Thyroidhistory

Note this one contains several notes describing treatment with desiccated Thyroid, Thyroidinum

extracts in date order from 1887 - 2001
(less than 10% of original manuscript to comply with copyright restrictions)

1887 Transactions Clinical Society London

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RETURN TO HOMEPAGE

XVIII.-A Case of Myxoedema in a Male. By ARTHUR DAVIES, M.B. Exhibited February 25, 1887.

GEORGE W. aet. 38. Was born in London, where he has always lived. Is married and the father of three children, of whom one is alive and healthy, one died in infancy, and one was stillborn. Always been temperate; drinks ale. Had scarlet fever at three years of age, water on the brain at nine years of age) and St. Vitus's dance at ten years of age. Eight years ago fell from the top of a tree to the bottom on his face.

Was formerly very active. About five years ago he noticed, or rather his friends told him, that his face was beginning to swell. The swelling appeared first in the eyelids, the sides of the nose, and cheeks. He noticed at the same time that his gait was unsteady, so that he was at times thought to be drunk; he had a tendency to fall on his right side. Formerly he could walk very quickly. He has always felt chilly. During the last four years he has been slower in action and thought, and for the last two years has had difficulty in articulating his words, owving to his tongue being too large for his mouth. He says that his teeth began to fallout and his hair to be loose before the swelling of face began. Patient has a heavy stolid appearance; the hair on the vertex is thin and scanty) the integument of forehead is thickened, of a yellowish pigmentation) and has a few wrinkles. The eyebrows are very arched and the eyelashes thin. The eyebrows are puffy, transversely wrinkled and pearly in aspect; the root of the nose is broad and thick and the alaei nasi thick, fixed and broad; the cheeks are puffy and full, and present a defined

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delicate pink flush, whilst the lips are thick, especially the lower, which is often of a purplish hue, the tongue is broad and thick, ana there is very marked thickening of the mucous membrane of the cheeks ana palate. The gums are lobulated and thickened, and the teeth loose. The voice is monotonous and articulation slow. The thyroid is not perceptible. The hands are clumsy and expressionless, and the skin over the extensor surface of arms ana hands is dry and scaly; has occasional numbness in fingers. Pulse is 72, regular, small volume.

The chest ana abdomen are normal. There is some slight pitting along the course of left tibia. Reflexes (patellar) fairly marked no ankle-clonus. Some solid oedema over the backs of feet. Urine 1016, no albumen or sugar, urea 1.1 per cent., phosphates. Taste perverted. Temp. subnormal. Hearing fair. Gait slow and heavy. Father died of apoplexy. Has one sister, who is dropsical.

XIX. - A case of Myxoedema. By ARTHUR DAVIES, M.B. Exhibitred February 25, 1887.

ADA ELIZABETH B., 41, single, was born at Brighton, but has lived in London always. Five or six years ago she noticed " suffocation feelings and risings " in stomach. About three years ago she noticed that she was swelling all over, especially in the legs and feet, so that she was unable to bend them. Very shortly afterwards her hands began to swell, especially across the knuckles; one year ago her friends told her that her face was getting stout, ana she noticed swelling, especially about the eyelids, nose, and lips, so that she appeared " to look cross and to pout at people." At the same time her throat ached whilst talking, and she was obliged to give up singing, and to talk slowly on account of the thickness of her lips. She was formerly very active and quick, but during the last year or two she has been obliged to give in on account of the difficulty she felt in exerting herself.

She has complained of dryness of the skin for two years, and also partial loss of power in her arms. Her teeth have been loose for three or four years) and her hair has come out a good deal of late. During the last two or three years has bad a feeling at times as if everything " was going on her left

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side," and she has had occasional giddiness in walking. For three years she has been slower in thought and action, so that she used to get lost in her business, and her memory has been impaired for two or three years, and her taste and smell have been lost at times, also hearing. She had gastric fever eighteen years ago, and although never laid up except for this illness has never been quite weIl, especially during the last six or eight years. Her father is alive and well, her mother also alive, but delicate. Five sisters and brothers died in infancy. Her maternal grandfather died of angina pectoris, and a maternal uncle of "galloping consumption." One paternal aunt had epilepsy. Patieut is heavy looking in appearance; hair dark brown; irides grey; the eyelids are pearly in aspect and thickened. Skin of forehead has a yellowish tinge, hair still abundant on vertex; there is thickening of the alffi nasi and also of the lips, especially the lower. Cheeks are puffy, and present a delicate pink flush ; root of nose broad ; tongue is big and flab by; and the teeth are loose ; no swelling of gums. There is some thickening of interior of cheeks and soft palate. The voice is slow ; no special fulness above clavicles. Thyroid not felt. Pulse 60, regular, and of fair volume. Chest normal. No marked thickening of hands ; skin on the extensor surfaces dry and scaly. No marked oedema of legs or feet. Temperature subnormal. Urine sp. gr. 1020, trace of albumen ; no sugar. Patella reflexes absent.

1894 BOOK REVIEW: MYXOEDEMA, CRETINISM, AND THE GOITRES, WITH SOME OF THEIR RELATIONS. BY EDWARD T. BLAKE, M.D., M.R.C.S. Bristol : John Wright and Co. 1894. (Roy, 8vo, pp. 90, with 7 full page illustrations. 3s. 6d.) BMJ DEC 22, 1894 Vol. II, p1431
THE reader, Dr. Blake states in the first words of his preface, will soon find that the burden of this book is the septic or the infective nature of disease. This being so the title is somewhat misleading, and if the reader expects a complete and up-to- date account of these diseases, which have excited so much interest of late, he will be very much disappointed. Dr Blake's work is, in fact, a thesis in support of certain peculiar views which he holds as to the etiology of myxoedema, etc. Incidentally he mentions a number of facts in regard to these diseases, but they are disconnected and ill arranged, and the whole is little calculated to be of much service either to the student or to the practitioner.
He regards Graves's disease as an autotoxis most frequently caused by the absorption of purulent products, that process being aided rather than induced by the toxins of terror or shock. The same products may produce rheumatism in males as well as myxoedema, mania, epilepsy, chorea, and possibly also Addison's disease. It would be easy to bring forward exactly the same arguments in favour of a similar etiology for any other disease. The toxins of a lively imagination have as real a claim to existence as some of those of which Dr. Blake so confidently speaks.
The book is well printed, and is furnished with copious indices. The illustrations are numerous, and although those of myxoedema are not as typical as they might have been, those of cretinism and exophthalmic goitre are excellent.

1897 ACQUIRED CRETINISM OR JUVENILE MYXOEDEMA. BY WILLIAM RUSHTON PARKER, M.A., M.D.CANTAB., Surgeon to the Kendal Hospital. BMJ MAY 29, 1897 Vol. I p1339 - 1340
CRETINISM is the result of loss of thyroid action in youth, and varies in proportion both to the extent of the loss and to the degree of youthfulness. Three varieties may be distinguished both etiologically and pathologically. In one the thyroid is embryologically not developed, or very partially developed, the cause being presumably akin to that which brings about any other embryological deficiency, such as acardia, acephalia, anencephalia, absence or abortion of uterus, ovaries, or testicles. In a second the thyroid undergoes the same changes as in endemic goître, and doubtless from the same cause, any differences being due to loss of thyroid function. In a third the thyroid, after functionating healthily for a time, atrophies, doubtless from causes akin to those of adult myxoedema. This third variety may be distinguished from congenital cretinism and from goîtrous cretinism by the term congenital cretinism (non-goîtrous) cretinism or juvenile myxoedema.

1898 CLINICAL SOCIETY OF LONDON. Friday, October 28th, 1898 JOHN LANGTON, F.R.C.S., President, in the Chair. p 1431 - 1432
p 1432

....MYXOEDEMA IN A CHILD
Dr. BERTRAM ABRAHAMS showed a case of myxoedema in a child, aged 7. She was unable to walk until five years of

age. When 6 1/2 years she rapidly became fat, her tongue grew large, and in ten weeks she became helpless and unable to feed herself. She was put on treatment with thyroid extract, and within thirty days her weight fell from 44 lbs. to 33 lbs., and she became more active and was able to go to school. The treatment was left off by her parents and the symptoms returned. There was a curious induration of the muscles of the calf resembling that of muscular pseudo-hypertrophy, probably due to the deposition of mucin. The child began with cretinic symptoms, and then developed symptoms of myxoedema. Her pulse was at first only 66 ; after treatment with thyroid extract it rose to 108.

LUPUS TREATED BY THYROID COLLOID
Mr. PEARCE GOULD showed a case of severe lupus in a woman, aged 47. She had suffered since childhood from glands in the neck, and in 1879 the glands broke down, and lupoid ulceration gradually extended over the face. Afterwards, tuberculous disease occurred in the foot, which was amputated, and she had abscesses in various parts. These had all healed

before she came under treatment. She then had an ulcer extending right across the face, reaching from the eyelids to the mouth, and from one mastoid process to the other. His house surgeon, Mr. Mannington, ordered tabloids of thyroid colloid which were begun on September, 1898, and in three weeks the face had entirely healed over. A single tabloid of the colloid was being still given daily, and the scar tissue had become more supple, and the ectropion much less marked ; and the pain, which was very considerable, had disappeared. He had seen similar but less rapid improvement in other cases.

Dr PRINGLE confirmed the value of thyroid treatment in such cases, but thought that thyroid colloid tabloids effected more improvement than anything else Unfortunately the cases when reported as cured were apt to relapse, unless the treatment was afterwards continued indefinitely. The scar following lupus was not ordinary scar tissue, as remains of lupus tissue could always be found in it.

Dr. A. WHITFIELD thought the case was one of scrofulodermia rather than of lupus vulgaris ; and remarked that thyroid treatment produced greater benefit in the ulcerative forms of tuberculous lesions than in the granular lupoid forms.

1898 THE DIAGNOSIS OF EARLY THYROIDAL FIBROSIS. BY GEORGE R. MURRAY, M.A., M.D.Camb., F.R.C.P., Health Professor of Comparative Pathology in the University of Durham Physician to the Royal Infirmary, Newcastle-upon Tyne. BMJ OCT. 1, 1898 Vol. II, p 942 - 944
THE object of this short communication is to draw more attention to a class of cases of early disease with partial disablement of the thyroid gland which are more common than is generally supposed. The symptoms in these cases are not as yet sufficiently well recognised, and are apt, therefore, either to be passed over or attributed to some other cause than the right one.

We are all perfectly familiar with the symptoms of advanced or even total thyroidal insufficiency which are seen in typical cases of myxoedema, symptoms which are identical and equally the result of loss of glandular tissue, whether it occurs in association with thyroidal fibrosis or as a result of removal of too much of the gland in the operation of thyroidectomy for goître. Minor degrees of thyroidal insufficiency are less easily recognised, and it is to some examples of this condition that I wish to draw attention. In my own cases the symptoms appear to be the result of a certain amount of atrophy of the glandular tissue of the thyroid with fibrosis, as this coincides with modern views as to the secondary nature of fibrosis to atrophy. It is, of course, possible that the fibrosis is primary, leading to atrophy of the secreting epithelium as a secondary result ; this question cannot, however, be discussed in this paper.

The following four cases are given as examples out of a larger number of similar cases which have come under my observation in both private and hospital practise.
p 943
....These four cases are good illustrations of the symptoms which occur in the earlier stages of thyroidal fibrosis. In the first place we find that the appearance of the patient may sometimes suggest the nature of the disease, even before any actual complaint of ill-health is made. The most striking changes in the appearance of these early cases may be due to an alteration in the complexion of the skin rather than in the expression of the face. Thus the yellowness of the skin of the face is often a striking feature, and accompanied as it generally is by the central pink flush in the cheeks, it imparts a false appearance of good health, as if the patient had spent much time in the open air in the country. When this appearance is seen in a patient who has not been thus exposed, it should always lead to further inquiries being made for other symptoms of thyroidal insufficiency. The presence of yellow subconjunctival fat I believe to be rare, though it may be mentioned in passing that I have seen all the fat in the body of a monkey, which died after thyroidectomy, of this same golden yellow colour.

In these cases the subcutaneous swelling is, as a rule, only slight. The cheeks may appear rather full and the chin be rounded, changes which may readily be attributed to the presence of subcutaneous fat. Swelling of the subcutaneous tissues of the eyelids may be slight or absent altogether, while there may be no visible swelling of the nose, lips, or tongue, although elevation of the eyebrows with transverse wrinkling of the forehead may be present early. Consequently the change in the expression of the face and hands is not nearly so marked as in the advanced stages of the disease. The skin may be rather drier than usual, and there are frequently dry scaly patches over the knees and elbows, but in some cases at this stage the skin is still soft and moist, and at time there may be free perspiration. Some hair may have been lost, but often it is not more than might be expected considering the age of the patient.

The subjective nervous symptoms are often striking. Complaint is made of lassitude, and fatigue is somewhat easily induced. Both visual and auditory hallucinations are not uncommon. The former take the form of ill-defined objects, sometimes thought to resemble mice or rats rapidly crossing the floor, or rats and cats are distinctly seen running across the room, while brightly coloured stars are also sometimes seen. Noises, such as bells ringing or voices, are heard. It is an interesting and suggestive fact that these hallucinations or subjective sensations resemble the aura of an epileptic fit, and although epilepsy is uncommon in ordinary cases of myxoedema, I have on several occasions witnessed a typical epileptic fit in a monkey after thyroidectomy. Patients show a certain disinclination to speak of these sensations, although they are perfectly aware of their subjective nature. These nervous symptoms occurring in women between 40 and 50 are sometimes mistaken for those which so commonly occur at the menopause, but from which it is of the greatest practical importance to distinguish them.

The temperature in these early cases is generally normal or only occasionally subnormal, consequently the cold is not felt nearly so acutely as in advanced cases. Another interesting point is that in some of these cases the thyroid gland can still be felt, and it is not appreciably diminished in size ; in one of the cases described it was even enlarged. None of the cases which I have seen have to my knowledge died, so that I have no actual observations of the condition of the thyroid gland to record. One of my objects in bringing forward the subject is to urge the importance of a careful microscopical examination of the

gland should the opportunity arise owing to death from some intercurrent disease. There can, however, be little doubt that the partial thyroidal insufficiency in these cases will turn out to be due to fibrosis similar to, but in an earlier stage than, that which is found in typical cases of myxoedema. In the latter the fibrosis may be extreme. In one of two advanced cases which I have examined not a trace of glandular structure could be found in fat and fibrous tissue, while in the other, an illustration of which has already been published, only the remains of a few alveoli were visible. It will be of much interest to ascertain how much fibrosis is already present in such early cases as those I have described.
If any doubt exists as to diagnosis in these cases it can easily be solved by a short course of treatment by thyroid extract. If the symptoms are due to thyroidal insufficiency they shortly disappear. For this purpose I find my original liquid thyroid extract, which has been included in the new Pharmacopoeia of 1898 under the name of liquor thyroidei, the most suitable preparation. It is most conveniently given in daily doses of five to ten minims in water.

1908 System of Medicine, Murray, G. R.; Allbut, C.; Rolleston, A. D. Macmillan and Company, London, 1908 Chapter 6
DISEASE OF THE THYROID GLAND
By HECTOR MACKENZIE, M.D. F.R.C.P.

p 336
..... - At first it is probably thought that the child is simply backward, and it is not until the child is nine months or a year old that it is recognised that there is anything seriously amiss mentally and bodily. But in some cases the child has seemed normal for the first few years, and then has fallen into the cretinoid state. It ceases to grow, its features alter, and it becomes dull and stupid. To these latter cases the term juvenile myxoedema has been specially applied. In them the thyroid gland has probably at first been normal, and subsequently has undergone an atrophic change.
The following description applies to the cretinoid condition when fully developed. The child is always stunted in growth and dwarfed in stature, being usually between 3 and 4 feet in height when it has ceased to grow. Exceptionally the height may be as much as 4 1⁄2 feet,
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and sometimes it is less than 3. Moreover, there is a want of proportion between the various parts of the body, so that there is a large plump head, a short deformed body, and thick podgy arms and legs, the latter being often crooked. The large head is flat at the top, spread out at the sides, narrow in front, and broad behind. The face is broad, stolid, and expressionless, and is often lined with wrinkles. The complexion is pale, sallow, waxy, or of a chalk-white colour. The forehead is low and broad. The eyes, which are small and dull but usually straight, appear half closed from the drooping of the swollen lids, and are wide apart, being set back at the ends of a furrow running across the root of the nose. The nose is broad, short, and stumpy, depressed at the root, and flattened and retroussé at the extremity, whilst the alae are thickened and the nostrils widely opened, as in the negro. The cheek-bones stand out, and the cheeks are loose and flabby, but do not show the flush so commonly seen in myxoedema. The ears are large and thick, although usually normal in shape. Exceptionally, the lips are well formed, but are usually coarse, everted, protruding, thick, and blubber-like, and the angles of the mouth are rounded. The mouth is usually open, and the tongue, swollen and lolling, projects from the opening. There is usually dribbling of saliva or drooling. The lower jaw is thick and broad. The neck is short and thick, and in many cases large fatty masses may be felt and seen above the clavicles. The head often hangs forward on the chest, the erector muscles being too weak to support its weight ; this produces a curvature of the cervical and upper dorsal spine. The breast is strikingly flat, and the chest is round and expanded at the base, whilst the costal angle is wide. There is usually bowing of the lower dorsal and lumbar spine, and the abdomen is characteristically large, protuberant, and pendulous. There is frequently an umbilical hernia. The hips are small and the limbs are short and thick. The hands are broad, short, and podgy, and their skin is thick, especially on the dorsum, and wrinkled. The legs are often bowed, the ankles are enlarged, and the feet are thick and square. The nails are short, thickened, cracked or chinky, and ill-shaped. The skin is yellowish-white, dry, branny, and rough to the touch. It feels doughy from the thickening of the subcutaneous tissues, and is loose and hangs in folds over the abdomen and at the flexures of the joints. Sweating is exceptional, but absence of perspiration is not so constant as in myxoexdema. Moles or pigment spots or patches of a yellowish or brown colour or warts are not uncommon on various parts of the body. The hair is short and scanty, and is coarse, dry, straight, and sometimes bristly, more like horse-hair than that of a human being. In adult cretins it is usually absent on the body. The eyebrows are often scanty, but may be well formed. The scalp is dry and scurfy, and is sometimes covered with yellowish or brownish crusts. The teeth are late in appearing and soon` become carious. In sporadic cases there is usually no evidence of the presence of the thyroid gland, but there may be enlargement of the gland or a goitre, and this is common in the endemic cases. The temperature is subnormal ; the child is always cold, p339
likes to be near the fire and is very sensitive to any fall in the thermometer. In cold weather the exposed parts of the body become blue. The bowels are frequently obstinately constipated, and the breath has a disagreeable odour. The urine is usually large in amount, but is otherwise normal. There is generally control over the sphincters, and when there is a sufficient degree of intelligence the patients are cleanly in their habits. The blood shews little change in corpuscular elements, but there is usually deficiency in the amount of haemoglobin, which may be no more than 50 or even 40 per cent of the normal. In some cases there has been a tendency to haemorrhages, especially from the nose. The intellectual condition of the cretin is always extremely low. The mental capacity varies from that of a low-grade idiot on the one hand to that of a child of four or five years old when the cretin is grown up, so to speak. The cretin does not learn to talk or to walk at the

usual time, and does not attempt to move about like an ordinary healthy child. Sometimes, so far from learning to walk, it remains unable to stand or sit unless propped up and supported. In other cases it may only be able to move about by crawling on all fours. Eventually, however, the power of walking may be acquired but the gait is waddling and clumsy. The power of speech sometimes remains altogether undeveloped. Sometimes the cretin cannot even cry or scream like an ordinary child, and expresses pleasure, anger, or fear by means of inarticulate grunts, howls or shrieks, barks or groans only. In course of time it may learn to say a few words, such as "Yes," "no," "Mamma," or "Pussy," and it may learn to understand a little when spoken to. It may also learn the signification of gestures. A small number acquire a more extensive vocabulary, which is, however, very much restricted, and is composed almost entirely of monosyllables. Many of the consonants are very imperfectly pronounced. The voice is often harsh and hoarse. The cretin is usually dull of hearing ; the degree of deafness is generally proportional to the stage of the disease. The deafness accounts for some of the mental dulness, and, to some extent, for the inaptitude for speech. Smell and taste are usually imperfect. Cretins often appear insensible to bad odours, and indifferent whether food is palatable or not. Sight is of all the senses the least affected. Usually it is normal, but he retina does not seem so sensitive to strong or dazzling light as in ordinary persons. The cretin has been observed to sit with the sun full in his eyes for a long time together.

In adult cretins the genital organs remain those of the child. There is absence of hair over the pubes, the axilla, and elsewhere on the body, and hair does not appear on the face in males. Males have a diminutive penis and small testicles, and females have the labia of little girls and an infantile uterus. The catamenia are absent or irregular, and sexual instinct is as a rule underdeveloped. In high-grade cretins there may, however, be some evidence of development of sexual appetite and instinct.
The cretins are usually good-natured and placid, and although stolid are easily amused. It is sometimes difficult to attract their attention by appealing either to the sense of hearing or sight, a somewhat cat-like
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characteristic. They are apathetic and phlegmatic, and very slow and deliberate in all their movements. They are somnolent, and will sometimes sleep almost indefinitely if undisturbed. During sleep they breathe noisily. When awake they are lazy and inert. They will remain in the same position and play for hours without moving or taking any apparent interest in surroundings ; one cretin would take a full minute to raise her arm when asked to shake hands.
Duration. - The life of the untreated cretin is seldom, if ever, a long one. A number are carried off in the early years, and it is quite exceptional for an age of over thirty to be attained. Forty is probably the extreme limit. Death usually results from intercurrent disease, the specific fevers, pneumonia, bronchitis, erysipelas, or kidney disease, or convulsions.
Diagnosis. - In a characteristic case with the symptoms just described, diagnosis presents no difficulties and can usually be made almost as soon as the patient is seen and without asking any questions. The disease, however, is rare, so that many practitioners have never seen a case, and on that account sometimes fail to recognise the disease or suspect its existence when some other condition is present. One disease, mongolian idiocy, has some resemblance to cretinism, and several patients afflicted with it have been sent to me as they were thought to be cretins. The mongolian idiot resembles the cretin in its stunted growth and undeveloped intellect ; the bridge of the nose is flattened, and the hands and feet are short and broad. The skin is rough and dry, and has given rise to the inappropriate designation of furfuraceous cretin. But there is no thickening of the subcutaneous tissues as in the cretin. The obliquely placed eyes, on account of which the name mongolian has been given, the finer features, and the greater alertness of mind and body are important points of distinction. The mongolian idiot is inclined to be restless, vivacious, mischievous, and destructive rather than stolid, slow, and inactive. Achondroplasia has sometimes been mistaken for cretinism, and Prof. Osler mentions that he was once asked to see two supposed cretins who proved to be suffering from this disease. The disproportion between the length of the limbs and the size of the head and body is its most striking feature. The long bones are very short, and their ends are much enlarged. The physiognomy is unaltered, the skin is natural and there is usually an ordinary degree of intelligence (vide Vol. III. p. 117). ....The slighter degrees of cretinism are those which are most difficult to diagnose, and when a child is not seen until after it has been treated by thyroid gland, it may be impossible to give a positive opinion. The
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effect of giving and the effect of suspending treatment by thyroid gland will, however, establish the diagnosis.
Prognosis. - Under the thyroid treatment this is eminently favourable in early cases. Suitably conducted, it will certainly enure rapid and complete bodily improvement, and though, as we shall see presently, mental improvement is not invariable, it is ever more remarkable when it occurs. The earlier in life the treatment is begun the more complete and lasting appear to be the results. The treatment, however, in some form will have to be persisted in throughout the life of the patient. Treatment. - "Not the magic wand of Prospero or the brave kiss of the daughter of Hippocrates ever effected such a change as that which we are now enabled to make in these unfortunate victims, doomed heretofore to live in hopeless imbecility, an unspeakable affliction to their parents and toe their relatives." So wrote Prof. Osler in 1897 of the wonderful results of the then recently introduced thyroid treatment of cretinism, treatment which the further experience of later years has shewn to be as lasting in its results as it is successful. Textbooks published as late as even 1894 contain such statements as the following : "By far the greater number of cretins arrive at their helpless condition by successive steps of degeneracy in their ancestors." "Treatment is very unsatisfactory." unsatisfactory ; it was worse than useless ! Previous to the year 1891 there was neither help nor hope for the cretin. The remedy we now possess and know how to use was discovered in 1891 , when Prof. George Murray announced his discovery, the effects of hypodermic injections of an extract of the thyroid gland o a sheep on cases of myxoedema a discovery which was followed by that made in 1892 by myself and by Dr. E. L. Fox of Plymouth and by Howitz of Copenhagen independently that thyroid gland administered by the mouth was equally potent in

dispelling the symptoms of myxoedema. The use of the remedy in cretinism quickly followed, and the results were found to be even more remarkable.
The preparation of thyroid gland which I have found most satisfactory in practice has been the tabloid prepared by Messrs. Burroughs Wellcome and Co., in this country. The dose which has to be given varies in different cases, and no definite hard- and-fast rule can be laid down as to its amount. In commencing treatment we must feel or way. If too large a dose be given great constitutional disturbance may be produced. Even a dose of 5 grains has made the patient very ill, causing fever, excitement, restlessness, headache, sleeplessness, vomiting, depression, and general pains in the body and limbs. A small dose, 1 grain of thyroid tabloid or 1 minim of liquor thyroidei, is sufficient to start with, and this should be cautiously repeated at short intervals treatment being suspended when any undesirable symptoms are observed. In one case a dose of 1 1⁄2 grains given every third day has sufficed to effect a cure and afterwards to keep the patient well. In another, gradually increasing doses up to 3 grains a day were found necessary. Sometimes as much as 10 grains daily has been required, and a smaller dose has not sufficed.

p 342
....When the discovery of the sovereign remedy was made cretins of all ages and in all stages were brought for treatment. For many of them the discovery had, unfortunately, come too late. Thus, such a case as that described by Dr. Coutts of a young man of twenty-four years "looking like a child of two, under 3 feet in height, entering the room with one hand clasped in his mother's and the other clutching a doll," was only too common. For such cases some degree of benefit would result from treatment, but that was all. Still, for some the remedy, although it came late, made all the difference between a useful existence and a living death. One of the most gratifying of my cases was a typical cretin who had reached the age of eleven when in 1893 the thyroid treatment was started. He grew very rapidly at first, and developed into a normal child except that his legs were disproportionately short. He has progressed satisfactorily in every way, and has gone on successfully from school to one of the universities. He always, however, remained about five years behind those of his own age.
p 343
He is now, at the age of twenty-five, in every respect a normal individual. The only evidence of his former condition is that he is of short stature, being only 5 feet 4 in height.

1908 System of Medicine, Murray, G. R.; Allbut, C.; Rolleston, A. D. Macmillan and Company, London, 1908 Chapter 6
DISEASE OF THE THYROID GLAND
By Prof. GEORGE MURRAY, M.D., F.R.C.P.

p 349
....Symptoms. - The onset of the first symptoms of myxoedema is usually so insidious that it is often difficult to ascertain their real duration. This is because the morbid changes in the thyroid gland develop extremely slowly, and the supply of the secretion fails very gradually. In secondary myxoedema, the symptoms may appear rapidly or slowly according as the removal of the thyroid gland has been complete or partial. In the former case, the symptoms may develop acutely within a period of a few days ; in the latter case the acuteness of the onset will be proportional to the amount of secreting thyroidal tissue left. At the commencement of the disease the patient complains of gradually
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increasing sense of languor, associated with disinclination for exertion. Thus, ordinary daily duties, which previously were performed without conscious effort, become extremely irksome. The more energetic struggle against this tendency but are conscious of the effort it entails, whilst others tend to limit their sphere of action more and more. There is also about this time undue sensitiveness to cold which in cold weather especially is apt to induce the adoption of an indoor life of very limited activity. At this stage slight alterations take place in the facial appearance, due to the gradual development of the characteristic subcutaneous swelling. The face becomes somewhat rounded, the eyelids and lips slightly swollen, and there may be slight flush in the centres of the cheeks. These changes take place gradually, and in the earlier stages do not cause the striking alteration in the aspect of the patent which we are accustomed to see in fully developed examples of the malady. t this time there may be some increase in weight, so that the change in appearance may be attributed to obesity. The skin becomes rather fry, though it may still be most at times, and the hair may begin to come out to a slight extent. The temperature is usually normal or only slightly subnormal. On inquiry, it is not unusual to find that at quite an early stage of the disease the patient is subject to slight auditory and visual hallucinations. These subjective sensations are not so clearly defined as in the later stages. The progress of the disease may be arrested at this early stage, and no further advance take place for along period. In the great majority of cases, however, the symptoms gradually become more distinct until the disease is fully developed and assumes the form which we shall now consider in detail.
Solid Oedema. - The most characteristic symptom of myxoedema, and that to which the malady owes its name, is the swelling of the subcutaneous tissues. The swelling is most abundant where the subcutaneous tissues are lax, and imparts a peculiar appearance to the face and hands of the patient. On palpation the swelling feels somewhat more elastic in consistence than ordinary adipose tissue, and does not pit on pressure. In the early stages of the disease it is only slight and causes no very striking alteration in appearance, but in advanced cases it may be sufficient in amount to add several stones toe the weight of the body. The face as a whole becomes full and rounded, and the skin of the eyelids and infra-orbital regions looks translucent and distended as if with watery oedema, as is well shewn in Fig. 5, which was taken from a man at the age of 48, fifteen years after the first onset of the disease, who, however, did not come under my observation until ten years later. The cheeks are thick and rounded, and the centre of each is reddened owing to dilatation of the minute venules in

this region. The subcutaneous tissues beneath the chin are often considerably thickened. The lips are thick and everted, and the nose and ears are also swollen. The tongue is often considerably enlarged, and causes in part the peculiar alteration in the speech which is often quite characteristic. As a result of the swelling the upper eyelids tend to droop, and to compensate for p 351

this there is an instinctive contraction of the occipito-frontalis muscles, with well-marked transverse wrinkling of the forehead. The normal mobility of the face is lost, and so advanced cases of myxoedema have a fixed mask-like expression, which varies but little with passing emotions.
The swelling is often present to a notable degree in the supra-clavicular fossae. Over the trunk and limbs it is uniformly distributed, and is full extent is not always realised until after it has been removed by treatment. The backs of the hands are usually much swollen and form a contrast to the palms, where the swelling is scanty. The hands appear to be broad and relatively short. The range of movement of many joints is limited by the solid oedema. This is noticed chiefly by the patient in such movements as fastening a collar at the back of the neck or stooping to lace up the boots, whilst some of the finer movements of the fingers, such as are required in doing needlework, can no longer be executed.
Circulatory System. - In the early stages of the disease the skin gradually becomes dry and the superficial layers of the epidermis are shed more readily than in health. In consequence of this the insides of the
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stockings, when removed at night, look as if they had been sprinkled with some fine white powder-like flour, owing to the presence of numerous fine dry scales of epidermis. In more advanced stages the skin becomes very dry as sensible perspiration gradually ceases, and even insensible perspiration is so much diminished that only half the normal amount of water may be lost as aqueous vapour. The skin of the face and neck in some cases is yellowish in colour, which, combined with the red flush on the cheeks, helps to make up the characteristic facial appearance in myxoedema. The skin covering the palms of the hands, the soles of the feet, and the extensor surfaces of the elbows and knees is especially thick, rough, and dry. Warts and pigmented moles are present on the skin in some cases.
Some loss of hair may occur in quite the early stages of myxoedema. In advanced cases almost all the hair may be absent, the head being quite bald, as in Fig., and the eyebrows and eyelashes quite scanty. When bald the skin of the scalp is often dry and scaly. If the hair is not lost it becomes finer in texture. The nails also give evidence of malnutrition, and are often cracked, grooved, and discoloured.
The mucous membranes are paler and less translucent than in health. The lips are usually swollen and dry, and the mucosa of the mouth, nose, and throat is also often dry.
The thyroid gland in the great majority of cases of myxoedema is diminished in size, and the longer the duration of the disease the smaller the gland In cases of some duration in which the subcutaneous swelling has been removed by treatment little or no isthmus can be felt in front of the trachea, and the lateral lobes cannot be made out. In a few cases the gland has been found to be larger than normal ; it is, however, but rarely that the diminution is functional activity is accompanied by an increase in size.
In the early stages of myxoedema the temperature may be quite normal or only slightly subnormal. In later stages patients are very sensitive to cold, and in winter complain that they are unable to keep warm. The hands and feet feel cold to the touch. Such patients are much more comfortable in summer or in a warm climate. In fully developed cases the temperature is nearly always one or two degrees below normal, and in some it may be as low as 95o F., or even 93o . In fatal cases it has fallen as low as 77o, or 66o shortly before the end.
Mental Symptoms. - All sufferers from this malady shew more or less mental hebetude. They are slow in fully comprehending a new subject, or in carrying out any new line of thought or action. About one-fourth of the cases shew a tendency to spend an undue amount of time at the same employment, and so may dawdle away an hour in dressing in the morning or in eating a meal. The memory is deficient for recent events, but is not apparently affected in regard to those which occurred before the onset of the disease. The temper is usually good, though there may be irritability at times. Many patients are acutely sensitive in regard to the alteration in their appearances, and in consequence become shy and
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retiring. This tendency, added to the general hebetude, leads in advanced cases to a secluded and indoor life. Sleep is generally sound at night, though it may sometimes be disturbed by dreams, and there is often drowsiness during the day. visual and auditory hallucinations are often very vivid in advanced cases, and even in quite early cases they occur in a less realistic form. In slight cases, ill-defined objects, which are compared to a mouse running across the floor of the room, are seen, or noises re heard. In advanced cases well-defined figures are seen, which sometimes can hardly be distinguished from those of real persons. They may take the form of near relations or of entire strangers. Voices are heard to speak distinctly, or familiar sounds, such as that caused by the opening of a door, may be heard, either separately or in association with the visual phenomena.
Insanity. - A few advanced cases of myxoedema when they were untreated, became insane. When treatment is commenced in the early stages of the disease this rarely occurs. The peculiar mental symptoms just described may gradually become intensified until the patient becomes insane. Acute or chronic mania, melancholia, or dementia have developed in such cases. The special tendency to avoid observation may pass into a condition of suspicion. The mental weakness is apt to increase until finally dementia combined with general weakness is established. in other cases irritability, doubt, or exalted ideas may be present, and there may be terminal convulsions and coma immediately before death.
Special Senses. - In about one-half of the cases the sight is found to be defective ; in many of them, however, this is due to causes unconnected with myxoedema. In a small number of cases watering of the eyes and a general diminution in acuity of

vision may be attributed to the malady itself. Hearing is found to be diminished in about 50 per cent of the cases. One or both ears may be affected. Occasionally the deafness is nearly complete, but disappears as the result of treatment by thyroid extract. The senses of smell and taste are diminished in about one-third of the cases. sexual feeling is usually diminished or in abeyance, though certainly one case has been recorded in which a man with myxoedema married and became the father of two children.
Sensory Symptoms. - In addition to sensations of cold due to the depressed temperature, frontal and occipital headaches, neuralgic pains and prickling sensations are felt in various regions of the body. Attacks of aural vertigo and tinnitus occur in some cases. Tactile sensation may be diminished, whilst appreciation of heat and cold is unaffected.
Reflexes. - The superficial reflexes are diminished but are rarely exaggerated in the presence of some complication, such as lateral sclerosis, as in two cases which I have seen.
Circulatory System. - In slight cases of myxoedema there are usually no symptoms of cardiovascular disease. In advanced cases the symptoms of cardiac disease may be very severe. The chief symptoms in these
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cases are dyspnoea on exertion, with palpitation, and in some cases severe attacks of syncope, one of which may prove to be fatal. The cardiac impulse is feeble and ill-defined, and the heart-sounds are distant, but no murmur is audible unless some valvular lesion is present as a complication. These cardiac symptoms in cases of myxoedema which have gone for long periods without treatment are due to fatty and fibroid change in the heart muscle. The recognition of this condition is of great practical importance, as when it is present treatment with thyroid extract must be carried out with great car e. Even slight additional exertion undertaken by such patients during the early stages of the treatment has caused fatal attacks of syncope. Before I had realised this danger , one of my cases died in this way while walking up a hill, and another after stooping down to lace her shoes. The pulse is usually less frequent than in health, slow, and regular. When renal disease or arteriosclerosis is present the tension will be high.
Blood. - There is generally a moderate degree of anaemia, the red corpuscles being diminished in number and deficient in haemoglobin. As a rule the number of red corpuscles is reduced to between 3,000,000 and 4,000,000 pr c.mm., and the hemoglobin to 60 or 70 per cent and occasionally to 40 or 50 per cent of the normal amount. Except for an occasional leucocytosis the white corpuscles are normal in number and appearance.
It is generally stated that haemorrhages from the uterus and mucous membranes are common in myxoedema. In the cases which have come under my own observation, however, I have not found any special haemorhagic tendency.
Alimentary System. - Loss of appetite and constipation are common. The lips, gums, and tongue are more or less swollen, according to the severity of the case. The tongue is sometimes so large than when it is protruded it fills the space from one angle of the mouth to the other. The teeth are generally carious and the gums may be sort, spongy, or ulcerated. Many patients complain of a thick mucous discharge which runs from the mouth during sleep. (Vide Vol., IV. Part II. p. 208) Genito-urinary System. - In the early stages of the disease the urine is generally quite normal. In advanced cases, however, it may be pale in colour, have a lowered specific gravity varying from 1008 to 1018, and contain a diminished amount of urea. In about one-fifth of the cases there is albuminuria, which in many of these is due to the myxoedema, as it entirely disappears under treatment by thyroid extract. In others it persists and is due to fibrosis of the kidney. Albumosuria has been observed by Fitz. In some cases menorrhagia occurs during the early stages of the disease, though more commonly amenorrhoea is present. In some this is of course simply due to the age of the patient, in others, however, it is a result of the myxoedema, as menstruation has been re-established after treatment. Pregnancy seldom occurs after the onset of myxoedema in a woman, but it must be remembered that the disease very frequently first appears at or about
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the time of the menopause. In a man sterility is not a necessary result. In both sexes the external organs of generation may be somewhat swollen, and the skin covering them is dry as in other parts of the body. The pubic hair is usually scanty, and may be lost in advanced cases.

1915 Pluriglandular Insufficiency: Its Incidence and Treatment Henry R. Harrowere, M.D., Sometime Professor of Clinical Diagnosis, Loyola University, Chicago, Fellow of the Royal Society of Medicine; Member of the American Medical Editors' Association New York City The Practitioner January 1915 Special Number on Internal Secretions Part I

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Pluriglandular insufficiency, or hypoendocrinism, is a comparatively recent term, rarely found in the medical literature published seven or more years ago. To appreciate the full import of the subject which has been allotted to me, it is necessary, first, to realise the fact that the endocrinic system is a very essential part of the organism, since by its various internal secretions practically the whole of the workings of the body are regulated and correlated.

.... The active principles of these internal secretions are now generally called hormones, and we are beginning to realize that they are a factor of extreme importance in the regulation of metabolism. In the body every motive force is balance by a retarding force and this nice balance is essential to health; hence if one or another of these factors gain the ascendency, or is diminished in activity, disorganization must naturally result and the extent of this disorganization can hardly be confined to this single area in which it is initiated.

The intimate relations of the secretions of the various endocrinous organs predicate pluriglandular disturbance as the result of an initial monoglandular disorder, thus explaining the dictum of Bayard Holmes: :"During the past year much evidence

has accumulated to show that diseases of the ductless glands are usually plural rasher than isolated and single. Pluriglandular disease is the rule rather than the exception."

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The only reason that we study disease is that we may be the better able to appreciate its influence and satisfactorily treat it, so the consideration of pluriglandular insufficiency would be incomplete without reference to the treatment of these conditions. The natural corollary of pluriglandular insufficiency is pluriglandular therapy, and the most practical consideration of this subject concerns the comparatively recent form of therapeutics which the knowledge of the influence of hypoendocrinism has made possible.

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For several years the writer has been studying the application of various combinations of pluriglandular extracts in pluriglandular insufficiencies, particularly in the so-called "run-down" conditions, where no positive evidence of any defective action of the gland or series of glands can be demonstrated. 'Such cases include many forms of neurasthenia and functional neuroses, and it is obvious that in the majority of these cases there must be a disturbed endocrinism. It is hardly reasonable to suppose that in an individual with prominent manifestations of half-speed function, such as constant fatigue on slight exertion, defective oxidation as evidenced by low urinary solids, nerves that are easily set "on edge," circulation that is poor, with cold, clammy extremities, and not infrequently reduced tension and ambition, and mental powers much below par, that the production of the essential chemical messengers is not reduced just as are all the body activities. This being the case, pluriglandular therapy not only serves to replace, in however slight degree, the missing secretions, but favours an increased production of them by the homostimulant action already referred to.
Theoretically this sounds very plausible and practically it has been found to work very nicely. Pluriglandular therapy is undoubtedly empirical, for in the class of cases under discussion at least, there is no definite proof as to which of the ductless glands is deficient and to what extent. For this reason it has been ridiculed by some who forget that nine-tenths of our present therapeutics was at one time purely empirical, while a good share of it still has no positive scientific basis. A procedure that has secured results before may do so again, hence it is worth trying. This is the present position of pluriglandular therapy, and it is believed that the successes already obtained are an earnest of what is in prospect.

1915 Thyroid Insufficiency Léopold Lévi, M.D. Médicin de l'Hôpital H. de Rothschild; Lauréat de l'Académie de Médicine, Paris, etc. The Practitioner February 1915 Special Number on Internal Secretions Part II

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.... Physiology.- The function of the thyroid gland is manifold. It controls the nervous system, the nutritional exchanges, and the humoral equilibrium. There is increasing evidence to show that it is in part responsible for the processes which I propose to describe as thermogenic, oregogenic, morphogenic, antigenic and prophylactic.
There are disorders affecting some or all of these processes, which give rise to symptom-complexes of varying character. The origin of these syndromes, though more or less easy of recognition, has not until recently formed the subject of research.
General Definition of Thyroid Insufficiency.- Within the last few years, however, the notion of thyroid insufficiency has become very much broader in its application.
In the first instance, the term thyroid insufficiency was applied to extreme forms of the condition only. This was the logical outcome of the discovery by the Swiss school, that myxoedema resulted from spontaneous absence or surgical removal of the thyroid gland.
(2) At a later day, the term was extended to include partial or attenuated conditions, as well as the formes frustes. These belong to the category of slight thyroid insufficiency and are of far more frequent occurrence than the severer manifestations.
(3) More recently, however, the question has been found to be one of greater complexity than was at first supposed. Thyroid insufficiency, especially in its benign forms, is rarely pure. It is associated with a reaction to hyperactivity on the part of the gland, provoking a syndrome of by no means infrequent occurrence, which has been described by me in collaboration with H. de Rothschild under the name of thyroid instability.
(4) Having once established thyroid insufficiency and thyroid instability as clinical entities, it is possible to recognise in the subjects of these conditions the presence of other glandular syndromes, wither existing in juxtaposition to thyroid insufficiency, or directly or inversely related to it. Whether it be cause or effect, in cases such as these thyroid insufficiency is frequently the dominating factor of the syndrome.

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Attenuated or partial manifestations of thyroid insufficiency are the ones most frequently encountered, and these may affect persons of all ages, from sucklings to old people. They explain the entire symptom-complex of old age, and are observed with considerable frequency in infants, adolescents, and persons of mature age. The predominant role played by the thyroid gland in the sexual life of women, renders them peculiarly liable to the slighter forms of thyroid insufficiency.

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1. Signs of Uncomplicated Slight Thyroid Insufficiency-.
Before entering on a description of the symptoms of subthyroidism, there are one or two points to which it I as well to direct attention.
The signs of thyroid insufficiency are numerous, but they are rarely all present in the same individual. As a general rule, the symptoms are trifling, in the sense that they do not seriously affect the general health. Indeed, certain of them are so commonplace, that they fail to attract the attention of the physician. Taken singly, they are not characteristic of thyroid insufficiency, for they may arise from other causes, more especially from other glandular disturbances. Finally, symptoms of a general similarity may be produced by the opposite poles of thyroid activity. Thus, constipation may occur in both subthyroidic and hyperthyroidic states, as the result of thyroid atony or thyroid spasm. Vasomotor derangement consistently combated (vaso-dilation, passive or active) may bring about headache or either subthyroidic or hyperthyroidic origin.
The facts which have led me to regard as significant the slighter symptoms of thyroid insufficiency are as follows:-
(1) That these symptoms are present in myxoedema;
(2) That they yield to thyroid medication;
(3) That the reverse symptoms are observed in Graves's disease;
(4) That these reverse symptoms may be produced by means of thyroid extract given by the mouth.
The presence in an individual of the slighter signs of thyroid inadequacy constitutes what may be called the subthyroidic temperament. These signs are as follows:-
1. Transitory Infiltration.- Apart from the presence of cardiac or renal affection, a white indolent oedema, which does not pit on pressure, makes its appearance in the vicinity of the eyelids, the forehead, and the cheeks; occasionally, there is transitory swelling of the feet, and the subject finds that his boots are temporarily too tight for him. Or the fingers may become sufficiently swollen to render the removal of the rings a matter of difficulty. This transient oedema occurs with varying frequency; it may or may not be periodic in its occurrence, and it is observed in the earlier part of the day, or as the result of worry, fatigue, menstruation, migraine, or an asthmatic attack.
2. Hirsute Derangements.- Such are partial congenital alopecia, capillary nanism, premature baldness, premature greyness. The eyebrow sign is most important; it consists in absence or premature falling of the eyebrows or rarefaction or disappearance or the outer third. it is referable either to what Hertoghe describes as a process of "keratose pilaire" or to defective development (agénésie pilaire).
3. Caloric Disturbance.- (a) In its most attenuated form, this manifests itself as coldness of the extremities, especially of the feet. It is frequently unconscious, particularly in children, or it may be subconscious.
(b) A second form appears as chilliness, either general, or confined to one or other of the extremities, or localised in the back or thighs. The sensation is conscious, the patient making frequent complaints and employing measures of all kinds to guard against it.
(c) A third manifestation is shivering fits, which come on after meals or in the earlier part of the day. They may be momentary, or they may be prolonged and accompanied by chattering of the teeth and trembling of the whole body.
(d) The temperature as measured by the thermometer is frequently several points below normal, especially at night.
(e) People with subnormal temperatures are frequently exquisitely hypersensitive to cold (Hertoghe). The slightest draught provokes rheumatoid or neuralgic pain, or brings on a lumbago, torticollis, or migraine.
4. Chilliness is associated with vasomotor derangement, of which aero-asphyxia, cyanosis, and chilblains are the manifestations. The pulse is usually small and slow.
5. An intestinal symptoms which is the stamp of the subthyroidic temperament is constipation. Like the preceding symptoms, constipation is a feature of myxoedema and is susceptible to thyroid treatment.
6. Fatigue, especially matutinal fatigue, is very common. Subthyroidic people are usually loth to get up, and they are not at their best in the morning. They usually brighten after they have breakfasted and have begun to move about. These subjects sometimes say that they were "born tired".
7. Anorexia.- Subthyroidic children have rarely much appetite, and this is frequently the case with adult. They have to be forced to eat and eating gives them no pleasure. This symptoms improves, sometimes to a surprising extent, under the influence of thyroid extract.
8. Somnolence.- Subthyroid subjects require a great deal of sleep, and they fall asleep readily after meals. Thyroid extract frequently has a marked effect in reducing the need for sleep.
9. The subthyroidic temperament is associated with a tendency to obesity; in other words, the subject possesses a nutritive orientation which, under the influence of exogenous conditions, such as an over-abundant dietary coupled with insufficient exercise, predisposes to the formation of fatty deposits.
10. The skin is dry, rough, harsh, thick, scaly, and ichthyotic.
11. The stature is small, generally below the medium. The subject has either always been small, or has ceased to grow as the result of some illness which affected his thyroid gland.
12. Certain developmental processes are retarded (dentition, walking, speech); sometimes development of the testes, brain, hair, teeth, etc., is arrested.
13. On the other hand, there is sometimes a tendency to premature senility. It is manifested by varicose veins, haemorrhoids, excessive development of the veins of the hand, a tendency on the part of the teeth to loosen and come out, premature baldness and greyness.
14. Subthyroidic persons are subject to muscular and articular pain, and to frontal and occipital headache. The latter is more severe in the morning, and is so persistent that they end by becoming accustomed to it.

15. To these must be added apathy, indolence, and depression, the combination uniting to form the syndrome of partial neurasthenia (neurasthénie fragmentaire).
16. The eyes are frequently deep-set, small, atonic, and lacking in expression; they resemble glass eyes.
17. Views as a whole, the subthyroidic temperament is characterised by attenuation of the vital reactions and diminution of the nutritional exchanges.

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.... It is exceptional to find all these signs present in one individual. The greater the number, however, the greater the likelihood of their disappearance under thyroid medication.

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.... Evolution of Thyroid Insufficiency.- Thyroid insufficiency is, as a rule, insidious in its onset. When the condition has set in during infancy, its nature is frequently perceived in retrospect at a later stage. Occasionally it appears as the sequel to an acute malady, or as the outcome of Graves' disease. Once the condition is established, it may remain stationary; it may undergo spontaneous amelioration; it may develop in the direction of myxoedema, or in that of hyperthyroidism (thyroid instability); or it may be susceptible to treatment by thyroid extract,.
As a general rule, the evolution of thyroid insufficiency is a matter of time, though manifestations of the condition may be of a transitory, paroxysmal, or periodic character.
Among the conditions in which thyroid insufficiency may terminate, the most important, with the exception of myxoedema and Grave's disease, are arteriosclerosis and premature senility.

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.... Having established the diagnosis, it should be confirmed by treatment with thyroid extract. This is essential, for even in the case of manifestly subthyroidic subjects, the usual accompaniments, such as adenoid growths and the incontinence of urine, are not necessarily of subthyroidic origin, and they may even prove refractory to thyroid treatment. When the results are immediate, continued, constant, and pronounced, they may be regarded as a diagnostic factor.
In the case of pluriglandular syndromes, the results of thyroid treatment serve to distinguish between symptoms of thyroid origin and those provoked by derangement of other endocrinic glands. Even in cases where thyroid insufficiency is proved, the endocrinic balance must be maintained and the coexistence of other endocrinic insufficiencies and instabilities (testicular, ovarian, parathyroid, suprarenal, pituitary) must be allowed for.

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... The pulse and the weight should be watched, and a careful look-out should be kept for the appearance of nervous symptoms. The effect of the treatment in modifying certain symptoms is, in some instances, positively magical. It is pertinent to ask, at what age should thyroid therapy be instituted? The earlier, the better. Remarkable results are sometimes obtained with infants. The treatment may be employed with advantage in the case of old people, though with this reservation, that the drug must be exhibited in small doses.

1915 Thyroid Insufficiency in General Practise J. Parlane Granger, F.R.C.S. The Practitioner February 1915 Special Number on Internal Secretions Part II
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..... The practitioner may legitimately regard the whole history of a disease as his peculiar province. He need not be too scientific, so long as he can cure his patient. The pleasure and satisfaction of confirming a diagnosis by post mortem examination may safely be left to the pathologist. To the practitioner, a living patient is better than a dead pathological curiosity.

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.... This disease is not one about which Hippocrates wrote, not indeed, so far as is known, any of the Greek or Roman practitioners. Paracelsus, the chemical physician, was the first to give a trustworthy account of cretinism, and to point out its association with goitre. This treatise was written in the early part of the 17th century, and Hirsch, commenting on it, says: "Before this, as regards cretinism, its history is involved in complete obscurity." Cretinism was the only form of thyroid insufficiency before Sir Wm. Gull published his paper, "On a cretinoid condition supervening in adult women," in 1874. Who first suggested the phrase "Thyroid insufficiency," I have never been able to discover.
In many of the cases in adults I have had under treatment, thyroid insufficiency has been a subsequent development to an hyper-thyroidism occurring over a more or less prolonged period. It is not, therefore, straining the premises too severely to conclude, that the vicious circle of to-day was the vicious circle of yesterday, and that thyroid insufficiency, cretinism and myxoedema, although all of comparatively modern nomenclature, must refer to conditions of unhealth as old as goitre itself. Now, although the Greeks knew not goitre and the Roman physicians wrote no treatises on it, historians, poets, and later, churchmen and travellers of that Empire, left quite distinct records of the disease; even more interesting is their naming the places where the disease is found endemic to-day. Vitruvius writes, "The neck of man is frequently found to be swollen among the inhabitants of Maurienne and the Middle Alps." Juvenal calls attention to this "guttur tumidum" and adds "this swelling of the neck is found among the Alps." Ovid, in the Fasti, refers to the slight swelling of the neck that occurs in the

first months of pregnancy, a condition with which we are al familiar, which, no doubt, is due to the general disturbance among the endocrinic glands caused by the cessation of ovulation and the interdependence of the hormonal contents of these glands. Pliny even goes the length of blaming "the water which is drunk," a very shrewd guess in view of the now well ascertained fact that there are undoubted gotre-producing wells in these regions. If, therefore, the assumption be correct, that wherever goitre exists, there also will thyroid insufficiency be found, this condition of unhealth must be possessed of quite a hoary antiquity.
Its wide-flung ramifications are equally remarkable. Marco Paola, in his journey to China early in the 14th century, saw and remarked on the prevalence of goitre in Yarkand and the Central Asian plateau. Humboldt found it prevalent in the Cordilleras of the New World, and Mungo Park gives an account of it occurring in the Cong Mountains and upper basin of the Niger.
Although the intimate association of cretinism with goitre was well known in the early part of the 17th century, owing to the works of Paracelsus, its true pathological significance was now known until a much later date. That a cretinoid condition could develop in an adult did not dawn on the medical world until 1874, when Sir Wm. Gull published his five cases, all of them being adult women. It was not until 13 years later (1887), when Dr Savill published a paper in the British Medical Journal, in which he recorded the disease as occurring in a male subject, that medical knowledge advanced another step, and rose to the conception of the disease being common to both sexes.

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.... It was thus that thyroid therapy began. Not even its nimble-witted pioneers had any idea of the immensity of the new fields they had discovered. Desiccated thyroid was too important a therapeutic agent to confine within the narrow limits of its discoverers. Men began to use it in all sorts and varieties of ill health, and met with astonishing results in cases that bore no resemblance whatever to myxoedema. The physiological content of the gland had no meaning, when it was confronted with the variety and diversity of the symptoms, that sometimes cleared up like mists before the sun when thyroid was administered. Burroughs Wellcome & Co. placed the "Tabloid" Thyroid Gland upon the market in 1894. This did not contain an extract, but a dried preparation of the whole gland substance. When Baumann, in 1896, pointed out that the chief ingredient of thyroid secretion was an organic iodide, this firm standardized their thyroid preparations, so that to-day each product represents a definite amount, and contains not less that 0°2 per cent. of iodine in organic combination. This is important. I have tried the dried thyroid o the Pharmacopoeia, but it varies so much that, if one desires to get the best and speediest result of treatment, it is necessary to use either the "tabloid" thyroid gland, or some other standardized preparation.

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.... The third case to which I wish to draw attention to is that of Mrs M., whose history I will give in her own words:-
" Married in March 1898. Had good health till about the beginning of 1899, when I contracted kidney trouble, and was treated by Dr. S. for Bright's disease. In about a year it was completely cured.
In September, 1900, my child was born, and I believe he was a healthy boy, but he developed convulsions when he was 8 months old, and died on 23rd May 1901. A month afterwards, my father died suddenly, and no doubt the grief for the loss of my child and my parent caused me to get low-spirited, and I began to feel my health giving way. I felt about that time that I had not sufficient strength or energy to do my ordinary household duties, was despondent and irritable and could not make myself interested in anything. Could not be bothered even to read.
In August, 1902, I was on holiday at Callander, and at that time was 6 months pregnant. Whether I had over-exerted myself or not I cannot say but I gave birth to a living child then; I remained in Callander a fortnight after the birth. When I got home, I was far from well, and I had to take to my bed. Up to this time I had not thought there was anything very seriously the matter with me, but I now began to think I had some disease.
Previous to my marriage I earned my living by singing - "I was a professional vocalist - but I now found my voice was getting husky, and I suffered from shortness of breath. I also had fainting turns, and felt at times that I was losing the power of my legs. On one occasion, I had rather a severe attack of this numbness in my legs, and I collapsed altogether. My neighbours called in Dr. B., and he said my nerves were out of order.
At this time I should say I had much trouble at my periods, and there was always an excessive flooding, which lasted sometimes for a week and 10 days. This was a matter of great concern to me, and worried me terribly. It got gradually worse.
Nearly the whole of 1903 I attended Dr M. for my voice, but his treatment had absolutely no effect. My trouble in this direction really got worse rather than better, and because of this and the fact that my periods were still causing trouble, I again put myself into Dr. B.'s hands, and shortly afterwards again became pregnant.
At 6 months there was a miscarriage, and still the trouble remained. Dr. B. cauterized the womb without effect, and ultimately he advised me to undergo an operation. This operation, which I think was called "curetting," was performed by Dr. K. I think this operation took place in March, 1906.
I was still occasionally troubled with these floodings and my other troubles were as acute as before. My face was swollen out of shape, so were my hands and feet and also my legs. My voice was completely gone and when it came back at intervals I had great difficulty in articulating. The numbness also continued, legs particularly. My complexion was ghastly, and people who knew me very well passed me in the street at times not knowing me. My hands and feet were always like ice. Up till this time (1908) things went on just as described, and I had really come to think that so long as I got no worse I should be thankful, but it never occurred to me that I would ever be better. In October of this year I met Dr. G. in my

mother-in-law's house and after having a conversation with him I decided to place myself in his hands. He prescribed a certain treatment, and almost immediately I began to feel an improvement. The swelling began gradually to disappear. I got to feel that my household duties interested me, for I could perform them with some degree of pleasure and without any fatigue. My voice gradually came back, and in the winter of 1909, I sang again in public without a trace of any weakness or unreliability in my voice. Realizing the improvement I got quite cheerful, entering into company in a quiet way as before the trouble, and sang at various small concerts.
In March, 1909, I went to a dance, and danced all the dances. I became pregnant again about then, and in November a healthy child was born. She is still a healthy child, and my own health never was better in all my life. "
The clinical history of Mrs M., beginning as it does in the year 1901 and extending to her recovery in 1910, covers a period of 10 years,. It is particularly interesting, not only because of the perfect relief which thyroid therapy brought, but because it exhibits, within the compass of a single life, the wide ramifications of unhealth that can be caused by thyroid insufficiency. In the second place, w have here the history of a type. During the early years of her illness, hyper-thyroidism, and not insufficiency was the prevailing condition. Mrs. M. was one of those cases of goitre that show very little or no enlargement of the gland throughout the whole course of the disease. ....

1915 Clinical Errors In Diagnosis Adolphe Abrahams M.D., B.C., M.R.C.P. Medical Registrar to the London Temperance Hospital, etc. Paper read before the Abernethian Society of St. Bartholomew's Hospital. The Practitioner 1915

p380
The subject of this paper was suggested by a series of lectures given some time ago, under the auspices of a well-known post-graduate college, by a member of distinguished consultants and specialists. Each had selected his own particular branch, and dealt with the common mistakes which he had encountered, almost invariably, be it added, at the hands of somebody else. .....
It is hardly protesting too much that three or four decades back such a series of lectures could have been comprised under perhaps half-a-dozen subjects. But to what a degree have we now attained? It is not enough that the naso-laryngeal expert shall deal with this region of the body; the nose has its own errors so clearly defined, that a separate lecture was regarded as necessary. The chest as a speciality has long since passed away; the man on the lungs had no mention of the heart. and even the cardiac specialist exhibited a marked tendency to dichotomy, for a struggle between displaying his experience as a clinical diagnostician and his skill as a mechanical cardiologist was manifest. So far from abdominal surgery sufficing as an entity, the general surgeon, although allowed his say, was supplemented by a kidney man and by various specialists upon the alimentary tract. For behold! the intestinal tube itself has been parcelled out. Has not the special study of proctology originated? Has not the appendix its special devotees? Are there not surgeons with options upon the large intestine?
All this terrifying display of human knowledge and wisdom makes the prospect for the future still more terrifying. In all sincerity, one asks where will specialization end, or rather how far can it extend? Shall we have men who will confine their enterprise to the Eustachian tube, as today the labyrinth has its faithful adherents? Will there be, perhaps, labio-glosso- lingual specialists? Or will even such a category be too diffuse, and its separate constituents require special consideration? The specialists who were invited to contribute their lectures were in all cases distinguished; many might be described as eminent, and to two, or perhaps three, the qualification pre-eminent might justly be applied. Yet, although the majority of the lectures were as excellent as the prestige of their contributors would have led one to expect, in many cases the material was bad, and in a few cases almost incredibly bad. ....

p383
CLASSIFICATION
THE CAUSES OF MISTAKES
A. Before the patient is seen.
Mistakes made before the patient is seen are naturally few, and the method ofavoidance is sufficiently obvious.
B. In the management of the patient,.
1. Social - Mistake in manner or tact.
2. Clinical -
a. Mistakes due to ignorance.
b. To errors of judgement.
c. To obsessions.
d. From failure to think anatomically.
e. From failure to think at all.
f. From a reluctance to accept responsibility.
g. From incomplete examination.
h. From inherent difficulties in the case.
B. 1. SOCIAL.- Mistakes in manner or tact.
Sheer bad manners denote without doubt that a fundamental mistake has been committed, that the doctor has mistaken his vocation.

p386

b. MISTAKES DUE TO ERRORS OF JUDGEMENT.
The distinction of errors due to inexperience from those which may be attributed to ignorance is in reality artificial, but I want to err on the side of multiplying headings rather than otherwise. No case, for example, ever corresponds to a text-book description, which is a composite picture, as it were, of everything that is prominent, and only experience can teach what may be regarded as a sufficient sign of a certain condition. Want of experience applies particularly in chest cases, for there is the difficulty of setting a standard of sounds which are healthy, and it is quite a common enough thing to be in doubt which is the healthy and which the diseased side.
Indeed, it requires no little degree of experience to recognise what may be called normal. "Show me normal on the plate," was a favourite saying of Mr. Lockwood's, and the greater one's experience the more one appreciates the wisdom of his criticism.

p388
C. MISTAKES DUE TO OBSESSIONS.
With all respect, I venture to think there is not one member of our profession who is immune to this cause of error. None of us will need reminding of the gross obsessions for which many eminent physicians and surgeon are notorious, or, perhaps I should say, famous. With the best intentions, it often seems impossible to avoid concentrating one's attention upon a certain hypothesis and unconsciously distorting phenomena to agree with it, whilst blinding oneself to other conditions which might have caused revision of judgement. ....
p390
g. MISTAKES FROM INCOMPLETE EXAMINATION.
The category of errors due to incomplete examination is far and away the largest of all. Nearly all avoidable blunders result from this cause. Although mistakes may b perpetrated through one of other of the reasons I have already enunciated, how many mistakes would e avoided, if we made a point of a complete examination from head to foot, including the use of the ophthalmoscope and investigation of the urine! This is a preposterous counsel of perfection, but do we not all err on the side of examining incompletely? ....
What are the causes of incomplete examination? First of all, because there is no time, owing to extreme pressure of work, for more than what, as a photographer, I should term a snapshot diagnosis. Very little removed from this and more culpable is the diagnosis, which is made upon the patient's symptomatic description without examining the part.
p392
.... An enormous number of grave errors may result from simply neglecting to take the temperature. ....

p395
CONCLUSION
In the contemplation of our successes we are naturally most pleased to indulge, but it is more instructive, if less edifying, to travel again the path of some past error. W are told by the poet that others' folly teaches not. Everybody makes some gross error in the course of his experience, and happy is he who makes it on some relatively unimportant occasion; happier still, if the only result is a determination never to make it again.
The cynical philosopher laments the pity, that in life we only get our lessons when they are of no use to us. It is worth while, nevertheless, to keep burning brightly that purifying fire, the fear of making a mistake, remembering in all humility that most mistakes were in reality avoidable, avoidable simply by method, the harness without which only the horses of genius can travel.

1915 The Thyroid Gland Dr H.R. Unwin, M.B. F.R.C.S. Yeovil The Practitioner

p702
.... There is an interesting group of cases, which is classed under the heading of "thyroid insufficiency." These cases vary from mild myxoedema to such ordinary complaints as headaches. The commoner symptoms of the disorder are:- malnutrition; varying degrees of alopecia, of which the most constant is a thinning or absence of the hair in the outer one- third of the eyebrows, and known as the "eyebrow sign;" decay of the teeth, and brittle nails; the feeling of being bone tired; articular and muscular pain; poor circulation; cold extremities, and a tendency to chilblains; constipation and nocturnal enuresis; asthma, dyspnoea; neuralgia, headache, migraine, noises in the ears, somnolence, and obesity; various skin affections; infantilism of the sexual organs, cyptorchidism, mastodynia, varying menstrual disorders from amenorrhoea to menorrhagia with passage of clots, and leucorrhoea. The majority of these symptoms are met with commonly in one's patients, and will respond, with varying degrees of success, to thyroid medication.
TREATMENT.
The surgical treatment of affections of the thyroid gland is eminently satisfactory. A patient presents herself with an adenoma of the gland; it is removed, and not more is heard of it. Or, again, in some cases of exophthalmic goitre, a portion of the gland is removed, and the symptoms subside. This is not the case with the medicinal treatment; some brilliant results have been obtained, but on the whole the results are disappointing, chiefly, no doubt, because one is apt to blame the thyroid for conditions it has no part in producing.

p 705
Mrs. F. consulted me for severe rheumatoid pains, chiefly in the cervical joints and lower limbs. She complained too of loss of hair, constipation, lassitude, passage of clots at menstrual periods and leucorrhoea. She has two sisters suffering from exophthalmic goitre, and a baby with cryptochildism. She is showing some improvement under thyroid medication, starting on 1⁄2 grain of fresh gland three times a day and gradually working up the dose. Previous to my seeing her, she had gone through every other known form of treatment without effect.

.... (d) In children, the results are often most gratifying. Pale children, with no appetite, show in thought and speech, slack and easily tired, will often improve bodily and mentally to an astonishing degree on 1⁄2 gr. of fresh thyroid gland, three times a day.

1927 BOOK REVIEW - BASAL METABOLISM IN DISEASES OF THE THYROID. BMJ 2: 1228- 1229, 1927
P 1228
THE volume under review is entitled Clinical Investigations into the Basal Metabolism in Diseases of the Thyroid Gland. p 1229

....Turning to other thyroid conditions, it was found that almost without exception cases of simple goitre gave normal basal metabolism values. On the other hand, every case of myxoedema gave a low value. The lowest was never less than 60 per cent. of the normal - a level which was consequently taken to represent that attained when there is complete functional inactivity of the thyroid. The effect of thyroid treatment was always to cause a rise towards normal basal metabolism, but the maximum effect was not attained for two to eight weeks. This rise is an early symptom of mitigation of the condition, as it generally precedes the disappearance of the subjective symptoms.

1940 EDITORIAL: AUTHORITY, OBSERVATION, AND EXPERIMENT JULY 20, 1940 Vol. II p 88 - 89
Authority, Observation and Experiments in Medicine. By W. W. C. Topley M.D., F.R.C.P., F.R.S. Linacre Lecture, 1940, Cambridge ; University Press
p88
....Prof. Topley particularly dislikes the double label, "The Science and Art of Medicine," and has some pungent criticisms to make on the loose application of the word "art." In so far as that label is used to shelter "the didactic assertion of inadequately tested working hypotheses" from criticism he is justified in his contention that "a physician who, regarding himself as an artist, fails to realise that he is performing a series of peculiarly difficult experiments, is not likely to add greatly to his own knowledge or that of others." Nevertheless, if the term "art" is interpreted to mean the method of approach to the patient, and inducing him to consent to the adoption of appropriate measures, it is a convenient one.
...."No physician would now observe and treat his patients, in all their ills, guided only by his trained but unaided senses." On the other hand, he utters a strong protest against the growth of the pernicious habit of relying upon a collection of second-hand information to construct a diagnosis : "All concerned must be in constant personal touch and know enough of one another's methods to talk a common language." He does not refer, however, to a still more lamentable practice which is on the increase - the piling up by a certain type of laboratory worker, often not medically qualified, of a mass of biochemical statistics from which he draws far-reaching conclusions as to the metabolic disorders of a patient without an ordinary clinical examination. The mass of figures is doubtless intended to impress the patient that he has been very scientifically investigated, whereas many of them are superfluous and quite irrelevant. This is pseudo-science, which is as much to be condemned as the behaviour of a clinician who spurns laboratory aid.
The imperfect sympathy sometimes shown by the laboratory worker towards the clinician's difficulties may be attributed to his not being confronted by the dilemma between scientific controls and the immediacy of human suffering that clamours for relief.

1942 BASAL TEMPERATURE VERSUS BASAL METABOLISM BRODA BARNES, M.D. DENVER JAMA 119:1072,1942

p1072
Basal temperature is defined here as the body temperature taken under conditions which are usually considered as necessary for determining basal metabolism. That is to say, the individual should have had a good night's rest, no food for twelve hours and no exercise or excitement. Unless the patient is in the hospital or the test is run in the home a true basal metabolic rate is not obtained, for the exercise of dressing and going to the laboratory will have an appreciable influence on the oxidative rate. The half hour or hour rest is a poor compromise for basal conditions. This is not the most serious criticism of the determinations of basal metabolism, however. Many more errors are made when the patient is unable to relax because of nervous tension. Although the normal person would not be excited by such an examination, the person needing such a test is not normal and many of them are unable to relax after repeated tests.

....It is well established clinically that the hyperthyroid patient has an elevated body temperature. Thus is appears from the experimental data and from clinical observations that body temperature might serve as an index of thyroid activity in hypothyroidism.

There is considerable disagreement in the literature as to whether all patients with low metabolic rates are hypothyroid. There is no doubt that starvation will lower the metabolic rate. This must be taken into consideration when malnutrition is so prevalent even in our own country. The extreme effect of starvation on metabolism is illustrated by Benedict's patient, who fasted thirty-one days. The metabolism fell 30 per cent. It is interesting to note that the body temperature remained relatively constant during this entire period. Hence it seems that body temperature might well distinguish between cases of inanition and those of true hypothyroidism. Other instances in which the metabolic rate goes down have not been followed, but at present it seems that the body temperature can be safely used.
The present group includes some patients with neurasthenia, chronic nervous exhaustion, arthritis and other diseases which are not generally considered to occur with hypothyroidism. The initial low temperature and the improvement seen when the temperature is elevated by thyroid therapy indicate that further work should be done in this field.

p1073
Very few patients with subnormal temperatures fail to respond to thyroid therapy, both as to relief of symptoms and as to elevation in temperatures.
....Another group of cases in which body temperature would be useful is illustrated by the following:
A woman aged 22 had been very nervous and underweight for several years. She suffered from palpitation of the heart, had a pulse rate of 110, blood pressure of 155 systolic and 100 diastolic, a fine tremor of the hands and hyperactive reflexes. Prior to entrance to the university her basal metabolic rate was +18 per cent, and she had been advised to have a thyroidectomy. She had refused the operation. Her body temperature was 97.6 F. The basal metabolic rate was found to be +8 per cent. The curve was smooth, but observations during the test left no doubt that she was not relaxed. She was given phenobarbital, 1⁄2 grain (0.03 Gm.) three times a day for one week and the metabolic rate was then found to be -8 per cent. She was started on thyroid therapy 1⁄2 grain daily and seen at weekly intervals, The dose was gradually increased to 2 grains (0.13 Gm.) daily. Over a period of sixty days the blood pressure gradually fell to 115 systolic and 85 diastolic, the pulse rate came down to 84 and the hyperactive reflexes became normal. The body temperature gradually rose. The nervousness and tremor of the hands improved.
The therapeutic results would leave no doubt in the mind of the physician or the patient that what had appeared to be a classic hyperthyroid syndrome was in reality hypothyroid in causation. The body temperature was the only criterion on which a correct diagnosis might have been made.
That such cases are not rare is indicated by 6 additional cases that I have observed during the past twelve months. In 5 of these an operation had been performed, and the subsequent history left no doubt of a mistaken diagnosis.
....The procedure followed at present for the diagnosis of subnormal body temperature is as follows: The patient places a thermometer and book by his bedside. When he awakens in the morning the thermometer is left in the mouth without interruption for ten minutes by the block (the use of the book is obvious). It will be found that in the absence of a cold or other infection the daily variation in one's temperature is comparatively slight. The menstrual cycle causes about 1 degree variation with the low point at the time of ovulation and a gradual rise to a peak occurring a day or two before menstruation. It will be necessary to determine the basal temperature in a number of cases before setting a standard. Hence the tentative standard set here may be modified slightly by more data, but it will serve as a safe working range for the present. It is based on observations on patients without symptoms as well as on patients with symptoms which were relieved by adequate doses of thyroid over long periods. For the male the basal temperature seems to be near 98.0 F. For the female the average for the entire period has been found to be about 98.0 F. with the low point at the time of ovulation at 97.5 and the peak near 98.5.

p1074

SUMMARY
1. From a study of over 1,000 cases the results indicate that subnormal body temperature is a better index for thyroid therapy

than the basal metabolic rate.
2. The differential diagnosis between hypothyroidism and hyperthyroidism is sometimes difficult. In 7 cases reported the diagnosis was wrong, in 5 of which an operation had been performed. The temperature was subnormal in each case.

1950 THE RESPONSE OF THE THYROID GLAND TO THYROTROPIC HORMONE AS AN AID IN THE DIFFERENTIAL DIAGNOSIS OF PRIMARY AND SECONDARY HYPOTHYROIDISM A. QUERIDO, M.D. AND JOHN B. STANBURY, M.D. from the Thyroid Clinic of the Massachusetts General Hospital, Boston, Mass. Journal Clinical Endocrinology Vol. !0, 1950p p1192 - 1201

p1192
THE differentiation of hypothyroidism of pituitary origin from that due to primary impairment of the thyroid gland may be very difficult. Proper treatment is dependent upon correct distinction of the two conditions. The problem is met whenever hypometabolism is encountered along with evidence of diminished function of other endocrine glands, such as the adrenal cortex or the gonads. One must first decide whether the hypometabolism is a result of hypothyroidism; for in many conditions, such as anorexia nervosa, severe hypometabolism may exist when there is ample laboratory evidence of a normally functioning thyroid gland.
The usual laboratory data on thyroid function do not suffice to distinguish between primary thyroid failure and pituitary failure. The trends are the same in both, and elevated serum cholesterol and axillary hair loss also may prevail in both.

Diminished function of other target glands of the pituitary favors a diagnosis of hypothyroidism of pituitary origin. However, there may be diminished function of these glands in primary myxedema also (1) : for instance, in a thyroidectomized rat the weight of the adrenal glands diminishes and the cortex shows changes in cellular pattern compatible with hypofunction. The clinical situation is further complicated by the existence of a bi-glandular disease (thyroid fibrosis accompanied by adrenal atrophy) recently observed by one of us (2). Thus, there are three conditions in which hypothyroidism is a feature of pluriglandular disease: i) pituitary insufficiency, ii) severe hypothyroidism causing hypoadrenocorticism, and iii) bi-glandular disease of the thyroid and adrenal glands with a normal pituitary gland. p1193

It seemed reasonable to attempt a differentiation of these conditions by testing the responsiveness of the thyroid gland to thyrotropic hormone. This was based on the consideration that hypothyroidism arising from atrophy of the thyroid gland secondary to hypopituitarism should respond toe thyrotropin, whereas the fibrotic thyroid of primary myxedema should not. It was borne in mind however that atrophy from pituitary failure of long standing might lead to unresponsiveness, probably through fibrotic changes as described by Sheehan (3), and as we also have observed.

p1196
....This test has value only because of the great difficulty which may exist in making a clear differentiation between primary and pituitary myxedema on any other basis at present. Properly interpreted, it may prove helpful. Much more experience is needed before it will be possible to evaluate the significance and the limitations of the test.
SUMMARY
1. Thyrotropic hormone was given to a series of 9 patients with hypometabolism. One of these except for an elevated serum cholesterol concentration, was otherwise normal; 6 were considered to have primary
p1197
myxedema; and 2 were given a final diagnosis of hypopituitarism. Thyroid gland was assessed by determinations of basal metabolic rate, the serum protein-bound iodine, and by radioiodine studies.
2. Following administration of thyrotropic hormone there was a rise in the indices of thyroid function in the patient with nonthyroidal hypometabolism, in the 2 patients with hypopituitarism, and in 1 of the patients with primary myxedema. The last was interpreted as a response of remnants of functional thyroid tissue.
3. The results suggest that repeated injections of thyrotropic hormone may be an aid in the differential diagnosis of primary and secondary hypothyroidism.
4. The limitations of the test are discussed.

1950 THE EFFECT OF ADRENOCORTICOTROPIN AND CORTISONE ON THYROID FUNCTION: THYROIDADRENOCORTICAL INTERRELATIONSHIPS S. RICHARDSON HILL, JR., M.D., ROBERT S. REISS, M.D., PETER H. FORSHAM, M.D. AND GEORGE W. THORN, M.D. From the Medical Clinic, Peter Bent Brigham Hospital, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts Journal of Clinical Endocrinology Vol. 10 1950 p 1375 - 1400
p1375
INTRODUCTION
THE thyroid-adrenal interrelationship has interested medical investigators for over fifty years. A protective action of adrenocortical steroids against thyroid intoxication has been shown repeatedly (1-11). The experiments of Marine and Baumann (12, 13), which were confirmed by others (14-16), demonstrated an apparently increased activity of the thyroid in the presence of partial adrenal cortical insufficiency. The lymphoid and thymic hyperplasia in hyperthyroidism, as well as in adrenal cortical insufficiency (2, 17-20), the involution of these tissues by adrenal cortical steroids (21-23), and the inactivation of thyrotropic hormone by the same tissue (24) all point to a close physiologic relationship between the thyroid and adrenal glands.
p1382
....Summary: It would appear that both ACTH and cortisone administered to subjects with normal thyroid and adrenal function consistently induce a depression of I131 accumulation gradient. In 8 out of 13 subjects, a decrease in the serum protein-bound iodine level occurred. At a time when both the I131 accumulation gradient and the serum protein-bound iodine were slightly to moderately decreased, the basal metabolic rate either increased slightly or remained unchanged. As the decrease in serum protein-bound iodine and I131 accumulation gradient became more marked, the basal metabolic rate also decreased. Serum cholesterol levels tended to be decreased when measured.
Following discontinuance of hormone, there tended to be a return of I131 accumulation gradient and the serum protein- bound iodine level toward or above the control value and a rebound decrease in basal metabolic rate.
Among patients with the nephrotic syndrome some, especially those with an initially low serum protein-bound iodine, show an anomalous response
p1383
to ACTH or to cortisone in that there is a rise in protein-bound iodine and accumulation gradient rather than a fall, during administration of these hormones.
Administered TSH proved capable of stimulating a thyroid response following inhibition by, and in the presence of, a high level of circulating adrenal steroids.
p1387
....Hypothyroidism

Relation of adrenal cortical response to thyroid activity: Nine of 11 patients with hypothyroidism given a single 25 mg. injection of ACTH had an inadequate adrenal cortical response (23), as measured by the four-hour decrease in circulating eosinophils and increase in uric acid-creatinine ratio. Three of these patients were given a similar test following thyroid hormone (desiccated thyroid) therapy, at which time their response had reverted either to or toward normal (Fig. 10), whereas the adrenal response of 2 others similarly treated was unchanged following thyroid hormone therapy.

Eight out of 10 patients with hypothyroidism had an initially low urinary 17-ketosteroid excretion. Seven our of these 10 had an inadequate or delayed response to forty-eight hours of ACTH administration as
p1388
measured by the increase in urinary 17-ketosteroid excretion (Fig. 11). When the more sensitive circulating-eosinophil decrease was used as a criterion of adrenal cortical response, only 3 had an inadequate response in forty-eight hours. One patient with untreated hypothyroidism, who showed a delayed rise in urinary 17-ketosteroid excretion during forty-eight hours of ACTH, responded more promptly following administration of desiccated thyroid and a consequent rise in basal metabolic rate (Fig. 12). Another patient with myxedema whose 17-ketosteroids did not respond to forty-eight hours of ACTH administration prior to thyroid hormone therapy did have a response as measured by an increase in both 17- ketosteroids and basal metabolic rate following therapy (fig. 13). Two other patients with myxedema who failed to respond to forty-eight hours of ACTH administration prior to thyroid hormone therapy also failed to respond to similar adrenocortical stimulation following adequate thyroid hormone replacement therapy.

p1390
....Summary: It would appear hat adrenal cortical response is delayed and at times inadequate in some patients with hypothyroidism. A more prompt and adequate adrenal cortical response may be restored in some of these patients by thyroid hormone therapy.
These studies suggest that both ACTH and cortisone acetate are capable
p1391
of increasing the basal metabolic rate without changing the serum protein-bound iodine level in patients taking a constant dose of thyroid, in the absence of any endogenous compensating mechanism.
Hyperthyroidism
Six patients with classic Graves' disease given a single injection of 25 mg. of ACTH showed a normal adrenal cortical response, as measured by the 4-hour fall in circulating eosinophils. Three out of 5 of these patients had an adequate adrenal cortical response to ACTH administration, as measured by the 48-hour fall in circulating eosinophils. Three out of 5 of these patients had an adequate adrenal cortical response to ACTH administration, as measured by the 48-hour increase in urinary 17-ketosteroid excretion. The 2 patients who failed to respond adequately in forty-eight hours, subsequently had an adequate increase in urinary 17-ketosteroids following more prolonged ACTH administration.
Six patients with Graves' disease were treated with ACTH in doses of 40 to 200 mg. per day for five to twenty-three days. The degree of adrenal
p 1392
cortical response, as measured by the increase in urinary 17-ketosteroid excretion, was variable; the maximum excretion ranged from 17.7 to 65.9 mg. per twenty-four hours following five to twelve days of ACTH administration.
Five of these 6 patients treated with ACTH had a decrease in "iodine space," and 3 of the 6 had a decrease in I131 accumulation gradient. Three of 5 patients had a decrease in serum protein-bound iodine, whereas only 2 of the 6 had a decrease in serum protein-bound iodine, whereas only 2 of the 6 had a significant decrease in basal metabolic rate. Three patients of the 6 had a decrease in gland size and improvement in clinical symptoms. Creatine tolerance tended to increase in the 2 patients in whom it was followed. Serum cholesterol levels, which were followed in 2 patients, remained unchanged in one and decreased slightly in another.
In all patients there was an initial period of increased thyrotoxicity for four to twenty-four hours following the initiation of ACTH therapy. In 5 cases the I131 accumulation gradient and serum protein-bound iodine were measured during this period of increased thyrotoxicity and found to be slightly elevated in 2 and decreased in 3. Basal metabolic rates were elevated in all during this period of increased toxicity.
p1395
....DISCUSSION
From the present studies and the experience of many other investigators (1-29), evidence has been obtained which strongly suggests a close interrelationship between the thyroid and adrenal glands.
We consider the I131 accumulation gradient a measure of iodine uptake and turnover within the thyroid gland, the serum protein bound iodine
p1396
as an indication of the quantity of circulating thyroid hormone, and the basal metabolic rate a measure of the tissue response to thyroid hormone or other calorigenic agents. By the use of these tests, a three-dimensional picture of thyroid function is obtained. In the present studies, changes in serum cholesterol levels possess limited value in interpreting changes in thyroid activity, since ACTH is thought to exert an independent action upon cholesterol (36).
From the present study it would appear that an increase in circulating adrenal steroids elicits two distinct alterations in thyroid function, viz., 1) a calorigenic action, associated with an increased basal oxygen consumption, and 2) an inhibitory action on all phases of thyroid function. To date, some patients with the nephrotic syndrome and Addison's disease constitute the only major exception to these findings.

The increase in oxygen consumption following adrenal steroid therapy is evident to some extent in all of the patients studied, with the exception of those with the nephrotic syndrome (37).
The most obvious substantiation of the possible ability of adrenal cortical steroids to increase oxygen consumption without increasing thyroid hormone utilization was obtained in 2 athyreotic patients maintained on a constant dose of desiccated thyroid while receiving ACTH and cortisone. All patients demonstrated a small but significant increase in basal metabolic rate, with a rebound decrease following discontinuance of adrenal steroids, with no change in the level of serum protein- bound iodine. In all of these determinations the basal metabolic rate was corrected for the alterations in respiratory quotient induced by ACTH or cortisone therapy.
In subjects with a normal thyroid-pituitary axis and the increase in oxygen consumption due to adrenal steroids may be masked by their concomitant inhibitory effects of thyroid function. It can, however, be appreciated even in normal subjects if it is realized that at a time when both the I131 accumulation gradient and serum protein-bound iodine are slightly to moderately decreased, the basal metabolic rate either remains unchanged or increases. During more prolonged adrenal steroid therapy, when the decrease in serum protein-bound iodine and I131 accumulation gradient becomes more marked, the basal metabolic rate also decreases, but not to the extent that one would anticipate.
The calorigenic effect of adrenal steroids may be the result of an increased peripheral effectiveness of thyroid hormone and/or a direct calorigenic effect of the adrenal steroids. It is apparently not the result of increased utilization of thyroid hormone.
The second phase of adrenal steroid influence on thyroid function is an inhibitory one in which all aspects of thyroid function are depressed. This inhibitory effect was demonstrated to some extent by all of the subjects studied, especially the normal subjects and patients with Cushing's
p1397
syndrome. It was also demonstrated by an occasional patient with classic thyrotoxicosis, who was given ACTH or cortisone. Such inhibitory changes could best be explained by assuming that a constant high level of adrenal steroids induced pituitary inhibition of both ACTH (38) and TSH production. Such a theory would imply that patients in whom the thyrotoxicosis was dependent upon increased TSH production would be the most susceptible to this mechanism, and that patients with thyrotoxicosis arising primarily within the thyroid gland would prove refractory.
That the thyroid inhibitory effect of adrenal steroids occurs as a result of pituitary inhibition and not through peripheral or end-organ inhibition of TSH is suggested by the fact that administered TSH is capable of stimulating a thyroid response following inhibition of the thyroid by, and in the presence of, a high level of adrenal steroids. The data presented do not preclude the possibility that adrenal steroids might have some other inhibitory effect on thyroid tissue independent of TSH. The suppression of thyroid activity by ACTH leads to a gradual reduction in BMR during prolonged high dosage therapy with this agent. Since adrenal cortical activation is definitely reduced with a lowering of the BMR and since general metabolic activity is decreased, one might expect to find a gradual unresponsiveness to ACTH during prolonged courses of therapy. Thus, the effect of decreased thyroid function must always be thought of as a possible cause for a gradually developing unresponsiveness to ACTH.
The accumulation gradient was chosen as a criterion since it did reveal definite changes under ACTH or cortisone therapy. Whenever 24-hour iodine uptakes were also determined it was found that they did not change, confirming previous observations by Knowlton, et al. (39). It would appear that with the suppression of TSH secretion, iodine uptake is merely retarded rather than inhibited completely.
The changes in thyroid activity induced by the administration of cortisone to patients with Addision's disease are comparable to those seen in normal subjects. There is, however, in some cases a transient increase in I131 accumulation gradient, basal metabolic rate, and a decrease in serum protein-bound iodine, suggesting an increased utilization of, and demand for thyroid hormone. This increase in thyroid function is usually temporary, but occasionally is progressive despite continued cortisone therapy. Indeed, in 1 adolescent girl, thyrotoxicosis was apparently initiated by this mechanism.
The increase in thyroid function has not been observed in all patients with Addison's disease and does not occur if they have had adrenal extract therapy immediately prior to cortisone administration. In these situations the thyroid response is comparable in every respect to that seen in normal subjects following adrenal steroid therapy.
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SUMMARY AND CONCLUSIONS
1. An attempt has been made to evaluate the effect of ACTH and of cortisone on thyroid function, as well as to follow thyroid and adrenal activity in various disease states.
2. In the present studies the I131 accumulation gradient has been used to indicate the iodine uptake and turnover within the thyroid gland, the serum protein-bound iodine to indicate the quantity of circulating thyroid hormone, and the basal metabolic rate to measure the tissue response to thyroid hormone or other calorigenic agents.
3. In normal subjects, ACTH and cortisone appear to induce a depression of the I131 accumulation gradient and serum protein-bound iodine. The basal metabolic rate either increases, remains unchanged or decreases, depending upon the degree of thyroid depression. In contrast, ACTH and cortisone may induce an increase in I131 gradient and serum protein-bound iodine, if the latter value is initially low, while inducing a slight decrease in the basal metabolic rate in patients with the nephrotic syndrome.
4. Exogenous thyroid-stimulating hormone (TSH) is capable of eliciting a thyroid response following inhibition by and in the presence of a high level of adrenal cortical steroids.
5. The majority of patients with Addison's disease have normal I131 accumulation gradients, serum protein-bound levels

and basal metabolic rates. The mean values of these determinations are, however, slightly below the corresponding mean values for a group of normal subjects.
6. In some patients with Addison's disease, cortisone acetate may induce an initial increase in thyroid activity which may be followed by a more persistent decrease if cortisone is continued.
7. Patients with Cushing's syndrome have normal thyroid function, which, however, is markedly depressed upon a further increase in adrenal cortical steroids, either spontaneous or induced by ACTH.
8. Some patients with hypothyroidism exhibit a delayed, and at times inadequate adrenal cortical response to ACTH, which may be restored to normal by thyroid hormone therapy in some instances.
9. ACTH or cortisone induce a slight but definite increase in the basal metabolic rate (by a calorigenic action) without changing the thyroid hormone level, in athyreotic patients receiving a constant dose of desiccated thyroid.
10. The majority of patients with hyperthyroidism have a normal adrenocortical response to ACTH administration.
11. Following an initial exacerbation of hyperthyroidism, both ACTH and cortisone appear to depress thyroid function in some patients with Graves' disease. The best results correlate with the shortest duration of the hyperthyroid state and greatest degree of adrenal cortical response.
12. ACTH appears to induce a slight, temporary, clinical improvement
p1399
in both the so-called thyreotropic and thyrotoxic varieties of exophthalmos.
13. Adrenal steroids appear (a) to have a calorigenic action and (b) to suppress thyroid activity through pituitary inhibition. Their effect on the basal metabolic rate appears to be a resultant of these two opposing actions.

1950 IODINE COMPOUNDS IN THE BLOOD AND URINE OF MAN Van Meter Prize Award Essay J. E. RALL, M.D. From the Mayo Foundation, Rochester, Minnesota Journal of Clinical Endocrinology 10, 1950 p 996 - 1006 p996
THE nature of the circulating organic iodine compounds in normal and hyperthyroid man has not been determined with certainty despite many investigations utilizing chemical procedures for the determination of iodine. The came situation pertains to the nature of the iodine compounds which may occur in the urine, although fewer investigations have been made on urine than on blood.

p1004
....SUMMARY
The thyroxine-like, diiodotyrosine-like and iodine fractions in the blood of 8 hyperthyroid, 5 euthyroid and 3 myxedematous patients given
p1005
radioiodine were determined by radioactive analysis. The major constituent of the serum radioiodine under these conditions was thyroxine-like in nature, in most of both the euthyroid and hyperthyroid patients.
The organic radioiodine compounds were studied in the urine of hyperthyroid, euthyroid and myxedematous patients after administration of radioiodide. In hyperthyroid patients, by the third day after ingestion, from 12 per cent to 40 per cents of the urinary radioiodine was present in organic form. In the euthyroid patients, by the third day after the administration of radioiodine, less than 2 per cent of the total urinary radioiodine was in the form of organic iodine compounds. Further studies on the organic iodine compounds by means of butanol, alkali and silver solubilities demonstrated the presence of thyroxine-like and diiodotyrosine-like fractions in the urine of both euthyroid and hyperthyroid patients. That thyroxine was present as part of the organic urinary iodine was also suggested by recrystallization technics and filter paper partition chromatography.

1950 THE VARIABILITY IN THE HYALURONIC ACID CONTENT OF THE DERMAL CONNECTIVE TISSUE UNDER THE INFLUENCE OF THYROID HORMONE Mast Cells - the Peripheral Transmitters of Hormonal Action BY G. ASBOE-HANSEN COPENHAGEN, DENMARK ACTA DERMATO-VENEREOLOGICA 1950 30:221-230,1950

p221
The intercellular and interfibrillar ground substance of the skin is made up of a viscous mass, consisting, in human skin, mainly of hyaluronic acid, but also of chondroitin sulphuric acid, both of which are mucopolysaccharides containing uronic acid. It is particularly hyaluronic acid which lends the ground substance its slimy, viscous character.
....In certain pathological conditions, sometimes accompanied by cutaneous manifestations, there is an accumulation of hyaluronic acid in the corium. Among such conditions is myxoedema which is rarely met with in its fully developed form - i.e. with visible cutaneous swelling resembling oedema. Accumulation of hyaluronic acid may, however, also be demonstrated by various methods in hypothyroidism unaccompanied by visible cutaneous manifestations.
p 222
- Accumulation of "mucin" in myxoedematous skin was mentioned as early as 1895 by Horsley and confirmed in 1893 by Halliburton. - Reuter demonstrated mucin by means of mucicarmine staining of tissue sections.
....The following experiments and investigations were designed to study
(1) histochemically the variations in the amount of the mesenchymal mucopolysaccharide, hyaluronic acid, in patients with hypo- and hyperthyroidism,
(2) The relation between the histological appearances of the dermal connective tissue in hypothyroidism and in thyrotoxic

subjects with localized myxoedema,
(3) the origin of hyaluronic acid.
p223
The material (consisting of patients suffering from hypo- and hyperthyroidism) is derived from four medical and two dermatological departments in Copenhagen.

Since patients with myxoedema are rare, the writer suspended thyroidin medication in certain cases of compensated myxoedema, experimental causa, in order to procure experimental subjects.
A total of 48 specimens from 26 patients with hypothyroidism and 37 specimens from 37 patients with thyrotoxicosis were studied. Two cases of thyrotoxic, circumscribed myxoedema were included.
In 24 of the 26 patients with hypothyroidism, accumulation of metachromatic ground substance was seen in the corium, particularly in the papillary layer, where the substance is usually diffuse, whereas somewhat deeper it is disposed in irregular strands, often of a very intense purplish red colour. Constant, diffuse metachromasia was observed around the vessels, the lumina of which were more or less open. In and around the vessels - be they capillaries, arterioles, or venules - and free in the connective tissue, wherever there is metachromatic ground substance, and in particularly large numbers where the metachromasia is most intense, there is a very striking type of cells, Ehrlich's mast cells. Their size is extremely varied, but in myxoedematous connective tissue they are usually large, with ample cytoplasm, round, oval or polyhedric, and, when in a perivascular situation, usually spindle-shaped all more or less saturated with granules taking an intense metachromatic stain with toluidine blue. In the deeper layers of the corium, fibres showing an intense blue stain are as if split apart in a very irregular and loose arrangement. Compared with normal dermal connective tissue stained in the same way, in which the fibrillar structure
p 224
is very indistinct, the fibres taking only a faint stain, the phenomenon is striking and pathognomonic of myxoedema. ....Normal skin shows only very faint metachromasia, as a rule only in the papillary layer, in the basal membrane, in the vessel walls, around hair follicles and around sebaceous glands.
If a myxoedematous subject is treated with thyroid hormone, both metachromasia and the phenomenon of split fibres subside rapidly.
p226
....So far, the function of the mast cells in the connective tissue has been unknown. They have been attributed with a multitude of tasks, but no proof has been advanced of any of them.
Sylvén has mentioned the possibility that mast cells might form the "chromotropic substance" in granulation tissue during epithelial regeneration.
It is evident from the studies of Holmgren & Wilander that the mast cells contain an anticoagulant, an ester of sulphuric acid of high molecular weight, which is presumably heparin. - It must be contemplated now, whether the metachromatic substance in the connective tissue around the mast cells could be heparin. Heparin, however, is not affected by hyaluronidase (Humphrey), and tissue containing ample amounts of this substance has no anticoagulative properties. Nevertheless, heparin might be imagined to be a precursor of hyaluronic acid. Chemically, these two mucopolysaccharides are closely related, both containing glucuronic acid and glucosamine, but, unlike hyaluronic acid, heparin contains a few radicals of sulphuric acid. The conversion of heparin into hyaluronic acid must be presumed to be effected by tissue sulphatases. In this connection it should be mentioned that recent Swedish experiments on sulphonation of hyaluronic acid have resulted in a strong anticoagulant (Högberg).
The increased content of water in connective tissue in cases of myxoedema is presumably a result of the strong osmotic action of hyaluronic acid (Bauer et alii).
p227
It appears to beyond doubt that thyroid hormone exercises a regulating influence on the hyaluronic-acid content of dermal connective tissue. It is not out of place to mention here that Ropes et alii found increased amounts of hyaluronic acid in the joint fluid in myxoedema.
....According these considerations, the rôle played by thyroid hormone is confined to its inhibitory effect on the hypophysis or its ability to inactivate the thyrotropic hormone.
Perhaps, oestrogenic hormones also influence the variations in the hyaluronic acid content of the connective tissue (Bachmann et alii, Ogston et alii).
The adrenocorticotropic hormone of the pituitary (ACTH) and cortisone also act upon the hyaluronic acid of the mesenchymal tissues. In biopsies from the skin of patients suffering from rheumatic fever, the writer observed a subsidence of the metachromatic ground substance in the connective tissue of the corium and a decrease in the number of mast cells in the course of treatment with ACTH and cortisone. At the same time it has been noted that the ability of the organism to form granulation tissue is reduced and the power of wound healing is inhibited or lost. Schmidt & Faber have reported a decreased hyaluronidase inhibition of blood serum during ACTH treatment of rheumatoid arthritis.
It is reasonable to assume that the mast cells play a rôle as the peripheral transmitters of hormonal action, and their localization in the vascular walls may support this interpretation.

Conclusion

The thyroid hormone exercises a regulating influence on the amount of hyaluronic acid in the dermal connective tissue (possibly by inhibiting the actual regulator, the thyrotropic hormone of the pituitary).
Hypofunction of the thyroid gland is accompanied by an accumulation of hyaluronic acid in the dermal connective tissue,

and in rare cases, there is localized accumulation of hyaluronic acid in hyperthyroidism too. The histopathological appearance of both conditions is identical.
Influenced by hormones, the mast cells secrete the mesenchymal mucopolysaccharide, hyaluronic acid, perhaps by way of a precursor resembling heparin.

The last-mentioned hypothesis unites and elucidates two hitherto unsolved problems: (1) The origin of hyaluronic acid and
(2) the function of the mast cells in the connective tissue.
p228

SUMMARY
Hyaluronic acid is demonstrable in the connective tissue histochemically and by means of the specific enzyme

hyaluronidase.
In myxoedema and in the rare lesion called circumscribed, thyrotoxic myxoedema there is an accumulation of hyaluronic acid and large mast cells. The fibres appear to be split apart and the fatty tissue is atrophied.
In thyrotoxicosis there is usually no demonstrable hyaluronic acid in the dermal connective tissue and only few and small mast cells.
In the course of new-formation of hyaluronic acid following enzymatic breakdown, there will be perivascular accumulation of mast cells of a widely different degree of granulation.
Numerous large mast cells have been found in eyes and in synovial membranes, the fluids of which contain hyaluronic acid. The variations in the cytoplasmatic load of granules are interpreted as a sign of various functional phases.
In addition to thyroid hormone, a number of other hormones influence the variations in the hyaluronic acid content of the connective tissue.
The writer advances the hypothesis that mast cells, under hormonal influence, secrete the mesenchymal mucopolysaccharide hyaluronic acid, perhaps by way of a precursor resembling heparin.

1955 HISTOPATHOLOGIC EXAMINATION OF THE SKIN IN THE DIAGNOSIS OF MYXEDEMA IN CHILDREN HENNING ANDERSEN, M.D., GUSTAV ASBOE-HANSEN, M.D. AND FLEMMING QUAADE, M.D. Children's Endocrine Clinic, Dronning Louises Børnehospital, and the Connective Tissue Research Laboratory, University Institute of Medical Anatomy, Copenhagen, Denmark Journal Clinical Endocrinology 15:459-468, 1955 p459
FOR years it has been known that hypothyroidism may be associated with an accumulation of a mucinous substance in the dermal connective tissue.
p460
Since hyaluronic acid has a marked capacity to bind water (Ropes et al.(13)), its accumulation in the tissues explains the large water content. These alterations in the connective tissue are not signs of degeneration, but of lively cellular activity, and the condition is reversible.
Myxedematous connective tissue shows accumulations of mast cells, partly in a perivascular position and partly free in the tissue. Several investigations indicate that these cells are the origin of hyaluronic acid in the mesenchymal tissues. Chemical and histochemical studies have shown that they contain a mucopolysaccharide and that they are the only type of cell in the connective tissue containing this substance.
....Pathologic accumulations of mucinous substances in the connective tissue occur when the function of the pituitary is increased in relation to the thyroid gland. This state is in most cases a result of reduced inhibition, due to a reduced production of thyroxine from the thyroid gland. The thyrotropic hormone is known to act directly on the connective tissue, without the intermediary of the thyroid gland.
p462

CLINICAL MATERIAL
The series comprised 99 children, ranging in age from 3 months to 15 years, from various children's hospitals and out-

patient departments in Copenhagen. A distinction was made between the following three groups:
1. Definite clinical signs f hypothyroidism (26 children). As we felt that it was essential to define a group of children in whom the diagnosis of hypothyroidism was beyond doubt, this group includes only patients who fulfilled the ordinary criteria of thyroid hypofunction and who exhibited nothing of any relevance which could contradict the diagnosis. Particular stress was laid on the following signs: stunted growth, retarded osseous development and dentition, epiphyseal dysgenesis, the appearance of the skin, the temperature and moisture of the skin, typical facies, bodily proportions and appearance on the whole, bradycardia, low pulse pressure, constipation, subnormal temperature, increased sensitivity to cold, sluggish mentality and low intelligence. All the children were observed in the hospital for long periods and all gave a convincing response to the administration of thyroidin.
2. Suspected hypothyroidism (21 children). In these children a definite diagnosis could not be made on the basis of the foregoing criteria. The clinical data in this group are given in Table 1.
3. No signs of thyroid hypofunction (52 children).
p463
....DISCUSSION
It is possible that the following factors may have caused the negative result of the histologic examination in nearly half the

children with definite clinical signs of hypothyroidism:
1. Failure to withdraw thyroidin therapy in children treated in outpatient departments. The children whose mothers admitted such failure were excluded.
2. Thyroidin may have been withheld for too brief a period. According to our latest experience, the histologic changes may take up to six weeks to re-appear, especially following overdosage of thyroidin.
3. Provided increased metachromasia and accumulation of mast cells in the skin are results of the action of thyrotropic hormone - as indicated by many findings - a negative result of histologic examination must be expected in cases of pituitary insufficiency. As there was no possibility of examining the patients by determining thyroidal I131 uptake, serum protein- bound iodine concentration, or the blood level of thyrotropic hormone, we did not feel justified in distinguishing between pituitary and thyrogenic hypothyroidism.

CONCLUSION
The histologic findings on examination of a skin biopsy specimen were positive in more than half the children with

unmistakable clinical hypothyroidism, whereas they were negative in children without a reduction in thyroid function. In a group of 21 children with doubtful hypothyroidism,
p 467
the findings were positive in 8. When compared with previous reports on hypothyroidism in adults, our results warrant the following conclusions:

1. A skin biopsy specimen which shows the foregoing characteristic changes appears to afford a reliable diagnostic criterion for hypothyroidism, provided certain local dermal changes can be ruled out.
2. Negative skin biopsy findings do not exclude hypothyroidism.

SUMMARY
The histologic structure of the dermal connective tissue in hypothyroidism is described, with special reference to the ground

substance, mast cells, fibrillar structure, vessel walls, and epidermis, as well as the action of the thyrotropic hormone on these tissue elements.
Histologic examination is evaluated as a diagnostic test of hypothyroidism, and the technique is described.
By this method 99 infants and children were examined. The results were as follows:

In 15 of 26 patients with definite clinical hypothyroidism the skin biopsies showed changes in the epithelial and connective tissue structures of the skin. In 8 of 21 patients suspected of hypothyroidism skin biopsies showed similar findings. A control group of 52 euthyroid children had normal skin.
In all patients with a pathologic condition of the skin, the changes disappeared during administration of thyroidin, and could be reproduced by its withdrawal.

The possible causes of negative results in hypothyroidism are discussed.
The method is a simple and handy aid in the diagnosis of hypothyroidism, especially in children. Positive findings seem to indicate hypothyroidism; negative findings do not exclude it.

1955 Editorial WILLIAM H. BEIERWALTES, M.D. University Hospital, Ann Arbor, Michigan Journal Clinical Endocrinology Vol. 15, 1955 p148 - 150
p148
RESPONSE TO THYROID

WHEN desiccated thyroid is administered orally to myxedematous humans, the resultant metabolic changes are quite different from those observed in the euthyroid subject. The clinician can diagnose or treat hypothyroid patients much more intelligently if he is aware of these difference in response to thyroid. In addition, an unworked field for clinical research becomes evident when one reviews the known major differences between the myxedematous patient and the euthyroid subject in response to desiccated thyroid administration.
The most striking difference observed may be summarized by the statement that the patient who is truly deficient in circulating thyroid hormone responds dramatically and with predictable regularity to the administration of small doses of desiccated thyroid. The euthyroid subject, on the other hand, shows no obvious clinical response to small doses of thyroid. A simple and readily available diagnostic test for borderline hypothyroidism, therefore, is the administration of 1 grain of desiccated thyroid per day for a period of six weeks after a careful history and physical examination have been made and basal metabolic rate and serum cholesterol determinations have been performed. The patient who is truly deficient in thyroid hormone will generally respond to the administration of 1 grain of desiccated thyroid per day for six weeks with an increase in basal pulse rate and metabolic rate and a fall in the serum cholesterol level. The patient not truly deficient in thyroid hormone will show no significant change in these indices of thyroid hormone effect.
p149
....The myxedematous patient and the euthyroid subject also show a different response to sudden cessation of desiccated thyroid medication. The myxedematous patient at first shows a rapid drop in his serum precipitable-iodine level and basal metabolic rate, then a slower fall to pre-treatment levels over a period of six to eight weeks (3). On the other hand, when the thyroid medication of a euthyroid person is suddenly stopped, the serum precipitable-iodine value falls to myxedematous levels in three to four weeks, but the basal metabolic rate may take as long as nine to fifteen weeks to reach its lowest level (3). These values then rise to pre-treatment levels. The radioiodine uptake is also falsely depressed by thyroid administration and has taken as long as eleven weeks to recover (4). Furthermore, when the thyroid does recover its ability to concentrate I131, the I131 pickup rate may rebound temporarily to hyperthyroid levels. Obviously, if a physician were to stop the

desiccated thyroid medication of a euthyroid patient in an attempt to evaluate the patient's underlying thyroid status, these ensuing changes in indices of thyroid function, when sampled, might prove very misleading and confusing.
The daily output of thyroid hormone by the normal thyroid gland is thought to be equivalent to not more than 3 grains of desiccated thyroid per day. Consequently, when the daily dosage of desiccated thyroid is raised to 4 grains or more per day, any differences observed between athyreotic and euthyroid subjects can not be explained on the basis of further suppression of normal thyroid function. Most practicing physicians have probably observed a euthyroid patient who was comfortable while voluntarily taking 5 to 20 grains of desiccated thyroid a day, in an attempt to reduce

p149
his weight and rid himself of fatigue. Rarely, if ever, does one see an athyreotic patient voluntarily take more than 3 grains of desiccated thyroid per day. This situation suggests that the athyreotic patient is more sensitive to thyroid substance than is the euthyroid person, even after his myxedema has been controlled with medication.
....WILLIAM H. BEIERWALTES, M.D.
University Hospital, Ann Arbor, Michigan

REFERENCES
1. MEANS, J. H,: The Thyroid and Its Disease, ed. 2. Philadelphia, J. B. Lippincott Co., 1948, p 249
2. WINKLER, A. W.; RIGGS, D. S., and MAN, E. B.: Serum iodine in hypothyroidism before and during thyroid therapy, J. Clin. Invest. 24: 732, 1945
3. RIGGS, D. S.; MAN, E. B., and WINKLER, A. W.: Serum iodine of euthyroid subjects treated with desiccated thyroid, J. Clin. Invest. 24: 722, 1945
4. GREER, M. A.: The effect on endogenous thyroid activity of feeding desiccated thyroid to normal human subjects, New England J. Med. 244: 385, 1951
5. JOHNSTON, M. W.; SQUIRES, A. H., and FARQHARSON, R. F.: The effect of prolonged administration of thyroid, Ann. Int. Med. 35: 1008, 1951
6. THOMPSON, W. O.; THOMPSON, P. K.; TAYLOR, S. G., and DICKIE, L. F. N.: Calorigenic action of single large doses of desiccated hog thyroid: comparison with the action of thyroxine given orally and intravenously, Arch. Int. Med. 54: 888, 1934

1967 LABORATORY PROCEDURES Their Clinical Significance Common Tests of Thyroid Function in Serum Herbert A. Selenkow, MD, and Samuel Refetoff, MD JAMA, 202:155-156, 1967
p 155
Correct diagnosis of most common disorders of thyroid function can usually be achieved by a thorough clinical evaluation and confirmed by a few carefully selected laboratory procedures. There are now available a number of relatively specific and accurate tests for measurement of thyroid hormone synthesis, secretion, transport, and metabolic action. Unfortunately, none alone is fully diagnostic of any single thyroid disorder and all can be misleading as a result of a wide variety of factors which influence their patho-physiologic significance. This presentation will be limited to a brief discussion a a few serum measurements of thyroid function of clinical importance to medical practice.

....It is not commonly appreciated that PBI levels differ depending upon the particular thyroid hormone product used. In hypothyroidism, for example, full metabolic replacement doses of 0.3 to 0.4 mg daily of sodium levothyroxine (Synthroid Sodium, Letter) give PBI levels higher than expected normal values. In contrast, hypothyroid patients rendered fully euthyroid on a regimen of 0.075 to 0.0125 of sodium liothyronine (Cy-

p 136
tomel) have low PBI values. Thyroid, USP (90 to 180 mg daily), usually produces PBI levels which are normal to low normal, depending upon the particular preparation used. Certain lots of thyroglobulin (Proloid) have reduced ratios of T4:T3 and give low PBI levels despite full metabolic effects. Thus, the PBI level must be interpreted differently depending upon the particular thyroid hormone preparation selected for therapy.
....There are numerous other serum tests which measure related aspects of thyroid function under a variety of special circumstances. These will not be discussed here. The PBI (or serum thyroxine) test used in association with the resin-T3 test, if indicated, usually serves adequately as a laboratory procedure for appraisal of thyroid function in the majority of patients with common thyroid disorders. Like all laboratory procedures, thyroid function tests must be interpreted knowledgeably and in concert with clinical findings. If the laboratory results are not in accord with the physician's objective evaluation, it is always necessary to resolve the conflict definitively by further examinations or by special procedures since selection and regulation of therapy depends critically upon accurate assessment of thyroid function.

1971 FUNDAMENTALS OF INTERNAL MEDICINE A Physiological and Clinical Approach to Disease ROBERT P. McCOMBS, B.S., M.D., F.A.C.P. Professor of Medicine, Tufts University School of Medicine; Senior Physician, New England Medical Center Hospital
FOURTH EDITION, 1971 YEAR BOOK MEDICAL PUBLISHERS • INC. 3 EAST WACKER DRIVE • CHICAGO p 613....CLINICAL CONSIDERATIONS

Laboratory aids in diagnosis of thyroid disorders.- BASAL METABOLIC RATE.- This test has been widely used, but as it is generally done in office or hospital practice it is not a reliable guide to the diagnoses of hyperthyroidism or myxedema. In the overt cases, no laboratory confirmation is necessary, but in the doubtful case, treatment should not be instituted solely on

the basis of an abnormal BMR.
Basal metabolism, as it is ordinarily determined, is a measure of the heat produced by the body under basal conditions (patients at rest in the fasting state). It is determined by measuring the amount of oxygen consumed in a definite period. Corrections must be made for room temperature and barometric pressure. If the height and weight of the patient are known, the surface area of the body can be calculated from standard tables. The number of calories per square meter of body surface per hour is the common denominator in comparing energy production. Normals have been established for the various age groups. The final determinations are usually expressed as percentages of the mean normal values. The figures usually given as "normal variations" are +10 to -10 per cent. In clinical practice, however, these standards must be taken with considerable latitude. In hospitals, normal values considerably be
p614
low the "accepted" standards will be found to be the rule (+5 to - 15 or -20 per cent). This probably occurs because the "standards" were established from ambulatory healthy individuals, whereas hospitalized patients may be debilitated and have usually rested (often under sedation) for at least 12 hours prior to the test. It must also be remembered that the perfectly normal individuals may have basal metabolic rates moderately above or below the "normal" limits.
There are technical factors that must be taken into consideration. Leaks in the apparatus and gas leaks due to perforation of an ear drum may give falsely high readings. Hysterical hyperventilation and sighing also are apt to increase the apparent oxygen consumption. An inspection of the tracing made during the test, noting the evenness of breathing and any discrepancies in the rate of oxygen utilization, usually will serve to disclose these artifacts.
Elevation of the basal metabolic rate is regularly observed in hyperthyroidism. The rate is also increased by pregnancy, fever, hematologic disorders (anemia, leukemia and polycythemia), diabetes insipidus, malignant disease, pulmonary diseases and heart failure.
Depression of the metabolic rate is found in hypothyroidism. Other causes of abnormal depression of the metabolic rate are: nephrosis, hypopituitarism, Addison's disease, prolonged cachexia from any cause (such as starvation, terminal malignancies and anorexia nervosa).

1973 LETTER P.B.I./E.T.R. for Routine Screening of Thyroid Function BMJ Vol. I 10th FEB, 1973 p 352
SIR, - As members of an endocrine unit with heavy clinical commitments we require a reliable screening test of thyroid function.
....The findings in the 81 patients out of the whole series of 1.000 in whom the P.B.I. put the patient into one clinical category while the E.T.R. put the patient into a different category are shown in the table. For the purpose of this analysis the normal ranges have been strictly applied; no allowance has been made for the error on each result.
....The cost of a single P.B.I. determination is approximately 10p, and that of a single E.T.R. determination is approximately 110p. One must ask, therefore, whether the additional information obtained from the E.T.R. justifies its routine use for all patients suspected of having thyroid abnormalities. - We are, etc.,
MARGOT BOSS A. W. G. GOOLDEN MARION GORE R. A. LUCAS F. R. OWEN Endocrine Unit, New End Hospital, London N.W.3

1973 Occasional Review Grades of Hypothyroidism D. C. EVERED, B. J. ORMSTON, P. A. SMITH, R. HALL, T. BIRD BMJ, 1973, 1, 657-662
p657
Summary

Seventy-nine patients with hypothyroidism and autoimmune thyroid disease were studied, and allotted to one of four categories on the basis of clinical and biochemical features. Firstly, patients with overt hypothyroidism had obvious clinical features of hypothyroidism and abnormal results from routine tests of thyroid function. Secondly, those with mild hypothyroidism, however, had minor and non-specific symptoms, but the routine measurements of circulating thyroid hormone concentration generally lay within the normal range, although they were significantly lower than those seen in subclinical hypothyroidism or in normal subjects, The serum concentration of thyroid-stimulating hormone (TSH) was raised in this group and their symptoms resolve with treatment. Thirdly, patients with subclinical hypothyroidism were asymptomatic, had a raised serum TSH concentration, but all other measurements of thyroid function are indistinguishable from those recorded in people with autoimmune thyroid disease without disturbance of thyroid function and in normal subjects. Lastly, subjects with circulating thyroid antibodies, normal indices of thyroid function, and a normal serum TSH concentration were indistinguishable biochemically from normal subjects.
Thus hypothyroidism is a graded phenomenon, the most valuable features for defining the individual grade being the clinical manifestations, the serum TSH concentration, and the presence of circulating antibodies to thyroid tissue.
p658
....Patients
Seventy-nine patients were examined in detail and allotted to one of four groups on the basis of the clinical and laboratory features.
Group 1: Overt Hypothyroidism (21 patients). - These patients had the well known features of hypothyroidism - namely, lack of energy, cold intolerance, acroparaesthesiae, weight gain, constipation, and hoarseness of the voice. Confirmation of the diagnosis presented no problem. This state results from a major degree of thyroid failure.
Group 2: Mild Hypothyroidism (19 patients). - These patients, with minor but non-specific symptoms suggestive of

hypothyroidism, were investigated and found to have evidence of mild thyroid failure. The only presenting symptom in 11 cases was fatigue. In the remainder complaints were of either dryness of the skin or constipation or hair loss as isolated symptoms. The possibility of a minor degree of thyroid failure was raised in the earlier patients in this group by the presence of a family history of thyroid or other organ-specific autoimmune disease or by the finding of either a small, form goitre or vitiligo on routine clinical examination. Thyroid function was investigated routinely in later patients, who presented with either fatigue or constipation which could not be explained. Conventional tests of thyroid function often gave equivocal results, but the serum TSH concentration was found to be raised and the symptoms remitted after treatment with thyroid hormone.

Group 3: Sub clinical Hypothyroidism 22 patients). - These patients were asymptomatic and were detected in one of several ways: (a) observation of a small goitre in relatives or friends visiting outpatients (6 patients); (b) the finding of a raised serum TSH concentration in "normal" controls (10 patients); (c) observation of a thyroid-related ophthalmopathy in asymptomatic subjects (5 patients); (d) observation of vitiligo (1 patient). Conventional tests of thyroid function showed nothing abnormal in this group but they were all found to have a rased serum TSH concentration. None of these patients had been subjected to destructive therapy to the thyroid by surgery or radioactive iodine, both of which are known to lead to rased TSH levels with and without symptoms.

Group 4: Autoimmune Thyroid Disease Without Disturbance of Thyroid (17 patients). - These subjects were derived from three sources: (a) observation of a goitre (6 patients); (b) detection of antibodies in the routine investigation of the relatives of patients with thyroid disease (5 patients); (c) observation of thyroid-related ophthalmopathy in asymptomatic subjects (6 patients). All these patients were asymptomatic, gave a normal response to conventional tests of thyroid function, and had a normal serum TSH concentration.

p660
Discussion
This study showed very clearly that hypothyroidism is a graded phenomenon. It became evident that the most valuable observations for defining the grades of thyroid failure and identifying subjects with thyroid failure were the clinical features, the serum TSH concentration, and the presence of circulating antibodies to thyroid tissue. It was also possible to review critically many of the other tests used for the diagnosis of hypothyroidism.
The clinical features of overt hypothyroidism are well known and confirmation of the clinical diagnosis rarely presents a problem since the results of conventional tests of thyroid function are rarely normal in this group.
The recognition of minor degrees of thyroid failure presents many difficulties, since subjects with mild hypothyroidism have minor and generally non-specific symptoms. Tiredness was the only symptom present in more than half of the subjects in this group. The remainder presented with either dryness of the skin or constipation or hair loss. These symptoms are, of course, common in middle-aged women and are usually not associated with thyroid disease. Possibly these symptoms in the group 2 subjects were unrelated to thyroid failure and that the response to therapy was merely a placebo effect. However this group, who were distinguished from those with subclinical hypothyroidism (group 3) only by the presence of a single symptom, had a significantly lower P.B.I. and free thyroxine index and a significantly higher serum TSH concentration. Direct evidence that subjects in group 2 represented a different, albeit overlapping population from those in group 3 can be provided only by a double-blind crossover trial using L-thyroxine and a placebo, which is at present under way. But, the diagnosis of mild hypothyroidism on the basis of primary thyroid disease can be confidently excluded by the finding of a normal serum TSH concentration.
Subclinical hypothyroidism has been defined as an symptomatic state in which a reduction of thyroid activity has been compensated by an increased TSH output to maintain a euthyroid state. The date presented here support this definition. These subjects all showed a serum TSH concentration which was significantly raised compared with the sub
p661
jects in group 4 and also significantly raised when compared with the normal population. The estimation of circulating thyroid hormone concentrations (P.B.I., T-3 Sephadex uptake free thyroxine index, and serum T-3) gave values which were indistinguishable from those observed in subjects in group 4 and in normal subjects. However, two subjects (both with large goitres) had greatly raised T-3 concentrations, and possibly this was a part of the adaptive mechanism to developing hypothyroidism in some subjects. A trial of thyroxine therapy was carried out in six of these subjects (group 3) but none of them reported any symptomatic change. Subclinical hypothyroidism has been defined in rather different terms by others Bastenie et al., defined this stage in terms of circulating thyroid antibodies, whereas Fowler et al., based their definition largely on raised serum cholesterol concentration. Although most subjects in this group had circulating thyroid antibodies and some had a raised concentration or both of these phenomena, neither of these findings was diagnostic of subclinical hypothyroidism. The results of the TSH stimulation teste are almost invariably normal in these patients and the diagnosis can be made only by finding a high serum TSH level in an asymptomatic subject. The abnormalities of thyroid function observed in this group can be restored to normal by the administration of thyroid hormone, but he need for hormone treatment in these asymptomatic subjects remains to be proved. At present neither the frequency of their progression to symptomatic hypothyroidism nor the possible time course of such progression is known.
Circulating antibodies to various thyroid components are frequently found in symptomatic hypothyroidism. They may also be detected in a group of subjects who have no evidence of thyroid failure and who are in all respects indistinguishable from normal. The natural history of these subjects is also unknown.
Evidence has been presented that in a hospital population (1) people with hypothyroidism have an increased incidence of ischaemic heart disease; (2) subjects with positive thyroid antibodies and lymphocytic infiltration of the thyroid, but without

overt thyroid disease, have an increased incidence of ischaemic heart disease and a raised serum cholesterol concentration. There is a recognized association between hyperlipoproteinaemia (Fredrickson types II and IV) and hypothyroidism. The nature and frequency of this association and its clinical significance were not apparent from the present study. The serum choloesterol and triglyceride concentrations were raised in all groups when compared with a control group drawn from the general population matched for age and sex. The hypothesis that subclinical hypothyroidism or autoimmune thyroid disease without disturbance of thyroid function are significant risk factors for coronary artery disease remains to be tested adequately in the general population.

The present study made it possible to review a number of the investigations which are currently used in the diagnosis of hypothyroidism. The commonly used indirect measurements of circulating thyroid hormone concentration (the P.B.I) and the T-3 Sephadex uptake) showed clearly that hypothyroidism is a graded phenomenon, but there was considerable overlap between the various groups. These indices of thyroid function were almost invariably abnormal in subjects with overt hypothyroidism. In patients with mild hypothyroidism values for these tests frequently fell within the conventionally accepted normal range but were still significantly different from those observed in normal subject. Normal values for P.B.I. and T-3 Sephadex uptake cannot therefore be used to exclude a diagnosis of thyroid failure in an individual patient. The computation of the free thyroxine index does not appear to increase the diagnostic value of these tests in hypothyroidism. The TSH stimulation test was performed on a significant number of subjects in groups 2,3, and 4. The response to TSH stimulation was normal in half of the subjects with mild hypothyroidism in whom this investigation was carried out. Similarly a normal response was found in 77% of subjects with subclinical hypothyroidism. The standard TSH stimulation test cannot therefore be relied o to identify subjects with mild hypothyroidism, nor can it be used to identify subjects with subclinical hypothyroidism. For many years the TSH stimulation test has been regarded as the absolute criterion for establishing the presence of impaired thyroid reserve. However, critical evaluation by comparison with more sensitive tests of hypothalmic-pituitary function clearly shoed that he standard TSH stimulation test is not an entirely satisfactory test of thyroid reserve. Probably thyroid 131I uptake can be significantly increased by the very large an unphysiological dose of TSH used even in the face of mild thyroid failure. Clearly a more sensitive test of thyroid reserve is required.

Estimation of the serum TSH concentration proved to be the most sensitive index of thyroid failure. Now that the range of serum TSH concentrations in normal subjects has been defined it may be assumed that any increase in serum TSH concentration reflects a downward deviation from the optimum level of circulating thyroid hormones and to some extent gives an indication of the magnitude of this deviation. These data show a general inverse correlation between circulating thyroid hormone concentrations and serum TSH and thus support earlier findings. The hypothalamus and pituitary may therefore be regarded as the most sensitive peripheral tissues in terms of a reduced circulating thyroid hormone concentration. Although a prolonged and exaggerated rise of serum TSH concentration is observed after the administration of TRH in hypothyroid subjects this investigation rarely does more than confirm the already raised basal serum TSH. A TRH test may occasionally be of value in detecting minimal thyroid failure in subjects who have a basal serum TSH concentration close to the upper limits of normal.

Tests of peripheral tissue function were carried out in members of all groups. Abnormalities were found with increasing frequency as thyroid failure became more severe, but the scatter in each group was so great that the diagnostic value of these investigations was found to be extremely limited. Abnormalities were found in most subjects with overt hypothyroidism in whom the diagnostic difficulty was not encountered, and the sensitivity of these tests appeared to be no greater than those of indirect estimations of thyroid hormone concentration. The possible significance of raised lipid concentrations has already been discussed.

The sera of all patients were examined for circulating thyroid antibodies, which were found in over 85% of subjects with hypothyroidism. It was noted that there was a much closer correlation between the presence of cytoplasmic antibodies and thyroid failure rather than between thyroglobulin antibodies and thyroid failure. These findings are consistent with current views on the relation between thyroid autoimmunity and thyroid failure. the prevalence of thyroglobulin antibodies in the subjects with thyroid failure was lower than that reported by other workers. The titre of thyroglobulin antibodies was also considerably lower than has been generally experienced, and probably this was the result of a reduced sensitivity of the antigenic material used in the assay as well as of more precise methods of serum dilution.

1973 Thyroxine "Addicts" RICHARD F. HARVEY BMJ 1973, 2, 35-36

p 35
Summary
Four patients are described who were surreptitiously taking thyroxine-containing tablets. in two cases this caused considerable diagnostic problems. The diagnosis should be considered in patients with clinical features of hyperthyroidism (but without goitres of proptosis), who appear psychiatrically abnormal and whose thyroid function tests show conflicting results.
Introduction
Difficult diagnostic problems may be posed by patients who take unusual medications without telling their doctor. This report draws attention to one such instance - namely, the development of apparent thyrotoxicosis due to surreptitious self- administration of thyroxine. Four patients attended the Middlesex Hospital in the course of a 14-month period with clinical features suggestive of hyperthyroidism, and a combination of thyroid function tests indicated that all were taking exogenous thyroxine.
p 36

....
A patient taking excessive amounts of thyroid hormones and concealing this from her doctors can pose a difficult diagnostic problem. A combination of thyroid function tests is essential to make the diagnosis with confidence, but awareness of the possibility of self-medication is also important. In the four patients described here the characteristic combination of a high serum thyroxine with a very low neck uptake of radioiodine could have been due to only a few possibilities. Probably the most likely is thyrotoxicosis in combination with excessive iodine ingestion sufficient to "swamp" the thyroid uptake of radioiodine, which was found in about 4% of a recent series of thyrotoxic patients. A history of iodine ingestion or recent exposure to x-rays with iodine-containing material, an appreciable discrepancy between the levels of serum thyroxine and protein-bound iodine (P.B.I), or the presence of a greatly increased urinary iodide excretion should make the diagnosis clear. Measurement of the serum thyroxine level is preferable to measurement of the P.B.I. alone, as the combination of a raised P.B.I. and a low thyroid uptake of radioiodine is a frequent finding in euthyroid subjects who have received excess iodine from exogenous sources.
....Self-medication with thyroxine has been reported previously from France and the United States, and most of the patients described have shown psychiatric abnormalities, often sever and requiring definitive treatment. Bricaire at al., when describing four such patients, reported that they often showed emotional immaturity and dependency, with a strong aggressive emotional claim on their mothers or a mother substitute. Of the 11 cases described in these three previous reports and the four cases described here all but one were women. The four patients in the present series all showed evidence of psychiatric abnormality, and two had required compulsory inpatient psychiatric treatment. Similar findings have been noted among purgative addicts and among surreptitious takers of other drugs, such as diuretics or anti-coagulants. Self-administration of thyroid hormones should be considered in patients with clinical features of hyperthyroidism (but without goitres or proptosis) who appear psychiatrically abnormal and whose thyroid function tests show conflicting results. It is a pleasure to thank Professor A. Kekwick, Dr. G. D. Hadley, Dr. P. A. J. Ball and Dr. J. A. J. Macleod for allowing me to study patients under their care. This paper is based on part of an M.D. thesis submitted to the University of London.

1973 Achilles Tendon Reflex in Accidental Hypothermia and Hypothermic Myxoedema D. MACLEAN, D. R. TAIG, D. EMSLIE-SMITH BMJ 1973, 2, 87-90
Summary
The photomotogram (P.M.G.) of the Achilles tendon reflex was studied in 26 patients with hypothermia (rectal temperature 33.3°C or less), 10 of whom also had myxoedema (serum protein bound iodine 2.8 mg/100 ml or less). No reflex could be elicited in eight (31%) of these patients, including three of those with myxoedema. Hypothermia increases both the contraction and the relaxation times of the reflex, the relaxation phase being particularly prolonged in those with myxoedema. In those patients from whom the reflex was elicited the ratio of the contraction time to the "half-relaxation time" in the P.M.G. was less than unity in six of the seven with myxoedema, and considerably greater than unity in eight of the 11 (73%) who were euthyroid. Thus, analysis of the Achilles tendon reflex P.M.G. correctly predicted the thyroid status in 14 of the 18 hypothermic patients in whom the Achilles tendon reflex was present (89%). The wider use of this rapid test of thyroid function would allow a more rational use of thyroid hormones in hypothermic patients and so lead to a better assessment of their value.

Introduction
Hypothermic myxoedema usually involves a very grave prognosis. (Asher, 1960). its immediate recognition is difficult, for many of its clinical features are shared by cases of accidental hypothermia uncomplicated by hypothyroidism (Duguid et al., 1961; Mathews, 1966; Cooper, 1968; Hockaday and Fell, 1969).
The place of rapidly acting thyroid hormone preparations in the treatment of hypothermic myxoedema is controversial, but their use may sometimes be beneficial. During spontaneous rewarming the patient's body temperature often fails to rise at the satisfactory rate of 0.55-0.83 ° per hour (Cooper, 1968; Burton and Edholm, 1955; Rees, 1958; Hardwick, 1962; British Medical Journal, 1964; Taylor, 1964), so vital organs are subjected to increasing risks of damage as the hypothermia is prolonged (Davies et al., 1967.
p 89
....Discussion
Slow ankle jerks are characteristic of myxoedema (Ord, 1884) and they have often been studied (Fogel et al., 1962; Sherman et al., 1963; Miles and Surveyor, 1965; Abraham et al., 1966; Nuki and Bayliss, 1968). Indeed, delayed relaxation of the ankle jerk has routinely been used in the Mayo Clinic for about 50 years as an aid in the diagnosis of myxoedema (Lambert et al., 1951.
....Because the precise requirement of, and the least hazardous way of using, thyroid hormone in hypothermic myxoedema have yet to be established, we restricted their use to those patients who had not begun to rewarm spontaneously within 12 hours of their admission to hospital, and to those in whom rewarming did not continue. Other complications of myxoedema, as mentioned above, which threatened the patients' chances of survival would provide additional indications for their use. Nevertheless, the Achilles P.M.G. enabled the treatment of the patients to be decided before the serum P.B.I. results became available and no serious harm resulted from misdiagnosis. The study and fuller statistical evaluation of such results in a much larger series of patients with accidental hypothermia and hypothermic myxoedema will decide whether or not this form of earlier diagnosis if regularly confirmed by the serum P.B.I. results or other tests of thyroid function and will determine the effect of the earlier use of thyroid hormone on the overall prognosis of these patients.

1973 Diagnosis of Thyrotoxicosis BMJ 1973,2,131-132

The diagnosis of thyrotoxicosis is rewarding to both doctor and patient, for the treatment is specific and usually effective. In florid cases it should be obvious and not require confirmation by specific tests of thyroid function. A physician versed in thyroid disease will also recognize most cases of intermediate severity on clinical grounds alone and may hot need any confirmatory tests. Yet these will often be done if only to convince sceptical colleagues or to provide objective data for those who may have to deal with the patient in future.

At the lower end of the scale of clinical severity and in atypical cases we all come to rely increasingly on tests of thyroid function. But it should be borne in mind that such tests are liable to interference by man factors unconnected with the gland itself, and that they are just as subject to misinterpretation as are the clinical findings.
....A new dimension has been introduced into the diagnosis of thyroid disease by the discovery of T-3 thyrotoxicosis. This is characterized by excessive secretion of triiodothyro-

p 353
nine. The secretion of thyroxine (T-4) is normal, though later it may become excessive. it is thought that this disordered pattern of secretion may be due, in some cases at least, to iodine deficiency. The patient is clinically thyrotoxic, but he conventional tests of thyroid function are normal. A firm diagnosis can be made only by direct measurement of T-3 and T-4 in the plasma. These techniques are not yet generally available, but a failure to suppress uptake of iodine-131 by the T-3 test will support the diagnosis.
1. Davis, A G., British Medical Journal, 1972, 2, 206

1973 Discriminant Value of Thyroid Function Tests DAVID B. BARNETT, ANTHONY A. GREENFIELD, PETER J. HOWLETT, JENNIFER C. HUDSON, ROBERT N. SMITH BMJ 1973, 2, 144-147
Summary
Different thyroid function tests permitted a final classification of 204 consecutive patients with suspected thyroid disorders into three populations (thyrotoxic, euthyroid, and hypothyroid). Linear discriminant analysis was applied to all test results (10 variates) on adjacent population pairs. Two in-vitro tests (serum protein bound iodine (P.B.I.) and triiodothyronine (T-3) uptake values) gave good separation of thyrotoxic from euthyroid patients and fairly good distinction of hypothyroid patients. If a 131uptake figure was then added to the in-vitro results most patients (95.55%), including these initially classified as equivocal, were correctly diagnosed. Other tests, including clinical questionnaires, were poor discriminants. Two new techniques of utilizing the test data were devised. firstly, the data from the two in-vitro tests were also displayed graphically, and oblique boundary lines derived form the discriminant functions gave better separation of patients than previously used limits or mathematical expressions of "free thyroxine." Secondly, a nomogram incorporating the best four discriminants was designed as a diagnostic aid and proved to be the best means of interpreting the tests.

Discriminant analysis of this kind can be used in the interpretation of diagnostic tests in any branch of medicine, and it allows the best use to be made of the available data.
Introduction
A clinician needs a screening test to decide whether suspicion of a thyroid disorder is substantiated or not and then requires confirmatory tests before any treatment is begun. The present study was undertaken to decide the best single test or combination for these purposes, and, if possible, to select in-vitro tests which avoid radiation exposure.

p 146
Discussion
Tests of thyroid function are needed which without undue risk or inconvenience accurately separate patients with thyrotoxicosis or hypothyroidism from those who are euthyroid. Most physicians and their colleagues in medical physics would like to reduce the number of radioiodine tests; there has been some disquiet about the radiation risk to all concerned. In fact, these requirements were fulfilled when linear discriminant analysis chose a combination of in-vitro tests as the best two discriminants. In this series of patients 127 out of 204 were euthyroid and really needed no further investigation with consequent radiation exposure.
In judging the results of thyroid function tests it is customary to rely on so-called "normal" ranges and limits of each test, which immediately restricts the discriminant value of any combination of tests because each is effectively taken as a single variate. When these test results are contradictory or borderline it is also difficult to decide which is the best discriminant. In this study the clinicians attempted to collate 10 parameters concurrently and to give appropriate weightings when these tests diverged from each other, but some patients were categorized as "equivocal." This approach was clearly inferior to at least one brand of multivariate analysis which considered several variates in combination and chose the best discriminants without reference to the "normal" range of test values. The optimum combination of tests placed these "equivocal" patients in the correct diagnostic category and this was supported by long-term clinical observation. The addition of more variates to the best three tests increased the errors and this explained our difficulties in trying to collate all test results.
....Discriminant analysis can be applied in any situation where several parameters attempt to identify two or more populations but its use in medicine has been limited. Firstly, it can select those tests which place patients into the correct diagnostic category with least risk of error. Many clinicians have difficulty in accepting this radical change in their interpretation of a group of tests, but the evidence from this and other studies can convince them.
This study has identified the best thyroid function tests for routine clinical use and led to the construction of simple desktop diagnostic aids for interpreting the laboratory test data. We would recommend the combination of serum P.B.I. and T-3 uptake measurements using either of the commercial kits as a screening procedure. the new boundaries would indicate any

borderline patients and these together with patients in the thyrotoxic or hypothyroid sections would require further assessment. Physicians usually request confirmatory evidence from a 131I uptake test before instituting life-long thyroxine replacement or before destructive therapy (thyroid surgery or radioiodine treatment) and the nomogram with the discriminants displayed is the best way of interpreting three tests.
(these as in original article)

1973 LETTER Discriminant Value of Thyroid Function Tests JAMES CROOKS BMJ 1973, 2, 488

....Though I accept the conclusions of the authors that the combination of serum protein-bound iodine and triiodothyronine uptake tests is at present the most effective routine laboratory-based method of arriving at the diagnosis of thyrotoxicosis, I regret their implied denigration of clinical evidence as part of the diagnostic process. I also regret that they did not include the results of a therapeutic trial of the various methods of treating thyrotoxicosis in their paper since, in terms of the practicality of patient care, this is a more acceptable diagnostic criterion than that provided. - I am, etc.,

JAMES CROOKS
Department of Pharmacology and Therapeutics, University of Dundee
1. Crooks, J., Murray, I. P. C., and Wayne, E. J., Quarterly Journal of Medicine, 1959, 28, 211 2. Billewicz, W. Z., et al., Quarterly Journal of Medicine, 1969, 38, 255

1973 Treatment of Hypothyroidism: A Reappraisal of Thyroxine Therapy
DAVID EVERED, E. T. YOUNG, B. J. ORMUSTON, RUTH MENZIES, P. A. SMITH, REGINALD HALL BMJ 1973, 3, 131-134
p131
Summary
Twenty-two subjects with hypothyroidism have been studied in detail before and during replacement thyroid therapy with L- thyroxine (T-4). All subjects were stablized on the minimum dose of T-4 which was necessary to suppress their serum thyroid-stimulating hormone (TSH) concentration to normal, and on this dose most subjects had a normal or impaired TSH response to thyrotrophin-releasing hormone (TRH). The daily dose of T-4 required to suppress TSH was 0.1 mg (13 subjects), 0.15 mg (six subjects), and 0.2 mg (three subjects). It was shown that all subjects were euthyroid on these doses and, using a range of thyroid function tests, that they were normal in all respects when compared with a group of euthyroid controls, with the exception of a small group who had a marginally raised serum triiodo-L-thyronine (T-3) concentration. It has been shown that those subjects who required the larger doses of T-4 had a more advanced degree of thyroid failure than those who where stabilized on 0.1 mg T-4 daily. it is concluded that conventional doses of t-4 (0.2-0.4 daily) are often associated with subclinical hyperthyroidism.
Introduction
It is generally accepted that all patients with symptomatic hypothyroidism require treatment, and L-thyroxine (T-4) is now used almost exclusively in the management of patients with hypothyroidism. The dose recommended by the major textbooks of medicine (Selenkow and Ingbar, 1970); Stanbury, 1967; Strong, 1968) and endocrinology (Ingbar and Woeber, 1967; Hall et al., 1969; Means et al., 1963) lies between 0.2 mg and 0.4 mg daily, and there is general agreement that 0.3 mg daily is the average replacement dose. IT is well known that the serum thyroxine concentration is raised on this dose and in the past it has been assumed that since the patient was receiving only T-4, and no replacement with the metabolically more potent triiodo-L-thyronine (T-3), that this was essential to maintain the euthyroid state (Ingbar and Woeber, 1968). Cotton et al., (1971), however, found that the serum thyroid-stimulating hormone (TSH) concentration can be restored to normal with much smaller doses of T-4. It has also recently been shown that there is considerable extrathyroidal conversion of T-4 to T-3 (Pittman et al., 1971; Sterling et al., 1970) and that raised serum T-3 levels are found in athyreotic subjects receiving T-4 only (Braverman et al., 1970). These findings raise the possibility that many subjects on replacement therapy with T-4 are mildly hyperthyroid but this state escapes detection in view of the insensitive methods available for the clinical assessment of thyroid status (Larsen, 1972). Goolden and his colleagues (191) provided some support for this view by showing that the red cell sodium concentration which is increased in hyperthyroidism is also raised in subjects receiving 0.3 mg T-4 daily. The availability of a wide range of precise diagnostic techniques has made it possible to test this hypothesis and to study the thyroid hormone requirements of a group of unselected patients with hypothyroidism.
Patients, Materials, and Methods
Twenty-two consecutive patients with untreated symptomatic hypothyroidism attending an endocrine clinic were studied. The diagnosis of symptomatic hypothyroidism was accepted in all patients who presented with symptoms consistent with hypothyroidism and were found to have a raised serum TSH concentration (Evered et al., 1973).. Seventeen of the patients had developed hypothyroidism spontaneously, three after 131I therapy and two after partial thyroidectomy for hyperthyroidism. None of the subjects had overt ischaemic heart disease.
p134
....The results of this study suggest that many subjects have received excessive doses of T-4 in the past, inducing a state of mild hyperthyroidism which is generally not clinically apparent. These findings confirm the isolated findings which have been reported previously (Braverman et al., 1970; Cotton et al., 1971; Goolden et al., 1971) which suggested that conventional doses of T-4 for replacement therapy were often excessive. It is not possible to be certain whether this state of mild hyperthyroidism is detrimental to the patient - but the disadvantages of untreated mild hyperthyroidism, particularly in relation to the skeleton and the cardiovascular system in the elderly, are well known. There would, therefore, seem to be a

good prima facie case for establishing patients with hypothyroidism on the optimal dose of T-4.
It is, of course, not possible to investigate all patients with hypothyroidism in such detail. It is, however, possible to stabilize all patients on thyroid hormone replacement therapy by increasing the dose of T-4 until the serum TSH concentration falls within the normal range. Experience with this study has shown that patients' symptoms are abolished at this dose. Replacement therapy can also be controlled by following the serum thyroxine concentration (measured by direct or indirect means in the absence of the facilities for estimating serum TSH concentration.

1973 LETTER: Discriminant Value of Thyroid Function Tests J. VESTERDAL JØRGENSEN BMJ 1973, 3, 170

....From these data the authors postulate that their boundary lines have a grater discriminatory power than a free thyroxin index calculated on the basis of serum protein-bound iodin and T-3 uptake. however, these differences are not statistically significant (P> 0.05 ). Therefore it still remains to be shown whether linear discriminant analysis is superior to free thyroxine index in this respect - but certainly, this problem is subtle in comparison to the problem of supplying the clinical with self-explanatory laboratory data - for example, in the form of "cartoons." - I am, etc.,

J. VESTERDAL JØRGENSEN

1974 LETTER: Thyropac-5 Test J. G. HARDY G. M. NEWBLE BMJ 1974, 1, 536

....All the tests, with the exception of the 24-hour 131I neck uptake: thigh ratio, were more reliable for the diagnosis of hyperthyroidism than for hypothyroidism. Of the in vitro methods the normalized thyroxine ratio tests were the most reliable and the least affected by abnormal serum protein levels. The diagnostic accuracies of these tests were comparable with that of the best in vivo test, the 24-hour 131I neck uptake. The in vitro tests offer the advantage of greater convenience to both hospital staff and patients and do not involve the administration of radioisotopes to the patients. We have demonstrated the usefulness of the normalized thyroxine ratio tests and found the additional serum thyroxine figure available as part of the Thyopac-5 test to be a valuable feature of the kit. - We are, etc.,
J. G. HARDY G. M. NEWBLE Regional Radiotherapy Centre, Essex County Hospital, Colchester

1974 Occasional Survey Which Test of Thyroid Function? C. W. H. HAVARD BMJ, 1974, 1, 553-556

P 553
Tests measuring the levels of thyroid hormone in the blood stream are now being used increasingly in the diagnosis of thyroid disorders. Correspondingly, less emphasis is placed on in vivo tests of thyroid uptake. The proliferation of in vitro tests of thyroid function has led to such confusion of nomenclature that many doctors do not know what they are asking for, much less the limitations of the particular investigation in question. As tests of thyroid function are being sought with increasing frequency and with fewer indications, it is hardly surprising that many erroneous diagnoses are made.
Two important points need emphasizing to begin with: the first is that clinical criteria may be a better guide to the diagnosis of thyrotoxicosis and of hypothyroidism than any laboratory investigation, particularly in the younger patient. A detailed medical history and a full physical examination are mandatory, and will lead to many few diagnostic errors than asking for a variety of tests after a few hasty observations in the clinic. The second point is that doctors tend to have a naive faith in the validity of laboratory reports. Laboratory workers are human and are subject to the same errors as are clinicians; furthermore, errors may also be contributed by the methods used. Even when investigations are carried out in the best laboratories values outside the normal range occur in at least 5% of euthyroid people. In addition, the tests themselves are subject to limitations, which are often not appreciated by those asking for them.
....At the other end of the scale, when hypothyroidism develops there may be a sequential failure of thyroxine production preceding a failure of the gland to produce T-3. Hence results of the conventional tests (PBI and serum T-4) may be low when the patient is euthyroid as a result of adequate T-3 production - a condition first reported in treated thyrotoxic patients but subsequently in iodine deficiency and in autoimmune thyroiditis.
Physiology
It is useful to review the normal physiology of thyroid hormone synthesis and transport to understand the limitations of in vitro tests. The average British diet contains 100 μg of iodide per day. This is absorbed from the gut into the inorganic iodide pool of the body. About one-third of the absorbed iodide is trapped by the thyroid gland and oxidized to iodine and the remainder is excreted in the urine.
p554....In Vitro Tests
PROTEIN-BOUND IODINE (PBI)
Measurement of PBI has dominated in vitro tests of thyroid function for over 20 ears. It is cheap, has a high degree of reproducibility, and can be automated. Its major drawback is the lack of specificity in that it measures non-hormonal forms of iodine in the blood. The iodine contamination of the environment is increasing steadily and a recent report from Edinburgh suggested that 48% of a healthy euthyroid population had a spuriously raised PBI level. Possibly this is due to the fact that with greater use of laboratory facilities by general practitioners more patients are being referred to the endocrine clinics on account of a raised PBI. Our experience in London gives much greater reliability to the PBI. Indeed, when patients on the contraceptive pill are excluded, only 2% of a hospital population have falsely high PBI concentrations.
All these facts, together with the advent of a specific assay for thyroxine by saturation analysis, means that there has been a swing away from the use of PBI estimations. Nevertheless, it is probably still the most commonly used in vitro test of thyroid function in Britain, and when using it the risk of contamination must always be considered. The PBI also has the disadvantage that it does not differentiate hyperthyroidism from raised levels of thyroxine-binding protein. Nor can it

differentiate between hypothyroidism and a reduction in available TBG. The available TBG may be reduced without any total reduction, because drugs such as phenytoin and salicylates are bound to the same plasma proteins as T-4 and so reduce the sites available to bind thyroxine.
The PBI test has a special use in thyroiditis, as the presence of iodoproteins released from the damaged gland can be detected in the serum: these iodoproteins are not T-4 so that measuring the serum levels of thyroxine will not detect them. p555
SERUM THYROXINE
Most methods of measuring serum T-4 use the principle of competitive protein binding.
If a small quantity of labelled T-4 is added to a solution of TBG the proportion of T-4 which binds to protein can be determined. As more unlabelled T-4 is added to the system the proportion of labelled T-4 bound to protein decreases. This added portion of labelled T-4 bound to protein decreases. This added unlabelled T-4 can either be a known concentration and used to calibrate the system or T-4 derived from a teste serum. To determine the fraction of T-4 bound to protein the bound T-4 must be separated from the free T-4. This is done by adding a secondary binder such as resin or Sephadex. This competitive binding analysis has a precision comparable to that of the PBI test, and has been adapted for use as commercial kits, of which there are at least six currently available.
As it measures total T-4, the test does not differentiate between hyperthyroidism and raised levels of thyroxine-binding globulin or between hypothyroidism and reduced levels of available TBG, whether this is due to a total reduction or merely a reduction in available sites because of drugs bound to the same proteins. The normal range may vary slightly from laboratory to laboratory. Though the serum T-4 overcomes the problems of iodine contamination it does not overcome the problem of changes in TBG concentration produced by the ever-increasing use of oral contraceptives and other drugs. Nor does it give any indication of the level of T-3 in the serum.
....FREE THYROXINE INDEX
It has already been mentioned that wen there is an alteration in the TBG the serum thyroxine levels and the T-3 resin uptake move in opposite directions. Thus in patients with an increase in TBG the serum thyroxine rises into the hyperthyroid range and the T-3 resin uptake moves into the hypothyroid range. A mathematical combination of serum thyroxine (or PBI) and T- 3 resin uptake has been derived which gives normal values in euthyroid patients with abnormal levels of TBG. This combination of tests is called the free thyroxine factor or free thyroxine index and correlates closely with the level of free thyroxine in the serum and reflects accurately the thyroid status of the individual.
Two new testes, the "effective thyroxine ratio" (ETR) and the "normalized thyroxine ratio (NTR) have recently become available and give similar information in a single test. Normalized T-4 tests promise to be useful screening tests of thyroid function and will be especially valuable if they can be automated.
....SERUM FREE THYROXINE
Non-protein-bound or free thyroxine can be measured by a variety of techniques, none of which is suitable for routine use. Dialysis across a semipermeable membrane will separate the free T-4 from the bound T-4 and enable the proportion of free thyroxine to be determined. With a knowledge of the total serum T-4 level it is possible to calculate an absolute level of free hormone. The method is time-consuming and requires the use of isotopes. An indirect way of determining the free hormone level in the serum is to measure the urinary excretion of T-4. Similarly the urinary T-3 level offers an indirect means of estimating circulating levels of free T-3. These methods require the collection of timed specimens of urine and so have considerable disadvantages.
SERUM TSH
The serum concentration of TSH is measured by immunoassay.
A mixture of unlabelled TSH and TSH labelled with a radioactive isotope is incubated for several days with a specific antiserum. Both the labelled and unlabelled TSH compete for binding sites on the antibody and at the end of this time a mixture of unlabelled TSH-antibody complex and labelled TSH-antibody complex is obtained. This mixture is precipitated using a second antibody and the amount of labelled TSH-antibody complex is counted. If there was little unlabelled TSH in the original sample there will be much labelled complex, and conversely if there was much unlabelled TSH there will be little labelled complex. By using a series of different known concentrations of unlabelled TSH and recording the amounts of labelled complex it is possible to construct a standard curve which can be used to estimate unknown samples.
The normal serum TSH level is low, being about 1 μU/ml. It is raised in primary hypothyroidism and almost undetectable in hyperthyroidism. Because the normal levels of TSH are so low it is little help in the diagnosis of hyperthyroidism but it is a good test of hypothyroidism. The circulating TSH level is always raised in primary hypothyroidism, often to over 50μU/ml, but it is possible to find a raised level in a patient who is euthyroid. Indeed, raised TSH levels with normal circulating hormone levels will precede overt thyroid failure. Possibly such increased stimulation from the pituitary may prevent thyroid failure for many years.
Dynamic Tests
When the hypothalamic releasing factor TRH is given intravenously in a dose of 200 μU/ml the level of TSH in the serum rises from a basal level of about 1 μU/ml to a mean peak concentration of about 10 μU/ml at 20 minutes and returns to normal by 120 minutes. The response is usually greater in women than in men. In hypothyroidism there is an exaggerated rise of an already raised TSH level and in hyperthyroidism there is no response of a depressed TSH level.
p 556
The TRH test is a useful test of hypothyroidism when the rise in the basal TSH level is marginal and it is also useful in equivocal cases of hyperthyroidism. It is particularly relevant to the diagnosis of T-3 thyrotoxicosis if it is not possible to

measure the circulating levels of T-3. The test will render redundant the T-3 suppression test, in which the autonomy of the thyroid gland was assessed by measuring the radioactive iodine uptake of the thyroid before and after five days of administered tri-iodothyronine. As with most tests, many drugs interfere with the results. Thyroxine antithyroid drugs, corticosteroids, oestrogens, and levodopa will modify the TSH response to TRH. At present the use of TRH is restricted to those specialized centres that can monitor its effects - namely, those which can measure TSH by immunoassay. the main indications for the TRH test are in cases of mild hypothyroidism or hyperthyroidism when the diagnosis is in doubt, in hypopituitarism and in ophthalmic Graves's disease.

Plan for Diagnosis
In most cases of thyroid dysfunction confirmation of the diagnosis can be made by an estimation of the PBI or serum T-4 and a T-3 resin uptake. Calculation of a free thyroxine index should be made when there is any change in TBG and this is usually the result of pregnancy or of taking the contraceptive pill. An effective thyroxine ratio (ETR) or a normalized thyroxine ratio (NTR) gives similar information but has the distinct advantage of being a single test. When the serum T-4 and T-3 resin uptake confirm the clinical assessment there is no diagnostic problem and if a discrepancy can be accounted for by an abnormality in TBG further investigation is not needed. When, however, the clinical appraisal and the initial test disagree further investigation is required. If the patient is clinically thyrotoxic and the conventional tests are normal, the likely diagnosis is T-3 thyrotoxicosis and the serum T-3 level should be estimated or a TRH test performed. If the patient is clinically euthyroid and the tests are in the hyperthyroid range, the clinical assessment should be reviewed and if the same clinical judgement is made no action should be taken. If there is any doubt a TRH test should be done.
If the patient is clinically hypothyroid but the results of the conventional tests are normal, the serum TSH should be estimated; if the serum TSH is not raised the patient is not suffering from primary hypothyroidism. The possibility of pituitary hypothyroidism has, however, not been excluded and an x-ray film of the pituitary fossa, an electrocardiogram, and a TRH test may help. If the patient is clinically euthyroid but the test results are in the hypothyroid range, the serum T-3 level should be measured. The probability is that T-4 production is reduced but the patient is kept euthyroid by adequate production of T-3. A raised TSH in this condition does not prove the patient has primary hypothyroidism but a normal level excludes it.
Conclusion
All tests of thyroid function have their limitations. All are subject to interference by factors unrelated to the thyroid, especially drugs. All thyroid function tests are performed by human beings and are therefore subject to both human error and errors resulting from problems in methodology. The initial test of thyroid function should be the thorough, unhurried clinical assessment. A knowledge of the limitations of the various in vitro tests of thyroid function will lead to their more fruitful application and will reduce the diagnostic errors that so commonly result from their premature request.

1974 In Vivo Test of Thyroid Function C. W. H. HAVARD, MARGOT BOSS BMJ, 1974, 3, 678-681
p 678
Despite the increasing emphasis on in vitro tests of thyroid function, in vivo tests are still widely used. The major applications of in vivo techniques are in the diagnosis of thyrotoxicosis and in the assessment of the functional activity of thyroid nodules by scanning the gland. The application of in vivo tests to the diagnosis of hypothyroidism is limited. Technetium-99m is now being used to determine thyroid uptake because of its low energy and short half-life and because the isotope is not organically bound to tyrosine - thug it is concentrated in the thyroid gland in the same way as iodine. In vivo tests may be subdivided into: (1) thyroid uptakes, (2) suppression tests, (3) stimulation tests, and (4) scans.

Thyroid Uptake
For nearly 20 years the uptake of 131I by the thyroid gland has been used as a routine test of thyroid function. In general the p 679
rate of trapping of iodide by the thyroid gland reflects the rate of secretion of thyroid hormone into the circulation. Therefore in thyrotoxicosis the uptake of iodine by the thyroid gland is increased. The patient is given a tracer dose of 131I of between 10-50 μCi by mouth and after a specified time (which usually varies between 10 minutes and 48 hours) the amount of 131I in the neck is measured with a suitable radiation-detecting system. This value is then compared with that obtained by measuring an aliquot of the original dose in similar conditions and the result expressed as a percentage of the dose administered.
In hyperthyroidism both the proportion of the tracer dose accumulated by the gland and the rate at which this takes place are increased. The enhanced rate of accumulation is more appreciable in the early phases than it is 24 hours after administration. It is therefore advantageous to measure the early uptake by the gland and the time usually selected varies from 10 minutes to two hours. Ideally the uptake should be measured before any appreciable discharge of radioactivity from the gland as labelled hormone has occurred. Though the information obtained by the early uptake is more significant physiologically the physical measurement is technically more difficult. Early uptake measurements are of little help in the diagnosis of hypothyroidism.
Theoretically one of the problems of neck uptake measurement is to differentiate between the radioactivity coming from the thyroid gland itself and that coming from the blood traversing other tissues in the neck.
Corrections should therefore be made for extrathyroidal activity. Nevertheless, when an early iodine uptake is used these corrections are not necessary, for it has been shown that the uncorrected 30-minute 131I uptake is diagnostically as efficient for differentiating between the hyperthyroid and the euthyroid patient as a corrected measurement, provided that due allowance is made for the change in the normal range. Another advantage of the early uptake measurement is that there is no

need for patients to return to hospital the next day; this is obviously necessary when the 24-hour uptake is used.
There are other disadvantages of a 24-hour uptake. The uptake measurement does not take into account the amount of radioactivity discharged from the gland as labelled hormone and this may be appreciable after six hours. Also the clearance of iodide by the kidneys influences the amount concentrated in the gland and this effect is more definite at 24 hours than at two hours. If a 24- hour uptake is selected an additional measurement at two or four hours is necessary.
The amount of radioactive iodine taken up by the gland will be influenced by the amount of inorganic iodide in the serum. If the body store of iodide is low and the serum level of inorganic iodide reduced, the uptake of 131I will be raised, though the total amount of iodide entering the gland may be normal. When stores of iodide are low most of the iodide derived from peripheral degradation of thyroxine is re-used. The thyroid hypertrophies to maintain a normal output of hormone by trapping a greater proportion of the circulating iodide from the blood. this gives rise to the hyperplastic non-toxic goitre of iodine deficiency. A high radioactive iodine uptake in a patient with a simple goitre of iodine deficiency may thus give rise to an erroneous diagnosis of toxic goitre. Conversely if the inorganic iodide stores of the body are increased owing to contamination there will be a decrease in the uptake of 131I. Iodine is a constituent of health foods such as kelp, and of many cough mixtures. Organic iodide is a constituent of compounds used as radiographic contrast media. Iodine contamination has already been considered with reference to its effects on some of the in vitro tests of thyroid function.
The 131I uptake should not be used in children or during pregnancy because of the relatively high whole body radiation dose. If an uptake is required in these circumstances an isotope with a shorter half-life and lower energy such as 132I or 99m-Tc should be used.
p 680
....Conclusion
In vivo tests of thyroid function receive less emphasis today with the advent of more reliable in vitro tests which do not require the administration of radioactive isotopes to the patient. Nevertheless, the kinetic information provided by in vivo tests offers a particular advantage and the speed with which the result is available enables the clinical diagnosis to be confirmed at the patient's first attendance at the clinic.

1974 LETTER: T.S.H. Level and Thyroid Function

SIR, - I should like to raise some points about the patients described by Dr. W. M. G. Tunbridge and others (13 July, p. 89) as showing a persistently elevated thyroid-stimulating hormone (TSH) level but not found to be hypothyroid on clinical examination and by most "routine" thyroid function tests during the period of observation reported in their paper.
....With a more complete understanding of the regulation of thyroid function and with the availability of better ways of separating the, at present, clinically not discernible forms of hypothyroidism from euthyroidism, it would seem timely to use diagnostic terms reflecting the progress in this field. The normal ranges for all the presently measurable criteria for characterizing thyroid status are adequately defined. In my view once any one of these measurements falls outside the normal range the use of the term "euthyroid" is no longer acceptable. Thus the term "subclinical hypothyroidism," mentioned in the discussion of the article in question, would seem a physiologically more correct way of referring to such patients.

....evidence is presented that the elevated TSH in 131I-treated patients may be a useful guide in selecting those who can be expected to develop clinically manifest hypothyroidism. Thus it would appear that the biological and clinical significance of the persistently elevated TSH may be established, at least in this respect.
There is little firm clinical evidence and considerable controversy about the extra-thyroidal effects of TSH and TRH in man. It would seem certainly appropriate and desirable to look for ways of detecting effects of this kind in patients who are exposed to supra-physiological concentrations of these substances over prolonged periods of time, - I am, etc., G. ANTONY School of Paediatrics, University of New South Wales, Kensington, N.S.W.

Asboe-Hansen, G., American Journal of Medicine, 1959, 26: 470
Asboe-Hansen, G., Archives of Dermatology, 1960, 82, 32
Bland, J. H. and Frymoyer, J. W., New England Journal of medicine, 1970, 282, 1171 Kastin, A. J., et al., Lancet, 1972, 2, 740
Prange, A. J., et al., Lancet, 1972, 2, 999
Mountjoy, C. Q., et al, Lancet, 1974, 1, 958

1974 Comparison between Determination of Free Thyroxine Index and Effective Thyroxine Ratio in Human Serum E. G. M. D'HAENE, F. J. L. CROMBAG, J. F. W. TERTOOLEN BMJ, 1974, 3, 708 - 711
p 708
....Introduction

There are many in-vitro methods now used to determine thyroid function, of which the estimation of total thyroxine (T-4) in serum based on competitive protein-binding analysis introduced by Ekins (1960) seems to be increasingly accepted as a specific and reliable procedure. A good correlation between serum T-4 concentration and thyroid function has been shown (Murphy et al., 1966). An important objection to this method is that alterations in the concentration of T-4 binding proteins may invalidate the results.

The percentage binding of T-4 to thyroxine-binding globulin (TBG) is 60% and to thyroxine-binding prealbumin and albumin, respectively, 30% and 10%. A variety of diseases and drugs may influence the binding capacity and concentration of these proteins, especially of TBG (Selenkow and Ingbar, 1970). As a consequence of raised TBG concentration, for

instance, euthyroid women taking oral contraceptive or pregnant women may have a raised serum T-4 level (Murphy et al., 1966; Goolden et al., 1967)
The estimation of the true free T-4 concentration gives the quantity of hormonally active T-4 and is not influenced by binding-protein abnormalities. Technical difficulties are the principal reason why this determination has been considered only as a research procedure until now.

Clark and Horn (1965) introduced the free T-4 index: they divided their protein bound iodine (P.B.I.) results by the respective T-3 uptake values, thus correcting for binding-protein abnormalities. They showed that this index was proportional to the concentration of free T-4, assuming that this triiodothyronine resin uptake (T-3 B.C. index) was proportional to the concentration of free sites on T-4 binding proteins.

Wellby and O'Halloran (1966) reported a highly significant linear correlation between the free T-4 index and the free T-4 concentration. They showed the usefulness of the free T-4 index as an index of thyroid function in routine diagnosis in patients having binding-protein abnormalities. To get this free T-4 index, however, one has to carry out two separate determination for total T-4 (or P.B.I.) and for T-3 B.C. index.

Recently Thorson et al. (1972) described a new in-vitro test for the determination of thyroid status, which they called the effective thyroxine ratio (E.T.R.). The authors claim that this test has a high diagnostic accuracy (99%) and that the results are proportional to the free T-4 concentration. Wellby et al. (1973) studied 76 patient sera and reported a linear relationship (r=0.93) between E.T.R. and free T-4 concentration. This could be confirmed by others (Rudorff et al., 1973).

Because we were interested to know whether this rapid single procedure could replace our more time-consuming free T-4 index determination we compared the results of E.T.R. and free T-4 index determinations from the sera of 181 patients.
p 711
....If one has reason to believer that a given variable (in this case a thyroid function test) has a normal distribution pattern in the total population then one has to select the test persons or samples by random sampling. That the latter is frequently difficult has been emphasized by Yule and Kendall (1958). They concluded that in practice man is a poor subject to use random selection procedures on and to prevent or to eliminate the appearance of human bias in the election. If one has a sufficiently large representative then the variable in the sample wil also show a normal distribution. If, however, the sample is not representative then it is possible to select the results so that both of the variables to be compared have a normal distribution. This can be carried out by means of a normalization table which shows that percentage of the results should fall within a given area. If a representative of normalized sample is not taken - that is, if the sample does not comply with the requirements for a normal distribution of both variables - then considerable falsifications of the correlation can occur. We have the impression that the authors we mentioned have not considered the specific requirements concerning distribution which are necessary when the Pearson product-moment correlation calculation is used. For these reasons the results of Wellby et al. (1973) and Thorson et al. (1972) should be interpreted differently.

Because in retrospect our own sample was neither normally distributed nor strictly random we would like to point out that the differences in correlation between E.T.R. and free T-4 index values as shown in table I when compared with the Pearson correlation calculation show the flattening effect due to the incorrect application of the correlation calculation.
Conclusions

We found a correlation between E.T.R. and free T-4 index which was poorer than could be expected from the literature (Thorson et al., 1972; Wellby et al., 1973; Rudorff et al., 1973). We think there are two explanations for this fact: firstly the E.T.R. uses a different method of correction for binding-protein abnormalities, and, secondly, the statistical approach we used is more justified. At present there are no convincing reasons for us to use the E.T.R. determination instead of the free T- 4 index determination as an index of thyroid function.

1974 LETTER: TSH Level and Thyroid Function W. M. G. TUNBRIDGE P. HARSOULIS A. W. G. GOOLDEN BMJ, 1974, 4, 226
SIR, - Dr. G. Antony in his letter (14 September, p. 688) commenting on our paper (13 July, p. 89) has expressed the opinion that patients with normal levels of circulating thyroid hormones and raised serum thyroid-stimulating (TSH) levels should be described as having subclinical or compensated hypothyroidism.

....In our opinion the prognostic significance of an elevated TSH level in these patients remains to be established and we consider that therapy should be introduced only when there is evidence of inadequate circulating thyroid hormone levels and symptoms or signs of hypothyroidism.
Part of the difficulty in this situation is that none of the terms are entirely satisfactory from a clinical, biochemical, and physiological point of view.
....Until it is established that a sustained elevation of TSH in the presence of normal levels of circulating thyroid hormones has an adverse effect we feel that our understanding of the condition of such patients is better served by careful follow-up. ....We do not, however, consider therapeutic intervention justified in patients who have normal serum levels of both T-4 and T-3. - We are, etc., W. M. G. TUNBRIDGE Royal Victoria Infirmary, Newcastle upon Tyne P. HARSOULIS A. W. G. GOOLDEN Hammersmith Hospital, London W.12

1974 LETTER: Tests of Thyroid Function W. J. IRVINE A. D. TOFT BMJ, 1974, 4, 291

....In our paper, to which they refer but unfortunately misinterpret, a single estimation of serum TSH, and not the TSH response to TRH, was as valuable as the time-consuming TSH stimulation test in the assessment of thyroid reserve. ....Indeed, we have stopped using serum T-3 uptake measurements for some two years, these being perhaps indicated only if

one suspects a diagnosis of binding protein abnormality that has not been induced by pregnancy, oral contraception, or other medicaments. We are, etc., W. J. IRVINE A. D. TOFT Department of Endocrinology, Royal Infirmary and University Department of Therapeutics, Edinburgh

1996 (available on web) Education and debate Consensus statement for good practice and audit measures in the management of hypothyroidism and hyperthyroidism M P J Vanderpump, senior registrar, J A O Ahlquist, consultant physician, J A Franklyn, professor of medicine, N Clayton, professor of medicine,a, on behalf of a working group of the Research Unit of the Royal College of Physicians of London , the Endocrinology and Diabetes Committee of the Royal College of Physicians of London and the Society for Endocrinology BMJ 1996;313:539-544 (31 August)

Thyroid disease is common and may present to a wide range of doctors. With the widespread availability of thyroid function testing in recent years increasing numbers of patients with symptoms which might be attributable to hypothyroidism and hyperthyroidism are being tested. Many aspects of the management of thyroid disease have not been subjected to controlled clinical trials yet there are established practices which have never been questioned. The Research Unit of the Royal College of Physicians of London, the Endocrinology and Diabetes Committee of the college, and the Society for Endocrinology set up a working group to produce a consensus statement for good practice with associated audit measures which could be used to ensure that purchasers of health care are obtaining an acceptable standard of care for patients with thyroid disease. The working group focused on patient management rather than presenting symptoms and signs, which were detailed in a similar report by the American Thyroid Association.

This report summarises the consensus views reached by members of the working group.
....Subclinical hyperthyroidism
* Subclinical hyperthyroidism is defined as a persistently suppressed serum thyroid stimulating hormone concentration with normal thyroxine and triiodothyronine concentrations in a patient who does not have symptoms
* There is as yet no consensus on whether such patients (not taking thyroxine) should receive antithyroid treatment
* It is debatable whether there is significant excess morbidity from subclinical hyperthyroidism, though a higher risk of atrial fibrillation in patients over 60 and decreased bone density in postmenopausal women (unassociated as yet with an increase in fracture rates) have been recorded.
Conclusion
This report highlights several aspects in which further study would be useful to clarify some of the uncertainty in the management of hypothyroidism and hyperthyroidism. These include the relative costs of the options for treatment of hyperthyroidism, the cost effectiveness of a centralised computerised thyroid disease register, and whether patients with atrial fibrillation and hyperthyroidism should be anticoagulated. This consensus statement represent the collective opinion of the members of the working group, all of whom support this publication. The essential standards and associated audit measures for purchasers of health care and general practitioner fundholders are summarised in the box and can be used to ensure that a high standard of care is being achieved.

1996 ASPECTS OF A COMMON MISSED DIAGNOSIS: THYROID DYSFUNCTION AND MANAGEMENT Durrant-Peatfield, B.J Journal of Nutritional & Environmental Medicine, Dec96, Vol. 6 Issue 4, p371

The all too common misdiagnosis of hypothyroidism is the result of poor clinical appraisal and undue reliance on flawed blood tests. The condition is simply and satisfactorily treated by replacement therapy and a plea is made for greater awareness among clinicians.

INTRODUCTION

The syndrome which results from a deficient output of thyroid hormone or deficient utilization is at once extraordinarily common and as commonly misdiagnosed [1]. Why it is that the diagnosis of such a frequently seen illness is so often missed is the primary purpose of this survey and attention will be given to the failure of correct management of an easily and rewardingly treatable illness. The term 'myxoedema' was used by Ord [2] (in 1878) when he found atrophy and fibrosis of the thyroid in association with the presence of a water-containing mucopolysaccharide throughout the tissues.
....

HYPOTHYROIDISM: THE UNSUSPECTED ILLNESS

....The thyroid is easily damaged by many disease processes and is five times more likely to be damaged in women than men; autoimmune diseases in particular may affect its integrity. Environmental hazards are having an increasing affect on thyroid activity in the present day. Placing on one side carcinomatous change, there are two pathological changes with which we must be concerned.
First, overactivity of the thyroid, properly called hyperthyroidism or Grave's disease. This is much less common than underactivity and its incidence is largely unchanged at present.
....
Barnes [6] estimated that up to one-third of people approaching mid-life could be affected, though not all require treatment.

The term 'myxoedema' should probably be reserved for those patients with little or no thyroid activity. Hypothyroidism may occur in any degree, from a few per cent down on nominal to true myxoedema. Probably anything more than a 15% loss will produce symptoms, which will vary widely from patient to patient leading to diagnostic confusion, which regrettably leads to a diagnosis being missed more often than it is made.

The causes of hypothyroidism may be summarized as follows: (1) primary or secondary failure of hormone production;
(2) receptor uptake deficiency;
(3) receptor resistance;

(4) conversion failure of T4 to T3.

Failure of Thyroid Hormone Production

This may be conveniently classified into the following: (1) iodine deficiency;
(2) genetic;
(3) secondary to antibody damage;

(4) pituitary failure (i.e. failure of TSH production), secondary to antibody damage;
(5) environmental toxins or insufficiencies;
(6) surgery, i.e. a major operation--hysterectomy, cholecystectomy or tonsillectomy (damage to blood supply); (7) major trauma;
(8) infectious mononucleosis [7];
(9) treatment of previous thyroid overactivity.

Receptor Uptake Deficiency

This may be primary, owing to failure at the site of the portal of entry into the cell, or secondary, due to a lowered metabolic activity at the receptor site, resulting from long exposure to hypothyroidism.

Receptor Resistance

Less often seen, this may prove a puzzling diagnostic problem, since all thyroid levels may be normal, yet the symptoms are perfectly clear. It may be associated with partial adrenal insufficiency.

Conversion Failure of T4 to T3

The 5'-diiodase enzyme system may be damaged (often as the result of prolonged hypothyroidism) so that, with normal levels of T4, the T3 levels are low. This is again seen in adrenal insufficiency and other conditions as in iodine, iron and selenium deficiency.

SYMPTOMS AND SIGNS OF HYPOTHYROIDISM

One of the diagnostic difficulties is the fact that the symptoms are legion; they vary from patient to patient and may be put down to any number of other causes [8]. Yet taken together, with a high index of suspicion on the part of the physician, there should really be no problem.
....

DIAGNOSIS

This should be a clinical one and should already be clear to the clinician. Further useful evidence is the basal body temperature, first described by Broda Barnes [6, 12].
....
In many cases, a careful history, physical examination and the basal body temperature should be quite enough to establish the diagnosis.

Clinicians rely unreasonably on the blood pathology, estimating the serum T4, the THUT, the free T3 and TSH. The reference ranges are impossibly too broad [13] and a number of factors may vitiate the results. A reduced blood volume concentrates the blood levels, there is slow clearance from the blood and thyroid hormone varies in a dynamic way. Receptor failure may mean that the blood level bears little relation to the intracellular T[sub 3]. For these and other reasons the blood chemistry must be used with great care and not used only diagnostically. Undue reliance on the chemistry has meant that, in the present writer's experience, in nine cases out of ten, where the symptoms and signs are perfectly clear, the diagnosis is missed. This is regrettable and sad, since hypothyroidism is so easily and successfully treated and the main purpose of this paper is to draw clinicians' attention to this common and unfortunate diagnostic omission. If the history, examination and basal body temperature add up, the diagnosis may be properly and successfully made. A trial of treatment

will soon confirm the diagnosis.

TREATMENT

The satisfactory management of the hypothyroid state is extraordinarily rewarding for both the clinician and patient. It is not difficult and does not require repeated blood estimations as is commonly believed and, again contrary to common belief, has almost no hazards. The aim is to restore tissue levels to normal, correcting all the functional deficits in the working of all the organs of the body. In this, clinicians should take as their primary purpose the treatment of the patient and not the disease and, most especially, not the blood test.

....
In its simplest classical form, replacement therapy employs 50 mug thyroxine tablets. Treatment may be initiated by the use of 25-50 mug daily. This dose, over a period of 2 or 3 months, may be slowly increased every 2, 3 or 4 weeks according to response. It is most important to realize that the response is slow and requires 2 or 3 weeks to evaluate.
....
Replacement is for life, albeit with dosage variations. It can be discontinued at any time, of course; the improvement will then slowly wear off over weeks and provide any further conviction the clinician or patient needs.
While this simple management is satisfactory for simple, uncomplicated hypothyroidism, of not too long duration, many patients will not fully respond or, worse, report unpleasant palpitations or flushes or headaches, sometimes within days, thus casting doubt on the diagnosis. It is of great importance that the reason these problems occur should now be considered. First, a poor response may simply be due to insufficiency in the dose. If the dosage regime outlined above is adhered to, there should be a positive response within 4 weeks. If not, clearly there is a failure of uptake and/or utilization. Similarly, apparently toxic symptoms may be the result of an initial overdose, but may equally well be due to the above, causing an effective overdose owing to non-utilization. Assuming the vitamin, mineral and trace element levels are acceptable, the problem is due to either receptor deficiency, adrenal insufficiency or conversion deficiency of T4 to T3 by a weak 5'diiodase enzyme,
....
A low adrenal reserve is a likely problem with marked and long-standing hypothyroidism and the poor response or toxic symptoms may be completely prevented by the use of a low, physiological dose of hydrocortisone [ 17]. A dose of 5 mg of hydrocortone qds is usually sufficient. However, 2.5-5 mg of prednisolone, or deltacortril, daily is often a preferred alternative. This should be continued for 2 months or so and then stopped, since the general improvement the thyroid hormone will have provided will normalize the adrenal function and supplementary glucocorticoid is not then required. It is not usually necessary to stage the reduction; at most halve the dose for a week, then stop. This regime will provide a speedy, safe and smooth response to thyroid hormone and should be used whenever a poor adrenal reserve is suspected. A low blood pressure--which does not rise on the patient standing--a history of collapses and prostration and arthralgia should raise suspicion, and prolonged undiagnosed hypothyroidism will most frequently be paralleled by adrenal insufficiency. The most satisfactory regime is to initiate glucocorticoid for a week prior to the use of thyroid hormone; there may be a general improvement at once since receptor uptake may rapidly be increased. If, in spite of these precautions, problems of response are still worrying, T4 to T3 conversion deficiency may be suspected. Five or ten per cent of cases may suffer this problem. ....
The thyroid produces two thyroid hormones, T4 and T3 in a 5:1 ratio, but a third is suspected [18]. Since replacement should logically be as close to the natural as possible, there is a strong case for the use of T4 and T3 in combination. While most authorities consider this to be an unnecessary complication, it is a rational approach and consideration should be given to it; ,,,,
Two further matters require attention. One is the fear of precipitating cardiovascular collapse, which worries many clinicians. It cannot be too strongly emphasized that the risk to the healthy heart, using the correct dosage regimes outlined above, is non-existent. It is overworking a heart damaged by disease and coronary artery insufficiencies or in failure that problems arise.
....
The detection and treatment of hypothyroidism in children is desperately important but sadly often missed. Cretinism is rare and well recognized, but lesser degrees of hypothyroidism may blight a life if untreated. The child may be sleepy, with an overweight tendency and may develop slowly and below its percentile. Often, however, the child may be of poor stature, with a lumbar lordosis and protuberant belly, underweight and sickly, with a tendency to acquire any infection that is going and, surprisingly, hyperkinetic.
....
Hypothyroidism i.n women is of special importance and some elaboration is necessary. The first symptoms may occur at the menarche; menses may occur unusually early--age 10 or 11 years--or unusually late--16 or 17 years. They may be irregular and unusually heavy or light, often with more dysmenorrhoea and clots than is usual. As the years pass, these symptoms may worsen and severe PMT is frequently found [26]. Fertility is downgraded and pregnancies may be associated with all sorts of problems, including inexplicable miscarriages. The production of extra T3 by the foetus which may occur results in unusually large babies; if diabetes of pregnancy can be excluded, a birth weight over 8 lb 8 oz (4 kg) should raise suspicion. ....
The diagnosis should be essentially clinical and a trial of treatment instituted. Thoughtful management of the trial eliminates

any risk of inappropriate treatment and in the writer's view is an entirely acceptable method of confirming the diagnosis without any risk to the patient. Many people suffer needlessly and have their lives blighted by the failure to treat this common and easily diagnosable illness.

REFERENCES

[1] Jackson AS. Hypothyroidism. JAMA 1957; 163: 2.
[2] Ord W. On myxoedema. Trans Med Chiurg Soc 1878; 6061: 57.
[3] Murray GR. Notes on the treatment of myxoedema by hypodermic injection of extract of thyroid gland of sheep. BMJ 1891; ii: 796.
[4] Murray GR. Life history of first case of myxoedema treated by thyroid extract. BMJ 1920; ii: 359.
[5] Hertzog E. Treatment of myxoedema. Int Clin Week 1915; 14 April.
[6] Barnes B. The Unsuspected Illness. London: Harper & Row, 1976.
[7] Demitract et al. Evidence for impaired activation of hypothalamic axis in chronic fatigue. J Clin Endocrin 1991; 73.
[8] Editorial. Puzzling cases and low thyroid function. BMJ 1970.
[9] Whybrow PC, Prange AJ, Treadway CP. Mental changes accompanying thyroid dysfunction. Arch Gen Psychiatr 1969; 20: 48-63.
[10] Furunculosis: aetiology & treatment. J Clin Endocrinol 1943; 3.
[11] Chaery WC. Tendon reflexes in myxoedema. JAMA 1924; 82: 2013-16.
[12] Barnes B. Basal temperature verses basal metabolism. JAMA 1942; 119: 1072.
[13] Barnes, Barnes. The Fallacy of Thyroid Function Tests. Riddle of Heart Attacks. Robinson Press, 1976.
[14] Jeffries WM. Safe Uses of Cortisone. Charles C. Thomas, 1981.
[15] Present status of ACTH, cortisone and related steroids. New Engl J Med 1955; 253: 441.
[16] Jeffries WM. Cortisol and Immunity. Medical Hypotheses. Longman, 1991.
[17] Jeffries WM. Low dosage glucocorticoid therapy. Arch Int Med 1967; 119: 265.
[18] Barnes B. Is there a third thyroid hormone? J IAPM 1982.
[19] Barnes B. Eighteen year follow up on thyroid therapy in prophylaxis & treatment of coronary heart disease. Fed Proc 1969; 28516.
[20] Buslenio PA et al. Pre clinical hypothyroidism: a risk factor in coronary heart disease. Lancet 1971; 1: 203-4.
[21] Barnes B. Prophylaxis of ischaemic heart disease by thyroid therapy. Lancet 1958; 11: 149.
[22] Fishbeng. Atherosclerosis in thyroid deficiency. JAMA 1924; 82: 463.
[23] Modesc, Danoski. Alterations in cholesterol and lipoprotein in euthyroid adults. Circulation 1958; 18: 761.
[24] Barnes J. Clin Exp Pharmacol Physiol 1975; 167 (suppl. 2): 170.
[25] Menof. New method for control of hypertension. S Afr Med J 24: 172-80.
[26] Bradshaw et al. Thyroid hypofunction in premenstrual syndrome. New Engl Med 1986; 315: 23.

1999 Psychiatric Treatment of the Medically Ill

edited by Robert G. Robinson University of Iowa College of Medicine Iowa City, Iowa William R. Yates University of Oklahoma Health Sciences Center Tulsa, Oklahoma

ii

Series Introduction

The post-world War II burgeoning interest in psychiatry and psychoanalysis, spurred by the experience of treating physically wounded and psychologically traumatized soldiers and civilians, reinforced medicine's interest in the borderlines of mind and brain.
While it had an older history in the work of William James, Hughlings Jackson, and Paul Schilder, the new focus on "psychosomatic illness," on "the mysterious leap from the mind to the body," made us acutely aware of the impact of affect and fantasy on bodily function. Gastric and duodenal ulcers, ulcerative colitis, rheumatoid arthritis, and asthma were thought to have important psychogenetic origins in repressed memories, fantasies, and conflicts. Unfortunately, many of these older theories and the practices derived from them have proven to be either in error or too simplistic.

The positive aspects of these misguided notions included the research into mechanisms that resulted, and which played an important role in introducing biological research into psychiatry, and the reinforced continuing interest in the mind-brain interface. The consequent development of consultation, and particularly of liaison psychiatry, turned our attention back to the problems of living with medical illness, acute or chronic, of adapting to disabilities, of accommodation to disease and to approaching death. Being physically ill is stressful and can produce psychiatric symptoms and syndromes either directly or indirectly, and the treatments we use can also create psychiatric difficulties and disorders.

Recovery-room deliria, the wish to discontinue renal dialysis, poststroke depression or denial of disability, and anticholinergic confusional states are common places in medical practice. Drs. Robinson and Yates present us with a well- organized, scholarly review of the multiple ways in which patients experience illness, the impact of being

iv

sick, the things a disordered physiology can do to the mind, and a comprehensive course on the psychopharmacology of the medically ill. While many of the authors are from Dr. Robinson's own distinguished department in Iowa, the chapter authors represent distinguished institutions in New York, Maryland, Oklahoma, Rhode Island, and Connecticut, as well as Canada, England, Argentina, Israel, and Germany. The result is a nonparochial view of the current state of our knowledge, of both our science and our art.

William A. Frosch, M.D.

v

Preface

Medical illnesses induce psychological as well as physical distress. This relationship has been known for many years but has only recently been systematically documented by studies of the epidemiology of psychiatric disorders in various medical disorders. Studies of community and clinical populations demonstrate that medical and psychiatric disorders occur together much more commonly than would be expected by chance. Both primary care physicians and psychiatrists are likely to find that a significant number of their patients have both a medical and a psychiatric diagnosis.

Acute and chronic medical illnesses produce significant psychological distress and may contribute to the production of psychiatric symptoms and psychiatric disorders.
Patients with medical illness are frequently dealing with psychological threats created by the illness. These come in many forms, such as a threat to physical integrity and hody image, to social and occupational functioning, or to financial self- sutficiency.

Handling these psychological stressors can be crucial in a physician's overall patient-management plan.
Patients with psychiatric disorders frequently suffer physical symptoms such as pain, fatigue, dyspnea, and headache. These physical symptoms are often produced as part of the psychiatric illness and will resolve once the psychiatric illness is successfully treated. However, patients are often unaware of the source of their physical symptoms and seek relief from primary care physicians rather than a specialist in mental health care. This psychiatric link to physical symptoms is responsible for a significant number of visits to primary care physicians.
Both medical and psychiatric treatments can produce adverse effects, some of which cross the domain of treatment. A significant number of medical drugs can have

vi

psychiatric effects on mood, anxiety, or cognition. Primaty care physicians often need to determine if a patient's new psychiatric symptoms are a result of the intervention they have initiated so that a proper adjustment to the treatment program can be made. Likewise, psychiatric medications can produce physical symptoms and interact with medical illnesses. A psychiatrist prescribing a tricyclic antidepressant needs to be familiar with elements of cardiac conduction and the toxic effects of tricyclic medications on the heart and the brain. The mind-body dualism is no longer valid. We now understand better that it is impossible to provide adequate care for the mind and brain without attention to and knowledge of the body. This book is divided into three parts: an introduction, description of specific medical disorders, and discussion of psychopharmacological treatment in the medically ill. In the introductory section, issues of screening for psychiatric illness in medical patients provides a framework for psychiatric assesment. A discussion of the specificity of psychiatric symptoms then leads into a review of the epidemiology of psychiatric disorders in medical populations.
The section on specific disorders includes 18 chapters targeted to the most common medical disorders ac' well as those in which psychiatric issues play a key role: organ transplantation, HIV infection, and neuropsychiatric disorders. These chapters provide the clinician with a ready reference addressing the issues related to psychiatric treatmcnt in these medical conditions.
The final section focuses on specific psychopharmacological treatment issues found in medically ill populations, including absorption and metabolism, the role of serum-level monitoring, and the effects of aging and psychotropic drug interactions. This section provides clinicians with information relevant to the pharmacology of psychotropic drug use in the medically ill. We hope that this volume will provide both primary care physicians and psychiatrists with a resource for managing the patient with both a medical and a psychiatric disorder. The shift to increased managed care has placed pre,sure on primary care physicians to handle common psychiatric disorders. Psychiatrists are encountering forces targeting their work and reimbursement to areas in which their medical training and background are required. Both these forces encourage a better understanding of the interface of medicine, surgery, and psychiatry. This book seeks to provide a timely and comprehensive review of this interface.

Robert G. Robinson William R. Yates

Chapter 9
Endocrine Disorders
Caroline Carney University of Iowa College of Medicine Iowa City, Iowa

173 .....

Overview

Hypothyroidism is a clinical condition resulting from decreased secretion of thyroid hormone from the thyroid gland. The vast majority of cases (90-95%) are the consequence of failure of the thyroid gland (e.g., primary hypothyroidism). The remainder of cases are attributed to pituitary disease (secondary hypothyroidism) or hypothalamic disease (tertiary hypothyroidism) (49) .The prevalence of hypothyroidism ranges from 1 to 10% depending on the population studied (62). Hypothyroidism occurs more frequently in iodine-poor geographic areas, among females, and among the elderly.

Etiology

Primary hypothyroidism occurs with processes related to the destruction of the thyroid gland. The most common cause of destruction is from an auto immune process such as Hashimoto's thyroiditis or end-stage Graves' disease. Destruction of the thyroid gland can also occur secondary to an iatrogenic procedure such as external radiation orthryoidectomy performed for the treatment of another thyroid disease. Additionally, infiltrative processes such as lymphoma, scleroderma, or amyloidosis may destroy the gland. Congenital hypothyroidism is rare, affecting 0.003-0.02% of American neonates (49). Iodine deficiency or excess may interfere with thyroid hormone synthesis, leading to hypothyroidism.

Drug-induced hypothyroidism develops when biosynthesis of thyroid hormone is altered. It has been attributed to lithium and carbamazepine, but does not appear to be caused by antipsychotics, tricyclic antidepressants, or benzodiazepines (63) .Lithium interferes with both the synthesis and release of thyroxine and may also inhibit the acrion of TSH. Lithium-induced hypothyroidism usually occurs within the first 2 years of initiation (64). Some authors recommend checking TSH levels every 2-3 months for the first 2 years, then biannually thereafter (64), although all authors are not in agreement on the frequency (63). Lithium-induced hypothyroidism usually fully reverses upon discontinuation of the drug. Carbamazepine's reduction of T4 levels is dose dependent. TSH levels usually remain normal, and patients remain clinically euthyroid. Other drugs thought to induce hypothyroidism include sulfonamides, interleukins, and thionamides (49).

Secondary forms of hypothyroidism result from pituitary gland failure secondary
174
conditions such as neoplasm or surgery. Hypothalamic failure occurs secondary to ltrative and infectious processes (49). Patient Presentation

As with hyperthyroidism, hypothyroidism affects many organ systems and can cause a myriad of symptoms and signs. The onset of symptoms is usually insidious and may go unnoticed by the patient or close relatives. Patients present with complaints including forgetfulness, low mood, fatigue, menorrhagia, impotence, headache, tinnitus, hearing loss, constipation, muscular stiffness and cramping, joint pain, intolerance to cold, dry or rough skin, weight gain despite diminished appetite, and paresthesias, commonly in the carpal tunnel region. Relatives may note social withdrawal, personality changes, snoring, or vocal hoarseness.

Physical Examination

The physical examination may reveal changes in the skin that include dry, rough skin with hyperkeratosis. The hair may be thinning and have a coarse, brittle texture. Non-pitting edematous skin changes may be found in the face, limbs, and supraclavicular fossa. The voice may be dysarthric, and an ataxic gait may be noted. A distal peripheral neuropathy may be detected. Deep tendon reflexes are slowed with a delayed relaxation phnase. A pleural effusion may be present. Bradycardia and hypertension are detected cardiovascular examination (49,58).

Mental Status Examination

Mental status examination may be remarkable for an irritable or anxious individual a depressed, puffy, or stoic-appearing facies. Speech may be slow and toneless.

Psychomotor retardation is noted. Memory may be diminished. Formal memory testing reveals deficits in all scales except mental control on the Wechsler Memory Scale (65). The affect may be depressed, with mood complaints including dysphoria, anhedonia, and suicidality. In severe cases, a thought disorder characterized by agitation, paranoid ideation, persecutary delusions, hallucinations, and disorientation may be observed.

Laboratory Examination

Laboratory abnormaalities confirm the diagnosis. Grade I, or overt, primary hypothyroidism is characterized by an elevated TSH (>6 /lU / ml), diminished free T 4 (< 0.9ng /dl), and diminished total T4 < 4.5 μg/dl). The T3 usually remains normal early in the course, but later becomes diminished ( <80 ng/ dl) (49) .A hypothyroid state induced by hypothalamic or pituitary disease will be distinguished by a normal or low TSH in spite of a decreased free or total T 4. The presence of antithyroid antibodies is compatible with Hashimoto's disease. Thyroid-releasing hormone (TRH) testing may

175

be used to delineate the cause of secondary hypothyroidism. Other laboratory findings include hypercholesterolemia; normocytic/ normochromic, hypochromic/ microcytic, or macrocytic anemias; prolonged bleeding time; elevated serum lactate dehydrogenase, serum creatinine kinase of MM origin, and serum aspartate aminotransfetase. Cerebral spinal fluid protein may also be elevated (62).

Role in Psychiatric Conditions

The psychiatric syndromes in hypothytoidism date to 1874, when Gull first described a "cretinoid state" in an adult woman. Within the next 15 years, the mental changes associated with advanced hypothyroidism were well documented and the term "myxedema" was coined. In 1949, Asher described 14 cases of "myxoedematous madness" in patients who were thought to suffer from a primary psychotic process (66). It is currently believed that 5-15% of myxedema patients have overt psychoses, although these figures may be lower as thyroid disease is now generally diagnosed earlier. Hypothyroidism may reduce central 5-hydroxytryptamine and result in depression (67). Other proposed mechanisms include reduced cerebral flow resulting in a relative cerebral hypoxia.

Psychiatric syndromes occurting with advanced hypothyroidism are variable and include psychotic depression, delirium, dementia, manic-like syndrome, and a schizophrenic-like syndrome. Patients may present with depressed mood, personality change with lability of mood, anxiety, emotional withdrawal, generalized agitation, mental slowing, persecutory delusions, paranoid ideation, and auditory hallucinations (58,62,63,66). Myxedema is an important cause of reversible psychiatric and dementia syndrome. Psychiatric symptoms usually respond to thyroid hormone replacement, but reversal may take days to months. A manic-like state can ensue if replacement is too rapid. During the initial treatment, psychotropic medications may be needed to control symptoms while the thyroid replacement is taking effect.

The literature evaluating the role of hypothyroidism in unipolar major depressive disorder, bipolar affective disorder, and dysthymia is mixed. The issue becomes further complicated when considering the influence of subclinical hypothyroidism on the affective state. Subclinical hypothyroidism (grades 2 and 3) denotes the circumstance in which free T 4 and total T 4 are normal but TSH is elevated. Typical symptoms of hypothyroidism are either absent or present to only a minimal degree (68).

Some studies suggest that clinical depression occurs in over 40% of hypothyroid patients (57,69) and at a rate of 12% in depressed inpatients (70). Antithyroid antibodies are found in 9-20% of those with unipolar depression (71,72). Patients over 65 years old who have subclinical hypothyroidism have a lifetime history of major depressive disorder (68). These findings must be interpreted with caution, however, because of small sample populations and/ or lack of control groups (68). More recently, Haggerty and Prange (68) showed that 50% of a population of general medical patients with TSH values of >3.0 IU had been treated for depression compared with only 18% of those with TSH of <3.0 IU. Using structured psychiatric interviews, they

176

further showed a higher lifetime prevalence of depression in a group of young and middle-aged women with grade 2 or 3 hypothyroidism than in women who were euthyroid (68).
Subclinical hypothyroidism has been associated with rapid cycling bipolar affective disorder in some, but not all, studies (73). Some findings suggest that subclinical hypothyroidism may be present in up to 40% and overt hypothyroidism in 25- 50% of rapid-cycling bipolar patients (68). Antithyroid antibodies have been found in 33% of mixed episodes, but the frequency of subclinical hypothyroidism is no different between subjects with and without mixed states (68,73). The role of lithium-induced hypothyroidism complicates the interpretation of the role of thyroid hormone in bipolar affective disorder. A review of comorbidity in dysthymia showed that a subgroup of patients with dysthymia are at risk for subclinical or overt hypothyroidism (74).

Treatment

Levothyroxine sodium remains the primaty treatment for overt hypothyroidism and may be used for treatment of subclinical hypothyroidism and as adjuvant treatment for affective disorders. Most patients with primary hypothyroidism can be treated with levothyroxine at an average daily dose of about 1.6 μg/kg ideal body weight. Healthy, young adults ( <65 years old) may be initiated at the full treatment dose, generally 100 μg daily, but those older than 65 years old or who have a history of cardiac disease should begin with 25 μg/ day with increases at approximately 6- to 8-week intervals. The goal of therapy is to normalize TSH and improve symptoms. TSH levels should be checked 2-3 months after initiation of treatment, as they are unlikely to normalize until that time. Symptomatic improvement may be noted within 3-4 weeks of initiation of therapy. Therapy is usually lifelong, although dose adjustments may be needed over time (75). Laboratory evaluation should be conducted on an annual basis once the TSH has normalized. Complications of overreplacement include the development of hyperthyroidism, increasing the nocturnal heart rate, and increasing bone resorption leading to osteoporosis (76).

Treatment of subclinical hypothyroidism remains controversial (75,76). Levothyroxine replacement has been recommended for patients with TSH of > 10 μU/ml for those with TSH of >5 μU/ml when a goiter or antithyroid antibodies are present (75). Treatment may be particularly important in the elderly (>65 years). Elderly persons with an elevated TSH and antithyroid have an 80% chance of developing hypothyroidism in a 4-year period. Some authors recommend that the list of index symptoms for initiating treatment of subclinical hypothyroidism should be broadened to include depression, memory faults, and fatigue (68).

Adjuvant treatment with thyroid hormone may be beneficial in the treatment of both unipolar and bipolar affective disorders. Data regarding the usefulness of adjuvant therapy are limited by a paucity of large sample sizes and few double-blind crossover trials. Persons with depression refractory to antidepressant therapy, especially those with

177

subclinical hypothyroidism, may benefit from triiodothyronine (T 3) or levothyroxine supplementation. Additionally, levothyroxine has been reported to benefit patients with bipolar affective disorder who are euthyroid or have subclinical hypothyroidism (73).
Until larger, well-designed studies are done to address this issue of adjuvant treatment, clinical judgment remains the best alternative.

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75. Mandel SI, Brent GA, Larsen PR. Levothyroxine therapy in patients with thyroid disease. Ann Intern Med 1993; 119:492-502.
76. Toft AD. Thyroxine therapy. N Engl J Med 1994; 331:174-180.
77. Swanson lW, Kelly II, McConahey WM. Neurologic aspects of thyroid dysfunction. Mayo Clin Proc 1981; 56504-512. 78. lsley WL. Thyroid dysfunction in the severely ill and elderly: forget the classic signs and symptoms. Postgrad Med 1993; 94:111-128.

1999 Diagnostic Strategies for Common Medical Problems Edgar R. Black, MD, FACP, Donald R. Bordley, MD, FACP, Thomas G. Tape, MD, FACP, Robert J. Panzer, MD, FACP American College of Physicians Second Edition

Chapter 41

473

Hyperthyroidism and Hypothyroidism
James G. Dolan, MD, and Steven D. Wittlin, MD KEY POINTS

Pretest Probabilities

- Sensitive clinical indices exist for the diagnosis of both hyperthyroidism and hypothyroidism in ambulatory patients. Little information exists on the diagnostive value of these indices in patients with serious nonthyroidal illnesses.

Diagnostic Strategies

- The ultrasensitive, third-generation thyroid-stimulating hormone (TSH) immunoradiometric asay is the best test to establish or exlude thyroid dysfunction both in ambulatory patients and in patients with severe nonthyroidal illnesses.

- To diagnose hyperthyroidism when the ultrasensitive TSH assay is not available, the free triiodothyronine (T3) assay, free thyroxine (T4] assay, or free T4 index should be used in ambulatory patients. The free T4 assay or T4 index is best in patients with severe nonthyroidal indexes.
474<

....

ESTIMATING PRETEST PROBABILITY

Weighted clinical indices have been developed for the diagnosis of both hyperthyroidism and hypothyroidism. This type of index maximizes the diagnostic usefulness of clinical information because the evidence provided by both abnormal and normal findings is appropriately considered. These clinical indices were derived in ambulatory populations. The value of clinical signs and symptoms for the diagnosis of thyroid dysfunction in patients with severe underlying disease is unknown.

Hyperthyroidism

The best available estimates of the prevalence and annual incidence of hyperthyroidism in the general population are 0.3% and 0.05%, respectively (1). Crooks and colleagues developed a clinical index for the diagnosis of hyperthyroidism in patients suspected of having the disease (Table 41-1). In their original population, the index achieved a sensitivity of 100% and a specificity of 88% using a cutoff score of 10.

....

Hypothyroidism

The best available estimate of the prevalence of hypothyroidism in the general population is 0.35% (1). Billewicz and colleagues (6) developed a weighted clinical index for use in patients with suspected hypothyroidism (Table 41-2). In the original population, this index achieved a sensitivity of close to 100%, but with a specificity of just 50% (6).

475

Table 41-1. Crooks index*

Symptom or Sign

Present

Absent

Dyspnea on effort

+1

0

Palpitations

+2

0

Tiredness

+2

0

Preference for heat

-5

0

Preference for cold

+5

0

Indifferent to temperature

0

0

Excessive sweating

+3

0

Nervousness

+2

0

Appetite increased

+3

0

Appetite decreased

-3

0

Weight increased

-3

0

Weight decreased

+3

0

Palpable thyroid

+3

-3

Thyroid bruit

+2

-2

Exophthalmos

+2

0

Lid retraction

Lid lag

+2

0

+1

0

Hyperkinetic movements

+4

-2

Fine finger tremor

+1

0

Hands hot

+2

-2

Hands moist

+1

-1

Atrial fibril'ation

<80 bpm

+4

0

Heart rate

-3

0

80-90 bpm

O

O

>90 bpm

+3

O

*Euthyroid if 10 or less; hyperthyroid if more than 10.

DIAGNOSTIC TESTS

The operating characteristics of thyroid function tests, using average values or best estimates obtained from the available literature (8-20), are summarized in Table 41-3 (p 477). Values are given separately for

476

479

DIAGNOSTIC STRATEGIES

If available, the best test of thyroid function in any patient suspected of thyroid disease is a third-generation TSH assay (Table 41-4). This test is equivalent to a TRH stimulation test in the diagnosis of hyperthyroidism and to the older TSH radioimmunoassay (RIA) in the diagnosis of hypothyroidism.
If a third-generation TSH assay is not available, the free T3, free T4, or the free T4 indices are all acceptable substitutes in the workup of suspected hyperthyroidism in ambulatory populations. In patients with severe nonthyroidal illnesses, the free T4 or the free T4 index should be used.

....

REFERENCES

1. dos Remedios LV, Weber PM, Feldman R, et al. Detecting unsuspected thyroid dysfunction by the free thyroxine index. Arch Intern Med. 1980; 140:1045-9.
2. Crooks J, Murray IPC, Wayne EJ. Statistical methods applied to the clinical diagnosis of thyrotoxicosis. Q J Med. 1959;28:211-34.

3. Gurney C, Hall R, Harper M, et al. Newcastle thyrotoxicosis index. Lancet. 1970;2:1275-8.
4. Trivalle C, Doucet J, Chessagne P, et al. Differences in the signs and symptoms of hyperthyroidism in older and younger patients. J Am Geriatr Soc. 1996;44:50-3.
5. Davis PJ, David FB. Hyperthyroidism in patients over the age of 60 years. Medicine. 1974;53:161-81.
6. Billewicz WZ, Chapman RS, Crooks I, et al. Statistical methods applied to the diagnosis of hypothyroidism. Q J Med. 1969;38:255-66.
7. Seshadri MS, Samuel BU, Kanagasabapathy AS, et al. Clinical scoring system for hypothyroidismis it useful? J Gen Intern Med. 1989; 4:490-2.
8. Goldstein El, Mushlin AI. Use of a single thyroxine test to evaluate ambulatory medical patients for suspected hypothyroidism. J Gen Intern Med.1987;2:20-4.
9. Marsden P, McKenon CG. Serum triiodothyronine concentration in the diagnosis of hyperthyroidism. Clin Endocrinol. 1975;4:183-9.

482

10. Sawin CT, Chopra D, Albano J, Azizi E. The free triiodothyronine (T3) index. Ann Intern Med. 1978;88:474-7.
11. Wiersanga WM, Touber JL. Thyroid function tests. II. Studies in patients with thyroid disease. Neth J Med. 1980;23:200-9.
12. Ho worth PJN, MacLagan NF. Clinical application of serum total thyroxine estimation, resin uptake, and free thyroxine index. Lancet. 1969;1:224-8.

13. de Los Santos ET, Starich GH, Mazzaferri EL. Sensitivity, specificity, and costeffectivensss of the sensitive thyrotropin assay in the diagnosis of thyroid disease in ambulatory patients. Arch Intern Med. 1989;149:526-32.
14. Seth J, Eeckett G. Diagnosis of hyperthyroidism-the newer biochemical tests. Clin Endocrinol Metab. 1985;14:373-96. 15. Seth J, Kellet HA, Caldwell G, et al. A sensitive immunoradiometric assay for serum thyroid stimulating hormone. A replacement for the thyrotropin releasing hormone test? Er Med I. 1984;289:1334-6.

16. Caldwell G, Kellett HA, Gow SM, et al. A new strategy for thyroid function testing. Lancet. 1985;1:1117-9.
17. Spencer CA, Lai-Rosenfeld AO, Guttler RB, et al. Thyrotropin secretion in thyrotoxic and thyroxine treated patients: assessment by a sensitive immunoenzymometric assay. I Clin Endocrinol Metab. 1986;63:349-55.
18. Klee GG, Hay ID. Assessment of sensitive thyrotropin assays for an expanded role in thyroid function testing. Proposed criteria for analytic performance and clinical utility. J Clin Endocrinol Metab. 1987;64:461-71.
19. White GH. Recent advances in routine thyroid function testing. Crit Rev Clin Lab Sci. 1987;24:315-62.
20. Surks MI, Ocampo E. Subclinical thyroid disease. Am I Med. 1996;100: 217-23.
21. Eorst GC, Eil C, Burman KD. Euthyroid hyperthyroxinemia. Ann Intern Med. 1983;98:366-78.
22. Gooch ER, Isley WL, Utiger RD. Abnormalities in thyroid function tests in patients admitted to a medical service.(Arch Intern Med. 1982;142:1801-5.
23. Kaplan MM, Larsen PR, Crantz FR, et al. Prevalence of abnormal thyroid function test results in patients with acute medical illnesses. Am J Med. 1982;72:9-16.
24. Wong ET, Eradley SG, Schultz AL. Elevation of thyroid-stimulating hormone during acute nonthyroidal illness. Arch Intern Med. 1981;141:873-5.
25. Chopra IJ, Soloman DH, Hepner GW, et al. Misleadingly low free thyroxine index and usefulness of reverse triiodothyronine measurement in non thyroidal illnesses. Ann Intern Med. 1979;90:905-12.
26. Gavin LA, Rosenthal M, Cavalieu RR. The diagnostic dilemma of isolated hyperthyroxinemia in acute illness. IAMA. 1979;242:251-3.
27. Chopra IJ, VanHerle AJ, Chua Teco GN, Nguyen AH. Serum free thyroxine in thyroidal and nonthyroidal illness: a comparison of measurements by radioimmunoassay, equilibrium dialysis, and free thyroxine index. J Clin Endocrinol Metab. 1980;51:135-43.
28. Spencer C, Eigen A, Shen D, et al. Specificity of sensitive assays of thyrotropin (TSH) used to screen for thyroid disease in hospitalized patients. Clin Chem. 1987;33:1391-6.

483

29. Wenzel KW. Pharmacologic interference with in vitro tests of thyroid function. Metabolism. 1981;30:717-32.
30. Evered DC, Tunbridge WMG, Hall R, et al. Thyroid hormone concentrations in a large scale community survey. Effect of age, sex, illness, and medication. Clin Chem Acta. 1978;83:223-9.
31. Tunbridge WMG, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Whickham Survey. Clin Endocrinol. 1977;7:481-93.
32. Woeber KA. Subclinical thyroid dysfunction. Arch Intern Med. 1997;157:1065-8.

2000 (available on web as .pdf file) Subclinical Hypothyroidism Is an Independent Risk Factor for
Atherosclerosis and Myocardial Infarction in Elderly Women: The Rotterdam Study A. Elisabeth Hak, MD, MSc; Huibert A.P. Pols, MD, PhD; Theo J. Visser, MD, PhD; Hemmo A. Drexhage, MD, PhD; Albert Hofman, MD, PhD; and Jacqueline C.M. Witteman, PhD Ann Intern Med. 2000;132:270-278
Overt hypothyroidism, with its accompanying hypercholesterolemia and hypertension, has been found to be associated with cardiovascular disease (1–3). Subclinical hypothyroidism, defined as an asymptomatic state characterized by normal serum concentrations of free thyroxine and elevated serum concentrations of thyroid-stimulating hormone (TSH) (4), is highly prevalent in elderly women (5, 6). Whether subclinical hypothyroidism is related to risk for cardiovascular disease is contro- versial. Casecontrol and cross-sectional studies on the association between subclinical hypothyroidism and cardiovascular disease have been done (7–11). Results from these studies are not consistent, but many of the studies were small. The same controversy surrounds thyroid autoimmunity. In the late 1960s and early 1970s, autopsy studies (12, 13) and studies in hospital inpatients (12, 14) suggested that asymptomatic autoimmune thyroiditis was an important risk factor for coronary heart disease. These findings, however, were not confirmed by other studies (7, 8, 11, 15). In our population-based study, we examined whether subclinical hypothyroidism and thyroid auto-immunity are associated with aortic atherosclerosis and myocardial infarction in elderly women. We conducted our study in a random sample of 1149 postmenopausal women who were participating in the Rotterdam Study.
....In conclusion, we found that subclinical hypothy-roidism is highly prevalent in elderly women and is strongly and independently associated with aortic atherosclerosis and myocardial infarction. The population attributable risk percentage for subclinical hypothyroidism associated with myocardial infarction was within the range of that for known major risk factors for cardiovascular disease. Additional research should be done to determine whether this association can be confirmed in a prospective study. If not, subsequent studies may focus on the effectiveness of possible therapies for subclinical hypothyroidism in elderly women and the desirability of screening such women for this disorder.

200 Clinical Response to Thyroxine Sodium in Clinically Hypothyroid but Biochemically Euthyroid Patients G. R. B. SKINNER MD DSc FRCPath FRCOG, D. HOLMES, A. AHMAD PhD, J. A. DAVIES BSc and J. BENITEZ MSc Journal of Nutritional & Environmental Medicine (2000) 10,115-124

CLINICAL RESEARCH

Vaccine Research Trust, 22 Alcester Road, Moseley, Birmingham B13 8BE, UK

Abstract
Purpose:To examine clinical response to thyroid replacement therapy in patients considered to be clinically hypothyroid but with normal thyroid biochemistry.
Design: Practice-based open intervention study; control group used for baseline laboratory values only.
Materials and Methods:Clinical response to thyroxine (T4 only) was examined in 139 patients who were considered hypothyroid by 16 recognized criteria but whose free thyroxine (FT4) and thyroid stimulating hormone (TSH) fell within 95% laboratory reference intervals (133 patients) or whose FT4 or TSH fell within these intervals (6 patients). Patients were treated with 25 μg day-l thyroxine sodium for 1 week followed by 50 μg day -1 for 6 weeks and an increase thereafter of 25 μg at 6 week intervals until the patient was clinically euthyroid. Clinical response was adjudged by improvement or disappearance of clinical features of hypothyroidism; thyroid chemistry was estimated in 41 patients at 6-12 months following institution of thyroid replacement.
Results:There was improvement or disappearance of all 16 clinical features in 30 patients (22%) and in over 12 features in 106 patients (76%), with a decrease in the mean number of clinical features from 13.3 ± 0.18 before treatment to 3.0 ± 0.23 following treatment over a minimum follow-up period of 6 months. Energy loss and poor memory and concentration were most responsive to treatment while reduction in tongue size and weight gain improved in 57% and 24% of patients respectively. Clinical response correlated with the level of thyroid replacement but not significantly with pre-treatment or post-treatment levels of FT4 and TSH nor with duration of illness or treatment.
Conclusions:Clinically hypothyroid but biochemically euthyroid patients had favourable clinical response to thyroid replacement which correlated with the level of thyroid replacement. It is suggested that these findings be examined in a prospective placebo controlled clinical trial.

123 ....

DISCUSSION

This study indicates that patients considered to be hypothyroid on clinical features but with either FT4 or TSH or-as in most cases - both FT4 and TSH within the 95% reference interval had favourable clinical response to thyroid replacement; this was adjudged by improvement or disappearance of a proportion of the 16 clinical features.

122
<FIG. 3. Relationship between clinical improvement and final dosage of sodium thyroxine.>

Our results may under-, or over-, represent purported clinical improvement. There was no attempt to quantify the extent of improvement in any given clinical feature and it is accepted that the record of "improvement" may represent marginal or total improvement where both situations will be recorded as "improvement". Conversely the finding that (for example) 129 of 139 patients (~ 93%) have improvement or disappearance in at least 10 of the 16 pivotal clinical features under- emphasizes the fact that improvement or disappearance in even one critical feature represents a significant and dramatic improvement in clinical well-being for an individual patient.

In the absence of a control group, a placebo effect cannot be excluded in this or any study. However, the average duration of illness was 7.5 years in patients who had usually undergone an alarming array of traditional and alternative medications without significant improvement as evidenced by their wish to seek further medical advice. Secondly, certain clinical features allowed objective assessment, namely change in appearance, hair or skin texture, reduction in size of tongue and thyroid gland and increase in pulse rate. Therefore, while acknowledging the criticality of formal clinical trial-and indeed we are pleased to report that such a trial has been instituted at Stobhill Hospital, Glasgow, UK-the

124

reconsidered towards the concept that there may be a spectrum of optimal health in terms of thyroid related body functions which relates approximately to levels of FT4 where (for example) patients whose FT4 levels are 17 or above feel better than patients with levels between 17-11, while levels 10 or 11 are associated with sub-optimal health. It is ridiculous-although one author (ORBS) has observed this on many occasions during the last decade-that a patient whose FT4 level is 0.1 below the lower limit of a reference interval is considered "hypothyroid" but if it is 0.1 above the lower limit the patient is considered "not hypothyroid" and thus should not receive appropriate thyroid replacement.

In summary we feel that the results of this study should be subjected to the scrutiny of formal clinical trial to examine not the relationship of abnormal thyroid chemistry to disease, which is well established, but the relationship between "normal" thyroid chemistry and ill health.

REFERENCES

[1] Holmes D. Tears behind closed doors. Avon Books. London: 1998.
[2] Chronic Fatigue Syndrome. Report of a joint working group of the Royal Colleges of Physicians, Psychiatrists and General practitioners. Cathedral Print Services, Salisbury 1996.
[3] Bayliss RIS. Thyroid Disease: the Facts. Oxford: Oxford University Press, 1982.[4] DeGroot LJ, Larsen PR, Refetoff S, Stanbury JB. The Thyroid and its Diseases. Wiley Medical, Chichester, NY 1984.
[5] lngbar SH, Bravennan LE. Wemer's The Thyroid, 5th edn. JB Lippincott Company, 1986.
[6] Burrow GN, Oppenheimer JH, Volpe R. Thyroid Function and Disease. Sanders, Philadelphia 1989.
[7] McDougall IR. Thyroid Disease in Clinical Practice. Chapman and Hall Medical, London 1992.
[8] Staub J-J, Althaus BU, Engler H, et al. Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin and thyroid reserve, and metabolic impact on peripheral target tissues. Am J Med 1992; 92: 631-42.
[9] Surks MI, Ocampo E. Subclinical thyroid disease. Am J Med 1996; 100: 217-23.
[10] Cooper DS, Halpem R, Wood LC, Levin AA, Ridgway EC. L-thyroxine therapy in subclinical hypothyroidism. A double-blind, placebo-controlled trial. Ann Intern Med 1984; 101: 18-24.
[11] Weetman, AP. Hypothyroidism: screening and subclinical disease. BM1 1997; 314: 1175-8.
[12] Nystrom E, Caidahl K, Fager G, Wikkelso C, Lunberg PA, Lindstedt G.A. Double-blind cross-over 12-month study of L-thyroxine treatment of women with "subclinical" hypothyroidism. Clin Endocrinol 1988; 29: 63-76.
[13] Billewicz WZ, Chapman RS, Crooks J, Day ME, Gossage J, Wayne Sir E, Young JA. Statistical methods applied to the diagnosis of hypothyroidism. Q J Med, 1968; New Series XXXVIII, no.150. 255-66.
[14] Meler CA, Malsey MN, Muller J, Smith MA. Inter individual differences in the pituitary-thyroid axis influence the interpretation of thyroid function tests. Clin endocrinol 1993; 39: 101-7.

2001 ( as pdf file) Review: Interpretation of thyroid function tests Colin M Dayan THE LANCET • Vol 357 p 619 - 624 • February 24, 2001
The introduction of sensitive thyrotropin assays and free thyroid hormone measurements has simplified the interpretation of thyroid function tests. However, important pitfalls and difficult cases still exist. In this review, thyroid function test results are grouped into six different patterns. We propose that if assays for thyrotropin, free T3, and free T4 are all done, knowledge of these patterns coupled with clinical details and simple additional tests allow a diagnosis to be made in almost all cases.

....Conclusion
In most cases, interpretation of thyroid function tests with free hormone assays and TSH is straightforward.However, unusual conditions can generate common patterns of thyroid function, easily confused with more straightforward diseases

(panels 2, 5, and 6), and unusual patterns of test results (panels 3, 4, and 7). One or more of the following features should prompt further investigation: (1) abnormal thyroid function in childhood; (2) familial disease; (3) thyroid function results incon-sistent with the clinical picture; (4) an unusual pattern of thyroid function tests results—eg, widely discrepant free T4 and T3 results or a detectable TSH with raised free T3 or T4; and (5) transient changes in thyroid function. In many cases, correct diagnosis of rare thyroid conditions from their thyroid function tests has very important implications for the management of individual patients and their family members. With the exception of detailed genetic analysis, the tests required to investigate the diagnosis are easily available. The challenge lies in applying them to the right individual at the right time.

2001 Serum Thyroglobulin and Urinary Iodine Concentration Are the Most Appropriate Indicators of Iodine Status

and Thyroid Function under Conditions of Increasing Iodine Supply in Schoolchildren in Benin1 Tina van den Briel*, Clive E. West2, Joseph G.A.J. Hautvast*, Thomas Vulsma**, Jan J. M. de Vijlder** and Eric A. Ategbo Journal of Nutrition 2001:131, 2701-2706

* Division of Human Nutrition and Epidemiology, Wageningen University, Wageningen, The Netherlands; Department of Gastroenterology, University Medical Center Nijmegen, The Netherlands; ** Emma Children's Hospital, Academic Medical Center, University of Amsterdam, The Netherlands; and Department of Food and Nutrition, Faculty of Agriculture, National University of Benin, Cotonou, Benin, West Africa

Abstract:

Iodine deficiency control programs have greatly reduced iodine deficiency disorders worldwide. For monitoring changes in iodine status,different indicators may be used. The aim of this study wasto evaluate the suitability of indicators of iodine status and thyroid function, thyroglobulin (Tg), thyroid-stimulating hormone(TSH) and free thyroxine (FT4) in serum, thyroid volume and urinary iodine concentration, in iodine-deficient schoolchildren under conditions of increasing iodine supply. The study was established as a double-blind, placebo-controlled oral administration of a single dose of iodized oil to schoolchildren (7–10 y old), living in an iodine-deficient area of Benin, with an observation period of 10 mo. However, 3–4 mo after supplementation, iodized salt became available in the area. The study population therefore comprised an iodized oil–supplemented group and a nonsupplemented group, both of which had variable, uncontrolled intakes of iodized salt during the last 6 mo of the study. Initial mean serum concentrations of TSH and FT4 were within the normal range, whereas serum Tg concentration, urinary iodine concentration and thyroid volume were indicative of moderate-to-severe iodine deficiency. At the end of the study, all indicators had improved significantly, except thyroid volume, which had decreased only in the supplemented group. The supplemented group also still had significantly lower serum Tg and higher urinary iodine concentrations than the nonsupplemented group. Serum Tg and urinary iodine concentrations are the indicators most influenced by a changing iodine supply. Current normal reference ranges of serum concentrations of TSH and FT4 are too wide for detecting iodine deficiency in this age group.

RETURN TO HOMEPAGE

*Euthyroid if 30 or less; hyperthyroid if more than 30.