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Thyroid History

Thyroid History
om Edna:
"One of the main reasons this website exists is that I am fortunate enough to live ten minutes away from the British Library where I have access to the huge archive of medical research.I am a wheelchair user and medically retired. I have trained as both a singer and a psychotherapist but no longer pursue these occupations.At the age of twenty in 1985, I was diagnosed with MS, although I have always questioned this diagnosis. I collapsed out of the blue with a high temperature, went yellow, lost a lot of weight, and deteriorated rapidly. I was in a wheelchair within two years. A few years ago, by chance, I met a doctor who studied thyroid medicine beyond the normal medical training. Due to receiving thyroid supplementation treatment, my health improved dramatically. I now have five times as much energy, am mentally much sharper, far less prone to infections, as well as many other improvements. Unfortunately, it seems too late to affect my walking or the associated nerve damage, but I always hope there is more to be discovered.
I am determined that the knowledge of thyroid function in many common illnesses is made available so that others don't have to go through what I did.
Trends in medicine have swept away vital research of many fine doctors.
This work is very important to me and I hope others will benefit from it. "
Oktober 2012 skrev Janie på stopthethyroidmadness at Edna var blitt dårligere og døde nylig, og Sheila Turner skrev også en tekst
”Today, holds over 1,200 abridged articles on the diagnosis and treatment of thyroid related illness, photocopied from books and journals in The British Library and scanned onto her computer at home. She said: “At one point I was spending £70 a week on photocopying. I just feel so passionately about this.” What has shocked Edna most, and what she talked about most animatedly, is the medical research by long-dead doctors that has been lost over the passage of time. Edna said “In the 1880s when they wrote about the thyroid they thought they’d found the elixir of youth. There is all this incredible work that had just been forgotten about.”The website sprang from a determination that the knowledge of thyroid function in many common illnesses is made available. Edna thought at the start that if she could just help one person it would be worth it, and she soon learned that she had helped many, many more than that – and will continue to help so many more in the future.

Edna’s health had declined in recent months and she was not getting to the British Library as much as she used to, but she continued adding to the website from a backlog of copied articles. She said “I worship The British Library and I feel I have this queue of long-dead doctors and physicians looking over my shoulder encouraging me,” and “This is what I have built my new life around – before all this happened I was a singer and a psychotherapist, I just can’t believe how much things have changed.”

Edna will be greatly missed, but her work lives on. I was fortunate enough to have met Edna and we have corresponded since. I first met her at Dr Skinner’s original IOP Hearing in London. Everybody found her to be a warm, kind, funny person who was totally dedicated to thyroid research and to make this available to all who will read it. I know that without her research, Thyroid Patient Advocacy would not be where we are today.

Edna and her work has been an inspiration to me personally. Thank you dear Edna. Details of the funeral will be posted as soon as possible.

Our condolences have been passed to Kieron Deahl, a very close and dear friend of Edna’s.

extracts in date order from 1874 - 1974
(less than 10% of original manuscript to comply with copyright restrictions)


1874 On a Cretinoid State supervening in Adult Life In Women. by Sir William W. Gull, Bart., M.D. Read October 24, 1873 Trans Clin Soc London 1874,7:180
p. 180
.... Mrs B., after the cessation of the catmenial period, became insensibly more and more languid, with general increase of bulk. This change went on year to year, her face altering from oval to round, much like the full moon at rising. With a complexion soft and fair the skin presenting a peculiarly smooth and fine texture was almost porcelainous in aspect, the cheeks tinted of a delicate rose-purple, the cellular tissue under the eyes being loose and folded, and that under the jaws and in the neck becoming heavy, thickened, and folded. The lips large and of a rose-purple, alae nasi thick, cornea and pupil of the eye normal but the distance between the eyes appearing disproportionately wide, and the rest of the nose depressed, giving the whole face a flattened broad character. The hair flaxen and soft, the whole expression of the face remarkably placid. The tongue broad and thick, voice guttural, and the pronunciation as if the tongue were too large for the mouth (cretinoid). The hands peculiarly broad and thick, spade- like, as if the whole textures were infiltrated. The integuments of the chest and abdomen loaded with subcutaneous fat. The upper and lower extremities were also large and fat, with slight oedema over the tibia, but this not distinct, and pitting doubtfully on pressure. Urine normal. Heart's action and sounds normal. Pulse. 72; breathing 18.

.... Had one not proof that such a patient had been previously fine-featured, well-formed, and active, it would be natural to suppose that it was an original defect such as is common in mild cretinism. In the patient whose condition I have given above, there had been a distinct change in the mental state. The mind, which had previously been active and inquisitive, assumed a gentle, placid indifference, corresponding to the muscular languor, but the intellect was unimpaired.

p. 182
.... I am not able to give any explanation of the cause which leads to the state I have described. It is unassociated with any visceral disease, and having begun appears to continue uninfluenced by remedies.

p. 183
.... 'The best suggestions I can make are to let events take their course very much, maintaining the strength by simple regimen and fresh air, and by the occasional or more or less continuous use of such remedies as quicken the peripheral venous circulation. Hot-air bath, or warm bath, frictions, &c., but the general good effect will, I think, be limited.'
In those about such a patient the whole morbid condition is likely to be attributed to indolent habits, and the apparent incapacity for exertion to be deemed dependent upon mere force of the will. No doubt extreme circumstances have a distinct influence upon these as upon other patients, but I believe the disinclination to mental or muscular activity is largely pathological.
There is certainly a degree of habitual and mental indifference, though this may under occasional circumstances be obviated, since the intellect seems to be unimpaired. It will be noticed that I have designated this state cretinoid. My remarks are rather tentative than dogmatical, my hope being that once the attention of the profession is called to these cases, our clinical knowledge of them will in proportion improve. That the state is substantive and definite one, no one will doubt who has had fair opportunity of observing it. And that it is allied to the cretin state would appear from the form of the features, the changes in the lips and tongue, the character of the hands, the alteration in the condition of locomotion, and the peculiarities, though slight, of the mental state; for, although the mind may be clear and the intellect unimpaired, the temper is changed. (also in: A Collection of the Published Writings of W. W. Gull ... Edited and arranged by T. D. Acland. 1894, 1896. ON A CRETINOID STATE SUPERVENING IN ADULT LIFE IN WOMEN p 315 -331)

1877 'On Myxoedema, A Term proposed to be applied to an essential condition in the "Cretinoid" Affection occasionally observed in Middle-Aged Women' by Sir William M Ord F.R.C.P. Medico-Chirurgical Transactions


P 58
.... She had first been taken ill, been very anxious in connection with the fatal illness of her husband. The first signs of illness were fits of shivering during her work. These were followed by the passage of bloody urine, as she believes, on several occasions. Then her hand became "dead", to use her own expression, when she used her needles; a great addition to her trouble, as she had to work very hard to support herself and her helpless husband. Later on she became "weak-headed," would be stupefied by a glass of beer at luncheon, experienced a general loss of muscular power, and was always falling asleep. After that she had constant pain and weakness in the back, so that she began to stoop considerably; her speech became slow and difficult, and a gradual swelling of the skin of the whole body set in; the skin of the face, and particularly of the eyelids, becoming thick, semi-transparent, and waxy. When first seen she exhibited in a very marked form the character of skin described by Sir William Gull. The face was generally pale, but she had the delicate blush on the cheeks. The eyelids, the lower in particular, were swollen and ridged, so as almost to hide the eyeball, and at the same time to hang down flaccidly on the cheek; they were remarkably translucent, and had somewhat the look of the eyelids in acute Bright's disease. But they were wrinkled on the surface instead of being smooth, and did not pit on being squeezed between the thumb and forefinger. The nose was swollen, broadened and flattened, the nostrils being widely expanded; the lips were swollen, expressionless, and pressed together, the mouth being a simple horizontal slit, opening but slightly in the vertical, more freely than usual in the transverse direction. The skin was again swollen into folds on the sides of the face and below the chin. The hands were swollen, the fingers looking very clumsy, and much limited in range of flexion and extension; very fairly describable as "spade-like."
The skin over the whole body was singularly dry. On the limbs and trunk it was harsh and rough to the touch; the hairs were feebly developed, and no trace of fatty secretion could be found. The skin was everywhere sensitive, but the limit of confusion in tactile discrimination was everywhere wider than the average. The same sort of swelling observed in the skin was visible in the fauces.
Her mode of speaking was very characteristic The voice was not harsh or hissing, but dull, leaden, and without intonation, reminding one to some extent of the voice in an early stage of quinsey. When about to speak she closed her lips throwing the under one forward, made a movement of swallowing, and then with much widened mouth commenced inhalation, at the same time expelling air explosively through the nose. The swallowing appeared to be necessary to move the soft palate. The speech was slow and measured. It was noticeable that whatever she did was done slowly and after delay. With the exception of some dimness of sight and the slight deficiency of tactile sensation her senses seemed perfect. But there was a marked slowness of perception, and a marked slowness of response of muscles to voluntary or reflex nerve-impulse. She stated that she could not act or think quickly, that her thoughts would only come slowly; that where any operation, such as dressing, took her half and hour formerly, it now took her two hours, so that she was perpetually behindhand with her work. Although her temper was placid, this was a constant source of distress to her. She could walk only very slowly, and the knees often gave way suddenly. She was consequently very nervous when out of doors, and was always expecting that people would run against her, she being unable to get out of the way; in fact, she was subject to a sort of waking nightmare. She very often had headache, and felt always tired, so that her life was utterly wretched. For some time she felt a strange taste in her mouth, which seemed to affect all food; it was partly sour, partly like the taste of blood. She often noticed a foul smell (as of bad breath) in her nostrils. The appetite was bad. The tongue was large and clean, not marked by the teeth, although too large for the mouth. The heart was feeble in its action, and not hypertrophied; there were no murmurs, and no important change of accents in the sounds. The breath was short on exertion or excitement, but not at other times, and there was no orthopnoea. The liver and spleen were not decidedly enlarged, but were somewhat tender, and undoubtedly firmer to the touch than normal. There was apparently a good deal of subcutaneous fat in all parts of the body, particularly in the neck, above the clavicle; and the thyroid body could not be felt. The blood examined under the microscope appeared healthy.

..... In January 1877, her state had undergone much change.
The complexion was pale yellow, and in the flush on the cheek were many enlarged vessels. With the occurrence of ordinary anasarca there was some abatement of the old nervous symptoms. She put out her tongue, spoke, and moved more quickly. The dryness of the skin was as marked as ever; but under any excitement she broke into excessive though short-lived perspirations. The skin of the body and limbs was shining, and exhibited flat smooth spaces, alternating with wrinkles and furrows. She "had lost that dreadful sinking in her inside," but was easily put out of breath, and could not lie down with comfort. The heart was decidedly enlarged; the first sound at the impulse was reduplicated, and so was the second sound at the base, between aorta and pulmonary artery. The second sound was greatly accentuated over the aorta. The arteries were everywhere hard and tense, and the right radial was dilated and irregular in form, as though from atheroma. Tracings were taken of the left radial, obtained with difficulty on account of the toughness of the skin, and obscured by irregular respiratory and muscular movements.

.... the post mortem examination .... one or two important points
.... 1. There was oedema of the skin generally; but the cut surfaces yielded less fluid than their appearance would promise. 2. There was much serous effusion in the pleurae, pericardium, and peritoneum.

3. The heart was of large size, weighing sixteen and a half ounces; the left ventricle hypertrophied, the wall being an inch thick; valves practically healthy.
4. The arteries were everywhere thickened, the larger ones atheromatous.
5. The cortical substance of both kidneys was much wasted and granular both on surface and on section. The renal arteries were thickened and atheromatous; and there was thickening of their outer coats.

6. There was a firm, almost solid oedema in many parts, e.g. in heart, sort palate, larynx, stomach, and neck of bladder. 7. The brain showed very considerable degeneration of the larger arteries.

1885 'The Brown Lectures' Victor Horsley British Medical Journal Jan 17th, 1885

... it comes about that I am prepared, in my first two lectures, to support the dictum (first completely enunciated by my friend, Dr. Felix Semon) that cretinism, congenital or acquired myxoedema, and cachexia strumipriva, are merely phases of one and the same state, and due to the same cause, namely, arrest of the function of the thyroid gland. I have artificially produced myxoedema in the monkey, and therefore hope to show you, in the following lectures, that the evidence in favour of the foregoing dictum rests on a sound basis of experimental fact.

... Various have been the surmises as to the function of the thyroid gland, it is not a little surprising that, although arrest of it had been vaguely known for hundreds of years to be connected with the cretinous state it was not until eighteen months ago, that it was suspected to be of serious importance to the animal economy.
The extraordinary condition, known as cachexia strumipriva, into which patients relapsed, in whom the operation of extirpation of goitres had been performed, was first discovered and published by the Swiss surgeons, Reverdin (quoted by Kocher; see footnote, p. 274) and Kocher (Archiv für Klin. Chirugie, Band xxix, p. 254, 1883); and the pressing need of settling the practical question of the justifiability of this surgical procedure has led to new discoveries in the relation of the thyroid body to the general nutrition of animals.

...Two further distinct views respecting the functions of the thyroid gland have been advanced by different writers, arguing from different points of view; first that it was a regulator of the cerebral circulation; and, secondly, that it secreted something necessary to the perfect nutrition of the brain. The first of these was originally advanced by Mr. Simon, but is generally attributed to Liebermeister and Guyon, and rested partly on the anatomical relationship which the gland bears to the carotid arteries in the human being; it also found support in the exceedingly elaborate researches of Mr. Simon, who found that, in all vertebrates which he examined, it was in close relation to the cerebral arteries. Guyon, relying on the fact that the pulsation of the carotidean branches disappears on prolonged effort, believed that this was beneficial to the central nervous system, by diminishing the flow of blood in those parts where venous stasis of course was already occurring from the prolongation of the effort; and considered it to be effected by the pressure of the thyroid gland on the common carotid artery, such pressure being produced by the contraction of the neck-muscles upon it. The physiological fact of the diminished pulsation in the carotid arteries anyone can at once confirm by experiment, but the explanation given above must be criticised by means of experiment in persons of animals deprived of their thyroid gland.

... So much for what was known and surmised up to 1883. I shall now proceed to lay before you evidence that this highly vascular mucin-excreting gland has a far wider relation to our general health than is even suggested in the foregoing theories.
Effects of excision. This brief retrospect of our knowledge up to last year will serve as an introduction to the next question, namely, what happens if you remove the thyroid body completely.
Kocher (loc. cit.) has shown that, under these circumstances, the human being becomes a cretin. Schiff (Revue Medicale de la Swisse Romande, February and August 1884), Wagner (Wiener Medicin. Blatter, 1884, Nos. 25 and 30, and the Italian experimenters, Sanquirico and Canalis (Archivio per le Science Mediche, vol. viii, Fascic. 2, Turin, 1884), have shown that dogs exhibit great nerve-disturbance, become idiotic, and die comatose; while I think I shall be able to demonstrate, from my observations during the last three months, that this operation produces, in monkeys, the disease first accurately described by Dr. Ord (Medico-Chirurgical Transactions), and called by him myxoedema. I shall afterwards attempt to show that this is only a phase of a loss of nutrition determined by the destruction of the thyroid gland, and, like cretinism, is the effect of some as yet undetermined law.

... The steps of the operation obviously had to be conducted so as to ensure healing by the first intention, and the avoidance of injury to, or irritation of, nerves; therefore it was performed under strict antiseptic precautions, and in the following way, the animal being under ether.

... Schiff's first series of experiments was performed septically; the wound was often not healed at the death of the animal, so that they cannot be adopted as trustworthy; but his second series, he states, was performed antiseptically, and although the duration of healing is not mentioned, I think we may assume that it was rapid; and it is these experiments that I shall quote.

... The phenomena which follow thyroidectomy in monkeys are very striking, and may be summarised as follows. At a variable period after the operation, but averaging about five days, the animal is found to have lost its appetite for a day or two, and, on closer examination, to exhibit slight fibrillar tremor in the muscles, of the face and hands and feet more especially. These tremors disappear at once on voluntary effort. At the same time, the animal is noticed to be growing pale and thin, in spite of the appetite returning quickly, with great increase, rapidly the tremors increase, affect all muscles of the body without exception; the animal becomes languid, paretic in its movements, and imbecile. Then puffiness of the eyelids and swelling of the abdomen follow, with increasing habitude. During these last stages, the temperature, gradually falling, becomes subnormal; and then the tremors gradually disappear as they came. Meanwhile, the pallor of the skin becomes intense; and, leucocytosis having been well marked, oligaemia follows, and the animal dies perfectly comatose in a variable period, but usually about five or seven weeks after the operation.

... This constant tremor is soon replaced, or rather is added to, by a series of powerful clonic spasms, so that a tracing (fig. 4) now shows large waves indicating massive movements of the trunk and limbs.
... I shall refer to the large waves as paroxysms, since you can see by this tracing that the intervals between them are often very considerable, namely, half a second or more. This paroxysmal stage usually appears about the second or third day after the tremors were first noted; but they rapidly (in twenty four hours) completely shape the curve in the way just indicated, which it preserves on the average for about twenty days. This stage of the tremors may be so violent as to deserve the term convulsive; but I have never witnessed true tetanus in the monkey as it occurs in the dog, nor have I ever seen the spasms produce pain, as in the latter animal.

... It would require much more minute analysis than I have been able to give the time for, to elucidate the origin of these tremors; but a very cursory observation shows the subject to be one of immense importance, as tending to explain, not the pathology of occasional fits of trembling, such as a rigor, etc., but, what is of infinitely more importance, the causation of a constant tremor, such as in paralysis agitans.

... Those familiar with paralysis agitans would have seen many similarities to it in these tremors; and, in connection with them, I may now mention that, although so-called voluntary effort abolished the tremors at their onset, it, if anything, increased them in the later stages.

... The condition of oligaemia can be recognised with the naked eye. In daily observations, one saw the animals becoming paler, until the equilibrium point referred to was reached, and when the drop of blood was drawn for the cytometric observations, it could be seen to be thinner than normal. At the same time, it clotted with difficulty and slowly, but when it did, it formed a well marked buffy coat.

... Possibly, the mere rapidity of death may seem to some the most striking result, considering the hitherto undreamed of importance of the thyroid gland; but, although the post mortem appearances about to be described my seem inadequate, it must not be forgotten that the perversion of nutrition indicated thereby, is really profound, and is the result of a small but constantly acting force.

'The Brown Lectures (II)' Victor Horsley British Medical Journal Jan 17th, 1885

... Cretinism, as is well known, has been attributed to every cause except destruction of the thyroid. Chalky water, damp close air, miasma, insufficient food etc., and hereditary influence, have all been credited with the power of causing the imbecile condition which is so familiar to everyone. So strongly prevalent was this idea, that the Commission (Rapport) instituted in 1845 by the Pidmontese Government came to the conclusion that cretinism as goitre were "essentially distinct", and that "their frequent coexistence in the same locality is due to a simple coincidence." First, it was ably urged by Fodéré (Traité du Goître et Crétísme, Paris an. iii) that cretinism owes it's origin to the same remote cause as goitre; and both Tourdes (Gazette Hebdomad) tome I, p. 784 - a review of his work) and himself saw in the hereditary of cretinism and goitre a strong proof of this position.

... No one could be prepared to formulate a theory of the full pathology of the conditions I have been describing in the present state of the subject, but certain facts are so striking, that it will, perhaps, aid in further investigation if they are enumerated in a tabular form - first the anatomical, and then the physiological.
1. The thyroid gland appears to consist of two distinct portions; (a) glandular, consisting of highly vascular acini, which excrete into their interior a mucoid substance, this substance, or something closely similar, being found in the lymph-vessels of the gland: mucin-excreting function? (b) highly vascular lymphoid nodule: haematogenous function.
2. Excision of the gland is followed, according to my experiments, by an increase in the amount of mucin in the tissues which normally possess it, by a retrograde histological change, by an increase in the activity of the glands which normally secrete it, and (what is still more striking) by the assumption of the muciparous function by an abnormal presence of mucin

by a gland which normally produces none, or very little, mucin - by the partoid gland.
3. Excision of the gland is followed by profound changes in the blood, namely, a diminution in the number of corpuscles, preceded, as regards the white elements, by a temporary increase in their number, by an alteration in their coagulability and albumins, and by an abnormal presence of mucin. (The latter facts were discovered in my specimens by Dr. W. D. Halliburton.)
4. Excision of the gland is followed by nerve-symptoms, indicating changes in the lowest motor centres, such providing imbecility, and, ultimately, death in the comatose state.

1887 Medical Society of London Monday, November 28th, 1887 J. Hughlings Jackson, M.D., F.R.S., President, in the Chair. Clinical Evening British Medical Journal

Case of Myxoedema in a Male.- Dr SAVILL showed this case. The patient was a man only 30 years of age, and the main feature of his case was the complete loss of memory, so that very little could be learned of his previous history. He presented the expressionless aspect, scanty hair, slow and feeble movements, great susceptibility to cold, and subnormal temperature characteristic of the disease.....
There was no paralysis, and common sensation, though much delayed, was otherwise good. The power of comprehension and reasoning were fair, but the volitional power was feeble and the memory almost completely lost. He was not emotional or melancholic, and had no definite delusions. The pulse tracing showed a low tension. There was no enlargement of the thyroid gland, and the abdominal and thoracic viscera were normal.....
Dr Savill pointed out that the disease was sufficiently rare in the male to make this example of interest. He was acquainted with only 19 recorded cases. About 13.5 per cent. only of the published cases were males. Slowness of all mental processes was a usual condition in the disease. He believed that some of the recorded cases had shown signs of insanity in the later stages, but he was not aware that loss of memory had been so marked and isolated a feature as it was in this case.

1888 Tansactions Clinical Society London




THE Sub-Committee for the examination of the morbid anatomy of the disease decided at its first meeting :
(a) To summarise the naked-eye appearances found in such fatal cases as were seen by the Sub-Committee, or reported by others.
(b) To examine microscopically the tissues from as many subjects as should be available. Thirty-one fatal cases have come under the notice of the Sub-Committee, but in several of these no autopsy was made. The tissues and organs have been examined microscopically in 20 cases, but some cases have been examined much more completely than others.

Naked-eye appearances.
The naked-eye morbid appearances have been analysed by the Sub-Committee in 15 cases. Some changes were obviously unimportant and accidental, but some demand special and detailed notice.
With two exceptions the subcutaneous fat was abundant, and often the fat elsewhere was markedly in excess. In one instance the subcutaneous tissue was described as " gelatinous," and in one as " oedematous," but no unusual physical appearances were noted in the remainder. In one case the body was emaciated, and in another there was no excess about the difference supplementing thyroid has made to your patients.


of fat, although there hact been a general swelling at one period of the disease.
In only 2 cases would it appear that special note had been made of the supra-clavicular regions, and in these no excess of fat was observed.
Anasarca to a slight degree was not uncommon, though in no instace was it excessive. On the other hand, passive effusions into the serous cavities, sometimes to a considerable amount, were frequently noted. In a few cases there was marked excess of the subarachnoid fluid.
The thyroid gland was in every case reduced in size, and is described variously as pale, yellowish white, or buff-coloured, firm, tough and indurated, fibrous and structureless. In two or three cases the affection was more advanced in one lobe than

in the other .
In about one third of the cases the kidneys were described as normal. In the remainder there was more or less interstitial change, in some not greater than might be anticipated in persons of adult or advanced life. In one case, described by Dr. Ord (' Clin. Soc. Trans., vol. xiii), " the kidneys were of average size, and of extraordinary firmness, giving to the touch a sensation like that of india rubber. The surface was smooth, the capsules not adherent."
The left ventricle of the heart was hypertrophied in a third of the cases, and in all these the kidneys were g-ranular. In one instance the muscular substance of the heart was fatty, and ol one " gelatinous."
In more than half the cases there was atheroma of the large arteries, but in only rare instances was the condition advanced. Arterial degeneration, indeed, does not appear to exist to any unusual extent, at any rate in the larger vessels. VARIOUS.
In a few instances there was tubercnlar disease


of organs, and in still fewer cases cirrhosis of the liver was noted.
Microscopical examination.
SKIN (8) .*
In 2 the sections were found normal. In one of these cases (Atkinson's, not published in the tables) the disease was in an early stage (compare description of thyroid). Very marked alterations were seen in the majority of cases, and the changes were very similar, whatever the region of the body examined. InI the coiled tubes of the sweat-glands the epithelium becomes swollen, then nuclear proliferation takes place, and the lumen of the tubes becomes obliterated. In the later stages a nucleated fibrous growth is seen in the tissue outside the tubes. The change in the sebaceous glands resembles very closely that in the sudoriparous glands, and is probably identical with it. The sebaceous glands are represented by irregular masses of nuclei, and sometimes there is cellular accumulation in the tissues outside them. These cellular accumulations in some cases seem to undergo partial or complete absorption. Around the hair-follicles a nuclear growth is apt to develop, and external to this growth all abundant nucleated fibrons tissue is sometimes seen.

In one case (39 in the tables) there appeared to be thickening of the perineurium of the nerve-tubes in the subcutaneous tissue, and in the same case the bundles of fibrous tissue in the corium were widely separated, an appearance which might be due to oedema. The same open-textured condition was seen in a section of lower eyelid from another case.
In one or two cases sections of the lower lip were examined, but nothing abnormal was detected, except in one instance an abundance of fat in the submucosa.

* The numher in brackets iudicates the number of cases in which the organ or tissue was examined. 38

The uvula in one case presented an appearance which might be termed oedematous, but in the remaining. 4 cases both it and the soft palate were healthy.
The submaxillary gland was quite normal in one case. In the other very marked changes were found. The description is given below in connection with the thyroid gland (case of Dr. Hale White).
The kidneys often exhibited ordinary interstitial change, of varying degree. In a half or more of the cases nothing abnormal was discovered.
Early tubercle was found in the cortical and medullary parts in one instance (No.42 in the tables) .In the remaining 4 cases no lesion was present.
LIVER (15) .
In cases the liver was found to present pathological change, and 3 of these had been described by Dr. Ord. Of these 3 cases, one showed two thick fibrous tracts ill the section examined by the Sub-Committee, but the liver-cells themselves were healthy.In the second (95 in the tables) there was a little thickening about the portal vessels, but the liver was otherwise healthy. In the third all excess of pigment was seen in the hepatic cells, and some of the cells were atrophied ; In addition, the fibrous septa were swollen and hyaline looking.
Of the remaining 4 cases, early cirrhosis was found in 2, fatty change with early tubercle in one, ancl granular pigment in the hepatic cells in one.
HEART (9).
In only 3 cases was there ally change of a pathological nature. The most marked alteration was seen in a section taken from one of Dr. Ord's cases (05 in the tables). The muscle-nuclei were very abundant, and many of them were voluminous. In addition, there were seen, copiously scattered between the fibres themselves, numerous nuclei,


some round and some oval. In Case 42 in the tables an increase in the interstitial nuclei was seen, and this may be looked upon as an early instance of interstitial myocarditis, of which Dr. Ord's case was all undoubted examp1e. In the third case there was simple pigmentary excess in the muscular fibres.

In 2 cases there was early catarrhal pneumonia and emphysema, the bronchial septa being thickened in one, and the vesicular walls slightly thickened in the other. In the third case there were miliary tubercles and anthracosis. BRAIN (5)
In a section taken from a frontal lobe, a cellular accumulation was present around the vessels, which was probably tubercular. The case is 42 in the tables, and the patient died from general tuberculosis.

The cerebellum was examined twice, the pons twice, and the medulla oblongata four times, but nothing abnormal was discovered- Other parts of the intracranial contents, including the pituitary body, were a1so examined in solitary instances, but the Sub-Committee failed to discover any patho- logical change.
The cervical and lumbar regions in one case (Dr. Ord's, No.95) were examined, but with the exception of some thick;ening of the septa, especially in the posterior colllmlls, the sections were healthy. In another case of Dr. Ord's there was some thickening of the pia mater .
In 5 cases fibrosis was present in the superior -cervical ganglion, and in 3 others there was probable interstitial change. VARIOUS.
The lymphatic glands, tongue, spleen, pancreas, uterus, intestines, and aorta have been occasionally examinec1. Early tubercular infiltration was found in the small and large intestine in one case, and some atheroma of the aorta in another case. With
these exceptions, the parts above mentioned were found healthy.
In every instance the thyroid gland exhibited striking and uniform disease, exactly in accord with Dr. Ord's original case.* In view of the importance of this observation, as it now appears, it is worth while to transcribe the record of each examination made by the Sub-Committee.
CASE 1 (Johnstone, Dr. Ord) .-Nearly the whole thyroid is converted into delicate fibrous tissue, which is here and there infiltrated with clumps of cells, which evidently replace the gland vesicles. The adventitia of the arteries is swollen. This is Dr. Ord's original case, and the description here given agrees with that stated in the paper. See footnote.
CASE 2 (Collings, Dr. Ord) .-The thyroid is in great part converted into pure fibre containing scattered masses of round- cells. In several parts these nuclei are invading and infiltrating the vesicles, which appear in other respects fairly healthy. There are other lobules which, while themselves almost natural, yet exhibit in all earlier stage the same change, the walls of the vesicles showing a round-celled growth.
From this specimen it is inferred that the disense in the gland commences as a small cell-infiltration of tho walls of the vesicles, that the next stage is one of gradual disappearanco of tho vesicles with substitution of nuclei, and that the last is the formation of fibrous tissue.
CASE 3 (Lockwood, Dr. Ord) .-Olltlines of the lobules seen ill parts as small islets of round-cells. * " In the thyroid gland the alveoli are compressed, and mostly nnnihilated by a growth of the kind whieh can here be seen in great perfection around the vessels " (Medico-Chirurgical Transactions, vol. lxi, p. 67).

THYROID GLAND ( continued)
Much fibroid tissue replacing the proper thyroid structure.
CASE 4 (McClean, Dr. Goodhart) The thyroid shows complete fibrous change. The glandular structure is altogether absent. The walls of the blood-vessels are much thickened, and here and there are groups of small stained cells, which appear to be remnants of vesicles.
CASE 5 (Arthur A-, Dr. Goodhart).- The thyroid structure is nnrecognisable, the gland substance being entirely replaced by a waxy fibrous tissue. In one or two places in the middle of this are clllsters of nuclei, no doubt relics of the original vesicular tissue in a diseased state.
CASE 6 (Dr. Hale White).-Thyroid. Vesicles filled with large round-cells apparently the nuclei of the epithelium. Much interstitial fibrous growth. Hyaline thickening around the vessels.
This specimen differs from the previous ones in the presence of epithelial accumulation in the vesicles.
To this may be added the following description of the examination of the submaxillary gland of the same patient :-Under a low power there is a confused appearance of gland acini, the ducts remaining distinct. The fibrous stroma is generally thick, while tracks of fibrous tissue appear iu places. Under a higher power the morbid changes are found to be epithelial accumulation in the gland acini, interstitial fibrous invasion, and cell-infiltration ; the latter is much less than that seen in the thyroid.
CASE 7 (S. K-, Mr. Hopkins).-Very advanced fibrous change in the thyroid ,with scanty islanc1s of round-cell infiltration iu

which the outlines of the vesicles are here and there preserved. One large cyst filled with colloid material, around which there is a similar round-celled infiltration to that seen in prevIous cases.

THYROID GLAND ( continued)
CASE 8 (Dr. Atkinson) .-Much fibrous change in the thyroid, with groups of richer cell-infiltration than in any of the preceding- specimens, and from which it may be inferred that the disease is in an earlier and more active stage. The submaxillary gland in this case was healthy.
cASE 9 (Mr. Barling) .-The sections examined had been cut from two separate parts of the gland. The one fairly healthy in places, in others much small cell-infiltration. In the other a similar small cell-infiltratioll with fibrosis, atrophy, and compression of the vesicles.
CASE 10 (Dr. E. White) .-The thyroid in a state of extreme fibrosis with clusters of nuclei and thickened vessels as in other cases.
Mr. Victor Horsley has forwrded to the sub Committee a report on the histological appearances seen in the thyroid gland in two cases formerly under the care of Mr. Lunn, of the Marylebone-Infirmary, and in a case of Dr. Savage, of Bethlem Hospital.
CASE 11. Edward D-.-(a) Stroma, including capsule, greatly increased; overgrowth of fibrous elements as well as corpuscles- Everywhere it is greatly infiltratcd yvith leucocytes. In many places these are collected into masses, but for the most part they are distributed around the remnants of the lobules of the gland, penetrating between the relics of the alveoli, and apparently overwhelming these latter. In some instances only a few scattered and enlarged epithelial cells, buried in leucocytes, indicate the former existence of a glandillar lobule.
(b) Gland tissue.-The alveoli nowhere contain mucinogenous substance. Very rarely is a little debris (? albuminous) seen here aud there. Atropbic. The epithelium is " proliferating " for the most part. The individllal corpuscles are much overgrown, penetrate into the lumen by pointed


THYROID GLAND (continued).
processes, and in many instances completely fill the cavity of the alvrolus by their bulk (possibly also the alveolus is compressed by the leucocytes, and certain it is that the alveoli are very much diminished in size) .Very rarely is a small alveolus seen with the characteristic cubical epithelium.
(c) Vessels.-(I) Blood, all notably congested.
(2) Lymphatic, empty.
CASE 12. George M- (56 in Tables).-(a) Stroma practically composes the whole gland. It is exceedingly densely fibrous. Very few corpuscles are to be seen.
(b) Gland tissue.-Here and there in the stroma, at distances from .5 to 1 cm., are to be seen minute nodules about 1 to 2 mm. in diameter, which stain darkly. On microscopic examination these are found to be composed of leucocytes, among which are a few degenerated and shrivelled epithelial cor- puscles.
(c) Vessels.-(l) Blood, partly filled here and there, majority empty. (2) Lymphatic, empty.
CASE 13. S. D-.-(a) Stroma everywhere represented as dense fibrous tissue, in which were scattered at distances varying from a few (3 to 5) mm. to 1 cm. minute foci or collections of leucocytes.
(b) Gland tis,sue.-The sole remains of the thyroid gland tissue were a very few epithelial corpuscles, which were shrunken and degenerated, buried in the collections of leucocytes seen in the stroma.
(c) Vessels.-The stroma was fairly vascular, the walls of the vessels being normal.

Remarks. -From the above account it would appear that the only constant pathological change exists in the thyroid gland. The lesion, moreover, was in every instance of the same nature. The only case known to us which is in any way an exception is the one recorded by Dr. Gulliver in the 'Tranaactions of the Pathological Society of London,' vol.


xxxvii, p. 511. The case is one of carcinoma of the thyroid gland in myxoedema. It is not expressly stated in the report that the thyroid tissue was anywhere in a state of atrophy, but the argument of the author is that carcinoma " invades by preference atrophic or functionally inert organs."
The nature of the lesion of the thyroid gland has already been described in each case examined by the Sub-Committee ; but a brief general account of the pathological process may be of service. The morbid condition seems to begin as a small-celled iufiltratioll of the walls of the vesicles, and this is accompanied or Soon followed by epithelial proliferation in the vesicles themselves.

In a more advanced stage the gland becomes converted into a delicate fibrous tissue in which clumps of small rouud-cJls, clearly the remains of the vesicles are scattered. In the last stage the gland structure is replaced by fibrous tissue, in which small islets of round-cells are sparsely placed.
It may be observed here that in most of the fatal cases the thyroid gland exhibited very advanced and general structural

alteration, but that in a few the pathological change was comparatively in all early stage. In one indeed (Mr. Barling's), the glandular elements in some places showed very little departure from the normal state; but in other sections the characteristic morbid change was very obvious.* It would appear therefore that death may ensue before the affection of the thyroid gland becomes advanced, and also before the entire gland becomes invaded.

The various changes which have already been mentioned as occurring in thc organs and tissues have not been found with sufficient constancy to lead the Sub-Committee to suppose that they could have any causal relation ,vith the disease; but some have been met with so often that they probably occur as secondary changes at some stage of the a:ffectioll in the great majority, if not ill all cases. As regards the skin, we have found very frequently the nuclear hyperplasia and the deve-

* The patient was a woman of seventy-six. under the care 0£ Dr. Suckling. Death resulted from asthenia, not from any accideutal complication (see' Lancet,'
1885, vol. i, p. 889, and 1886, vol. ii, p 970).

lopment of connective tissue which Dr. Ord describes in his original paper, and these occur maiuly in the neighbouhood of the sudoriparous and sebaceous glands, and around the hair-follicles.In a few instances the Sub-Committee has noticed an unusual interval between the bundles of fibrous tissue in the corium. This open-textured condition is, however, quite exceptional, and it differs in no respect from what is seen in ordinary oedema.
It may be mentioned here that, unfortunately, we had very few complete sections of the lower eyelid, and hence we are not in a position to offer a satisfactory explanation of the swelling so often seen in this situation during life. In one case, however, the same open-textured appearance, to which allusion has just been made, was distinctly present. The increase in bulk so frequent in myxoedema is due to an overgrowth of the subcutaneous fat, as is clearly shown by the results of post- mortem examination.The loss of hair, the absence or diminution of perspiration, and of the secretion of the sebaceous glands, may reasonably be ascribed to the anatomical lesions which are so often seen in the skin.
Interstitial changes in the internal organs have not infrequently been found, as will appear from the detailed account already given. These changes are most common in the kidney, and they presented the ordinary features of interstitial nephritis, though very often of no great intensity. The sub-Committee, however, is of opinion that such alterations, so freqllently found as they are in persons of adult or advanced life dying from various causes, cannot be considered peculiar to myxoedema. The liver was healthy in rather more than half the cases, and when alterations were present they were usually either partial or slight. Indeed, in two or three instances there is still some doubt whether the appearances were not within the limits of the normal state.
In two cases out of the nine examined the heart presented changes of the same nature, one exhibiting all early stage, aud one a comparatively advanced stage of interstitial myocarditis. It may here be observed that in neither of them was

there any history of syphilis. In the remaining two thirds of the cases the organ was healthy.
The changes in the sympathetic, though frequent, are not constant, and for this reason, and also on the ground that the superior cervical ganglion was usually the only part examined, the Sub-Committee feel that they are not justified in ascribing to such changes ally importance from all etiological point of vIew.
The thickening of the adventitia of the arterioles, originally described by Dr. Ord, has been very often seen by us, but in only one instance was there vidence of anyovergrowth of the perineuriu of the cutaneos nerves.
'l'he conclusions of the Su-Committee are as follows :
(1) That myxoedema is dependent On a destructive affection of the thyroid gland.
(2) That changes in he skin mainly in and around the sebaceous and sudoriparous glands and in the neighbourhood of the hair-follicles, are frequent, and prbbably in the later stages of the disease, constant. The morbid process in the skin is not passive or atrophic, but of an irritative character, resembling the inflammatory process.*
(3) That interstitial change does not occur in the organs as a generalised condition, though it occasionally is present to a varying degree in the sympathetic, the kidneys, the liver, the heart, and the submaxillary gland.
* This view was clenrly expressed by Prof. Virchow in the Berliner klinische Wochenschrift on fcbruary 2nd, 1887.

1888 Transactions Clinical Society London

CONSIDERING, in the first place, the collection of symptoms to which the term Myxoedema has been applied, the Committee have to state that they believe myxmdema to be a distinctly marked and defined disease that, in the accepted phrase of the day, they regard it as a " clinical entity ." The general uniformity of the more prominent symptoms is, indeed, remarkable, allowing of ready recognition of the malady in any freshly encountered case by an observer who has seen one well pronounced case. For, as cretins resemble one another so that they might be taken to be members of one family, so also

do the subjects of myxmdema, most approximately in physiognomy, character of voice, and mode of speech. These points are in part indicated by the analysis of symptoms, but are even more strongly suggested by the personal observations of the Committee and others, although such observations are more capable of general statement than of numerical record. Symptoms.-The elaborate table of analysis of symptoms which forms the basis of the clinical part of this report, shows clearly that a considerable number of cases presenting what may be called the type-signs, as described by Sir William Gull and Dr. Ord, have been observed, aud that a large number of minor or accessory signs noted by those observers have been associated with them.

Under the head of type-signs the following may be enumerated: the marked increase in the general bulk of

the body; the firm swelling' of the skin, not pitting on pressure, inelastic, adherent to the parts beneath, and not affected by gravitation; the dryness and roughness of the skin, tending, with the swelling, to obliterate all lines of expression; the imperfect nutrition of the hairs, leading to their loss the local tumefaction of the skin and subcutaneous tissue noticed in various parts of the body, but most frequently in the supra-clavicular regions; the turgescence and infiltration of mucous membranes, leading, in the mouth, to an affection of the teeth homologous with that of the hairs just mentioned; the remarkable physiognomy; the slow, painful utterance, monotonous voice, and leathery quality of tone thereof, with curious nasal explosion at short intervals during
speaking; the slo\vness of thought and movement; the slowness of perception and response; the defect of memory; the frequent occurrence of mental disorders of an irritable and suspicious character, or of hebetude and somnolence alternating with excitability; the tendency to fall, giving to disorder of co-ordination; the existence of subnormal temperature of the body; the aggravation of all symptoms during low climatic temperatures and the diminution or apparent absence of the thyroid gland. Among the minor or accessory signs, may be quoted abnormal subjective sensations, belonging particularly to taste and smell ; occipital headache; marked alterations of temper; and a curious persistence of thought and action, overriding all attempts at interruption by friends or observers.
But the larger table adds much and most interesting information to the earlier observations, chiefly in respect of the accessory symptoms, and of possible causal relations. The wider experience allows of some primary classification of the altered mental states. It shows that delusions and halluci-nations occurred in nearly half the cases recorded, mainly when the disease was advanced; that insanity was noted in about the same proportion; that it took the form of acute or chronic mania, dementia, or melancholia, with a marked predominance of suspicion and self accusation. It will presently be seen in Mr. Horsley's report that tremors and contractures

have occurred in monkeys after extirpation of the thyroid body. Tremors and contracture affecting both hands and feet have been noticed as late phenomena in one case which has been for twelve years under observation, and also in others.
As regards the skin, the tables bring out the frequent occurrence of moles and warts, certainly not remarked in the first cases. The distribution of the swelling of the skin in the early stages of the disease appears to be far from uniform. In many cases, instead of being general, it is localised, the head and face being most frequently first affected, next the lower extremities; lastly the upper extremities.
Haemorrhages. -The state of the tissues in myxoedema would at first sight make it probable that, in the event of pregnancy, a far from uncommon occurrence, haemorrhage would occur after delivery. In the first case observed by Dr. Ord, as far back as 1864, severe haemorrhage occurred in three successive parturitions. But the clinical record indicates a much more general tendency to haemorrhages. Severe bleedings from nose, gums, teeth, and bowels have been noted. Recently a case has come under observation in which dangerous haemorrhage came from an exposed tooth pulp. And, when the history of more recent cases has been carefully investigated by the light of the information accumulated, haemorrhages appear to be much more common than was at first suspected.
History and antecedents.-In respect of the previous history and antecedents of the persons affected by the disease, it is obvious that an extended record would offer much information in amplification aud correction of the necessarily restricted information afforded by the sulall number of cases whereon the first identification was founded. At first it appeared probable that the disease affected women only, and women again in middle life, It appears now that men are affected, though in much smaller proportion than women, namely, one man to six women, and that the disease may start in early adolescence, or be delayed to old age, The probable identity of myxoedema


with the so-called sporadic cretinism observed in children will be considered later on. Causation.-The most careful consideration of the information bearing on the causation of myxoedema affords nothing of a decisive character. The patients come from all grades of society, and from no particular localities. It is true that a considerable number, viz. eleven cases, are reported from Lower Brittany; and it is worthy of remark that those districts of England in which goitre and sporadic cretinism most frequently present themselves do not, so far as appears, contribute any excess of cases of myxoedema.

Heredity certainly appears to play some part. There is evidence to show that the disease may affect several members of one family, and there is evidence also of transmission from father and mother to children, chiefly on the female side. But behind

heredity lies still the question of ultimate causation. It appears probable that neither syphilis nor alcohol are factors in the production of the disease. Tubercle is recorded in sufficient proportion to justify its recognition as a well-marked associate, if not a predisposing cause. Mental disturbance and neuroses have been shown to occupy a large part of the portraiture of the disease. They are also occasionally recorded as predecessors of the actual symptoms; but it is, at present, impossible to say whether, on the one hand, they are to be considered causes, or to be, on the other, relegated to the position of early symptoms. In a few cases the appearance of the symptoms of myxoedema has been preceded by exophthalmic goitre, the evidence on this point appearing to be pretty clear. Subsequently, a great reduction of the thyroicl body to a bulk below normal has been noted concurrently with the development of the signs of myxoedema. So far most of the observations on myxoedema have been made on well-pronounced cases of some years duration. As experience grows, there will arise the possibility of recognising cases in early periods, and of determining the existence, at such periods, of changes in the thyroid body. It is not too much to say that in this aspect all cases of exophthalmic goitre ought be followed with much care.


The fact that myxoedema has been observed much more frequently in women than in men, suggests, prima facie, that we may find some helpful indication from investigation of the state of the sexual organs. In the broadest view no such help is afforded. The disease affects unmarried and married women. There is no obvious influence of catamenial disturbances. Pregnancy occurs, aud runs its normal course, recurring. in fact after the establishment of the disease. The above broad statement does not, however, preclude the possibility that myxoedema may, in part, depend upon uterine disturbance. It is known that alterations in the vascularity of the thyroid are observed in connection with both menstruation and pregnancy; but in the male we have little information concerning the functional activity of the gland in relation to physiological processes elsewhere. It is possible that the more frequent occurrence of myxmdema in the female sex may depend on the fact that the thyroid gland being functionally more active than in the male, is thereby more apt to be attacked by destructive degenerative changes.

One case has certainly presented a remarkable variation of myxoedema in connection with pregnancy. The patient, after presenting the full physiognomy of myxoedema, became pregnant, whereupon all the swelling passed away, to return after the birth of a child.This succession of phenomena occurred three times during seven years. The observation bears upon a point of some interest, and, as regards pathological anatomy, Some importance. The swelling of myxoedema turns out to be a fluctuating condition in many cases. It varies under differences of temperatme, being greater in cold weather, less in warm. It appears to vary under treatment, and very often it diminishes as the patient approaches the end of the term of life. Then, often the skin, previously plump and distended, falls into wrinkles and coarse inelastic folds, is no longer adherent to the parts beneath, but nevertheless has recovered none of the characters of health. The great majority of cases of myxoedema hitherto reported have reached, when first recognised, a well-advanced stage, We may hope that in the near future the disease may be detected


in its beginnings, and to have the matter of -variations carefully studied, both as regards the frequency of this occurrence and the conditions accompanying the presence or subsidence of the general swelling .
Modes of dying.-Death usually results from, intercurrent maladies, chiefly pulmonary; but occasionally it would appear to be directly dependent on the disease itself, the patients succumbing to exhaustion, general or nervous.

Treatment,- In many cases of myxoedema, periods of improvement have been observed, and in one instance an actual recovery is alleged to have taken place. The conditions under which these favorable remissions occur in the natural course of the disease are very imperfectly understood, and it is probable that more extended knowledge in this respect will lead to a very material advance in the treatment of the disease. There is no doubt, however, that the maintenance of warmth in the surrounding atmosphere has a marked beneficial influence, and this suggests the importance of studying climatic conditions in the treatment of myxoedema. It has been found practically that the regular remo-val of patients during the winter to southern climates has caused amelioration in the symptoms. Professor Horsley is led to observe, from his experiments, that "exposure to cold determines an earlier appearance of the symptoms, warmth delaying the same " (p. 80) .
As regards drugs, there is no doubt that jaborandi and pilocarpin exert a beneficial influence in myxoedollla, mainly, it would appear, from their action on the skin.
Nitro-glycerine deserves a more extended trial, as it seems to have proved of decided service in a few recordecl cases.
The use of tonics, particularly of iron, quinine, and the hypophosphites, has been adopted with a certain amount of temporary success.
Pathology.-The pathology of myxoedema has been studied bya sub-Committee. This report has to be considered in two aspects. First, as regards evidence bearing on the causation of the disease. Second, as regards concomitant tissue-changes. Under the first head the conclusion of the sub-Committee is

that myxoedema is dependent on a destructive affection of the thyroid gland. The basis of this conclusion is set forth in detail by the sub-Committee. The thyroid gland appears to be generally diminished in size, to have lost its dull reddish tint, and to have become yello\vish or pale. In its structure a delicatte fibrous tissue has invaded and replaced the proper

glandular tissue. To use the words of the report, "The morbid condition seems to begin as a small-celled infiltration of the walls of the vesicles, and this is accompanied or soon followed by epithelial proliferation in the vesicles themselves. In a more advanced stage the gland becomes converted into a delicate fibrous tissue in which clumps of small round cells, clearly the remains of the vesicles, are scattered. In the last stage, the gland structure is replaced by fibrous tissue in which small islets of round cells are sparsely placed " (p. 44) .

It is obvious that the results of post-mortem observation regarding the state of the thyroid gland are much more decisive than observations made during life. The thickened state of the skin and subcutaneous tissues in the neck involves difficnlty in determining the size of the thyroid gland, Nevertheless, the whole series of observations tend to the belief that in myxoedema the gland, with rare exceptions, is diminished in size.

The accessory conditions have next to be considered. The report of the sub-Committee deals in an important way with the changes manifested in the skin.
"As regards the skin we have found very frequently the nuclear hyperplasia and the development of connective tissue which Dr. Ord describes in his original paper, and these changes occur mainly in the neighbourhood of the sudoriparous aud sebaceous glands, and around the hair-follicles. In a few instances the sub-Committee has noticed an unusual interval between the bundles of fibrous tissue in the corium. This open-textured condition is, however, quite exceptional, and it differs in no respect from what is seen in ordinary mdema " (p. 45) .

(Note by DR. ORD.- I venture to observe in relation to this paragraph that the appearances thus regarded as in no respect different from what is seen in ordinary mdema, were,


as far as sections of my own cases are concerned, derived from skin which did not present during. life or after death the conditions of ordinary oedema. During life the skiu was tough and resistant, and after death remained firm on section without exudation of fluid from the cut surfaces. It appears to me important to bear in mind the importance of interpreting the microscopic appearances, at least in part, by the light of the macroscopic appearances. I contend that the conjunction of the two indicates that whatever material filled the unusual interval between the bundles of fibrous tissue, was at least something different from serous fluid, and had something of a gelatinous consistence.)

The loss of hair, the absence or diminution of perspiration and of the secretion of the sebaceous glands, are ascribed by the sub-Committee to the anatomical lesions which are so often seen in the skin. In passing, it may be noted that the decay and falling out of the teeth bear similar relations to changes in the mucous membrane of the mouth. The increase of bulk of the body commonly observed in myxoemdema is attributed by the sub-Committee to an overgrowth of the sub-cutaneous fat. The overgro\vth of interstitial fibrous tissue, which Dr. Ord has recorded in his earlier cases, does not appear to have been found with anything like corresponding frequency in the sections of other cases subsequently examined by the sub- Committee. They are, in fact, regarded by the sub-Committee as being, to a large extent, such interstitial changes as might be expected in a certain proportion of persons dying in adult or adva,nced life.As regards the nature of these less constant interstitial changes, and of the more constant changes in the skin, the sub-Committee express the opinion that they resemble the inflammatory process.

This view has been also clearly stated by Professor Virchow, who has also expressed an opinion agreeing with the final conclusion of the sub-Committee, namely, of that interstitial change does not occur in the organs as a generalised condition, though it occasionally is present to a varying degree in the sympathetic, the kidneys, the liver, the heart, and the submaxillary gland " (p. 46) .

The sub-Committee does not recognise the existence of any important changes in the central organs of the nervous system, nor in any important proportion in the sympathetic. In final overview of the extremly careful investigations of the sub- Committee, it will be seen that they definitely recognise a destruction of the thyroid gland, in which its proper elements are replaced by a delicate fibrous tissue, as at least a constant condition in myxoedema, and presumably its direct cause; that no explanation of the origin of this condition is at present apparent; that the interstitial changes Commonly
observed -in the skin and with far less constancy in the viscera, appear to be of an irritative or inflammatory nature. Chemical analysis of human tissues.- In sequence of the Report of the Pathological sub-Committee, Dr. Halliburton's report on the chemistry of myxoedema must, as respects its first portion, be next considered. It will be remembered that, in Dr. Ord's first fully recorded case (H. J--), Dr. Cranstoun Charles, examining a large mass of skin, and comparing it with similar quantities of skin obtained from the bodies of persons not affected with myxoedema, had found a -very large excess of mucin in the skin of the myxoedematous patient. Dr. Halliburton has made an extensive series of observations on the percentage of mucin present in the skin and also in connective tissue, in tendons, in heart-tendons, and else\vhere. He also quotes the results of observations by Dr. Stevenson and Dr. Bernays. The results obtained by all three observers are in complete agreement one with the other.
The outcome of these observations is that the increase of mucin, as found by Dr. Charles in Dr. Ord's first case, has not been found in anything like so great an amount in subsequent cases. It is to be observed that Dr. Ord's first case presented, at the time of death, the full swelling' of myxoedema. As Dr. Halliburton remarks, with regard to his observations, the non- existence of the increase of mucin is in certain cases accounted for by the fact that the patients have not died while in the typical swollen stage, but in the subsequent atrophic period of the disease; again, in other cases, the subcutaneous connective

tissue has become replaced by


fat; and in other cases still, the analyses are to a great extent vitiated by the keeping of the specimens for long periods under alcohol before analysis.Dr. Halliburton points out that the source of mucin in the body is twofold. His remarks on this point are So full of suggestion that we transcribe them in extenso.
1. "It results from the degeneration of the protoplasm of epithelium cells, as in the goblet cells of mucous membranes, and the cells of the acini of mucous glands like the submaxillary. In the myxoedema of human beings this source of mucin has not been to any great extent investigated. The

most important analysis bearing on this point is the one analysis of the parotid gland which has been made, and which showed a distinct increase of mucin. This is interesting in connection with Prof. Horsley's experiments on monkeys, in which it was shown that in the myxoedema artificially produced in them, the cells of the parotid, which normally secrete clear saliva, secrete a viscid saliva; by the microscope the cells were found swollen by mucinogen, and by chemical analysis mucin was found to be greatly increased in amount.

2. "It forms a constituent part of the ground substance or stroma of connective tissue in which the cells and fibres are embedded. This substance is chemically a muco-albuminous material. One of its constituents is mucin, the other a proteid of the giobulin class, which in its reactions resembles the
serum globulin or paraglobulin of the blood. In the chemical investigation of myxoedematous tissues only one of these constituents, -viz. the mucin, has been estimated. It would make the investigation more complete in future analyses if the globulin were also estimated and tho amount present compared with that in normal tissues. In new and loose connective tissue the ground substance is present in greater amount than when the fibrous (collagenous) material replacos it in a later stage. This is illustrated by the fact already noted of the higher percentage of mucin in the skin of infants as compared with that of adults. In myxoedema it seems that the swelling is at a certain stage due to the increase of this ground


substlance, and hence the increased percentage of mucin, but at later stages, when white fibres or fat cells have permeated it, the increase of mucin is not so marked " (pp. 55, 56 ).
The second portion of Dr. Halliburton's observations being made on animals subjected to experiment will be more appropriately considered after Professor Victor Horsley's statement of the results of the ablation of the thyroid gland in animals has been studied.

Experimental researches on the thyroid gland,-Professor Victor Horsley, F.R.S., has undertaken the investigation of the results of the removal of the thyroid gland in animals, and has placed his observations at the service of the Committee. Professor Horsley's report includes, in addition to the results of his experiments, a very large consideration of the function and pathology of the gland. In an historical sketch he mentions the fact that the first experimental investigation of the functions of the thyroid gland was made in England by Sir Astley Cooper. The rest of the sketch presents a record of various observations, some indecisive, some conflicting, leading up to the institution of his own experiments. In particular, he draws attention to the observations of Munk, who, admitting that extirpation of the gland had been frequently followed by stupor, convulsions, and coma, thought the results which he had obtained were due, not to loss of the thyroid gland, but to certain injuries inflicted on surrounding parts.In the second section of his report, Professor Horsley lays down, as a first condition of experiment, the necessity of obtaining asepsis of the \vound. In the next place he asserts that it is easy, in operating for the removal of the thyroid, to avoid injury of surrounding parts, notably of the nerves behind the gland, the sympathetic, -vagus, and recurrent laryngeal, Thirdly, he denies the occurrence of injury of the trachea, which has been regarded by Kocher and Lombard as giving rise to cachexia strumipriva, through the production of conditions leading to chronic asphyxia, Fourthly, he notes the importance of the presence or absence of accessory thyroid glands in cases where animals have survived the operation of excision.

In his third section (Details of Researches) Professor 188

Horsley remarks that all observers, from Huschke downwards, agree in admitting- the importance of the gland to the new- born and rapidly growing animal, and its degeneration and atrophy in approaching senility, which condition, he observes, closely corresponds in many particulars to the myxoedematous state. He regards the variation of the gland, in connection with certain states of physiological activity, as not at present accurately known. He next examines in detail the results of extirpation of the thyroid, macle in -various animals by various observers .From his statement it appears that while as regards rodents a number of observations have been made on rats and rabbits, with uniformly negative results, the removal of the gland in carni-vora has almost in variably been followed by death, preceded by symptoms of myxoedematous cachexia. It appears that in dogs 95 per cent. succumb, after supposed complete extirpation, within a period varying from a few days to rarelyas long as two or three months. The symptoms following the removal of the glancl are first dulness and apathy, next fibrillar twitchings in the muscles, going on to -violent clonic convulsions affecting all the extremities and the trunk. These spasms are accompanied by violent dyspnma, and often by a half comatose state, passing finally into complete

unconsciousness. Coupled ,vith spasm, and marching with it, paresis, mostly affecting the -voluntary muscles of the limbs, is noted, and various disturbances of nutrition occur. The temperature graclually falls, after a preliminary rise, and becomes sub-normal before death. In the blood the red corpuscles diminish in number, the leucocytes increase. In the fourth section, Compensatory hypertrophy of parts left behincl is considered, but no decisive conclusions are drawn. In the seventh section, headed "Further Relations of the Thyroicl Gland with other Processes in the Body notably Haematopoiesis," Professor Horsley, after discussing the anaemia following the removal of the whole gland in cats and dogs, relates an experiment which has certainly an important bearing on the clinical as well as the pathological aspect of myxoedema, The observation is of such importance that it is quoted at length.

" No, 2 sheep. Result: Died of acute myxoedema, brought on by accidental exposure to cold 1 1/3 years after extirpation, " The fatal case in the second shcep is one of much interest, since it entirely negatives the viee that the effects of total extirpation are due to injury of neighbouring. structures in the coarse of the operation, and proves that the myxoedematous state is produced by the loss of the thyroid. It is worth whiIe, therefore, to mention the leading- festures in this instance. The thyroid Ivas removed (October 3rd, 1885), with the usual precautions, and primary union of the eound resulted, The sheep emaciated aud eas well a fortnight later, but its tempetature was normsl aud appetite good. No markod change was observable in the animal except that it gradually recovered its general nutrition, and apparenty bocame more stupfid even than before the operation. In the meanwhile the wool grew, and not being cut covered the animal very thickly. In view of the approaching summer weather it was shorn in tbe first weck of May, 1887. The weather, which had been mild, became very cold; the animal was then observod to become ill, it lost its appetite, then exhibited the usual symptoms of the acute cachexia, viz. the spasms, paralysis, coma, anaethesia, tetanoid contracture, and fall of temperature to 25° C. It died on May 20th, 1997, i.e. 569 days after thc operation. The post-inortem examination showcd a 'gelatinous' infiltration of all the subcutaneous tissue, which under the
microscolJe (see PI. IX) was evidcntly mucinous dogeneration of the ground substance, and by chemical analysis (vide 'Chemical Report,' p- 60, by Dr, Halliburton) was shown to be actual!y mucin. The thyroid gland had been completeIy removed (pp, 76, 77).
It is impossible to mistake the value of thiss obscrvaton in regard to the fluctuations of the human subjects of myxoedema, In them the influence of surrounding temperature is always apparont. They fail in all ways during cold weather; they improve in warm weather ; and, in proportion as the advorse
influence of cold climate can be withdrawn or opposed, they improve in health, or cease to decline, An experiment made

by Professor Rorsley on a donkey lends strong support to the following observation.
We come now to the most decisive of Professor Rorsley's experiments, viz. those in which he removed the thyroid gland from monkeys. The general course of the symptoms which follow complete extirpation of the thyroid in monkeys, is related by Professor Rorsley under two headings: 1st, acute myxoedema, 2nd, chronic myxoedema or cretinism.
The symptoms of acute myxoedema, by which Professor Rorsley designates cases in which the symptoms following extirpation of the thyroid run a rapid and continuous course terminating in death, are stated to appear within a few days after the operation. The interval has -varied from the second to the twelfth day, being shorter in younger animals than in older; while in proportion as the symptoms appear later, the length of the subsequent illness is extended; in other words, death is further postponed. Exposure to cold determines an earlier appearance of the symptoms, warmth delaying the same. Professor Rorsley states as follows the phenomena of acute myxoedema: "Motion, tremor, clonic spasm (paroxysmal), contracture, paresis, paralysis. sensation, parresthesia, then anresthesia. Reflexes gradually diminished, Mental operationd, normal at first, are soon diminished in activity, and then follow apathy, lethargy, coma " (p. 81) .With these come fall of temperature to subnormal degree, after an initial rise, anaemia, leucocytosis, and fall of blood-pressure ; failure of nutrition with mucinous degeneration of the connective tissues, increase of mucous secretion, usually atrophy and falling out of the hair, and sometimes enlargement of the spleen. Professor Horsley draws attention to the remarkable correspondence of many of these symptoms with those of idiopathic myxoedema, of cachexia strumipriva, and of exophthalmic goitre.
First, in respect of the tremors in the early stage. Similar tremors certainly occur in the three conditions above mentioned; and it is of great interest to note that, in several recently observed cases of myxoedema, tremors and contractures have been observed, not only where the disease was commencing, but in cases of many years' duration. These


phenomena, indicating dissolution of nervous energy, appear indeed to be much more common in myxoedema tban was indicated by the earlier observations, and are among the things which are to be carefuly looked, for in the future.
Other correspondences consist in the lowering of temperature, in the anemia, and perhaps leucocytosis, and the excessive mucinous secretion. Moreover, Professor Horsley states that " the monkey shows the appearances which are characteristic of the disease known as ( idiopathic) myxoedema ; the eyelids become puffy with elastic oedema, the features grow heavy and coarse, the skin being rough in some cases and the hair falling out. At the same time the urine is normal, i. e. non- albuminous, &c," (p. 82).

It is hardly necessary to indicate the parallel between these changes and the more salient appearances of myxoedema. The

state to which Professor Horsley applies the term " chronic experimental myxoedema or cretinism " appears to be determined by the influence of temperature. VVhen monkeys, from whom the thyroid gland had been completely removed, were kept comparatively warm, in air at a temperature averaging 90' Fahr., acute myxoemdema was averted ; and the average duration of life, in five cases, was extended to 125 days instead of twenty-four. The character of the prominent symptoms was also remarkedly changed. Mucinous degeneration was replaced by marasmus, and mental disturbance became the most prominent feature among the special symptoms.
The animals in all the cases resemble cretins in every particular. " It seemed as if the animal had been enabled to pass through (1) a neurotic and (2) myxoedematous stage into (3) a marasmic and cretinic one " (p. 83)
As regards the post-mortem examination of these animals Professor Horsley makes a statement which has an important bearing upon the variation of conditions which constitute so great a difficulty in the morbid anatomy of myxoedema. " Post- mortem examination of these animals fail to show the mucinous degeneration noted in acute experimental myxoedema, but on the other hand revealed rather fibroid or cirrhotic changes in the tissues.


" Chemical examination, moreover, revealed the sanie fact. Allusion may be made here to the similar character of the course of the tissue changes in those cases of idiopathic myxmdema and cachexia strumipriva, where life is so prolonged that the disease passes fully into the cretinic stage (p, 85) .
Finally, we present Professor Horsley's summary and conclusion.

" Comparison of the foregoing facts with the clinical observation of the forms in which the myxoedematous cachexia presents itself in man, leads us to conclude that the loss of the thyroid gland is the determining factor in the production of the array of symptoms described in the Clinical Report. For the sudden ablation of the thyroid from a normal animal evidently produces in it the myxoedematous cachexia, this varying in intensity according to the importance of the gland to the particular animal the subject of the experiment. If we may form from this evidence a scheme of the pathology of idiopathic myxoedema and cretinism it would result that some as yet unknown condition (possibly of the central nervous system) causes atrophy of the thyroid gland, and consequent upon this are developed the symptoms of cachexia known in its various forms as myxoedema, cretinism, and cachexia strumipri-va " (pp. 86, 87) .
Chemica] analysis of the tissues of animals.- The second part of Dr. Halliburton's report may now be quoted in relation to Professor Horsley's investigations. It appears from this report that in acute experimental myxoedema, as observed in monkeys, Dr. Halliburton has found a remarkable increase in the percentag'e of mucin in the skin, in tendon, in the salivary g-lands, and in the blood. " The presence of mucin in large amount in the parotid, which normally contains none, is specially noteworthy. This chemical result was confirmed by microscopical examination, the cells of the acini being swollen with mucin, and simulating those of a mucous gland like the submaxillary " (p, 56) .
In the blood mucin appears to be present in increasing amount, more or less proportionate to the increasing development of the myxoedematous condition of the animal. In the


more chronic form of experimental myxoedema in monkeys, determined, as may be remembered, by the maintenance of a high surrounding temperature, excess of mucin in the various parts mentioned is not observed, Two observations on other animals than monkeys cannot pass without notice. First, the blood of a donkey from which the thyroid had been removed was examined 205 days after the operation. No mucin was found in it. Second, "the blood of a sheep from which the thyroid had been removed was examined twenty-seven days after the operation. No mucin was found in it....... The animal was killed nearly two years afterwards, it having developed myxoedematous symptoms when it was shorn and exposed to cold. It showed no signs of myxoedema before this. The blood, pericardial and cerebro-spinal fluids then contained no mucin. The peritoneal fluid contained a doubtful trace. The urine contained abundance of mucin. The 'gelatinous ' and fatty connective tissue from the anterior triangle of the neck contained .09 per cent. of mucin. Although there are no analyses in healthy sheep to compare with this result, it seems to denote a considerable increase in the amount of mucin present, normal adipose tissue in other animals yielding only imponderable traces. The sterno-mastoid muscle and lymphatic glands were also examined from the same animal, and found to contain a trace of mucin" (pp. 59, 60) .

There is much in this report of great physiological interest and strongly demonstrative of the skill and sincerity of the observer. The report cannot fail to be an important gulidc in further investigations, not only on the chemical aspect of myxoedema, but Upon the physiological chemistry both of the thyroid gland and of the mucous glands.
Results of total and partial extirpation of the goitrous thyroid gland in man.- This last report is presented by Dr. Felix Semon, but that it should be taken last is somewhat a case of (**). Seeing that the appointment of this Committee was determined by the fact that Dr. Semon had drawn the attention of the Clinical Society to a paper published in 1883 by Professor Dr. Theodor Kocher, of Berne, on " Thyroidectomy and its Sequelea," it would have

seemed proper to have taken this report earlier, But it will be readily seen, that while this report goes very deeply to\vards

the root of the causation of myxmdema, its importance is best estimated after a full survey of the remaining evidence. Professor Kocher's paper, written apparently without knowledge of the description of myxoedenla already published in this country, painted most graphically the picture of the disease as occurring in an entirely different aspect, viz. as the result of the extirpation of the goitrous thyroid gland.
It is not necessary to discuss the singular correspondence of details.This fact is already generally appreciated. At the request of the Committee, Dr. Semon put himself in communication with medical men in all countries who were reported to have performed excision of the thyroid gland, with a view to obtaining information as to the sequence of symptoms in any way resembling those of myxoedema, on the operation.
The results of the inquiry are set forth by Dr. Semon in a full and singularly impartial paper. It appears that, in reply to 115 circulars sent out, altogether 69 communications have been received, of which number 6 were sent by Austrian, 2 by Belgian, 16 by British, 2 by Danish, 1 by a Dutch, 2 by French, 20 by German, 1 by an Italian, 3 by Russian, 3 by Swedish and Norwegian, and 13 by Swiss surgeons. For various reasons, not more than 64 of such replies could be utilised, and these only in various degres, In the analysis of the information thus afforded, an important classification is first made. Some operators have adopted the principle of entire extirpation, others have been satisfied with less complete removal, and, e-ven in the case of intended complete removal, the possibility of the existence of accessory thyroid glands has to be remembered. 1he first class of cases investigated is that in which total extirpation has been made. 1'he evidence as to the occurrence of anything like myxoedema after the operation is very various and very conflicting. While, for instance, Professor Kocher, operating on 32 cases, and Professor Reverdin, of Geneva, operating on eighteen, have found the symptoms of myxoedema


subsequently appearing in a very large proportion of the subjects, the experience of Professor Billroth, of Vienna, and of Professor Bardeleben, of Berlin, is of an entirely different character. Among l40 total extirpations, performed in Professor Billroth's clinique, myxoedematous symptoms were observed onlyin two. Professor Bardeleben states, that in not one of the 15 total extirpations performed by him since 1876,symptoms of cachexia strumipriva have follo\Ved. Between these extremes many gradations are noticed. In the consideration of the whole group of reports, it is obvious that the evidence as to the sequence of myxmdema Upon extirpation of the thyroid gland could not be unanimous, or, on the record, conclusive. In the first place, as the replies show, many patients die shortly after operation; in the second place, many patients pass out of observation, or are not observed for a sufficient length of time. In the third place, the probability of the sequence has not presented itself in an equal degree to all observers. In the fourth place, it is not by any means certain that, even where the main thyroid gland has been entirely removed, accessory thyroid glands have not been in existence ; and it may be observed that recurrence of the tumour, frequently noted, may mean either that the operation was incomplete, or that supplementary thyroid existed.

As regards partial operations, the results are, as might have been expected, less conclusive.
Dr. Semon, reviewing the whole series of results submitted to him, draws the follo\ving. inference :
" That there is an affection, following, in a certain number of cases, total, and, in a much smaller proportion, partial extirpation of the goitrous thyroid gland in man, which is clinically identical with primary myxoedema. As in the primary disease, the symptoms are not always equally well developed in the operative variety, and in this respect important differences appear to obtain between the cases of total and those of partial extirpation of the goitrons gland. The only real addition, however, to the symptoms of the primary malady, which sometimes occurs in the operative variety,


When the operation has been performed on children, viz. the stunting of the growth of the body, finds its natural explanation in the fact that primary myxoedema almost always attacks persons in whom the period of evolution of the body has been completed.
" Another apparent difference between the two -varieties, viz. the tendency to improvement or even to complete disappearance of the cachexia in a certain number of cases of operative myxmdema, seems to be due, so far as we can conclude from the few hitherto carefully observed cases, to the fact, that in these cases the operation was either not total after all, or that accessory thyroids existed, and that in either case alate hypertrophy of the remnants of thyroid tissue with resumption of the function of the thyroid occurred.

"Of the pathological identity or otherwise of the two varieties, however, it is impossible to speak as yet with any certainty, because the number of post-mortem examinations made in cases of operative myxoedema is very small, viz, 8 : 1 case by Bruns, 1 by Fritzsche, 3 by Kocher, 1 by Reverdin, 1 by Wolkowitch, 1 by Hahn ; and because in the four instances in which somewhat fuller details are known to us (Brun's, Hahn's, Reverdin's, and Wolkowitch's) no pathognomonic lesions appeared to have been detected " (pp. 148, 149) .

Dr. Semon then investigates the sources of error above enumerated, and demonstrates that, under all the categories, there is considerable possibility that error, attenuating in effect the evidence against operative myxoedema, has been madeIn particular he finds that one thing is clear, namely, " that the frequency of aberring or accessory glands is a very frequent one." The section of his report which treats of this question is worthy of attentive study, and is evidently the fruit of much reading and thought.

The general results of sopposed complete removal of the thyroid gland are next presented in a tabular form. No less than 408

cases, furnished by 56 operators, are catalogued, In no more than 69 of these was definite cachexia strumipriva, or operative myxoedema, known to have followed the operation, We append Dr. Semon's remarks upon this table.

From this table the following results would appear to follow:
" In a total of about 408 intentionally complete thyroidectomies, performed by 56 different surgeons, there were 59 deaths in consequence of, or shortly after, the operation.
" In 20 cases the operation was performed for malignant disease of the thyroid gland.
" Deducting the cases of death from or shortly after the operation, the cases in which there was malignant disease of the thyroid gland, and the cases which were lost from observation almost immediately after the operation, there remain 298 cases in which total thyroidectomy was performed for simple goitre, and in which the patients are known to have fully recovered. Of these, in 277 instances the further fate of the patients could be followed up, with the result that in 22 cases in which the patients remained, or at any rate got well, either recurrence of goitre or development of accessory thyroid glands appears to have taken place; that in 186 cases the patients appear to have remained free from cachexia strumipriva without recurrence or development of accessory thyroids having taken place; and that in 69 cachexia strumipriva of a more or less severe type developed " (p. 164) .
It comes out, from further examination of this table and an analysis of the cases in which the cachexia \vas obsorvod, that of 57 cases in which sex was recorded, " the patients were male in 24 and female in 33 cases. There appears to be therefore by no means that preponderance of the female sex which is met with in primary myxoedema " (p. 167).
The age of the persons affected is also worthy of attention. Dr. Semon presents this in a table, to which he appends the following remarks :
" The great majority of the patients affiicted are between ten and thirty years old, which supports Kochor's view that the risk of cachexia developing is greater in individuals whose physical development is not yet entirely terminated. It must, however, not be forgotten that the great majority of operations have certainly been performed in patients between ten and thirty years of age, so that the large preponderance of these


two decades in our table ought not exclusively to be attributed to the greater liability of these ages to the disease. Our table shows, at any rate, that no age is actually exempt from it " (p. 167) .
Reviewing next the evidence bearing on the main subject of inquiry, namely, " the question of the frequency of cachexia strumipriva in proportion to the total number of those patients who underwent total thyroidectomy on account of benign goitre, who recovered, and whose cases could be followed up further," the Reporter concludes that " the proportion of the cases of cachexia strumipriva to the cases in which the patients remained free, apparently without possessing any acting thyroid tissue, would therefore be 69 in 186, or about 1 in 3.

" Considering that if cachexia strumipriva, actually depended Upon the total loss of active thyroid tissue, this proportion ought not to be 1 in 3, but 1 in 1, the statistical inquiry merely appears to bring out with greater force the general impression which will have been gained by the perusal of the replies of our correspondents, viz. that our investigation directly negatived the hypothesis of such a connection " (p. 168).
He proceeds to deal effectively with the sources of error already set forth, but still finds himself unable to decide that total removal of the thyroid, where the operation is free from objection, and where there is no evidence of the existence of accessory thyroid glands, is necessarily foll0\Ved by myxoedema.
Feeling the imperfection of the evidence on this point, he discusses the various suggestions offered in explanation of the undoubted sequence of myxoedema in a certain proportion of the cases submitted to operation. They are presented as follows:
" a. Deficient development or atrophy of the trachea, following the operation (Kocher) .
" b. Injury to the recurrent laryngeal nerves caused during the progress of the operation, or due to inflammation, adhesions, cicatrisation following it Baumgartner) .
" c. Injury to the sympa,thetic nerve (Baumgartner) .


" d. Mode of operation.
" e. Endemic influences; "
and are, one by one, as it appears to the Committee, successfully controverted. The Committee would observe that hypotheses (a), (b), (c), and (d) ha-ve been dealt with in a vigorous and effective way by Professor Horsley in his report, and that with regard to (e) the geographical distribution of cases lends no support to the contention.
When Dr. Semon, in his fairness, finally refuses to ans\ver definitely the question, " What is the cause of cachexia strumipriva ?" the Committee thinks that he might possibly have gone a little too far in his endeavours at being perfectly impartial, and that, in this connection, attention should be drawn to the fact mentioned by himself, viz. that the peculiar cachexia has not followed any other serious operation in the neck involving the great vessels and the sympathetic ner-ve. What applies to operation applies also to disease. The positive fact of the sequence occurring in one form only of operation

among many having similiar associations takes a first position. It is the explanation of the non-occurrence of myxoedema in operative cases which has to be sought, not the justification of the clearly established fact that myxoedema follows one operation and no other .
Conclusions-- Finally, it may be stated that there is strong evidence that myxoedema, sporadic cretinism, endemic cretinism, cachexia strumipriva, and the operative myxoedema of animals are severally species of one genus; that such clinical differences as exist between them are due to causes already sufficiently set forth; and that the one pathological fact common to all these conditions is the occurrence of morbid processes or of operations involving the annihilation of the function of the thyroid body.


1888 Transactions Clinical Society London CONCLUSIONS.
Report of Committee on Myxoedema.

THE following are the final conclusions arrived at by the Committee :
1. That myxoedma is a well-defined disease.
2. That the disease affects women much more frequently than men; and that the subjects are, for the most part, of middle age.
3. That clinical and pathological observations, respectively, indicate in a decisive way, that the one condition common to all cases is destructive change of the thyroid gland.
4. That the most common form of destructive change of the thyroid gland consists in the sobstitution of a delicate fibrous tissue for the proper glandular structure.
5, That interstitial development of fibrous tissue is also observed very frequently in the skin, and, with much less frequency, in the viscera; the appearances presented by this tissue being suggestive of an irritative or inflammatory process.
6. That pathological observation, while showing cause for the changes in the skin observed during life, for the falling off of the hair, and the loss of the teeth, for the increased bulk of the body, as due to the excess of subcutaneous fat, affords no explanation of the affections of speech, movement, sensation, consciousness, and intellect, which form a largo part of the symptoms of the disease.
7. That chemical examination of the comparatively few available cases fails to show the general.existence of an excess of mucin in the tissues adequately corresponding to the amount recorded in the first observation, but that this discrepancy


may be, in part, attributed to the fact that tumefaction of the integuments, although generally characteristic of myxoedema, varies considerably throughout the course of the disease, and often disappears shortly before death.
8. That in experiments made npon animals, particularly on monkeys, symptoms resembling in a very close and remarkable way those of myxoedema have followed complete removal of the thyroid gland, performed under antiseptic precautions, and with, as far as could be ascertained, no injury to the adjacent nerves or to the trachea.

9, That in such experimental cases a large excess of mucin has been found to be present in the skin, fibrous tissnes, blood, and salivary glands ; in particular. the parotid gland, normally containing no mucin, has presented that substance in quantities corresponding to what would be ordinarily found in the submaxillary gland.
10. That the full analysis of the results of the removal of the thyroid gland in man demonstrates, in an important proportion of the cases, the fact of the subsequent development of symptoms exactly corresponding with those of myxoedema.

11. That in no inconsiderable number of cases the operation has not been known to have been followed by such symptoms ; the apparent immunity being in many cases probably due to the presence and subsequent development of accessory thyroid glands, or to accidentally incomplete removal, or to insufficiently long observation of the patients after operation.
12. That, whereas injury to the trachea, atrophy of the trachea, injury of the recurrent laryngeal nerves, injury of the cervical sympathetic, and endemic inf!uences, have been by various observers supposed to be the true causes of experimental or of operative myxoedema (cachexia strumipriva) , there is, in the first place, no evidence to show that, of the numerous and various surgical operations performed on the neck and throat, involving various organs and tissues, any, save those in which the thyroid gland has been removed, have been followed by the symptoms under consideration ; that in many of the operations on man, and in most, if not all, of the experimental operations made by Professor Horsley on


monkeys and other animals, this procedure avoided all injury of surrounding parts, and was perfuctly aseptic; that rnyxoedema has followed removal of the thyroid gland in persons neither living in, nor having lived in, localities the seat of enclemic cretinism ; that, therefore, the positive evidence on this point vastly outweighs the negative ; and that it appears strongly proved that myxoedema is frequently produced by the removal, as well as by the pathological destruction, of the thyroid gland.

13. That whereas, according to Clause 2, in myxoedema, women are much more numerously affected than men, in the operative form of myxoedema no important numerical difference is observed.
l4. That a general re-view of symptoms and pathology leads to the belief that the disease described under the name of myxoedema, as observed in adults, is practically the same disease as that named sporadic cretinism when affecting children; that myxoedema is probably identical with cachexia strumipriva; and that a -very close affinity exists between myxoedema and endemic cretinism.

15. That while these several conditions appear, in the main, to depend on, or to be associated with, destruction or loss of the function of the thyroid gland, the ultimate cause of such destruction or loss is at present not evident.

WILLIAM M. ORD, Chairman.


1891 Notes on the Treatment of Myxoedema by Hypodermic Injections of an Extract of the Thyroid of a Sheep by George R. Murray, B.A., M.B. Camb., M.R.C.P. Lond., Newcastle on Tyne read in the Section of Therapeutics at the Annual Meeting of the British Medical Association held in Bournemouth, July, 1891 BRITISH MEDICAL JOURNAL 1891

p 796 Myxoedema has until recently been considered an incurable disease. Since the pathology of this remarkable condition, however, has become more fully understood, hopes of the possibility of greatly relieving the symptoms, if not of curing the disease entirely, have been entertained. The observation of the symptoms which followed the removal of the thyroid gland in man made by Professor Kocher, of Berne, and the results of the experimental removal of the gland in monkeys obtained by Mr. Victor Horsley have firmly established the view that this disease is due to the loss of function of the thyroid gland,. It was found by Dr. von Eiselsberg that if the thyroid gland was successfully transplanted from the neck of an animal to some other part of the body, it was capable of continuing its functions, and so preventing the onset of the symptoms which would otherwise have followed its removal from the neck. Mr. Horsley then suggested that grafting a healthy sheep's thyroid gland into a patient suffering from myxoedema should be tried as a means of arresting the progress of the disease. This suggestion has since been carried out. Bettencourt and Serrano, of Lisbon, introduced one half the thyroid gland of a sheep beneath the skin of the inframammary region on each side in a woman of 36, suffering from myxoedema. The operation was followed by an immediate improvement. Movements becomes more easy and the speech more natural. The number of red corpuscles in the blood steadily increased till it nearly reached the normal standard in a month. The temperature was raised. The subcutaneous swelling diminished, and the patient began to perspire once more. The period of menstruation, which before had lasted for two and sometimes three weeks, was reduced to four days. These authors considered that as the improvement commenced the day after the operation, it could not be due to the gland becoming vascularised and so functional, but suggested that it was due to the absorption of the juice of the healthy thyroid gland by the tissues of the patient.

Now it seems reasonable to suppose that the same amount of improvement might be obtained by simply injecting the juice or an extract of the thyroid gland of a sheep beneath the skin of the patient.
If we consider that myxoedema and cachexia strumipriva are due to the absence of some substance which is present in the normal thyroid gland, and which is necessary to maintain the body in health, it is at least rational treatment to supply that deficiency as far as possible by injecting the extract of a healthy gland. G. Vessale has made intravenous injections of an extract of the thyroid gland in dogs after thyroidectomy with beneficial results. As far as I am aware this means of treatment has not before been tried in the human subject. Since suggesting this treatment at the February meeting of the Northumberland and Durham Medical Society, I have been able to carry it out in a well-marked case of myxoedema. Such decided improvement has resulted that the details of the method of treatment employed and the results obtained are worth recording.

p 797
..... The following note gives the history and condition of the patient before the commencement of the treatment.
April 13th, Mrs. S., aged 46. Four or five years ago it was first noticed by her friends that her speech and actions were becoming very slow. She herself began to feel soon after that it required a great effort to do her ordinary housework. Her features gradually became enlarged and thickened. The hands and feet increased in size and became altered in shape. She has not perspired at all during the last four years. Six years ago she had a miscarriage; since then she has only menstruated once, four years ago. At the present time she presents most of the characteristic symptoms of myxoedema. She complains of languor, a disinclination to see strangers, and great sensitiveness to cold. The temperature is subnormal, and varies between 95.6 and 97.2 in the mouth. The pulse varies between 60 and 70. The face is blank and expressionless, and the features and notably thickened. This change is well seen in the alae nasi and lips. The subcutaneous connective tissue of the eyelids is so











swollen that she finds it difficult to look upwards. There is also considerable swelling beneath the eyes and of the cheeks. The hands and feet are both enlarged; the former have that peculiar shape which has been described as "spade-like". The skin is very dry, there is no perspiration, and the superficial layers of the epidermis are continually being shed as a fine white powder. The hair is very fine in texture, and a considerable quantity of it has been lost. She is slow in answering questions; all her actions are slow, and are performed with difficulty. The speech is remarkably slow and drawling, and the memory is bad. No thyroid gland can be felt in the neck. The urine contains no albumen or sugar.

July 13th. It is now three months since the treatment was commenced; it has not, however, been carried out continuously all the time, and at first a weaker preparation than that described was used. Extracts of five lobes of sheep's thyroid have been injected, that is altogether equal to the extract of two and a half thyroid glands. The patient has steadily improved since the treatment commenced, and, though three weeks were allowed to elapse between the injection of the last two extracts, she did not lose any of the ground she had previously gained. The swelling has gradually diminished, and has practically disappeared from the backs of the hands, the skin over them being now loose and freely movable. The lips are much smaller. The swelling of the upper eyelids has diminished so much that she can look upwards quite easily. The swelling beneath the eyes and of the cheeks has also much diminished. The face consequently , as a whole, has greatly improved in appearance, and has much more expression, as many of the natural wrinkles, especially about that forehead, have returned. The speech has become more rapid and fluent, the drawl being scarcely noticeable at the present time. She answers questions much more readily, the mind is more active in all her movements, and finds that it requires much less effort than formerly to do her housework. She now walks about the streets without any hesitation without a companion.

She has menstruated normally during the last six weeks at the regular interval. For the last four weeks the skin has been much less dry and she perspires when walking,. The hair remains as before. She is no longer so sensitive to cold. Unfortunately owing to circumstances a daily record of the temperature has not been kept, but out of four observations that have been made lately, about 11 A.M., three times the temperature has been 98.2'F, and once 97.4'.

Many cases of myxoedema doubtless do improve to a certain extent when untreated, and it is not wise to draw many conclusions from a single case; but the return of perspiration and menstruation when they have not occurred for four years, together with the many other signs of improvement which have followed the treatment, are, I think, sufficient indication that this treatment really has a beneficial effect upon the disease. The improvement, of course, cannot be expected to be continued if the injections are discontinued, but there seems no reason why it should not be maintained if the injections are repeated at intervals of two or three weeks.
This case is published in the hope that others may be induced to give the treatment a fair trial in myxoedema. It might also be tried in cases where it is found necessary to remove the whole of thyroid gland to prevent the onset of, or at least modify, the unpleasant train of symptoms known as cachexia strumipriva, which so often follows thyroidectomy.

1891 The Diuretic Action Of Fresh Thyroid Juice E. Hurry Fenwick F.R.C.S., Surgeon to the London Hospital, and St. Peter's Hospital British Medical Journal Oct. 10th, 1891
....I departed from the ordinary method, for I split each gland, and before I fixed it in its new position I rubbed the glairy secretion which oozed from the cut section into the subcutaneous tissue. I was greatly surprised next day to find that the patient's temperature had risen from its habitual subnormal level to normal, and that the amount of urine had increased from 20 ounces per diem to 50 ounces.

.... We cannot find any record of the function of the thyroid juice except "that it is quite unknown" (Landois): nor have we come across any intimation in the literature that it has been made us of as a diuretic in renal or cardiac disease, or in the treatment of myxoedema.
....The plan we have adopted is as follows: The urine having been measured and tested daily for a week, a sheep's thyroid, taken warm from the body of a carefully selected animal, is split, and ten drops of juice are mixed in a Koch's syringe with an equal amount of distilled water, and injected with aseptic precautions under the skin of the arm or shoulder blade. Some pain and slight swelling are sometimes complained of, but no inflammatory trouble has resulted. The urine increases in amount during the next day or the day after and the effect in the myxoedema case continues for fourteen to twenty-one days.


A PATIENT suffering from myxoedema was admitted to St. Thomas's Hospital on April 19th, 1893. After careful daily examination of the food and the urine, she began, on May 1st, to take 20 drops of a glycerine extract of the thyroid body of the sheep daily.

....We beg to present the following conclusions as the result of the treatment and observations in this case : 1. That the urine is increased in volume.
2. That the nitrogen excreted in the urine exceeds the total quantity of nitrogen in the food.
3. The phosphoric acid and chlorine elimination are practically unaffected.

4. That the increased nitrogenous excretion is chiefly in the form of urea.

5. That the body weight is rapidly diminished. 6. That the temperature of the body is raised.

1893 DISCUSSION ON THE PATHOLOGY OF THE THYROID GLAND BMJ SEPT. 23 1893 Vol. II, p676 - 678 1V. - DR. GEORGE R. MURRAY, B.A., M.B. Cantab., M.R.C.P.Lond. Lecturer on Bacteriology and Comparative Pathology in the University of Durham College of Medicine, Pathologist to the Hospital for Sick Children, Newcastle- on-Tyne.

MR. VICTOR HORSLEY has shown that in monkeys the symptoms which result from removal of the thyroid gland resemble closely those which occur in man. For this reason I wish to relate shortly the results of cutting off the supply of thyroid secretion in a bonnet monkey be removal of the gland, and renewing it again after a time by injecting a glycerine extract of a sheep's thyroid gland beneath the skin of the animal.
A male bonnet monkey was put under ether, and a longitudinal incision was made in the middle line of the neck in front, the sterno-hyoid muscles were separated, and the thyroid gland was dissected out and removed. The blood vessels were twisted out of the gland, so that no ligatures were required. The wound was sutured with horsehair, and dressed with carbolic gauze and collodion. There was some traumatic pain after the operation, and the wound healed by first intention. The monkey was kept in a room the temperature of which was from 62° to 66° F. During the first week no symptoms appeared. At the beginning of the second week after the operation there was a fine tremor of the arms and hands, the red corpuscles enumerated by Gower's haemocytometer numbered 56 in a square, the normal number being about 60 ; the white average 3 in a field, the normal number being 4. During this week the animal became much less active, the tremors became more marked, and there were occasional clonic contractions of the muscles of the arm and forearm. A sight swelling of the upper and lower eyelids appeared. In the fourth week the monkey was very inactive, and sat still most of the time with the trunk bent forwards and well-marked tremors. There was a distinct tendency to fall over backwards. The swelling of the eyelids and lips was well marked. The red blood corpuscles had fallen to 42 in a square, and the white were 4 in a field. The temperature chart showed considerable diurnal variations, the morning temperature being three times subnormal. On the twenty-sixth day after the operation mj of thyroid extract was injected ; this was repeated on the twenty-eighth, thirty-first, and thirty-third days ; after this injections of mj or mij were given each day, except on the thirty-ninth till the forty-fourth day. The result of the injections was that, during the fifth week, the tremors diminished, the swelling and anaemia became less, and he was distinctly more active ; the morning temperature, however, continued to fall, being as low as 95.4° on the thirty-second day, the evening temperatures rising to normal or higher. On the thirty-third day, when called by name, he suddenly fell off the perch and lay on the floor in clonic convulsions, followed by increased tremor and fibrillary muscular contractions ; after this the arms remained rigid in flexion for some hours. During the sixth week under influence of the injections the tremor and swelling both disappeared. The temperature rose to normal, the anaemia was less, the red corpuscles being 52 in a square and the white 3 in a field, and the general activity was much increased. The injections were discontinued in the middle of the seventh week, but the improvement continued to increase, and by the end of the seventh week the monkey was quite well again, though he weighed rather less than before the operation, as the symptoms had all disappeared. The temperature was normal and the blood had regained its normal number of red corpuscles. It is interesting to note with regard to the temperature chart that though each injection was followed by a rise of temperature of 3° or 4° in the evening, the morning temperature continued to fall at first, and it was only after the sixth injection that the morning temperature began to rise again gradually to normal, and that when it regained that level the diurnal variations became much less than they had been during the fall of the temperature to subnormal or its return to the normal level.
The injections thus had a double action on the temperature - one immediate and of short duration, the other deferred but more lasting, for the higher level of temperature was maintained for a week after the injections were discontinued. The chart of the changes in the blood shows the anaemia which followed the operation, accompanied by a slight increase in the number of white corpuscles, and also the return of each to their normal number under the influence of the injections.
These facts give support to the view that the functioning of the thyroid gland are carried out to a very large extent, if not entirely, by means of its secretion, which forms an important constituent of normal blood plasma. I would suggest further that the anaemia is due to the loss of the secretion, which, in some way, either stimulates the formation of red corpuscles or prevents their destruction in health, and that the thyroid gland is thus only indirectly concerned in the formation of red corpuscles by the action of its secretion on the activity of blood-forming organs. These observations are supported by the well-known results of the treatment of myxoedema in man by the administration of thyroid extract.

Mr. HORSLEY wished to draw attention, for purposes of criticism and discussion, to a point he had raised eight years ago, namely, that on comparison of the effects of thyroidectomy in animals of various ages, and in connection with Dr. Bramwell's remarks it appeared to him that the changes of old age (especially the diurnal ones) are so parallel to those of the cachexia due to loss of the gland that we might reasonably explain the origin of those changes as due to the loss of the thyroid, which in old age usually degenerates.

1896 AN ADDRESS ON THE PHYSIOLOGY AND PATHOLOGY OF THE THYROID GLAND. [WITH PLATES OF MICROPHOTOGRAPHS.] Delivered before the Medical Society of London. BY VICTOR HORSLEY, M.B., F.R.S., F.R.C.S., Surgeon to University College Hospital and to the National Hospital for the Paralysed and Epileptic.

BMJ DEC. 5th, 1896 Vol. II p1623 - 1625

....Nearly one hundred years ago, King, of Guy's Hospital, showed by direct experience that the colloid material of the acini of the gland passed into the lymphatics, and thus for the first time was suggested in a tangible form the modern view of the so-called internal secretion of the thyroid gland.
During the subsequent fifty years, and at a time when, with the exception of snake poison, no animal fluid was known to have a very powerful influence on the body when administered in extremely small doses, it is not surprising that the idea that the thyroid gland had any importance at all in the economy was scouted, and that very absurd opinions were formulated to explain its existence and presence in the neck.
The first great step from this state of disregard was the discovery by Schiff in 1859 that the organ was important to life ; but unfortunately his experiments attracted no attention, and as they were performed with a different object than the direct investigation of the function of the organ, the result was obscured.
However, the question was reopened by Schiff scientifically in 1884, and then placed upon an accurate basis, since he definitely proved for the first time that the removal of the organ alone was attended in the carnivora by striking symptoms preceding a fatal termination. At the same time Reverdin and Kocher had established the fact that total removal of goîtres was liable to be followed by certain symptoms analogous to myxoedema ; and it was on Semon drawing attention to this matter, that the Committee of the Clinical Society was appointed for the purpose of collecting what information was in existence relative to the disease myxoedema, which had been for some time well recognised in this country.
Up to this point, however, the final proof was wanting that the fatal symptoms of thyroid extirpation were due to the actual loss of the thyroid gland, and no proof existed of the loss of the gland being the cause of myxoedema and cretinism. The reason was that the experiments so far had been conducted for the most part on carnivorous animals, in which the gland is of such essential importance to life that removal of it is followed by an extremely acute cachexia, customarily fatal in a very few days. Such a class of animals consequently did not afford means for the determination of the rôle played by the gland in a disease which runs such an extremely chronic course as that of myxoedema. To really test the question, therefore, attention had to be turned to the possibility of removing the thyroid gland in classes of animals in which the progress of the malady might be supposed to be slower. It was for this reason I undertook an experimental investigation into the question, employing monkeys for this purpose, and later herbivorous animals, strictly speaking.
The result was to establish beyond question the fact that the typical symptoms of myxoedema could be produced in a monkey by simple removal of the thyroid gland, and the synchronous examination of the other structures of the neck - for example, the nerves, proved also that no injury was done to them, and that therefore the symptoms were solely and wholly due to the loss of the gland itself. In speaking of this fundamental position, it was forcibly brought to my notice in 1884 how a medical theory of the explanation of disease may survive without any basis whatever for nearly a century.
....Now this was really an evidence that the sympathetic theory of disease which Abernethy was at such pains to establish against the experimental methods of John Hunter, was still prevalent in the minds of many ; and more than that, when my observations were severely attacked by Professor Munk, in Berlin, it was wholly upon the assumption that the sympathetic and other nerves in the neck had been injured during the operation of ablation of the glands. Of course, as a matter of fact, Schiff had already shown in the carnivorous animal that in that class at least the fulminating symptoms observed were not due to injury of any nerve in the neck, and I also naturally examined both the sympathetic and vagus trunks in the monkeys operated upon, and with wholly negative results.
It is very difficult to understand how such a theory as that of the influence of the sympathetic nerve and its supposed ability to produce constitutional disease can ever have found a serious position in medical literature and work.
Long after it was started the discovery of the influence of the vasomotor system was additionally invoked to explain obscure general symptoms like those of myxoedema, and there was of course some basis for such an opinion in view of the fact that so many of the vasomotor fibres run in the sympathetic trunk, but the fact always seemed to have been lost sight of that in a general constitutional affection there must be some profound chemical change, and while we must be ready to admit that the chemical changes of the body are greatly under the influence of the nervous system, still it will always remain an inexplicable absurdity that one set of nerve fibres should have ever been accredited with the power of producing a widespread disturbance of metabolism.
Of the general character of the athyroideal state, few proofs are most striking that the researches of Hoffmeister and v. Eiselberg in producing artificial cretinism in young animals by excising the thyroid directly after birth.
....Since 1891 the microscopic morphology of the thyroid gland has undergone much and interesting extension. The experimental researches of Gley have attracted renewed attention to the organs originally discovered by Sandstrom, and independently observed by Baber, and the existence of which has been subsequently confirmed by a large number of observers, from myself in 1884 to Kohn in 1895.

....Now we know for certain that the thyroid is a secreting gland which has a very important relation to the metabolism of the body, we can re-examine the epithelium of the acini with a fresh interest. I will first direct your attention to the compensatory hypertrophy of one lobe when the other has been removed, a hypertrophy which both Wagner and myself independently have shown in the dog and cat is a true compensatory hypertrophy.
....In exophthalmic goître the acini become more irregular and more resemble a racemose gland, the colloid material tends to

disappear, and is represented by a granular débris. This is coupled with a general enlargement of the whole gland, just as in the artificial hypertrophic compensation.
....It is hardly possible to leave the point of exophthalmic goître without a few further observations. On the question of the symptomatology of exophthalmic goître I showed in 1884 that the tremor present in all forms of thyroidal lesions was exactly the same as the tremor of acute cachexia strumipriva of thyroidectomised animals, and the fact was subsequently recognised by Charcot and Marie. But he problem of chief moment in the pathology of exophthalmic goître is the question whether the anatomical changes we have just seen have a causal influence or are only a secondary consequence of some central nerve lesion. As yet the nerve supply of the gland shown in these photographs has not been demonstrated physiologically (that is, by excitation, etc. - Hurthle, self) to exert secretory influence comparable to the well-known effects on the salivary glands. The question has therefore been approached from a clinical standpoint, and in the suggestive papers by Maude and by Abram we have a reflection of the recent tendency to regard the symptoms as being due to perversion of the secretion of the gland, the changes in which therefore come to have a primary significance. It is plain that the symptoms are also explicable as being athyroidal, and I venture to suggest that where there is extensive perversion of secretion, that so in proportion there must be a certain degree of athyroidism. Take a single symptom such as the characteristic dyspnoea ; that again is exactly the most prominent symptom of the acute athyroidal cachexia in all kinds of animals. Coupled with the dyspnoea is not infrequently rise in temperature, and in cases where death has rapidly supervened after removal of one portion of an exophthalmic goître, the temperature may rise to 105° or higher, and the patient die with marked dyspnoea, although of course there is no mechanical interference with the air passages.

.... In conclusion, I wish for the opportunity of saying a further word on the retrogression of thyroidal epithelium. In myxoedema, as is now well known, the thyroid gland atrophies, and there is found a round-celled infiltration of the remnants of the lobes and acini.
.....By way of contrast, compare the myxoedematous retrograde cell with that of the compensating active transplanted thyroid in one of v. Eiselberg's striking experiments. In this last there is no colloid, and the secretion must have been a watery one, yet adequate. Estimation of the athyroidal condition, therefore, is rather to be looked for as yet in the changes in the epithelium itself than in the products of its secretory activity.
To summarise our present position and knowledge of the whole question, it is, I think, now generally agreed (and the more so since the recent extensive researches of Mr. Edmunds) that whereas myxoedema and cretinism result from simple loss of the function of the thyroid gland, exophthalmic goître in its various degrees result from a perversion of that function.

1897 ON THE ACTIVE CONSTITUENT OF THE THYROID GLAND. BY ROBERT HUTCHISON, M.D., Late Chemical Assistant to the Professor of Physiology, University of Edinburgh. BMJ JAN. 23, 1897 Vol. I p 194 - 197 p197
A few months ago I published in the JOURNAL, a preliminary note, in which I stated that the colloid matter of the thyroid is the only active part of the gland therapeutically.

....In the present article I wish to present the clinical evidence by which I believe my conclusions to be finally proved.
For the sake of clearness it will be well to begin with a brief summary of the chief facts in the chemistry of the thyroid. I have shown that the proteins of the gland are two in number.
1. A nucleo-albumin present in small amount, and probably derived from the cells lining the acini.
2. The colloid matter, which possesses certain striking chemical peculiarities. One of these is that it contains, in addition to phosphorus, a considerable quantity of iodine. Another is that on gastric digestion it readily splits into two parts - a protein part which yields abumoses and peptone, and a small insoluble residue which is entirely proteid free.

Most of the iodine and all the phosphorus of the original colloid is found in this non-proteid residue, but the albumoses and peptones derived from the proteid part are also found to retain a small amount of iodine in their constitution.
The extractives of the thyroid (creatin, xanthin, etc.) resemble those of other organs, but they are said (by Fraenkel and Drechsel) to include amino-bodies, hitherto unknown, to which an important part in the activity of the gland is to be ascribed.
These may be dismissed briefly. I have administered them both to normal subjects, whose reaction to the whole gland was well marked, and also to cases of myxoedema. The quantity given amounted in some cases to the equivalent of 30 g. of the fresh gland daily - (roughly = the thyroids of five sheep). In no case did I find any symptoms at all produced. Patients who had been progressively losing weight on the fresh gland began immediately to gain weight when put on the extractives. There was no rise of temperature or pulse, and no subjective symptoms were complained of.
The amount of this substance yielded by the fresh gland varies considerably, but on an average 10 g. of fresh gland yields rather more than 1 g. of dried colloid. I administered it always in the form of a powder. The usual dose employed was 0.1 g. This may be regarded as approximately equal to 10 gr. of fresh gland, or to two of the ordinary thyroid tabloids. I found this substance to be invariably active. It produced all the ordinary signs of thyroid activity in healthy individuals, and in large doses distinct "thyroidism resulted in some cases. I shall, however, only give the details of its action in one case - a well marked case of myxoedema treated entirely by the pure colloid matter, and with a very brilliant therapeutic result.

....From the effect on this case there can be no shadow of a doubt that the colloid matter is active. It acted rapidly and effectively, it was extremely well borne, and at no time did the dose exceed 0.2 g. (= 3 gr.) daily.
it is not enough, however, to have shown that the colloid matter is active as a whole. I have already pointed out that the colloid is to be regarded as a compound substance which can be very readily split up into a proteid and a non-proteid part. Does the colloid owe its activity to one of these constituents only or do both participate in the action? If so, what is the part played by each?
IS the proteid constituent of the colloid (that is, in this case the abumoses) active?
....From the result of this case we are able, I think, to answer in the affirmative the question as to the activity of the proteid constituent of the colloid matter. At the same time the activity is by no means the same as that of the colloid as a whole. Larger doses of the substance were required to produce a noticeable effect.
....The action of the abumoses differs also from that of the colloid as a whole in being more transitory. As soon as their administration is stopped the patient's weight returns to its former amount. The albumoses would seem to be more rapidly got rid of in the tissues than the colloid as a whole ; the latter seems to be fixed by the tissues, and to have therefore a cumulative action, while the albumoses are rapidly excreted.
I have not considered it necessary to put this part of the colloid to any elaborate clinical tests. p197
....It would appear, therefore, that the colloid matter owes its activity chiefly to its non-proteid part - that is to say, to the part of it which is richest in iodine. The objection may be raised that the albumoses, as I have prepared them, owe their activity to the incomplete separation from them of the non-proteid body. Inasmuch, however, as I have submitted specimens of the albumoses to a three hours' boiling with 10 per cent. sulphuric acid, and subsequent extraction for three times with boiling alcohol, and have found them still to contain iodine, I hardly think that the objection is valid.
From these observations it follows that the total therapeutic activity of the thyroid is to be attributed to the colloid matter. ....THE THERAPEUTIC ADVANTAGES OF THE COLLOID MATTER.
Seeing, then, that all the preparations of proved activity contain the colloid matter, the time has come, I think, when we should reconsider our methods of thyroid administration, and give to patients the colloid matter separated from the inert parts of the organ in a state of purity. The advantages of such a mode of administration are obvious.
1. Constancy of dose if ensured. The quantity of colloid present in different glands varies considerably ; hence the amount of active substance in dried preparations of the whole gland is really not constant. By isolating the active part and giving it alone the difficulty is removed.
2. The drug is quite pure. The pure colloid matter is entirely free from fat, which is always present in dried preparations of the whole gland and is apt to make such preparations disagree when given in large doses.
3. The pure colloid is entirely free from taste and odour, and keeps indefinitely. These advantages cannot be claimed for other thyroid preparations.
4. A very small dose is required. Thus it wil be found that as much of the dried gland as will lie upon a sixpence is equivalent in activity to three of the tabloids in common use.
5. The colloid is absorbed with great ease and rapidity. This is a point on which I desire to lay special emphasis. Incredible though it may seem, I have seen its effects begin to be manifested in a thyroidectomised dog within five minutes of its administration by the mouth.
6. The administration of the colloid matter is really the most economical way of giving the thyroid. In giving the colloid, one is giving the active part of the glands, nothing more and nothing less. There is no waste of active material such as occurs in the preparation of thyroiodin.
Are the subjective symptoms such as headache and pains in the limbs which are so often complained of by patients who are being treated by large doses of ordinary thyroid preparations produced also when the pure colloid is given? In other words, are these symptoms a necessary result of giving large doses of the active principle of thyroid, or are they merely by-effects due to the presence of impurities in the preparation employed? My own observations show quite clearly that such symptoms are unavoidable results of the physiological action of the gland whenever that action is pushed beyond a certain limit. These symptoms are produced whenever large doses are given, even if everything other than the active principle of the gland be excluded from the preparation. It cannot, therefore, be fairly claimed for the colloid or for any other thyroid preparation that it obviates the occurrence of such symptoms. At the same time, the advantages of giving the colloid matter isolated in a pure state are so obvious that I have asked Messrs. Oppenheimer and Co., wholesale chemists, to prepare it according to my directions. This they have done, and members of the profession can now obtain the substance in a convenient and reliable form for administration to patients.

p 481
YEAR after year the Registrar-General's reports keep on repeating that the cancer death-rate is the "highest on record," and

this has been going on continually for more than half a century.
....I believe that the tendency to cancer may be increased by unsuitable modes of living and vice versa. We must therefore seek out those conditions which favour its development ; and by avoiding them we shall be able to effect our object. In my opinion it is only by progress along such lines that the cure of cancer is ever likely to be effected.
p 482
....Thus while the cancer mortality for males from 1851 to 1890 has increased 167 per cent., the increase for females has been but 91 per cent. It seems to me probable that this undue incidence of the increasing cancer mortality in males may be ascribed to the fact that of late, as the result of urbanisation, the conditions of life for men have come to resemble more closely those for women than heretofore. Excess of food, with want of proper exercise and changed surroundings, are, I think, its chief causative agents.

1898 THE PHARMACOLOGICAL ACTION OF THE THYROID GLAND BY ROBERT HUTCHISON, M.D., M.R.C.P., Demonstrator in Physiology, London Hospital Medical College. BMJ JULY 16, 1898 Vol. II p142 - 145
p 142
The recent promotion of the thyroid to an official position in the British Pharmacopoeia makes this a suitable time to state what is known as to its pharmacological action. More especially is this the case owing to the fact that the literature relating to the thyroid has recently swelled to such enormous proportions that he who run is certainly no longer able to read it, whilst embedded in that literature there are yet a number of facts and observations which have a very direct bearing on the therapeutic use of the substance. It may, therefore, be permitted to one who, from the special nature of his own investigations, has been obliged to read all that has been written on the subject, to discuss briefly the present state of our knowledge as to the physiological effects of the administration of the thyroid, and the bearing of that knowledge upon its use as a medicinal agent.

Shortly after the thyroid began to be used in the treatment of myxoedema, it was noticed that the urine of patients who were taking it contained a large excess of urea.
....Briefly, then, it may be said that the effect of the administration of the thyroid is to increase oxidation in the body ; it makes the tissues, as it were, more inflammable, so that they burn away more rapidly.
....It is important to note the large increase of water which occurs under thyroid administration. Diuresis is often one of the first effects of the drug, and a considerable proportion of the very sudden fall of weight which is often to be observed at the outset of a course of thyroid treatment is to be attributed simply to loss of water.
....The use of the thyroid as a remedy in obesity has recently attained a wide prevalence.
....Some writers assert that the thyroid has a specific action on the proteid tissues, and a few even go so far as to maintain that under thyroid administration the proteid-sparing power of fat and carbohydrates is suspended. Others believe that the proteids are only attacked secondarily and after fat has been to a large extent got rid of, and it has certainly been shown by careful observations on cases of obesity that great loss of weight can occur while there is yet less nitrogen being eliminated than is ingested. For my own part I think there is a good deal to be said for the view that the increased elimination of nitrogen which is observed at the commencement of thyroid feeding is due to destruction of circulating proteid, and that the fixed proteid tissues are only attacked when the store of fat has been considerably diminished. The practical inference is that in treating cases of obesity by thyroid feeding the diet should not be much restricted, and especially that nitrogenous matter should be abundantly represented in it.
....In its action on metabolism the thyroid is unique amongst medicinal agents. No other drug that we are acquainted with is capable of increasing the oxidation processes of the body in such a way. It may best be compared, perhaps, to the effect of muscular exercise.
....It is interesting to reflect that the secretion of the thyroid is constantly finding its way into the circulation, and must there exercise its effects on metabolism. One is tempted to speculate whether the different states of nutrition in different individuals may not be due to variations in the activity of their thyroids. In cases of simple goître one is almost compelled to believe that there must be a great demand for the secretion, and that the hypertrophy of the thyroid is a response to the demand. This might explain the very remarkable effects of thyroid feeding in cases of simple goître. In such cases, especially if recent and the subject young, administration of thyroid by the mouth is followed by a steady diminution in the size of the goître, the latter tending to increase again when the treatment is stopped.
....The occurrence of glycosuria as a result of thyroid administration has frequently been observed, and recent experiments tend to show that the glycosuria may be of the alimentary typed. Thus Bettmann, in the Berliner klinische Wochenschrift, No. 24, 1897, found that if, after a week of thyroid feeding, one gives a patient 100g. or so of glucose on an empty stomach glycosuria results. He was successful in obtaining it in about half of the cases in which the experiment was tried, although the same patient showed no glycosuria if a similar amount of glucose was given without a previous course of thyroid. Such experiments seem to indicate that the thyroid may sometimes affect carbohydrate metabolism in such a way as to diminish the power of the tissues to utilise sugar.
Increased rapidity of the heart's action is perhaps the most constant of the effects observed from thyroid administration. The action of the drug can hardly be said to be manifested, unless the pulse rise by 10 or more beats per minute.

....This specific effect of the thyroid upon the heart renders caution necessary in administering the drug to patients with cardiac debility. In cases of obesity, where the fatty change may also have affected the heart, this is especially necessary. It has also been suggested that his action of the thyroid would be likely to render its administration useful in cases of functional bradycardia.

It has been found that the active part of the thyroid has no effect on the blood pressure.
....Notwithstanding this experimental evidence the sphygmometer shows a slight fall of blood pressure in patients who are under the influence of the thyroid. The fall seems to be due to enfeeblement of the heart rather than to any peripheral dilation of blood vessels.
The effects of thyroid administration upon the blood have been studied both clinically and experimentally. Perry found that the only change which resulted from the administration of medicinal doses in man was an increase in the relative number of the lymphocytes (that is, a physiological leucocytosis).
....On the other hand, Lebreton has compared the blood in a case of myxoedema before and after thyroid feeding, and has found all the constituents increased and a greater relative increase also in the lymphocytes.
....It would seem, therefore, that small doses of thyroid produce no effect on the blood of healthy persons, while large doses cause an increased destruction of blood corpuscles just as of other cells. In myxoedema, on the other hand, the stimulus which thyroid feeding gives to all growth and division is manifested in the blood by rise in the number of the corpuscles.
The active constituent of the thyroid appears to be excreted entirely by the kidney. I have found iodine present in the urine of a dog within three hours after the administration of 1 g. of the colloid matter. On the other hand, I have never been able to detect any iodine in the bile of animals to which thyroid preparations have been given, even in large doses. Baumann has also detected iodine in the urine of dogs whose thyroids had been removed and to whom iodothyrin had been administered. It is difficult, however, to detect iodine in the urine of patients who are taking thyroid preparations.
....If a healthy thyroid be present, therefore, iodine does not appear in the urine unless large excess has been administered. ....On the other hand, the absence of thyroid in myxoedema prevents the storage of iodine in the body, and accordingly it is more easy to detect that substance in the urine of cases of myxoedema which are under thyroid treatment.
It must be admitted that we have as yet get no satisfactory method of standardising thyroid preparations.
....Practically the difficulty is got over if the preparation be made from a sufficiently large mass of glands. The individual inequalities in these are then able to neutralise one another. thus one finds that the composition of the colloid matter as found on the market is almost constant, and the thyroid powder of the new pharmacopoeia, and wil no doubt be so too, if prepared in fairly large quantities at a time.
....Whatever the preparation employed experience seems to show that it is best to give it in small doses and frequently, rather than in large quantities at longer intervals. It is also very necessary to feel one's way in the administration of the thyroid, beginning with a small dose, and gradually increasing it. This is necessitated by the fact that idiosyncrasy plays a large part in the reaction which patients show to the drug, and the extent of the reaction in any particular case can never be foretold.

Postscript.- Since the above article was written there has appeared in this JOURNAL. (July 9th, 1898) a paper by Dr. William MacLennan describing a new thyroid preparation (thyroglandin"). As that paper contains a number of what (in my judgement) are serious errors as to the facts of the chemistry of the thyroid and the nature of its active constituent, I feel that I ought to make a short reference to it. Dr. MacLennan asserts that the thyroid contains two important principles - an iodoglobulin and iodothyrin - and that both of these are requisite to produce the specific effects of the gland itself. This assertion is quite unfounded in fact.
....The process which Dr. MacLennan describes as that by which "thyroglandin" is prepared will be perceived at once by anyone conversant with the chemistry of the thyroid to result in the extraction of the colloid matter, plus the salts, extractives, and any other substance which happens to be present, and which is soluble either in water or in boiling caustic soda solution. As the salts and extractives have been shown to be "useless", and as the other substances (for example, products of decomposition) may very easily be objectionable, I entirely fail to see the superiority of this process over those already in existence. That the product is simply an impure form of the colloid mater I entertain no doubt at all, and by the administration of 11⁄2 gr. of the latter thrice daily I have over and over again obtained quite a marked results as were produced by double that dose of thyroglandin. I therefore cannot regard the latter preparation as in any way superior to those with which the profession is already familiar.


SIR,- The BRITISH MEDICAL JOURNAL of July 9th contained a paper of mine on a new preparation of thyroid (thyroglandin), and in the issue of the following week there is a postscript in Dr. Robert Hutchison's paper on the Pharmacological Action of the Thyroid Gland, calling certain statements in my paper in question.
The views I have expressed with reference to the chemistry of this new preparation (thyroglandin) are those of its inventor, E. C. S., F.I.C. I shall therefore leave him to confute in detail Dr. Hutchison's contentions.

Dr. Hutchison does not deny that thyroglandin contains all the constituents that the raw gland contains in the form and proportion in which these are found in the gland itself. So far as my experience goes, I am convinced that none of the extracted preparations at present on the market give such satisfactory results as the raw gland. They are used instead of the

gland because of the obvious disadvantages connected with the latter. I am well aware that the specific symptoms of thyroid action (thyroidism) can be produced by the "colloid" material of Dr. Hutchison and other preparations, but have these preparations exactly the same therapeutic effect as the gland itself? I pointed out that there are two principles in the thyroid gland because cold water separates them. Both of these contain iodine. Dr. Hutchison denies this, and maintains that there is "only one iodine-containing compound, namely the colloid mater." When a constituent can be separated from an animal substance by means of cold water alone, no chemist would think of using caustic soda to effect this purpose. The caustic soda would dissolve everything, and there is not the least probability that any iodoglobulin thus dissolved could be precipitated by an acid unchanged. I believe Stanford's preparation avoid these objections, and represents really all the active ingredients present in the raw gland.- I am, etc.,

Late University Assistant to the Chair of Materia Medica and Therapeutics, Glasgow University ; Dispensary Physician, Western Infirmary, Glasgow.
July 28th.

1898 THE BLOOD CHANGES AFTER EXPERIMENTAL THYROIDECTOMY. BY ALFRED G. LEVY, M.D. From the Department of Pathological Chemistry of University College, London.) BMJ SEPT. 3, 1898 Vol. II p 608 - 609

NUMEROUS observations have now been made on the striking and diverse phenomena incident upon the removal of the thyroid bodies of animals, yet the fact remains that we are still very much in the dark regarding the physiological functions of the thyroid secretion, and of the pathological process which must occur when the secretion is absent from the body. ....In experiments of this kind, it is, of course, essential that the parathyroids should be carefully removed with the thyroid gland, and this, fortunately, in the dog is easy to accomplish ; but the small accessory thyroid bodies which are known sometimes to exist in the tissues around the aorta and large vessels, and which, according to Cunningham, have an active function, render it difficult to be sure that the thyroid influence is in all cases entirely withdrawn, and perhaps on this fact largely depends the somewhat variable character of the changes in the blood which I have observed.

Throughout the experiments I gave careful attention to the housing and feeding of the dogs after they had been thyroidectomised, for an animal in this condition is so peculiarly susceptible to external debilitating influences that otherwise it would not be fair to ascribe its blood changes entirely to the loss of the thyroid secretion, but when bled the majority of my dogs were in very good bodily condition, and one indeed increased in weight after the operation.
I may remark the striking want of interdependence among the various blood changes, and that none of these bear any relation to the severity or rapidity of onset of the general symptoms of the cachexia. This apparently irresponsible accentuation of certain structural blood changes, as also of certain objective symptoms, may perhaps be partly referred to the "conditioning circumstances" such as temperature, hygienic surroundings, food, and, as I have already mentioned, to the existence of accessory thyroid bodies ; but it is only a full knowledge of the physiology of the thyroid gland which can satisfactorily ascribe to these things definite causal relations.

1899 THE GOULSTONIAN LECTURES OF THE PATHOLOGY OF THE THYROID GLAND. Delivered before the Royal College of Physicians of London. BY GEORGE R. MURRAY, M.A., M.D.,CAMB., F.R.C.P., Health Professor of Comparative Pathology to the University of Durham : Physician to the Royal Infirmary, Newcastle- upon-Tyne. BMJ MARCH 11, 1899 Vol. I p 577 - 582

p 577 LECTURE I.

In selecting the subject for these lectures I have been guided by three considerations. First, the widespread interest which has been aroused in the pathology and treatment of diseases of the thyroid gland during the last few years. Secondly, the good example which the subject affords of how experimental research in pathology yields results which are of the greatest importance and assistance to the physician in his daily work of treating disease. Thirdly, the opportunity which I have had of devoting some attention to the subject, may, I venture to hope, enable me to present it in a manner which will interest you.
I shall not attempt to cover the whole ground, but shall for the most part deal with those parts of the subject which I have been able to examine for myself, nor will time permit me to allude to all the valuable work which has been done by the many workers in this branch of pathology. I trust, therefore, that this explanation will excuse any omissions I may make in not referring to the work of others.
It will be convenient, first, to consider the development and structure of the thyroid gland and the method in which its characteristic secretion is produced. This will clear the way for the consideration of the results which follow when this function is diminished or lost by excision of the gland in animals or by its destruction by disease in man. The removal of the thyroidal insufficiency thus induced by maintaining a supply of secretion from other sources will be considered as a means of treatment. I propose also to deal with the question of compensatory hypertrophy, as illustrated by the thyroid gland ; while, in conclusion, the pathology of exophthalmic goître will be considered as far as our present knowledge of the subject permits.
The embryology and comparative anatomy of the thyroid gland furnish us with important information as to the origin of its

present situation, structure, and function in man. The gland is developed in the embryo in three different parts.
....Thus both the ontogenetic and phylogenetic history clearly show that the gland as we now find it in man is descended from a secretory gland which originally was provided with a duct through which the secretion passed into the pharynx, just as the secretion of the salivary glands still flows into the mouth. In this we find an explanation of the fact that the activity of the thyroid secretion is not destroyed by passage through the stomach, but still can produce all its usual physiological effects when swallowed and absorbed from the alimentary canal, as it doubtless was by our remote ancestors.
....The gland is firmly fixed to the larynx and trachea by fibrous tissue, so that it follows the movements of these structures which take place during deglutition. The gland when freshly removed is of a dark brown-red colour. It usually weighs from an ounce to an ounce and a-half (30 to 50 grams).
Externally the gland is invested by a firm fibrous capsule from which septa extend inwards, partially dividing it into lobules of various sizes.
....Two kinds of cells are found in this epithelium, the chief cells, and the colloid cells. The chief cells are usually cylindrical, sometimes cubical in shape.
....The colloid cells are considerably shorter than the chief cells, thus Hürthle found in one specimen that while the chief cells measured 12 to 14 μ in height, the colloid cells were only 7 to 9 μ high. The colloid cells are also distinguishable from the chief cells by the readiness with which they take up those staining fluids which also stain the colloid substance in the centre of the follicle. Intermediate types may also be observed.
The colloid substance which occupies the central space of the alveolus is a yellow glairy fluid which stains uniformly in microscopical sections. Scattered through it may sometimes be seen white blood corpuscles, epithelial cells, and the remains of red blood corpuscles undergoing degenerative changes.
The colloid substance is the secretion of the epithelial cells which line the alveoli.
....The large amount of secretion which is found in many alveoli indicates that under ordinary circumstances it is not discharged as soon as it is formed, but that the central portion of the alveolus serves as a reservoir where the secretion is stored for a time before it finally escapes from the gland. As the thyroid is a ductless gland it is clear that the secretion can only escape by either the lymphatics or the veins.
....No doubt as in other glands the activity of secretion varies according to circumstances. Of these, however, we possess but little information.
....As already mentioned, the presence of an excess of bile constituents in the blood after ligature of the bile duct also stimulates thyroidal secretion. Removal of the greater part of the gland was also shown by Hürthle to serve as a stimulus to more active secretion in the remaining portion.
At one time the thyroid gland was considered to be an excretory rather than a secretory gland, and the excretion a mucinoid substance, the retention of which led to an accumulation of mucin in the body and the production of the subcutaneous swelling in myxoedema.
Further investigation has shown that the colloid substance is a true secretion which does not contain mucin. Our knowledge of the actual composition of this secretion is by no means complete, but several important constituent have been separated from it. Most of those who have examined the composition of the secretion have considered the proteids to be the important and active constituents of it.
p 579
....It is evident from these observations that the secretion is a complex body, and we cannot as yet say whether its remarkable properties depend on one or, as is more probably, several constituents. Be this as it may, we shall now consider what functions are fulfilled by the secretion as a whole, for that is the form in which it mingles with the blood, and is thereby conveyed to the tissues.
A large amount of valuable information as to the properties and functions of this secretion has been obtained by observing what occurs when it is no longer present in the blood. This state of affairs is easily brought about by removal of the gland from an animal.
....In man the results of failure of the normal supply of thyroid secretion from disease of the gland are seen in primary myxoedema, and from removal of the gland for goître in secondary myxoedema, or cachexia strumipriva, as it is also called. My own observations show of the results of thyroidectomy have been made on rabbits and monkeys. It has, however, been shown that although no effects have been observed in fishes ; in lizards, and snakes, the operation is followed by loss of strength and activity, ending in death in the course of a few weeks.
....My own observations show that, although the immediate effects of thyroidectomy are very slight, after a long interval a chronic cachexia develops closely resembling myxoedema in man. Thus in two rabbits which were kept for a long time under observation after the thyroid gland had been removed, there was an early development of hebetude and loss of appetite. No further change was noticed until an interval of eleven months in one case and twelve in the other had elapsed after the operation. After this, in addition to the hebetude already mentioned, swelling of the subcutaneous tissues, dryness of the skin, loss of hair, and subnormal temperature developed, an entirely different condition to that described by Gley after removal of the parathyroids as well.

....Dogs and cats both develop a rapidly fatal cachexia after thyroidectomy.
....In dogs the total duration of the symptoms induced by the operation may vary from a few days to five weeks, but rarely exceeds this period. Soon after the operation the animal becomes dull and listless, and loses its appetite. These symptoms are followed by fibrillary twitchings in the muscles and clonic convulsions of the trunk and limbs, during which the animal lies on its side with the head thrown back and the limbs extended. There is great dyspnoea during these attacks, and the animal is in a half-comatose condition which becomes complete before death. There is a general diminution of muscular power, and in many cases rapid emaciation. There is a slight rise of the temperature at first which becomes subnormal before death. The red corpuscles are diminished and the white increased in number. Very similar symptoms occur in cats.
....In the bonnet monkey (macacus sinicus), which I have used, with one exception, in all my experiments, a parathyroid gland lies in close connection with, or actually embedded in, each lobe of the thyroid gland, as is shown in Figs. 1 and 2. As a result of this, when the thyroid gland is removed the parathyroids are removed along with it. It would be difficult to remove the one without the other, for distinctly as the parathyroid can be seen in a transverse section, it is much more difficult to see it during life while the gland is in situ.
It is, therefore, important to bear in mind that thyroidectomy in this monkey involves removal of the parathyroids as well, so that the symptoms which occur afterwards are not solely due to loss of thyroid secretion, but in part are due to loss of the parathyroids as well.
....After the operation the animals have been kept in a room, the temperature of which ranged between 60° and 70° F. In about five days the symptoms first begin to develop, the early symptoms being entirely nervous. One of the first to appear is a fine regular tremor, which is most easily seen in the upper limbs, but which is also plainly visible in the lower limbs as well when the animal is held with the feet unsupported. Along with the tremor there is a marked change in the whole demeanour, which is the more noticeable owing to the naturally lively disposition and active habits of the healthy monkey. There is progressive apathy, with loss of natural curiosity and interest in surrounding objects, while the temper is irritable, interference being resented. There is loss of activity, as the animals sits still in one place on a perch or on the floor of the cage for long periods without moving ; and increasing loss of muscular power, as climbing is done more slowly, and evidently with greater effort, as the symptoms advance. The attitude assumed is characteristic, the head is bent, the trunk curved forward, and the knees drawn up, so that the chin rests upon them, the joints of all four limbs being in a position of flexion.
....In consequence of these symptoms the gait is stiff and unsteady, and when the contracture is excessive the animal is obliged to walk on the heels owing to the tonic spasm of the flexors of the ankle raising the toes and sole of the foot from the ground. There is a marked tendency to fall over backwards, and a very slight push when the animal is sitting has a similar effect. True epileptic fits of greater or less intensity may occur. There may be a sudden loss of consciousness, so that if the monkey is on the perch at the time, it falls to the ground.
....The course of the symptoms is much more acute than in man, partly because the supply of thyroid secretion is cut off suddenly by the operation, while in primary myxoedema the supply only gradually fails as the disease of the gland advances. In both conditions we have the same progressive loss of mental and bodily activity, subnormal temperature, elastic subcutaneous oedema, dry skin, and loss of hair. In the monkey we have, however, acute nervous symptoms which do not occur in primary myxoedema, though some have been observed after thyroidectomy in man. I would suggest, however, from the results of removing the glands in rabbits and other animals, that these symptoms are in part due to the loss of the parathyroids, which, as we have seen, are removed along with the thyroid.
Opportunities for observing the effects of total thyroidectomy in man have occurred in cases in which that operation has been performed for goître. It is well known that in a certain number of these cases, as a result of the loss of thyroidal secretion, symptoms develop which are identical with those of primary myxoedema. Indeed, it was the striking similarity between the two, noticed by Sir F. Semon, which led to the appointment of the committee by the Clinical Society, whose report proved the identity of the two conditions and their dependence upon loss of function of the thyroid gland.
In man only three of the disease which occur in the thyroid gland appear to be capable of causing a sufficiently destructive lesion of the secreting cells to materially diminish the amount of secretion. Syphilis and actinomycosis of the gland have thus caused myxoedema. If these disease are successfully treated the gland recovers, sufficient secretion is one more formed, and the myxoedema disappears. The great majority of cases of primary myxoedema are due to a fibrosis of the gland with atrophy of the secreting epithelium. Unfortunately we know very little as yet of the cause or mode of origin of thyroidal fibrosis.
....The symptoms of myxoedema which occur in man as a result of this destructive disease of the gland were so ably described by Dr. Ord in his Bradshaw Lecture last year that they are familiar to all. I should, however, like again to draw attention to the fact that there are many cases of early thyroidal fibrosis in which the symptoms are not nearly so definite as in the advanced cases. I have endeavoured in a recent paper to show what are the chief characteristics of these cases - such as slight subcutaneous swelling and dryness of the skin, normal temperature, certain striking subjective nervous symptoms, etc. The opportunity of examining the condition of the gland at this early stage can only arise if death should occur from some accident or intercurrent disease. In the absence of definite information we can only conjecture that a much earlier stage of fibrosis will be found, for it is evident that in any given case the severity of the symptoms will vary directly with the amount of atrophy of the glandular structure.

The gradual changes in the appearance of a patient suffering from slowly progressing fibrosis of the thyroid gland will be illustrated by some photographs which will be shown at the next lecture, in which I shall deal with results of disease of the thyroid gland in the young and the rational treatment of myxoedema and cretinism.

1899 THE GOULSTONIAN LECTURES OF THE PATHOLOGY OF THE THYROID GLAND. Delivered before the Royal College of Physicians of London. BY GEORGE R. MURRAY, M.A., M.D.,CAMB., F.R.C.P., Health Professor of Comparative Pathology to the University of Durham : Physician to the Royal Infirmary, Newcastle- upon-Tyne. BMJ MARCH 11, 1899 Vol. I p 649 - 657

p 649
....As in myxoedema in the adult so in cretinism were found different degrees of severity. As the success of treatment depended so much upon an early start being made with it, he urged the importance of carefully considering the possibility of cretinism in all cases where some arrest of development was noticed early in life, they find various intermediate types between the extreme form of which he had given an example and ordinary myxoedema dependent upon the age at which the disease first commenced. The older the child at the time of the onset the less marked the want of development, and the more nearly the disease resembles the adult type.
Dr. Murray then stated that when the supply of the secretion was renewed, metabolism was once more completed in a normal manner, and in cretins was so markedly reawakened that general growth again progressed even after it had been arrested for ten or twenty years.
....The administration of thyroid extract in animals deprived of their thyroid gland rendered it possible to distinguish between the symptoms due to loss of the parathyroid to those due to the loss of the thyroid. It seemed probable that the acute nervous symptoms in the monkey, such as the fibrillary twitchings, the spastic rigidity, and perhaps also the tremors and convulsions were largely due to loss of the parathyroid, while the subcutaneous swelling, dryness of skin, loss of hair, subnormal temperature, and changes in the blood were due to loss of the thyroid secretion. That conclusion received further support from the close resemblance of the latter symptoms to those of primary myxoedema in man, which they knew to be the result of disease of the thyroid gland, there being no evidence as yet to show that the parathyroids were affected in this disease. If that be the correct explanation, it was not surprising that these particular symptoms were not influenced by the thyroid extract.
In primary and secondary myxoedema in man were seen the results of loss of thyroid secretion pure and simple, and consequently they were able to remove the symptoms entirely by giving a sufficient supply of the secretion.
The main objects of the treatment were to remove the symptoms by restoring normal metabolism as rapidly as possible without risk to the patient, and when that had been accomplished so to regulate the treatment as to continue the supply of thyroid secretion in sufficient quantity to maintain the normal rate of metabolism of the tissues generally. For that purpose the treatment was divided into two stages. During the first stage the tissues were gradually brought back to a normal condition. That might, according to the severity of the symptoms, require from one to three months. As soon as the symptoms had entirely disappeared, the first stage was completed. The condition of the atrophied thyroid gland was not influenced by the treatment, so that if the artificial supply of secretion was discontinued at that or any other time of the patient's life, all the symptoms of myxoedema would gradually return, as he had found by actual experience. Thus the second stage of the treatment of necessity lasts as long as the patient lives. It is therefore necessary to make the permanent daily dose as nearly as possible equivalent to the normal amount of secretion. If the dose fell below that, slight symptoms of myxoedema would reappear, and if it was excessive a condition of thyroidism will be produced.
Dr. Murray observed that in out-of-the way places, and where expense was a consideration,, the actual gland itself containing the secretion might be administered. One-eighth to one quarter of a lobe of the sheep's gland was a suitable daily dose, one quarter being equivalent to about 10 minims of liquor thyroidei ; it should be minced.
In advanced cases the first stage of the treatment must be carried out with great caution, especially if any symptoms of degeneration of the cardiac muscle, such as attacks of syncope, dyspnoea on exertion, feeble or irregular pulse, or weak heart-sounds were present. Under these circumstances the patient should be confined to bed at first, and only small doses of three to five minims of liquor thyroidei given each night. This dose, if well borne, might be gradually increased up to ten minims. If not confined to bed these patients are apt to make use of their returning vigour too soon, before the heart has had time to recover, and to adapt itself to the altered conditions brought about by the treatment.
At the present day, however, the greater number which require treatment were seen in the early stages before any cardiac symptoms developed. Such patients were able to go about, but unusual exertion should be avoided during the first stage of the treatment.
....The second stage of treatment began after all the symptoms of myxoedema had disappeared. During this stage, which lasted whilst the patient lived, he must continue to take a daily dose equivalent to the daily output of the gland before it

became diseased. An occasional intermission of a week or so had little or no effect, but if it lasted three or four weeks the temperature fell one or two degrees, and the myxoedematous swelling of the face began again to develop. The most suitable dose during the second stage was, generally speaking, ten minims of the extract once a day, but if slight symptoms reappeared the permanent dose should be increased to twelve or fifteen minims. Though this had not been necessary in any of his own cases, in a few cases that dose had produced acceleration of the pulse, and the permanent dose had to be fixed at five or seven minims a day.

When the treatment of a well-marked case of myxoedema was carried out on the lines just indicated, very definite and interesting results were soon obtained. One of the earliest signs of improvement was in the return of the temperature to the normal level. This was illustrated by the chart shown; by which it would be seen that the temperature before treatment ranged from 95° to 96° F., whereas during the second, third, and fourth weeks of treatment it varied between 96° and 98°. As the temperature rises to normal the former sensitiveness to cold was lost, and the frequency of the pulse was increased. The most striking changes were those which took place in the skin with its appendages and in the subcutaneous tissues. The myxoedematous swelling gradually disappeared from all parts of the body, so that the face and hands once more assumed their natural appearance, and the free movement of the limbs, which had been considerably hampered by the swelling, was regained. The reduction of the swelling was accompanied by a loss of weight, which might amount to as much as two or even four stones. The skin, which, as a result of the removal of the swelling, may for a time remain loose and wrinkled, became warm and moist owing to a renewal of the secretory activity of the sebaceous and sweat glands. Not infrequently there was some desquamation which might occur in fine scales or in large flakes from the palms of the hands and soles of the feet, as observed by Byrom Bramwell. The hair follicles resumed their proper function, so that even where there had been complete baldness a good growth of hair was developed in the course of six or twelve months. Considerable changes are thus produced in the appearance of the patient.
In addition to these very obvious signs of improvement, the feeling of lassitude passed away and normal muscular strength and activity were regained. As a result of this, those who before treatment could barely walk a mile were enabled to walk long distances, climb mountains, and undertake various other forms of exercise. Mental processes became more active, the memory improved, and the hallucinations disappeared. In some cases in which actual insanity had occurred it also had been cured. If albuminuria without actual renal disease had been present it disappeared, while the amount of urine was increase. The observations of Ord and White showed that the total amount of nitrogen eliminated was increased, and that the increase was almost entirely due to the increase of urea in the urine. At first the amount of urea excreted might not only equal but actually exceed the normal average quantity. The number of red corpuscles in the blood were increased. In patients who had not reached the menopause menstruation returned, and took place regularly, even where there had been amenorrhoea for several years. In fact, the myxoedema was entirely cured, though the fibrosis of the thyroid gland remained unaffected by the treatment.
Dr Murray dwelt on the importance of carefully considering the possibility of disease or lack of development of the thyroid gland in every case of arrest or delay of development in children. In all such cases it was important to look for slight signs of cretinism. The importance of early diagnosis in such cases lay in the fact that the earlier the treatment was commenced the better prospect there was of normal development of the central nervous system. Experience had already shown that in cretinism of some years' duration rapid as the improvement in the physical condition may be, the intellectual development was much slower, so that when treatment was commenced late it was doubtful if the latter would ever advance nearly as far as when treatment was started early
When the necessary stimulus to the normal metabolism of growth was thus supplied to a cretin in the early stages of the disease the symptoms soon disappeared. The swelling gradually diminished in all parts of the body ; the tongue, lips, and nose diminished in size, so that the appearance became natural ; the skin became soft and moist and the temperature rose to normal. Growth, which at this early stage would only have been partially arrested, started afresh. If the treatment was continuously carried on in such a case from the earliest time at which the disease was recognisable, there seemed no reason to doubt that ultimately the child would grow up into a fully-developed adult, who, however, would, of course, at any time develop symptoms of myxoedema if his supply of the extract was discontinued.
p 652
....The intellectual development was always much slower than the bodily growth and general improvement in all other respects. The shorter the duration of symptoms had been at the commencement of the treatment the more rapid the improvement in the mental condition, and Dr. Murray thought it was only in cases in which the treatment was started early that they could expect normal intellectual development to take place. In cases of some duration it was important that a special education should be carried on at the same time as the treatment in order that the patient might be able to make the most of his renewed cerebral activity.

THE whole question of compensation and compensatory hypertrophy of organs in disease is of such great interest and practical importance that any facts which tend to throw light on the conditions under which they are developed are of value. In health we can by specially-arranged exercises bring into operation the pathological law that any muscle contracting

intermittingly against an increased resistance which it can overcome undergoes hypertrophy, and thus induce hypertrophy of the biceps or any other muscle. In some diseases our chief object is to favour and encourage compensating hypertrophy by every means in our power.
....The glandular organs of the body have also remarkable powers of development under the influence of appropriate stimuli - as, for example, the development of the mammary glands during pregnancy. Both secretory ands excretory glands can undergo compensatory hypertrophy when a portion of the gland has been disabled by disease or design in such a manner as to throw an increased amount of work upon the reminder.

....Owing to the special anatomical position and physiological properties of the thyroid gland it affords unusual facilities for observing some of the phenomena of compensatory hypertrophy.
....When sufficient hypertrophy has developed to supply as much secretion as is necessary, we do not find a simple hyperplasia of the original glandular tissue, but considerable change in the structure throughout. The alveoli, instead of being nearly circular, become irregular in outline. This change is due to the folding of the wall, which projects at different points into the lumen of the alveolus. in advanced hypertrophy the lumen may appear to be star shaped, or it may be almost obliterated by neighbouring folds of epithelium coming into contact. The appearance in places may thus closely resemble that of a racemose gland.

p 653
....The appearances just described are evidently those of glandular tissue working at high pressure, and just able to supply the necessary amount of secretion without storing any in reserve in the alveoli as is usual in the normal gland.
....In connection with this part of the subject I have tried the effect of prolonged administration of thyroid extract upon the healthy thyroid gland. It is well known that parenchymatous goîtres often decrease in size when treated by thyroid extract. One explanation of this result is that a partial atrophy from disuse is established when the full amount of secretion is supplied from an external source. Two experiments have been made to ascertain if any atrophic changes could be induced in the healthy thyroid gland by supplying secretion ready made as it were and so doing away with the normal stimulus to secretion. The thymus atrophies after the first year of life from disuse, and the thyroid does so itself in old age, possibly for the same reason.
The pathology of goître is a subject of much importance, for the disease is still endemic in this country in the valleys which drain the Pennine range of hills east and west from the Border as far south as the Peak in Derbyshire. Time will not permit me to discuss the question of the origin of endemic and sporadic goître, but I wish to draw attention to the interesting effects which have followed the treatment of simple parenchymatous goître by thyroid extract. At first sight such treatment may seem somewhat superfluous, but experience has shown, and to that of others I can add my own, that this method of treatment frequently leads to a notable diminution in the size of the goître.
....The beneficial effects of this treatment may be due to the iodine which is present in combination with a proteid in thyroid extract, for iodine has long been used with good results in the treatment of goître.
Exophthalmic goître, with its many varying phrases, is a disease of great interest from several points of view. The various clinical types in which it comes before us, and the great difficulties in treatment it often presents renders a true solution of the problem of its pathology of the greatest importance.
p 654
....For additional reasons which we shall now consider the most rational explanation of the complex symptoms of this disease appears to be that they are due to an excessive formation and absorption of the secretion of the thyroid gland, which may or may not be altered in composition, and to the constant presence of this excess in the blood, and to its action upon the metabolism of the tissues generally, but more especially of the nerve centres in the medulla.
According to this view exophthalmic goître is the opposite condition to myxoedema, the former being the result of excess as the latter undoubtedly is of lack of thyroid secretion in the blood. This is supported by the strong contrast which is presented by the symptoms of the two diseases, a contrast which is nearly as marked as that between the small fibrous and atrophied gland of myxoedema and the enlarged hypertrophied gland of exophthalmic goître. Associated with the former we have increase of weight, stolidity, subnormal temperature, dryness of the skin due to diminution of cutaneous secretion, with increase of electrical resistance and slowing of the pulse, while with the latter, we find emaciation, nervousness, normal or raised temperature, moist skin due to increase of secretion, with diminished electrical resistance and acceleration of the pulse. We may conveniently express the relationship of myxoedema to exophthalmic goître in their various degree of severity in the following diagramatic manner. If we take 100 as representing the normal amount of thyroid secretion in health, then 75 per cent. is probably about the amount of secretion formed in those cases of early thyroidal fibrosis with slight myxoedema to which I have already alluded. If half the glandular tissue is destroyed and only 50 per cent of secretion is formed, the symptoms will be moderate. If 25 per cent. the symptoms will be well marked, and if none at all is found they will be severe. In the reverse way, in exophthalmic goître 125 per cent. of secretion would be present in a slight case, 150 per cent. in a moderate one, 175 per cent. in a well-marked one, and 200 per cent. in a severe case.
In myxoedema these percentages are in all probability approximately correct. In exophthalmic goître, however, we have no means of ascertaining how much secretion is actually formed. It may amount to much more than double the normal quantity in a severe case, so that these percentages are purely relative, and must not be taken to indicate the actual mount of secretion present in the blood.

Another interesting point in the relationship between the two diseases is the repeatedly-observed fact that recovery from exophthalmic goître may be followed by myxoedema, while, as far as I am aware, exophthalmic goître has never been observed to develop in a patient already suffering from myxoedema. In some cases the symptoms of exophthalmic goître diminish as those of myxoedema develop, in others, there is an interval of good health between the disappearance of the exophthalmic goître and the onset of the myxoedema. In a case recorded by Baldwin, exophthalmic goître developed in 1887, and recovery took place the following year. Two years after, in 1890, myxoedema developed which three years later was successfully dealt with by the thyroid treatment. In a similar case recorded by Joffroy and Achard, and quoted by Moebius, the exophthalmic goître existed for twenty-three years and then subsided, to be followed by myxoedema.

After death the nervous system was found to be quite normal, and the thyroid gland in an advanced stage of atrophy. It thus seems evident that the development of thyroidal fibrosis in exophthalmic goître, by lessening the over-activity of the gland, leads to a subsidence of the symptoms, which, if the fibrosis and atrophy progress far enough, are replaced by those of myxoedema.

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....Still more important are the results which have been observed and follow large doses of thyroid extract in man. A condition of thyroidism seems to be more easily produced in those who have recovered from myxoedema than in those who have normal thyroid glands. It may develop rapidly if large doses are given, or more slowly if smaller, but still excessive doses are given for a long period. The earliest and most common symptom is increased frequency of the pulse. The patient complains of palpitation, and the heart beats violently 100, 120, or 130 times a minute. A fine tremor of the hands is often present, and the skin is flushed and moist. If the large doses are continued for some time emaciation also takes place.
In addition to these symptoms, elevation of temperature, restlessness, loss of sleep, polyuria, abuminuria, glycosuria, partial paraplegia, sensation of heat, and diarrhoea, all of which are occasional symptoms of exophthalmic goître, have been recorded.
....It is now well known that thyroid extract has a bad effect on patients with exophthalmic goître. Under its influence the pulse becomes more frequent and the other symptoms are increased. In some instances where other treatment had been followed by a marked improvement the administration of thyroid extract has been followed by a relapse into the former condition. In my opinion it should never be given in exophthalmic goître, as it is only adding fuel to the fire.
....It is a fact of considerable interest that along with the enlargement of the thyroid gland in exophthalmic goître other ductless glands may be increased in size.
....In acromegaly the pituitary gland is enlarged, and the enlargement seems to be analogous to that of the thyroid in exophthalmic goître, so that we have the remarkable fact that all these three ductless glands may be simultaneously enlarged. We know no explanation of this, but it suggests that possibly some common factor may be the cause of the enlargement. That some association exists between the thyroid and pituitary glands is further shown by the enlargement which takes place in the latter when the former is removed or disabled by disease.
These facts all indicate that in the treatment of exophthalmic goître attention should be directed to the thyroid gland. Time will not permit me to discuss the question of operative treatment, but there can be little doubt that removal of part of the enlarged gland is a rational method of treatment, and when the risks of the operation are diminished it should be more frequently employed in severe cases in which medical treatment has failed to do good.
....In conclusion, Mr. President and gentlemen, allow me to thank you for the kind help you have given me by your attention in my endeavour to place before you some of the facts which help to explain the function of the thyroid gland and the practical uses to which such knowledge can be put in the treatment of disease, and I trust that the wishes of the founder of this lectureship have thus been carried out in the spirit, if not in the actual letter, of his bequest.


The work reported in this paper was undertaken at the suggestion of A.J. Carlson, primarily for establishing a biological test for the active principle of the thyroid gland in the blood.
A few years ago Hunt, by means of the acetonitril test, thought that he had a reliable test for the active principle of the thyroid in the blood. Later investigators (Carlson and Woelfel, Lussky) failed to detect any active principle of the thyroid in the blood of the dog, and in rabbits and guinea-pigs in experimental hyperthyroidism by means of this test. Hunt studied the blood of clinical cases of exophthalmic goiter and obtained a positive test in two out of three cases. On the other hand, Carlson and Woelfel could not get a positive reaction in a case studied by them. Carlson also tested his own blood after having taken thyroid until toxic symptoms arose, with negative results. The presence of iodin in the blood in "hyperthyroidism" has recently been shown by Jones and Tatum. They found that intravenous injections of blood serum from hyperthyroid-fed rabbits increased the iodin content of the thyroid glands of the rabbits which were injected.
Another method of attack relates to the changes of excitability of the depressor nerve. Von Cyon and Oswald found that injection of thyroid extract increases the irritability of the depressor nerve. Asher and Flack reported some interesting results on the excitability of the depressor nerve before and after stimulation of the thyroid nerves, and the effects of small intravenous injections of epinephrin before and after such stimulation. The excitability of the depressor nerves is increased during or immediately following the stimulation of the thyroid nerves. They ascribe these results to the action of increased quantity of thyroid secretion poured into the blood on stimulation of the thyroid nerves. After extirpation of the thyroid

gland, stimulation of the thyroid nerves failed to produce increased excitability of the depressor nerve. According to their report, intravenous injection of thyroid extract acts similarly to stimulation of the thyroid nerves. Ossakin (1914) working in Asher's laboratory repeated and apparently confirmed Asher and Flack's work.
The experiments were carried out on cretin rabbits produced by complete thyroidectomy. Five lines of investigation were undertaken.

1. The transfusion of normal blood serum. 2. The transfusion of "hyperthyroid" blood serum. 3. The feeding of Standard U.S.P. thyroid products. 4. The feeding of Koch's thyroid metaprotein. 5. The feeding of Kendall's extract B.

The litters of rabbits were all raised from healthy albino stock of approximately uniform size. They were all kept in cages with their mother until 6 weeks of age, after which they were separated and the mother was again mated.
The animals were fed with oats, carrots, alfalfa hay and water daily. It is essential that the diet of the different litters be as uniform as possible, because of the great variation of growth curves with various foods. In this way the growth curves of various litters were made practically uniform.
Thyroidectomy was performed on the young rabbits at the age of 2 to 3 weeks, when their average weight was about when their average weight was about 175 gm. One or two members of each litter were kept as controls. In the removal of the thyroids, the method of Hofmeisfer was followed, with usual aseptic procedures. Through a median incision of about 2 cm. over the prominence of the larynx, the subcutaneous tissue and muscles were separated, bringing the thyroid cartilage into view. The thyroid glands lying on both sides of the trachea are, in rabbits, always connected at the lower pole by an isthmus, more or less flat and membranous. The gland is usually so closely adherent to the thyroid cartilage, especially at its posterior end, that it can be separated only with difficulty. With a fine pointed probe, the lower pole is carefully separated from the recurrent laryngeal nerve and the surrounding pericapsular tissue. It is essential that the recurrent laryngeal nerve should not be injured because of the fatal dyspnea following such an injury. Care was also taken to leave the external parathyroids intact. One or more may usually be seen in the pericapsular tissue. The arteries were either ligated before division or, if small, they were clamped and crushed with forceps before division. The thyroid tissue was carefully dissected away from the thyroid cartilage and this lobe, together with the connecting isthmus, was reflected over the remaining lobe. This love was separated in a similar way. Great care has to be taken to remove all of the thyroid tissue, because it is surprising how fast small remnants of tissue with hypertrophy. Such remnants, if present, postmortem examination were usually found on the posterior end, closely adherent to the thyroid cartilage. These nodules always showed marked evidence of hypertrophy. However, these remnants were never more than one-tenth of the size of one of the lobes.

In the present series the onset and development of the cretin symptoms were always similar. About two weeks after the operation the hair becomes noticeably drier and does not lie smooth and flat on the skin as normally. It stands up and can be pulled out very easily. At the same time there is a gradual retardation of growth. This is noticeable as early as the third week after the operation.

....The weight of the normal rabbit is 1,630 gm., while the weight of the cretins are 760 and 840 gm., respectively. The posture of the cretins is typical. The limbs are short and the muscles are too weak for support. The bones show a pseudorickety condition which Hofmeister calls "chondrodystrophia thyreopriva." The hair becomes coarse and can be pulled out in bunches. The skin becomes dry, thick and scaly, gradually turning into a typical eczema covered with crusty scales. This is always most marked about the head, ears, shoulders and legs. The proportionate growth of the abdomen over that of the rest of the body gradually increases and the cretin acquires the descriptive "pot belly" type of abdomen. They are slow, awkward and move about very reluctantly. If not disturbed, they may remain for hours in the same place.

The clinical literature on the beneficial effects of thyroid feeding on cretinism seems conclusive. In man, however, it is frequently difficult to decide whether we are dealing with cases of pure cretinism due to deficiency of thyroid activity, or with other diseases.

The cretins were produced experimentally according to the method described above. Eight cretins from four litters were fed with the desiccated thyroid. As soon as the symptoms of cretinism appeaared, which was usually at the beginning of the third or fourth week, thyroid feeding was started. The thyroid was weighed out in small-size gelatin capsules. Such capsules can be fed without much difficulty. The initial dose was 0.0015 gm. given daily. Cretin rabbits are very susceptible to thyroid feeding. Toxic symptoms develop with much smaller doses than with the normal rabbit of the same size. This is evidently due to the absence of the thyroid gland, which normally has been shown by Jones and Tatum to take the organic iodin out of the blood very quickly. The animals were weighed twice a week and if there was any evidence of toxicity as shown by the growth curve, and other symptoms, then the dose was reduced. This dose was gradually increased. By the twentieth week the amount given was on the average 0.075 gm. Great care had to be taken to prevent toxicity because

usually the animal lost so much weight that it took several weeks merely to recover his original weight.

.... Growth continues about eight weeks after the maximum growth of the normal rabbit has been reached. In no case was it possible to reach the growth of normal rabbits, as some investigators claim to have done. This was probably due to the fact that feeding experiments are difficult to control because of the lessened resistance to the thyroid feeding.
The symptoms of cretinism gradually disappeared. The hair became smooth and attained the moist, oily appearance of the normal rabbit. The scaly condition of the skin about the ears and legs disappeared. The pot belly, so characteristic of cretins about the eighth week, gradually disappeared. The animals became more active and the weakness of the muscles, bones and joints was not noticeable after six weeks' feeding. Deformities of the bones never appeared in any of the thyroid-fed rabbits. .... When the thyroid feeding in the cretins is discontinued for some time, certain symptoms of thyroid deficiency soon become evident. This is evident from figure 0. Thyroid feeding had been discontinued in the two rabbits for five months. They appeared perfectly normal when the thyroid feeding was stopped. The hair soon became dry, coarse, and could easily be pulled out in bunches. The skin became dry, scaly and gradually became eczematous. This was most evident on forehead, ears, legs and abdomen. The weakness of bones, muscles and joints also reappeared. The animals once more acquired the typical symptoms of cretinism and except for their size, which was induced by thyroid feeding, could not be differential from cretins which served as controls.

The feeding experiments show that experimental cretinism can be very effectively controlled by the use of standard thyroid preparations. It is evident from the experiments, that a very small dose given daily is sufficient to supply the physiological needs. This amount ranges from 0.015 gm. given daily at the beginning of the experiment, to 0.075 gm. at the age of 20 weeks. Toxicity from the thyroid feeding is more readily induced in cretins than in normal rabbits of the same age.
Since it is known that the thyroid gland has a great chemical affinity for iodin and iodin compounds, there would probably seldom be an excessive amount of the active principle of the thyroid in the blood of normal rabbits. This probably accounts for the greater toxicity in thyroidectomized rabbits.
1. Transfusion of normal blood serum into cretins has no effect on the condition of cretins.
2. Transfusion of "hyperthyroid" (thyroid-fed animal's) blood serum into cretins is effective in increasing the growth and in controlling the other symptoms of cretinism. The improvement, however, is not as marked ass with the thyroid feeding.
3. Standard thyroid preparations (containing 0.2 per. cent. iodin in organic combinations), when given in carefully controlled nontoxic doses, will increase the growth of cretin rabbits and prevent the development of, or counteract, the other symptoms of cretinism. But thyroid feeding fails to carry an absolute cretin to full normal stature. Discontinuing the thyroid feeding leads to a return of some of the cretin symptoms.
4. The thyroid metaprotein of Koch is somewhat more active than standard thyroid preparations, but also more toxic.
5. Kendall's thyroid Extract B. has no effect on any of the symptoms of cretinism. It is nontoxic, at least in ordinary doses. 6. Cretins are more susceptible than the normal animals to the toxic action of thyroid (thyroid feeding).
7. Cretin rabbits, despite their retarded rate of growth, continue to grow for a considerably longer time (four to six weeks) than the controls of the same litter.