tmm

■■

IMAGE EVALUATION
TEST TARGET (MT-S)

St'

:/i

1.0

I.I

1.25

♦" IM |||||22
2.0

140

1.8

U 1116

3
v3

Photographic

Sciences

Corporation

23 WEST MAIN STREET

WEBSTER, N.Y. 14580

(716) 872-4503

¥'

'■'!f m »M.»" r ' "!^t^ ; jt(CTW.piijlti ? v. ' 4 ' r!;j ! ;'.<s&iyu.^^;S,» r!" ;;-«ji^

,J*

CIHM/ICMH

Microfiche

Series.

Canadian Institute for Historical Microreproductions /

MH^l^i^BMa

ICMH
iche

CIHM/ICMH
Collection de
microfiches.

Microreproductions / Institut canadien de microreproductions hiatoriquos

Technical and Bibliographic Notes/Notes tech

The Institute has attempted to obtain the best
original copy available for filming. Features of this
copy which may be bibliographically unique,
which may alter any of the images in the
reproduction, or which may significantly change
the usual method of filming, are checked below.

r~/j Coloured covers/
1^^ Couverture de couleur

rrT^ Covers damaged/

L^ Couverture endommag^e

I I Covers restored and/or laminated/

Couverture restaur6e et/ou pelliculde

Cover title missing/

Le titre de couverture manque

Coloured maps/

Cartes g6ographiques en couleur

Coloured ink (i.e. other than blue or black)/
Encre de couleur (i.e. autre que bleue ou noire)

Coloured plates and/or illustrations/
Planches et/ou illustrations en couleur

Bound with other material/
Relid avec d'autres documents

Tight binding may cause shadows or distortion
along interior margin/

La reliure serree peut causer de I'ombre ou de la
distortion le long de la marge intSrieure

Blank leaves added during restoration may
appear within the text. Whenever possible, these
have been omitted from filming/
II se peut que certaines pages blanches ajout^es
lors d'une restauration apparaissent dans le texte,
mais. lorsque cela 6tait possible, ces pages n'ont
pas 6t6 filmdes.

Additional comments:/
Commentaires supplSmentaires;

This item is filmed at the reduction ratio checked below/

Ce document est film6 au taux de reduction indiqu6 ci-dessous.

10X 14X 18X 22X

12X

16X

20X

phic Notes/Notes techniques et bibliographiques

ast
of this

ange
ilow.

acit)/
>u noire)

istortion
3 ou de la

may

ibie, these

I ajoutdes
ns le texte,
iges n'ont

L'Institut a microfilm^ le meilleur exempiaire
qu'il lui Q §t6 possible de se procurer. Les details
de cet exempiaire qui sont peut-dtre uniques du
point de vue bibliographique, qui peuvent modifier
une image reproduite, ou qui peuvent exiger une
modification dans la m6thode normale de filmage
sont indiqu^s ci-dessous.

I I Coloured pages/

Pages de couleur

Pages damaged/
Pages endommag^es

Pages restored and/oi

Pages restaurdes et/ou pellicul6es

I I Pages damaged/

I I Pages restored and/or laminated/

□ Pages discoloured, stained or foxed/
Pages d6color6es, tachetdes ou piqudes

/
r^ Pages detached/

Pages ddtach^es

Showthrough/
Transparence

I I Showthrough/

I I Quality of print varies/

Quality indgale de {'impression

Includes supplementary material/
Comprend du materiel supplementaire

Only edition available/
Seule Edition disponible

Pages wholly or partially obscured by errata
slips, tissues, etc., have been refilmed to
ensure the best possible image/
Les pages totalement ou partiellement
obscurcies par un feuillet d'errata, une pelure,
etc., ont 6t6 film6es d nouveau de faqon k
obtenir la meilleure image possible.

eked below/
indiqud ci-desbous.

22X

26X

30X

20X

24X

28X

32X

The copy filmed here has been reproduced thanks
to the generosity of:

Library of Congress
Photodupllcation Service

The images appearing here are the best quality
possible considering the condition and legibility
of the original copy and in keeping with the
filming contract specifications.

Original copies in printed paper covers are filmed
beginning with the front cover and ending on
the last page with a printed or illustrated impres-
sion, or the back cover when appropriate. Ail
other original copies are filmed beginning on the
first page with a printed or illustrated impres-
sion, and ending on the last page with a printed
or illustrated impression.

The last recorded frame on each microfiche
shall contain the symbol -^ (meaning "CON-
TINUED"), or the symbol V (meaning "END"),
whichever applies.

Maps, plates, charts, etc., may be filmed at
different reduction ratios. Those too large to be
entirely Included in one exposure are filmed
beginning in the upper left hand corner, left to
right and top to bottom, as many frames as
required. The following diagrams illustrate the
method:

uced thanks

L'exemplaire film6 fut reproduit grdce d la
06n6ro8itA de:

Library of Congress
Photoduplication Service

St quality
i legibility
th the

Les images suivantes ont 6t6 reproduiies avec le
plus grand soin, nompte tenu de la condition et
de la netteti de l'exemplaire filmd, et en
conformity avec les conditions du contrat de
filmage.

s are filmed
ding on
ted impres-
iate. All
ling on the
impres-
1 a printed

Les exemplaires originaux dont la couverture en
papier est imprim6e sont filmds en commen9ant
par le premier plat et en terminant soit par la
dernidre page qui comporte une empreinte
d'impression ou d'illustration, soit par le second
plat, selon le cas. Tous les autres exemplaires
originaux sont film6s en commen^ant par la
premidre page qui comporte une empreinte
d'impression ou d'illustration et en terminant par
la dernidre page qui comporte une telle
err -treinte.

ofiche
g "CON-

"END").

Un des symboles suivants apparaitra sur la
dernidre image de cheque microfiche, selon le
cas: le symbole — ► signifie "A SUIVRE", le
symbole V signifie "FIN ".

ned et
arge to be
Filmed
)r, left to
nes as
trnte the

Les cartes, planches, tableaux, etc., peuvent dtre
film6s A des taux de reduction diffdrents.
Lorsque le document est trop grand pour dtre
reproduit en un seul cliche, il est film6 d partir
de Tangle sup6rieur gauche, de gauche d droite,
et de heut en bas, en prenant le nombre
d'images n6cessaire. Les diagrammes suivants
iilustrent la m6thode.

M^BBBBBBB^lBBlBSaaBHB^^HBaBBai^^Ba^BflB

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.

J. GEORGE ADAM!, M.A., M.D.

Rbprinteu fkom Vol. IV
TRANSACTIONS OK THE CONGRESS OK AMERICAN PHYSICIANS AND

SURGEONS
1897

'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

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

Disease.

Changes
Unaccompanied

Symptoms

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

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

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

¥.

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,

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

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

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