 
 
 ect. those of 
 I all demon- 
 very exten- 
 very exten- 
 niassociated 
 im a careful 
 ute and the 
 ion (of pan- 
 ! two others 
 ion of much 
 ; it may be 
 imperfect to 
 ish between 
 ssuc: Inn it 
 Williamson 
 I pancreatic 
 are to be 
 other. 
 
 lat where in 
 )cess within 
 
 WITH INTERNAIi SECRETIONS. 
 
 109 
 
 1 
 
 i! 
 ■I 
 
 I 
 
 the gland is some one or other form of atrophy and destruction 
 of the gland substance. Most connnonly it is a form of periacinous 
 fibrosis, originating it would seem secondarily to arterio-sclerosis, 
 in which with thickening of the arterial walls there is malnutrition 
 of the gland cells, atrophy and, what I iiave elsewhere termed, 
 replacement fibrosis. Other forms of atrophy and fibrosis have not 
 infrequently been observed — simply atrophy, congenital syphilitic 
 fibrosis, obstruction of the ducts with calculi, dilatation of the 
 ducts and atrophy of the gland tissue, scirrhous cancer of the 
 pancreas, and I have found recorded five cases of necrosis, or 
 ha;niorrhagic necrosis (two by I-'itz and a third, a case under Drs. 
 Bell and Finley, in my own experience at the Montreal General 
 Hospital). 
 
 There can, therefore, be no question that the pancreatic lesions 
 found in some cases of diabetes are such that there must be a 
 marked diminution in the secretory activity of the gland. To this 
 extent, in this one class of cases the results of autopsies are clearly 
 in accord with the results of experiments. We have here examples 
 of glandular inadequacy brought about by altered condition of the 
 pancreas leading to diminution of internal secretion. 
 
 Examples of diabetes unassociated with disease of the pancreas 
 are so well known that I need but refer to them. While such are 
 difficult to explain from purely anatomical considerations, the fact 
 that they are found, and found relatively frequently is, in itself, an 
 evidence that glycosuria is of at least a two-fold origin. That 
 they are found is in conformity with the results of experiments, 
 experiments which, on the whole, must be regarded as proving that 
 there can be heaping up of sugar in the organism beyond the trans- 
 forming power of the pancreatic internal secretion, or otherwise an 
 incomplete burning up of the sugar. If this heaping up be in 
 general due to increased glycogenesis, increased production of 
 sugar, we should expect to find some evidence of increased activity 
 of some glycogenetic organ, and here the recent researches of 
 Glenard (5) and Triboulet (6) tend to show that this may be the case. 
 Contrary to the older and generally accepted teaching, Glenard 
 finds that clinically in over sixty per cent, of diabetics, there is 
 evidence of some hepatic enlargement. Anatomically he finds that 
 three conditions may be recognized, each possibly a stage in one 
 morbid process, namely, hypenemia, general cellular hypertrophy 
 (hyperplasia) and hypertrophy with cirrhosis (hypertrophic cirr- 
 hosis). Thus while I will not say that anatomical considerations 
 prove the existence of my second sub-order in this connection, I 
 
no 
 
 PATHOLOGICAL ANATOMY OF CERTAIN GLANDS 
 
 must point out that the existence of this class of cases of diabetes 
 without adequate recognizable pancreatic disturbance, is best 
 explained on the supposition that there may be excessive production 
 or assimilation of sugar with accompanying relative pancreatic 
 inadequacy. 
 
 There is yet a third group of cases to be considered, that of 
 extensive atrophic disease of the pancreas without diabetes. Here 
 we have to proceed cautiously in our reasoning. As I have already 
 indicated, Sandmeyer (7) has found that if only one-fifth to one- 
 ninth of the organ be left in the dog, it niay be months before sugar 
 appears in appreciable quantities in the urine. Vaughan Harley (8) 
 gives an even smaller amount, namely, one-fifteenth, but evidently 
 he refers not to the eventual development of diabetes, but to its 
 onset within a few hours. We can thus state that so long as from 
 one-ninth to one-fifteenth of the glandular tissue of the organ is 
 functional, <"or so long glycosuria need not manifest itself in the 
 dog. There is no valid reason why we should not apply these 
 facts to the human being. Hence so long as a very small propor- 
 tion of fairly healthy gland tissue is left, we have a satisfactory 
 explanation why diabetes should not show itself, even the ;gh the 
 major portion of the pancreas exhibits fibroids and ati ^phic or 
 neoplastic changes. There are, however, aspects of that subject not 
 capable of so simple an explanation. I remember my friend, Dr. 
 H. D. Rolleston, of St. George's Hospital, showing to me a series 
 of sections of the fibroid pancreas taken from both diabetic and non- 
 diabetic cases, from which the only conclusion to be reached was 
 that a given extent of fibrosis might or might not be associated 
 with diabetes. Again, Hansemann has called attention to cases of 
 complete replacement of normal pancreas by a diffuse cancerous 
 infiltration without the development of diabetes. He seeks to 
 explain these by the hypothesis already indicated, that the cells of 
 a primary new growth of a ductless gland may continue to furnish 
 an internal secretion. This may or may not be the case. Where 
 there is primary cancer of the hepatic parenchyma, the new growth 
 m the liver may be devoid of bile ; the secondary growths are with- 
 out exception free from bile. A more simple explanation of these 
 and other examples of complete or almost complete destruction of 
 the pancreatic glandular tissue is that of compensation, whether 
 by vicarious function of Brunner's and other glands (the duodenal 
 glands have frequently been found enlarged) or by diminished 
 assimilation or production of sugar. However I will not venture to 
 say that Hansemann's hypothesis may not, after all, be the true 
 solution. 
 
 ■■ 
 
NDS 
 
 WITH INTERNAL SECHETIONS. 
 
 Ill 
 
 ses of diabetes 
 ance, is best 
 ive production 
 ive pancreatic 
 
 dered, that of 
 abetes. Here 
 I have already 
 2-fifth to one- 
 s before sugar 
 ia:i Harley (8) 
 but evidently 
 :es, but to its 
 long as from 
 the organ is 
 t itself in the 
 t apply these 
 small propor- 
 a satisfactory 
 :n the ;gh the 
 d atijphic or 
 lat subject not 
 ly friend, Dr. 
 
 me a series 
 )etic and non- 
 
 1 reached was 
 be associated 
 )n to cases of 
 ise cancerous 
 He seeks to 
 It the cells of 
 lue to furnish 
 :ase. Where 
 I new growth 
 /ths are with- 
 ition of these 
 lestruction of 
 :ion, whetl r 
 the duodenal 
 ^ diminished 
 ot venture to 
 
 be the true 
 
 THE SUPRAKENAL ROPTES AND ADOISON S DISEASE. 
 
 We meet with an identical scries of cases in connection with 
 another organ in which experimentally the existence of an internal 
 secretion has been fully demonstrated. We may have (i) Addison's 
 disease associated with disease of the suprarenal bodies, (2) 
 Addison's disease with intact suprarcnals, and (3) extensive, if not 
 complete, destruction of the suprarenal bodies without the symp- 
 toms of Addison's disease. 
 
 Here, as with the pancreas in diabetes, the affection of the gland 
 in Addison's is some form of atrophy or destruction of the specific 
 gland tissue. Most frequently, I need scarce say, the change is 
 tuberculous and nccrobiotic, resulting in the disappearance of the 
 gland tissue and its replacement by caseous material. But cases are 
 on record of simple atrophy, hsemorrhagic necrosis and malignant 
 growth of the bodies associated with or leading to all the symptoms 
 of Addison's disease. In the vast majority of cases both glands are 
 affected, but cases are on record (I have come across one such) 
 where only one of the bodies has been the seat of recognizable 
 disease. Of the three conditions above mentioned the most fre- 
 quent found is the association of the disease with complete or almost 
 complete destruction of the gland. So frequent is the association 
 that the attempts to explain away the other two rare states of 
 Addison's disease with intact suprarenal bodies and suprarenal 
 disease without the Addisonian symptoms, have been almost painful 
 in their ingenuity. Yet undoubtedly well authenticated cases are 
 on record of both of these conditions. 
 
 We have in this connection singularly full statistical collections 
 of cases. That of Lewin (9) is well known; he collected accounts 
 of 285 cases, of which 211 showed caseous lesions of the suprarenals 
 iy/^'f). Gilman Thompson (10) found an even greater proportion of 
 either primary or secondary tuberculosis (80^; in the remaining 
 20 per cent, there were either other forms of atrophic disease or 
 absence of recognizable disturbance. 
 
 The existence of cases of Addison's disease without obvious 
 disease of the suprarenal is generally acknowledged. Lewin found 
 that as many as \2^ of his cases were of this type. The explanation 
 generally given is that in these there had been alterations in the 
 neighbouring semilunar ganglia and abdominal sympathetics. 
 Certainly, disturbance of the nervous system, and especially of the 
 sympathetics, does lead to pigmentation of the skin. We see this 
 in cases of hysteria and again in Graves' disease, in which from 
 
112 
 
 PATHOLOGICAL ANATOMY OF CERTAIN OLANDS 
 
 whatever cause (I shall speak of this later) we have most marked 
 nervous chan-es, hut T nuist confess that I feel some little impa- 
 tience tcnvanls the ui^holders of this seniilimar ganj,rlion theory of 
 Ac (hson s disease, for scarce two of them describe the same order 
 of lesions. Most of the changes described would appear to be quite 
 common m the adult dying from other causes; thus Hale White 
 (I I) found that examiuing 33 semilunar ganglia removed indiscrimi- 
 nately, If wc leave out of account 3 perfectly normal taken from 
 young children. 24. or 80 per cent, of the remainder, exhibited more 
 or less extensive degenerative changes with frequent presence of 
 granular masses of pignient. l^ixon Mann (12) also, making a care- 
 ful comparative study of the abdominal sympathetics and semilunar 
 ganglia from two cases of the disease and from the unaffected 
 HKhvidual came to a like conclusion. He found them not more 
 affected than arc those of other individuals. Under the circum- 
 stances, therefore, I see no valid reason why cases in which the 
 bodies are found apparently unaffected niav not. in the light of our 
 present knowledge, be most satisfactorilv classed as possible 
 examples of relative glandular inadecpiacv of the second das. This 
 suggestion may to some appear rcvolutionarv but let me reiterate 
 my main argument: We acknowledge that glands like the supra- 
 renals produce an internal secretion: we must inevitablv admit 
 that the function of such secretion is to affect a chemical transforma- 
 tion of some substance or substances distributed in other parts of 
 the body: we must admit that when, for example, the suprarenal 
 bodies are diseased, or removed, some at least, of the symptoms that 
 follow are due to the absence of the internal secretion, or. in other 
 words, arc due to the accumulation in the svstem of the substance • 
 or substances acted upon by the internal secretion. The same 
 symptoms must b.- produced whatever the cause of the accumula- 
 tion of the substance or substances, whether by diminution of the 
 internal secretion or by excessive production or assimilation of the 
 aforesaid substance or substances. When, therefore, a morbid 
 condition, such as diabetes or Addison's disease, which may be 
 caused by destruction of a gland, is found to exist without reco-niz- 
 ablc disease of that gland, a very possible explanation of the condi- 
 tion IS what I have termed relative glandular inadequacy due to 
 excessive production or assimilation of the substance acted upon 
 by the internal secretion. I would but ask you clearly to picture 
 this, that in diabetes and Addison's disease it is not the internal 
 secretion that causes the symptoms, but, if experimental data are to 
 
 1 it 
 
 ¥. 
 
DS 
 
 WITH INTERNAL SECRETIONS. 
 
 113 
 
 lost marked 
 
 little impa- 
 )n theory of 
 
 same order 
 r to be quite 
 Hale White 
 1 indiscrimi- 
 taken from 
 lihitcd more 
 presence of 
 king a care- 
 d semilunar 
 
 unaffected 
 1 not more 
 he circum- 
 
 which the 
 light of our 
 IS possible 
 class. This 
 ne reiterate 
 
 the supra- 
 ably admit 
 ransforma- 
 er parts of 
 suprarenal 
 ptoms that 
 ir, in other 
 
 substance 
 The same 
 accumula- 
 :ion of the S|,; 
 tion of the v' 
 a morbid 
 h may be 
 
 recogniz- 
 the condi- 
 cy due to 
 ;ted upon 
 to picture 
 e internal 
 ata are to 
 
 be trusted, the lack of the same — and that this lack may be absolute 
 or relative. 
 
 I am far from suggesting that the whole corpus of symptoms 
 will be the same in both conditions. Thus as Harley and others 
 have pointed out, where the pancreas is atrophied there are pro- 
 found digestive disturbances not necessarily accompanying diabetes 
 unassociated with pancreatic disease. But I am inclined to think 
 that the cardinal symptoms in both will closely resemble each other. 
 
 A few words only are necessary concerning affections of the 
 suprarenal bodies without symptoms of Addison's disease. If 
 bronzing be required as the one essential symptom, then cases of 
 tuberculous disease of the suprarenal without "Addison's" are fairly 
 frequent. Addison himself noted this condition. We must how- 
 ever, it seems to me, acknowledge with Chvostek (13) and numerous 
 previous observers, that bronzing is but one of a group of symptoms, 
 even though we be not prepared to accept Bedford Fenwick's (14) 
 suggestion that bronzing is especially connected with disease of 
 the cortical layer. Leaving this category out of consideration, cases 
 of extensive atrophic or neoplastic disturbance of both suprarenals 
 without Addison's disease are few in number, far fewer than the 
 cases of extensive pancreatic disease without diabetes, and in 
 general the descriptions given are not sufficiently exact to be relied 
 upon. Nevertheless they exist. Greenhow (15) apparently met 
 with a case of almost complete atrophy without symptoms, and, 
 in 1050 autopsies upon subjects dying from diseases other than 
 Addison's, RoUeston (16) met with an example of caseation of the 
 right and atrophy of the left suprarenal and with three cases (under 
 the age of forty-five) in which both were peculiarly small. All these 
 were without symptoms intra-vitam. There are more frequent 
 examples recorded of cancerous growth destroying both bodies 
 without noticeable symptoms. There is a possibility that the new 
 [growth here was so rapid and so recent that symptoms had not time 
 [to develop. In the atrophic and tubercular cases it is not so easy 
 to accept this explanation. Therefore, I am inclined to believe that 
 compensation may occasionally manifest itself in man as it does 
 occasionally in animals which have suffered complete ablation of 
 both organs. 
 
 THE THYROID GLAND AND MYXOIDEMA. 
 
 I have already approached the limits of the time allotted to me 
 and there is yet for me to pass in review the gland and its affections, 
 
 8 
 
lU 
 
 1>ATU0L0(»ICAL ANATOMY OP CERTAIN GLANDS 
 
 which in this connection have created the most general interest. 
 I refer to the thyroid and to the conditions of myxoedema, cretinism 
 and exophthalmic goitre. 
 
 From an anatomical point of view there is little for me to say in 
 elucidation of the pathology of myxoedema beyond the one all- 
 important statement that, with very rare exceptions, there is dis- 
 coverable a well marked atrophy of the thyroid. About this all 
 pathologists are agreed. In the majority of cases the atrophy is 
 peculiarly extensive, the specific cells of the gland being replaced by 
 fibrous tissue: in some it is not so far advanced, and areas may be 
 found, not merely of degenerated remains of the vesicular epithe- 
 lium, but of vesicles which by the superabundant proliferation of 
 their epithelium would seem to be undergoing a compensatory 
 hypertrophy. Yet where these are present they are localized and 
 few in number; the main mass of the organ shows atrophy. A few 
 cases only are on record, like that of Gulliver (17), where there has 
 been a cancerous metamorphosis or replacement of the parenchyma. 
 
 That in these cases the myxoedema is associated with diminished 
 internal secretion of the gland is, I need scarce say, substantiated by 
 the good effects of treatment by thyroid extract or thyroid feeding. 
 
 It must next be asked whether myxoedema can show itself with 
 apparently intact thyroid, id est, whether there are any cases which 
 may possibly be explained by excess of the substance or substances 
 acted upon by the internal secretion of the gland. The Hterature 
 is peculiarly silent upon this point, I can find no example of 
 autopsies upon cases diagnosed clinically as myxoedema in which 
 the gland was found normal, or but little affected. Possibly rny 
 search was not sufficiently extensive. I can only recall an autopsy 
 upon a patient of Dr. J. Stewart at the Royal Victoria Hospital, in 
 which I found a large cancerous tumor of the pituitary. Here there 
 had been a myxoedematous swelling of the hands, and of other 
 regions to less extent, without bony overgrowth, and no change was 
 found in the thyroid. The condition, however, was not sufficiently 
 advanced to deter Dr. Stewart from diagnosing tumor of the 
 hypophysis. A somewhat parallel case (of apparent atrophy of the 
 pituitary), in which the symptoms of myxoedema were more 
 marked, is recorded by Codd (18), but the anatomical details are 
 given very briefly. Similarly we possess no exact records of 
 atrophic disease of the glands unassociated with myxoedema. I 
 can only point out that it is not uncommon in the aged, who show 
 no signs that can properly be regarded as myxoedema— unless 
 
*' 
 
 I 
 
 WITH INTERNAL 8KCRKTION8. 115 
 
 senility itself be regarded as such-to find a condition of very 
 extensive chronic interstitial thyroiditis (as it may be termed) with 
 arterio-sclerosis, calcification and hyaline changec, with retrograde 
 or pseudo-embryonic type of vesicles. I have come across more 
 than one case of this nature. There can be no doubt that here the 
 secretory activity of the gland tissue must be very greatly reduced 
 If, however, we turn to cases in which by surgical means the 
 equivalent of complete atrophy, namely, complete thyroidectomy 
 has been attained, we then possess abundant evidence that the 
 thyroid proper may be absent w-'thout myxoedema necessarily 
 intervening, and almost as abundant e -idence from the more recent 
 researches that the absence of symptom • is connected with vicarious 
 activity on the part of other organs, ;;nd especially of the parathy- 
 roids. These may be regarded cither as true accessory thyroid 
 tissue, or as distinct organs, according to the point of view of the 
 individual. Certainly when the thyroid is functional they do not 
 acquire the full characters of thyroid tissue, but similarly there are 
 often within the healthy organ scattered areas of embryonal tissue 
 This can be said with precision, that they are independent masses of 
 tissue, apparently most closely related to the thyroid, which are at 
 times capable of development to, or towards, the adult type of the 
 gland, and of assuming vicarious functions. In like manner the 
 pituitary body can at times undergo very definite compensatory 
 enlargement. This was first demonstrated experimentally by 
 Rogowitsch (19), while Boyce and Beadles more especially have 
 added to our knowledge of its enlargement in cases of myxoedema 
 cretinism and cachexia thyreopriva. 
 
 An interesting point in this connection, to which attention has 
 been drawn by Rogowitsch, is that the rabbit, from -vhich the 
 thyroid can be removed with impunity, has a pituitary body rela- 
 tively five times as large as that of the dog, in which ablation of the 
 thyroids leads rapidly to symptoms of acute athyrea; or more 
 correctly, the relationship of thyroid to pituitary is 3 to i in the 
 former, 15 to i in the latter animal. 
 
 On the whole, therefore, anatomical data in connection with 
 myxoedema and cachexia thyreopriva support and are capable of 
 explanation by this doctrine, that where glands afford an internal 
 secretion, the development or non-development of symptoms of 
 disease depends primarily upon the relative amount of internal 
 secretion produced and of the substance or substances acted upon 
 by the same. 
 
116 
 
 rATHOLOGIOAI, ANATOMY OF OERTAIX OLANDS 
 
 I 
 
 CRETINISM. 
 
 Cretinism presents a far more complicated histological picture — 
 so complicated that IJircher (20) argues with very considerable force 
 that "cretinic degeneration, as also dwarfism and chondrodystro- 
 phia fa-talis hypoplastica have no a'tiulogical coimection with the 
 functions of the thyroid." Hircher, however, fails to recognize 
 that if we accept the existence of an internal secretion, we must also 
 admit the presence of substances upon whicli thai 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 indistinguishable 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 
 larger number, according to Von Eiselberg (21) and Kccher (22) 
 there is a goitrous condition present, while according to Bircher the 
 goitres may be of all possible forms, from simple hyperplastic 
 through soft (parenchymatous) and cystic to fibroid. The only 
 point clearly to be made out from Bircher's very destructive criti- 
 cism is that while in several cases the thyroid has been found of 
 normal size, apparently no case exists in which by microscopical 
 observation it has been found of normal structure. 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 the 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 anatomically presents an equal contrast. There is to be found 
 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 
 
 * , • 
 
 ^ 
 
] 
 
 WITH IXTKUNAL SECUETIONH. 
 
 117 
 
 secretion. As T Iiavc already liintod, I do not think that from 
 I , anatomical considerations alone we can safely make this deduction. 
 
 There is, however, an important fact in favor of sucii deduction, 
 namely, the stronp likeness between the primary glandular changes 
 in Graves' disease and those described by Ila'.sted (24) and others as 
 occurring in the compensatory hyperplasia of the thyroid after 
 removal of large portions of the glaiKl; and if, togetiier with the 
 anatomical changes, we consider the favorable effects which so often 
 follow removal or destruction of the hypcrtrophied gland in this 
 disease or diminution in the blood supply of portions of the same — 
 of operations which nuist lessen the internal secretion— it is difficult 
 to arrive at any other conclusion than that in exophthalmic goitre 
 there is increased 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 'o decide, as again they are incapable of deciding 
 
 whether the 1. .;aoed secretion is altered or unaltered in quality. 
 I may here note that, as Joffroy and Achard (25) have indicated, the 
 symptoms of parenchymatous 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 condi- 
 tion 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, more especially 
 those of a nervous character. 
 
 The development of exophthalmic goitre without hyperplastic 
 alteration of the thyroid is a matter concerning which there is 
 \i little anatomical evidence. I find one case recorded by Joflfroy and 
 Achard in which the gland was of normal size and, while not 
 normal histologically, 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 believe in the existence of Graves' disease 
 without goitre. Among recent writers Buschan (26) especially 
 holds this view, but save in the above ca.se I cannot find anatomical 
 substantiation for the opinion. Clinically Graves' disease without 
 enlarged thyroid has very frequently been noted; in some cases