Thyroidhistory

1920 Prevention of Simple Goitre in Man David Marine, O. P. Kimball Fourth Paper Archives of Internal Medicine part 25 Cleveland

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In previous publications we have outlined the plan of prevention, presented the data of the incidence of thyroid enlargements as determined by annual surveys of all new pupils in the Akron public schools, and the results of the prophylactic use of sodium iodid for nineteen months. The present paper deals with the data obtained at the fourth general examination made October 13-17, 1919, together with summaries and conclusions based on observations extending over a period of thirty months.

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In the practical application of the preventive treatment, one must keep in mind the three periods when simple thyroid enlargements most commonly occur, viz., (1) fetal, (2) adolescence and (3) pregnancy.
(1) Prevention of goitre in mother and fetus is as simple as that occurring during adolescence. Practically, it would seem that it is a charge or responsibility of individual members of the medical profession supplemented with public education,.
(2) The prevention of goitre of adolescence, on the other hand, should be a public health measure under state, county or municipal control. The existing systems of organization of the schools, public and private, is sufficient to handle all the details without additional aid or expense. Education of the pupils would be combined with the actual administration so that after leaving school they could continue the treatment, if necessary. Physicians in industrial medicine could render an important service in this field. Thyroid enlargement is approximately ix times as frequent in girls as in boys. It is a social

economic question each community must decide whether it will include both sexes. Likewise, as to the age of beginning and stopping the use of iodin. In this climate probably the maximum of prevention, coupled with the minimum of effort, would be obtained by giving it between the ages of 11 and 17 years. As applied to our schools it would mean beginning with the fifth grade.

Manner and Form of Administration.- As previously stated, iodin is taken up by the thyroid gland when given by mouth, by inhalation, or by external application. Weith reports favorable therapeutic effects from inhalation of iodin as carried out by suspending a wide mouthed bottle containing a 10 per dent. tincture of iodin in the school room. Waste and lack of control of amounts taken are the most obvious objections. Similar objections hold in case of external application. Some form of oral administration seems most practical and economical. The addition of iodin or a salt of iodin to the water supply as we have done in preventing goiter in fish might be considered. There are obvious objections to such a plan. It would entail enormous waste. It is applicable only when there are installations, i.e., in towns and cities, and depending on the chemical impurities in water interactions might throw out the iodin. The most feasible oral method would seem to be the individual administration of definite small amounts, either in solution or as tablets. The cheapest salt, sodium iodid, could be given in either form. Manufacturing pharmacists state that sodium iodid could be prepared very cheaply in tablet form protected from the action of water and light. For private use, the well known U.S.P. preparations, syrup of ferrous iodid and syrup of hydriodic acid are excellent.

Amounts of Iodin to be used.- An ounce of syrup of ferrous iodid or hydriodic acid given over a period of from two to three weeks and repeated twice yearly would seem ample. As a public health measure, we have used 2 gm. of sodium iodid given over a period of two weeks and repeated twice yearly. This dosage has prevented enlargement of the thyroid in more than 99 pre cent. of the children in this mildly goiterous district. It is our opinion that much smaller amounts would suffice for healthy children and healthy pregnant women, provided the period of taking was prolonged, i.e. 1 gm. sodium iodid distributed over a month would accomplish as good thyroid effects as 2 gm. given over a period of two weeks.

The prevention of thyroid enlargement in individuals with other diseases or residing in extremely goiterous districts, as in some glacial valleys of Alaska and British Columbia; certain districts in the Alps and Himalayas, might require larger amounts of iodin for normals than above indicated. Our data of the clinical condition of four of the five cases that enlarged during the administration of 2 gm. of sodium iodid, twice yearly, suggest that in infections (chronic catarrhal or suppurative tuberculosis, syphilis, etc.,) and possibly also in conditions like chlorosis, osteomalacia, lymphatism and exophthalmic goiter, such amounts might no control the thyroid growth. In such conditions there may be a greatly increased demand for the thyroid hormone or the organism's ability to store iodin in the thyroid may be impaired. There is a great deal of clinical evidence for the first view and none at present in support of the second.

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SUMMARY
Observations on the prevention of simple goiter in man on a large scale have extended over a period of thirty months. The results show tat it may be prevented very simply and cheaply in normal individuals. While thyroid enlargements of adolescence are more common, they are not more important than those occurring in mother and fetus. Prevention of adolescent goiter is properly a public health problem, while the prevention of fetal and maternal thyroid enlargements is largely a responsibility of individual physicians. the presence of pathologic conditions may modify the result of the prophylactic treatment in individual cases. While such instances are rare they are important and merit detailed reports.

1922 Correlation of basal metabolic rate with pulse rate and pulse pressure. J. MARION READ, M. S. M. D. J. Am. M. Ass., 1922, 78: 1887 - 1889 Clinical Instructor in Medicine, Stanford University School of Medicine SAN FRANCISCO
p 1887

Extreme deviations from the normal basal metabolic rate are accompanied by very definite and easily recognized alterations in other functions. Some of these such as changes in blood pressure, pulse rate and respiratory rate, can be expressed quantitatively and utilized as rough guides to fluctuations in the metabolic rate. This study concerns itself only with pulse rate and pulse pressure in their relationship to the basal metabolic rate. It will be shown that these two measurable functions of the circulation tend to vary directly with the basal metabolic rate when they are obtained under the same "basal" conditions as are standard in basal metabolic work.

p 1888
....This series consists of 300 determinations made over a period of a year and a half. The data were obtained from three different sources, namely, the basal metabolic departments of St. Luke's Hospital, Stanford University Hospital and the San Francisco Hospital; a Sanborn-Ben edict portable calorimeter being used in all three laboratories. About one half of the determinations were made by the writer, the others being made by four personally trained physicians serving first and second hospital years. Blood pressure readings were taken on all patients on whom a basal metabolic test was made, the reading being made in the resting interval between two ten minute breathing tests. Frequent records of the pulse rate were made throughout the breathing periods. Thus, the basal pulse rate and the basal blood pressure were ascertained at the same time the basal metabolic rate was determined.
The only selection made of the material was elimination of all cases which showed changes in the pulse rate or blood pressure due to an obvious pathologic condition in the cardiovascular-renal system.
....The trend of the average pulse rates and pulse pressures having been established, and it being noted that individual

discrepancies in one were often accompanied by a discrepancy in the other but in the opposite direction, the problem then presented itself of combining these two in such a manner as to smooth out the apparent discrepancies. There are various means of combining these two values, but the one which seemed to present the greatest advantages was that which utilized the quantitative measure of relationship between the basal metabolism, on the one hand, and the pulse rate and pulse pressure, on the other.

p 1889
....Throughout this study it has been assumed that the relationship of pulse rate and pulse pressure to basal metabolic rate is a linear one. Such an assumption seemed justified by the data, though the possibility that a curved line might express the relationship equally well is not forgotten.
Aside from any value they may possess in prediction of the metabolic rate, the basal pulse rate and pulse pressure have greater usefulness and may be utilized with more accuracy in following hypothyroid and hyperthyroid patients under treatment. In individual cases the variations in these measures at different times are significant, provided always they are obtained under basal conditions. Their usefulness could be enhanced by first determining them simultaneously with the basal oxygen consumption. By thus establishing their relationship to the basal metabolic rate at one observation, future estimations of the basal metabolic rate of that individual could be determined by ascertaining the basal pulse rate and pulse pressure.

CONCLUSIONS
The pulse pressure and pulse rate vary in the same direction as the basal metabolic rate. Most individuals respond to

variations in the metabolic rate with proportionate changes in both pulse rate and pulse pressure; a few show disproportionate changes in the one with little or no change in the other. A combination of the two gives a better measure of the circulatory system's response toe variations in metabolic rate than either one alone. Basal pulse rate and pulse pressure combined can be used clinically as a guide to ascertain the direction and estimate roughly the amount of change in the basal metabolic rates of patients under treatment for hypothyroidism and hyperthyroidism.

1927 THE INCIDENCE OF INTRATHORACIC TUMOURS IN MANCHESTER. BY J. B. DUGUID, M.D. ABERD., LECTURER IN PATHOLOGY, WELSH NATIONAL SCHOOL OF MEDICINE: LATE LECTURER IN MORBID ANATOMY, VICTORIA UNIVERSITY OF MANCHESTER. Lancet 2:111-116, 1927
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MOST of those who have had recent experience of the post mortem work of the Manchester Royal Infirmary have formed an impression that the incidence of intrathoracic tumours there is high. This has led to the suggestion that air pollution, which is exceptionally great in Manchester, may be a factor in the production of these tumours. In various other centres, both in Europe and in America, recent investigations have made it appear that the incidence has increased in late years, and it has been thought that a similar increase was noticeable in Manchester. In order to ascertain so far as possible the actual state of affairs it was decided to make an investigation and analysis of all the cases which have been entered in the autopsy registers at the Infirmary up to the end of the year 1926. With regard to the problem of air pollution no satisfactory conclusion can be arrived at until the figures thus obtained can be compared with those from a number of other towns where there is more or less atmospheric purity, and it is with a view to arousing interest in the subject in other centres, so that investigations along similar lines may be carried out, that these findings are now being published. In this research it has been possible to study a large number of cases, and since it is only by the examination of large numbers, where numerous comparisons can be made, that many of the difficulties in differential diagnosis are made manifest, it has been thought permissible to discuss some of these difficulties for the guidance of those who may have less material on which to base their conclusions.
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In Manchester the figures point to no particular industry as being dangerous in this respect, but rather to those who are outdoor workers as being more prone to thoracic tumours than those who work in more sheltered conditions. It has been noted, however, that carters and drivers are comparatively numerous in the list of those affected. Obviously no conclusions can safely be drawn from such findings alone and all that can safely be drawn from such findings alone and all that can be done it to cite briefly some possible reasons for men of that class being so frequently affected.
In the fist place, men who work in the open and are constantly exposed to weather conditions in an excessively damp climate such as that of Manchester may possibly be unduly exposed to the danger of chronic bronchial catarrh, and it is conceivable that such irritation may be a factor in the production of bronchial cancer ; full enough information regarding the past histories of the cases to settle this point cannot now be obtained. In the second place, men who are much on the roads are exposed to an atmosphere which is very often heavily laden with dust and particles of most varied materials, and it may be that materials of a similar nature to those responsible for the high incidence of cancer among the Schneeberg miners may also be present in road dust. A relationship between cancer of the lungs and conditions of the highways has been suggested by other observers. Staehelin has suggested that the modern custom of tarring roads is responsible for the increased incidence and others have cited pollution of the air by exhaust gases from motor-driven vehicles as being a possible factor. Thus although the figures derived from Manchester are in themselves insignificant, they are of importance in so far as they yield evidence which is in concurrence with the propositions of other observers. In an article on Branchiogenetic Carcinoma, R. V. Hudson recently drew attention to the high incidence of such tumours in grooms, suggesting at the same time that these men are susceptible because they are liable to inhale much dust during the process of grooming horses.

Myer, Berblinger, and others have considered that there is a relationship between the great influenza epidemic of 1918 and the recent increase in the incidence of lung cancers. Staehelin, however, has shown that the increase in Basle dates from earlier than 1918, and from the figures herein given it is patent that the increase in Manchester is little affected by the 1918 epidemic.

1929 THE EFFECTS ON HUMAN BEINGS OF A TWELVE MONTHS' EXCLUSIVE MEAT DIET BASED ON INTENSIVE CLINICAL AND LABORATORY STUDIES ON TWO ARCTIC EXPLORERS LIVING UNDER AVERAGE CONDITIONS IN A NEW YORK CLIMATE CLARENCE W. LIEB, M.D. NEW YORK JAMA, 93:20- 22, 1929

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The question of minimal and optimal protein requirements has received considerable research attention in recent years. There is now very little disagreement among students of nutrition as to what these requirements are. On the effects of a high protein dietary, however, not only do opinions of authorities differ but the results of carefully controlled experiments show considerable variance. It is a traditional belief that a high protein intake leads to high blood pressure, arteriosclerosis or nephritis. Among physicians it has almost become a dietetic dogma to reduce or eliminate entirely the intake of meat whenever diets are prescribed. Unless proper interpretation is given to certain present-day investigations on protein metabolism, including the results of the experiment reviewed in this paper, there is a danger that the dietetic pendulum will swing too far in the opposite direction.
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....COMMENT ON DIET
Of interest in this dietary regimen was the apparent absence of monotony ; the subjects rarely craved for other food than meat products. What little calcium
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they had was obtained from eating the ends of ribs and gristle, averaging about 0.1 Gm. a day. The average water which they drank contained 0.01 Gm. of calcium per liter. Most of the meat eaten was cold storage meat. For a period of two months in the early part of their regimen they had freshly killed meat. During the remainder of the experiment their meat was ordinary, refrigerated, butchers' meat. The meat was usually boiled or stewed, the inside being left rare. Raw bone marrow was eaten as dessert at times early in the experiment but never during the last six months of it. Very little salt was added to the food by Andersen. No eggs were taken by Andersen during the year. Stefansson sometimes used them on journeys when meat was not available. Neither milk non its products were used. Coffee and black tea and water were the sole beverages and, of course, unsweetened. About 1,500 to 1,800 cc. of fluid was consumed a day. Usually four meals were taken by Stefansson but three by Andersen each day. The food was always relished and complete satiety resulted after eating. No headaches or digestive symptoms, other than those noted as the result of eating lean meat, were experienced. Both these men were ideal experimental subjects and science owes much to them for their whole-hearted cooperation in enduring as patiently the numerous annoyances incident to the complicated and frequent tests made on them. They were physiologically fit for the experiment since, having had years of experience in living on this diet, they had no mental hazards as to its course or outcome.
The diets on which these two experimental subjects have been for the past year have not been particularly high protein diets, being but 30 or 40 per cent above the average protein intake. Their protein intake amounted to between 100 and 140 Gm. a day. The remaining calories were derived from fat which was equal to about three fourths or four fifths of their caloric intake. Andersen showed little evidence of an adaptation to the utilization of the higher percentages of fat. The highest ketosis noted was in Andersen, the subject who weighed least. Stefansson, who is a better nourished type, tolerated the fat better than Andersen.

1931 ESTIMATION OF THE BASAL METABOLIC RATE FROM FORMIULAE BASED ON PfJLSE-RATE AND PULSE PRESSURE. By ANNABELLA M. GALE,* M.D., B.Sc. GLASG., AND C. H. GALE, M.INST.C.E., A.R.I.B.A. TliE LANCET, JUNE 13, 1931

1287

IN 1922 J. Marion Read I of San Francisco suggested that a simple clinical means of estimating basal roetabolic rate might be obtained by making use of the correlation between basal metabolic rate, pulserate, and pulse pressure. He suggested the following formula :
B.M.R. = 0.683 (P.R. + 0.9 P.P.) - 71.5,

but subsequently 2 altered the formula to :
B.M.R. = 0.75 (P.R. + 0.74 P.P.) - 72.
In 1926 Cameron, Kitchen, and McRae, of Canada, tested Read's formula during an investigation into the basal metabolic rate of young adults, and concluded " that the results do not justify the use of the formula clinically." 3
The determination of the basal metabolic rate is of the utmost importance clinically, but it is so involved that it can only be estimated in hospitals provided with a large scientific staff and the necessary apparatus, and it is out of the question for the general practitioner. It was thought that if a formula based on pulse-rate and pulse pressure could be evolved and could be shown to give reliable results, it would bring into the hands ot the general practitioner a new method of studying disease at

the bedsIde. With this end in view a letter was sent to Dr. Read which met with a most gratifying response. He forwarded all his original figures and perrnission to make full use of them. This most kind and generous action made the following inquiry possible. Prof. Cameron, of Manitoba University, was also kind enough to supply the unpublished figures on his test of Read's formula. The Russell Sage InstItute of Pathology, New York, very kindly supplied a full set of their papers dating back to 1915. The basal metabolic-rate deterrninations taken ip the Russell Sage Institute are conducted in the most scientific and accurate manner, and it is most unfortunate that their results could not be used, as observations of the pulse pressures are not included.

In Prof. Cameron 's 134 cases no less than 55.6 per cent. are included in the zone + 10 per cent. to -9.9 per cent. basal metabolic rate and, taking into account that Prof. Cameron's results were fully 10 per cent. or 15 per cent. higher than Dr. Read's, we decided to deal with Dr. Read 's cases only.

.....

SUMMARY.
1. Six formulae have been calculated and tested on the data of 1006 cases collected by Dr. Read and his staff during the estimation of the basal metabolic rate by the portable respiration calorimeter .
2. Gale's formula P.R. + P.P. -111 = B.M.R. has been found to give on the whole the most satisfactory results, as seen in Table II., where the total mean percentage of the percentages of all the zones of cases within 5 per cent. error of the observed basal metabolic rate is 27.5 per cent., and of cases within 20 per cent. error, 73.7 per cent. Allowing for the many possibilities of error in the observations of clinical data, thi& appears to be an excellent result.
3. This method of calculating the basal metabolic rate by the addition of the pulserate and the pulse preasure and subtracting 111 make it admirably adapted for use at the bedside by the general practitioller .

THE TWENTY-FOUR HOUR CURVE.
Fig. 2 Shows the typical curves of observations made of two subjects at frequent intervals during three years. The curves were fairly constant from day to day. The peak in curve B at about 12 A.M. (noon) was very persistent, but seldom rose above normal. In all cases examined there wasa rise from the minimum, at about 4 A.M. to 5 A.M., to the maximum, at about 12 A.M. to I P.M., and a tendency to remain steady between 2 P.M. and 8 P.M. For this reason the afternoon appears to be the best time for taking the basal metabolic rate. The curves were obtained by observations taken every two hours by Gale's formula, in some cases without waking the subject. It is doubtful if the curves could be obtained by any other method.

REFERENCES.
1. Read, J. Marion : Jour. Amer. Med. Assoc., 19)22. lxxviii., 1887.
2. Read: Arcb.Int.Med.,1924, xxxiv., 553.
3. Cameron, A. T., Kitcben, H. D., and Mc Rae, D. F. : Canad. Med. Assoc. Jour., 1926. xvi, 1201 4. Read: Proc. Soc. Exp. Biol. and Med.. I927, xxiv, 564.

1933 AN ELECTRICAL METHOD FOR USE IN THE DIAGNOSIS OF DISEASES OF TH4E THYROID GLAND. DR. M. A. B. BRAZIER PH. D., B. SC. LOND. RESEARCH WORKER AT THE CENTRAL PATHOLOGICAL LABORATORY, LONDON CONTY MENTAL HOSPITALS THE LANCET SEPT. 30, 1933 .
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IT has long been known that certain electrical properties of the body are affected by diseases of the thyroid gland. Vigouroux 1 made the observation in 1888 that the resistance of the body to a direct current is influenced by the thyroid gland. More modern work with alternating currents has followed this, and Lueg and Grassheim 2 have shown that what they term the " Kondenser-wert " of the skin -varies in thyroid diseases in such a way as to be of diagnostic value. The method used by these workers was that of Gildemeister .3

In the present research an improved method has been developed for studying the impedance of the human body to an alternating current; Thismethod has been published in full technical detail else where, 4 together with a detailed criticism of Gildemeister's method, giving the reasons why it was not adopted for the present work.
The electrical characteristic of the human body which is under investigation in this paper is termed the " impedance angle " ; a full discussion of this property, together with its mathematical derivation, will be found in the paper cited, 4 so that it is sufficient here to give a short definition of this term and to outline in brief the technique for its estimation.
In constant current work the impedance of the body can be measured by a single factor-namely, the resistance ; but with alternating currents the body functions not only as a resistance but also as a condenser. The ratio of these two factors is a property of the dielectric under 0 bservation (in this case the body), and it is a function of this ratio which shows variations in thyroid disease, and which is defined as the impedance angle.
The method in brief is as follows.
The patient sits on a chair with each aJ:m immersed to the elbow in arm-baths containing salt solution. Each arm-bath contains 10 litres of 1 per cent. NaCl at a temperature of about 25° C. It has been shown 4 that the results are unaffected by variation of the temperature of the arm-baths, by slight movements on the part of the patient, by the emotional state of the patient, or by the strength of the current passing through the body. No preparation of the patient by resting or fasting . is

necessary, and only a very slight degree of cooperation is required. The full test is accomplished in less than ten minutes. All these factors make it an extremely convenient method of investigating out-patients.
When the arms have been immersed in the arm.baths. an alternating current sufficiently low in intensity. to be imperceptible to the patient is led through hlm into a simple bridge circuit. The impedance offered by the patient to the current can be balanced on the bridge by adjusting a variable condenser and a variable resistance and from these readings the impedance angle can calculated. For the full details of this proceSs the paper already cited 4 should be consulted.

It may be mentioned that a new form of the appararatus has now been designed which is easily portable and has the advantage of being a direct reading instrument that calculation is eliminated.
Study 4 of the normal subject shows that dlly impedance angle remains almost constant from day to day in the same individual, and normal groups give only a small standard deviation ( S.D ) about the mean

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for the impedance angle (I.A.). The values for men and for women fall into two well-defined groups, the women giving higher values* ; they are thus always treated as two separate groups, the mean for each group being taken as the zero for that sex. This arbitrary system of units has proved more convenient for clinical use than the expression of the measured value of the impedance angle.
In the present work all the patients examined were women, and the results are therefore compared with the mean for normal women, which has been established4 to be O� (S.D.=I0.1). Any variation from this mean is expressed as a plus or minus difference.

...
It is concluded from the series of results detailed above that the impedance angle forms a very reliable aid to the diagnosis of toxic conditions of the thyroid gland. In this respect it is more specific and more certain than the basal metabolic rate. The test itself is open to less experimeental error than the B.M.R. estimation and is partIcularly adaptable to the investigation of out-patients.
This line of research is now being extended to include the study of myxoedema.and cretinism.
....

BIBLIOGRAPHY
1. Vigouroux, R. : Progres Med., 1888, xvi., 45.
2. Lueg W.,and Grassheim; K. : Zeits f Kli Med., 1929 cx.. 531.
3. Gildemeister, r.I. : Pfliiger's Arch 1919, clxxvi 84.
4. Brazier. M. A. B. : Jour. Inst. Elect. Engineers, 1933, Ixxiii 203
5. Kocher, T. (quoted by Crile, G. W.) : Diagnosis and Treatment of Diseases of the Thyroid Gland, Philadelphia, 1932, p. 75.
6. Dodds, E. C., La.vson. W., and Robertson, J.. D. : THE LANCET, 1932, ii., 608.
7. Booth by, W.M; : Ehdocrnol., 1921, v. 12.
8. Jbll, C. A. : Diseases of the Thyroid Gland, London, 1932, p. 235.
9. Troell, A. : Hygjea (Sweden), 1932 xciv, 45.
10. Bram, I. : EndocrinoJ., 1933, xvii 23.
11. Joll : Op cit (ref. 8), PP. 582 and 519

1933 THE RELATION OF THE ANTERIOR PITUITARY TO CARBOHYDRATE METABOLISM B. O. BARNES AND J. R. REGAN Endocrinology, 17: 522- 528, 1933
At the meeting of the American Physiological Society, April 11, 1933, we made a report on this subject which may be summarized as follows; (1) Spontaneous glycosuria had not been observed I a hypophysectomized-panreatectomized dog but glycosuria could be produced at will by injection of anterior lobe extracts. (2) Glycosuria had been produced in normal dogs by injection of suitable anterior pituitary extracts. (3) These same extracts did not produce glycosuria in a thyroidectomized dog. At this time we wish to report the details and extension of these experiments.

The experimental evidence for an interrelationship between the anterior hypophysis and carbohydrate metabolism will be briefly considered under three divisions, (1) hypophysectomy, (2) hypophysectomy and pancreatectomy, and (3) injection of anterior lobe extracts.
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....DISCUSSION
The absence of any glycosuria in our animal with both hypophysis and pancreas removed may be due to the loss of one thyroid. Houssay, Biasotti and Rietti (1932) have reported one similar animal in which both thyroids were removed and in which there was no glycosuria. These experiments seem to show a clear relation between the pituitary and carbohydrate metabolism. Why an animal can survive pancreatectomy for such an extended period if its pituitary is removed is not yet clear. There is a possibility that if the secretion of the pituitary were suppressed, a human diabetic might be benefited. To test this possibility on the dog, we have made use of the female sex hormone which Moore and others have found to suppress the secretion of the gonadotropic principle in the pituitary. Although the details will be published later, we wish to say that by injecting amniotin, we have observed an increased sensitivity to insulin in 4 dogs. Two of these dogs were completely pancreatectomized while still receiving amniotin, and the severe glycosuria which usually develops was not observed. These

experiments are being continued and extended to clinical diabetes.
SUMMARY
Spontaneous glycosuria was not observed in a dog with both the pituitary and the pancreas removed. The animal was sensitive to insulin and showed glycosuria when injected with suitable extracts of the anterior
p 528
pituitary. Seven normal dogs have shown glycosuria when injected with anterior lobe extracts while four others showed no effect. The glucose tolerance was reduced and the fasting blood sugar was higher than normal. After removal of the thyroids, six dogs did not show glycosuria when injected with these extracts. Four dogs receiving female sex hormone (amniotin) became more sensitive to insulin. Severe diabetes did not occur after removal of the pancreas in two of these dogs.
1934 CALORIGENIC ACTION OF SINGLE LARGE DOSE OF DESICCATED HOG THYROID COMPARISON WITH THE ACTION OF THYRONINE GIVEN ORALLY AND INTRAVENOUSLY WILLARD O. THOMPSON. M.D. PHEBE K. THOMPSON. M.D. SAMUEL G. TAYLOR M. M.D. AND LOIS F. N. DICKIE B.S. CHICAGO 1950 Arch. Int. Med. 54: 888 - 900, 1934
p 888
Several reports have recently been made from this clinic concerning the effects of administering thyroxine in various forms orally and intravenously in an alkaline solution. These observations have shown that single doses of 10 to 100 mg. of pure thyroxine administered by mouth or duodenum do not have a demonstrable effect on the basal metabolism of patients with myxedema, whereas the oral administration of single large doses of monosodium thyroxine and thyroxine in alkaline solution causes increases in the basal metabolism of 22 and 63 per cent. respectively, as great on the average as the increase produced by the intravenous injection of an alkaline solution. It seemed important to determine the effect o single large doses of desiccated thyroid of the same iodine content for comparison with these data. We have previously
p 889
reported observations which suggest that the oral administration of desiccated thyroid and the intravenous injection of thyroxine in doses which contain the same total amounts of iodine produce equal increases in the basal metabolism, when the comparison is made on the basis of the quantities of the two substances that have to be administered every day in order to hold the basal metabolism of patients with myxedema at the normal level.

...METHOD
Five patients with myxedema were used for this study, and in four of them the effects of giving thyroxine in various ways

have also been determined. In patients 1, 3 and 5 the myxedema was spontaneous; in the second patient it followed a subtotal thyroidectomy for exophthalmic goiter, and in the fourth patient, a subtotal thyroidectomy for a nontoxic nodular goiter. Various parts of the data on the first three patients have been published as they were collected to illustrate other points.
The desiccated thyroid was hog thyroid (Wilson's) containing 0.23 per cent. iodine and was used in the form of 1 grain (0.065 Gm.) tablets. All of the thyroid was from one lot except that given to the fifth patient. Since the mode of administration, particularly with reference to food, may be important, these details are incorporated in the legends of the charts.
For all the patients, curves are recorded showing the complete effect on the basal metabolism ofd each administration of desiccated thyroid or of thyroxine. These curves not only show the amount of increase in the basal metabolism, but make it possible to calculate roughly, by a method previously described, the total number of excess calories produced.
The monosodium salt of synthetic thyroxine was administered in the form of tablets each of which contained 1.03 mg. of the salt.
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....There are some differences between the curves for desiccated thyroid and those for thyroxine. In the first four patients the maximum increase in basal metabolism appeared to occur proportionately more quickly following the oral administration of single large doses of desiccated thyroid (three days on the average) than following the intravenous administration of large doses of thyroxine (seven days on the average). In the first three patients the maximum increase also occurred more quickly following the oral administration of desiccated thyroid (three days on the average) than following the oral administration of thyroxine in alkaline solution (six days on the average). In patients 1 and 4 the maximum increase in metabolism was sustained for a shorter period following the oral administration of desiccated thyroid than following the intravenous administration of thyroxin with the result that the total number of excess calories produced by desiccated thyroid was less than would be expected from the increase in basal metabolism. In the second and third patients, on the other hand, the number of excess calories produced by desiccated thyroid was roughly proportional to the increase in basal metabolism. In the first four patients, the effect of desiccated thyroid as only 60 per cent as great, on the average, as that of thyroxine given intravenously, when the comparison was made on the basis of the number of excess calories produced, as compared with 76 per cent when the comparison was made on the basis of excess calories, as compared with 97 and 84 per cent. respectively, on the basis of increase in the basal metabolism. The reason for this difference is unknown.
When the metabolism had shown its maximum change and had begun to decrease, the rate of change seemed to be similar for both desiccated thyroid and thyroxine.
....
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The higher the metabolism before treatment, the shorter is the duration of the effect, a phenomenon which appears to influence chiefly the number of excess calories produced rather than the absolute increase in the basal metabolism.

....Two observations which we have previously reported are pertinent to the interpretation of all data showing the calorigenic effect of thyroxine and of desiccated thyroid.
1. At levels of metabolism below the normal the effect of the thyroxine given intravenously every day appears to be roughly proportional to the dose when the dose is not sufficient to raise the rate above the normal.

2. A given dose of thyroxine has much less effect when the metabolism is normal before administration than when it is markedly reduced (minus 40 per cent).
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....SUMMARY
In five patients with myxedema the oral administration of single doses of desiccated thyroid caused an increase in basal

metabolism of from minus 37 to minus 15 per cent on the average, and the production of 7,405 excess calories on the average for every 6.5 mg. of iodine.
In four patients in whom the comparison was made, the calorigenic effect of the oral administration of a single large dose of desiccated thyroid varied from 59 to 97 per cent (average 76 per cent) of the effect of intravenous administration of a single large dose of thyroxine containing the same amount of iodine when the comparison was made on the basis of the increase in basal metabolism, and from 50 to 69 per cent (average 60 per cent) when the comparison was made on the basis of the number of excess calories produced.
In three patients in whom the comparison was made, the increased in basal metabolism produced by these large doses of desiccated thyroid were from 75 to 133 per cent as great as those produced by the oral administration of thyroxine in alkaline solution on the basis of equal iodine contents, and on the average the effects of the two were approximately the same.
p 900
If the data of the present study are combined with those previously reported, it is found that on the average the increases in basal metabolism produced by the oral administration of monosodium thyroxine, thyroxine in alkaline solution and desiccated thyroid are, respectively, 22, 63 and 69 per cent as great as that produced by the intravenous injection of thyroxine. If the comparison is made on the basis of excess calories produced, the corresponding figures are respectively 48, 58 and 48 per cent.

1937 STUDIES ON EXPERIMENTAL HYPERTENSION V. THE PATHOGENESIS OF EXPERIMENTAL HYPERTENSION DUE TO RENAL ISCHEMIA By HARRY GOLDBLATT, M.D., C.M., Cleveland, Ohio Annals Internal Medicine, 11:71-103
p71

THE production of persistent hypertension in dogs and monkeys has been reported in previous communications. This was accomplished by constricting the main renal arteries by means of a special sliver clamp devised for the purpose. In some of the dogs hypertension of severe degree has now existed for more than five years. The type of hypertension produced by this method depends upon the degree of constriction of the renal arteries. When the constriction is not very great, there is little or no disturbance of renal function accompanying the hypertension and it resembles benign hypertension in man. When the constriction is very severe, there is often accompanying damage of renal function which may also be severe. Such animals may die in uremia so that in this respect the hypertension resembles malignant hypertension in man.

p94
SUMMARY
The results of experiments that have been performed up to the present time on the pathogenesis of hypertension due to renal ischemia indicate that the mechanism of the development of this type of hypertension is primarily a humoral one of renal origin.
The failure of the various surgical procedures carried out on the nervous system to affect this type of experimental hypertension is evidently due to the persistence of the renal ischemia which cannot be altered by these procedures as long as the clamps remain applied. These experiments do not in any way controvert the results that have been obtained by the same procedures in the treatment of hypertension in man. They do emphasize, however, the importance of the reduced blood flow to the functioning
p95
components of the kidney as the primary cause of this type of experimental hypertension and perhaps of human hypertension that is associated with arteriolar disease of the kidneys. Since the reduced blood flow in the human kidney is frequently due to narrowing of the arterioles alone, without narrowing of the large arteries, improvement of the circulation may result from these procedures on the nervous system due to relaxation of the arterioles in which the organic changes are not fixed. The beneficial effects reported in about the same percentage of cases of hypertension by surgeons using various procedures affecting the vasomotor nervous mechanism in the abdomen may therefore all be due to one cause, the improvement of the circulation through the kidney and not, as has been suggested by some, to the effect on the vasomotor mechanism of a large part of the vascular bed in the abdomen. The latter view has no support in these experiments. Whether or not improved circulation through the kidney is
p95
responsible for the effect should be put to the test by a large series of renal denervations alone in cases of human hypertension. If improvement of the circulation through the kidneys be the common basis of improvement as a result of all of the various surgical procedures that have been carried out, then denervation of the kidneys alone, if it can be

accomplished, should give improvement in about the same small percentage of cases of hypertension.
The view that in the pathogenesis of hypertension due to renal ischemia a humoral mechanism involving a hypothetical effective substance of renal origin plays a part of primary importance is based almost entirely upon indirect evidence. Bilateral nephrectomy is not followed by hypertension, yet varying degrees of constriction and even complete occlusion of both main renal arteries are followed by hypertension. This difference is attributed to the absence of a hypothetical effective renal substance when the kidneys are absent. Even when both renal arteries are occluded, the hypothetical effective substance can still be formed and washed into the renal veins by the accessory circulation through the capsule. The constriction or occlusion of both main renal arteries, when accompanied by occlusion of the main renal veins, is not followed by the development of hypertension. This is interpreted as being due to interference with the entrance of the hypothetical effective substance into the circulation. Release of the constriction of the renal arteries, by unscrewing or removing the clamps, causes a prompt return of the blood pressure to normal. The release of the clamp on the main renal artery of only one of two ischemic kidneys is also followed by return of the blood pressure to normal, but it takes longer for the blood pressure to reach the normal than when both clamps are released. This is in keeping with the finding that the clamping of one main renal artery causes only a temporary rise of blood pressure for a varying period. Excision of the ischemic kidney at the height of the hypertension which follows constriction of one main renal artery is also followed by prompt return of the blood pressure to normal. These experiments indicate that if one or two normal kidneys could be transplanted into an animal with hypertension due to renal ischemia, the blood pressure would return to normal because the source of the effective renal substance would be eliminated. Such a study is being carried out at the present time in collaboration with Doctor J. R. Kahn and Doctor W. B. Wartman. Up to the present time the only direct evidence suggestive of the existence of an effective substance has been the demonstration by other investigators of an increased amount of pressor substance in ischemic kidneys as compared with normal ones.
Various experiments that have been carried out on the effect of complete adrenalectomy, with and without supportive and substitution therapy, and the effect of a small remnant of adrenal cortex only on the prevention or maintenance of hypertension due to renal ischemia, indicate that the medulla plays no part, but that the cortex of the adrenal gland may play an important part in the mechanism of development of this type of hypertension
p97
Complete bilateral adrenalectomy, without supportive or substitution therapy, interfered with the development of this type of hypertension. Even with supportive treatment, but without substitution therapy, the animals failed to develop or to maintain hypertension due to renal ischemia. In several bilaterally adrenalectomized animals, however, moderate hypertension did develop when adequate supportive and substitution therapy was given. Because of this and because an amount of cortex close to the minimum requisite for survival and even the absence of both adrenals, if supplemented by the administration of cortical extract, still permitted the development of hypertension due to renal ischemia, the rationale of partial adrenalectomy which has been proposed and practised for the treatment of hypertension is questionable to say the least, except in cases of suprarenal tumor with hypertension in which the improvement results from the removal of the tumor in the adrenal.
The exact way in which the adrenal cortical hormone acts in conjunction with the hypothetical effective renal substance in the development and maintenance of hypertension due to renal ischemia has not been elucidated. Although the cortical hormone is not by itself a vasopressor substance, yet it may prepare the arteriolar musculature for the action of the hypothetical effective renal substance, or the reverse may be the case. The two may even combine before exerting their synergistic effect on the arteriolar musculature or they may act in conjunction with other hormones. These various possibilities are now being investigated.
CONCLUSIONS
Persistent hypertension has been produced in animals (dog and monkey) by constricting the main renal arteries, which reduces the blood flow to the functioning components of the kidneys (renal ischemia).
Hypertension without or with disturbance of renal function, resembling in this respect the benign and malignant types, respectively, in man, can be produced by varying the degree of constriction of the renal arteries.
The results of various experiments indicate that this type of experimental hypertension is due primarily to a humoral and not to a nervous mechanism initiated by the ischemia of the kidneys.
The nature of the effective substance responsible for inducing the hypertension has not yet been elucidated.
The present indication is that the adrenal cortical hormone plays a part in conjunction with the hypothetical effective substance of renal origin in the pathogenesis of hypertension due to constriction of the main renal arteries.

1938 THE FREE AND TOTAL CHOLESTEROL CONTENT OF WHOLE BLOOD AND PLASMA AS RELATED TO EXPERIMENTAL VARIATIONS IN THYROID ACTIVITY 1. H. SCHMIDT AND HETTIE B. HUGHES Endocrinology 22: 474 - 482, 1938
From the Christ Hospital Research Institute and the Department of Biochemistry, College of Medicine, University of incinnati CINCINNATI, OHIO

474
There have been numerous clinical studies of the relation between thyroid activity and blood cholesterol content, the results of which have been widely divergent. The few experimental studies have given similarly conflicting results, hence, further experimental work seems justified in order to define more clearly the relations between thyroid activity and blood cholesterol content, to explain the discrepancies in the existing data, and to obtain a theoretical explanation for the changes

in blood cholesterol which do occur.
The present study concerns the variations in whole blood and plasma cholesterol in experimental hypothyroidism and hyperthyroidism in the dog, Both free and total cholesterol have been measured. The theoretical importance of considering the cholesterol partition is obvious, but this has not heretofore been done in an experimental study.

EXPERIMENTAL
The experiments were arranged to show a) , the normal fluctuations in the free and total cholesterol content of whole blood and plasma of normal dogs during a period of 5 to 6 months; b ), fluctuations in thyroidectomized dogs; c) , fluctuations in normal dogsS made hyperthyroid by ingestion of thyroxine; and d) , fluctuations in thyroidectomized dogs after ingestion of thyroxine. For these purposes 9 dogs were treated in the following manner. Two dogs, No. 1 and 2, served as untreated normal controls during the entire experiment. Dogs 3 and 4 were studied as normal controls for 9 weeks, then thyroidectomized and studied as 'thyroidectomy' controls for the remaining 18 weeks. A third group of 5 dogs, 5 to 9, were studied as normal controls for 4 weeks, then fed varying amounts of thyroxine (Oral Thyroxine, Squibb) for the next 5 weeks. At the end of this period, these dogs were thyroidectomized and studied as thyroidectomy controls for 5 weeks, after which thyroxine was fed for another 4 weeks; the remaining 9 weeks served as a recovery period from thyroxine treatment. The effects of these procedures on body weight are shown in table 1.
These dogs were all mongrels and, with the exception of dog 2, had been raised in our laboratory. Dogs 6 and 7 were litter mates 3 years old; dog 1 was 2 years old; dogs 3, 4, 5, 8, and 9 were litter mates 10 months old. Unless
481
.....
Continued administration of larger amounts of thyroxine intensified the reactions just noted. After ingestion of 2 mg, of thyroxine daily for 2 weeks, the total cholesterol content of the plasma was 7to 22 mg. lower than the lowest amounts previously found ( table 3) .The free cholesterol content also decreased, but the per cent of free cholesterol was unchanged, The total cholesterol content of whole blood was slightly lower than that of the preceding series, but none of the values was significantly less than those obtained prior to thyroidectomy ( table 4) .The per cent of free cholesterol in whole blood was greater than that of any other series; this was due to the small amount of esterified cholesterol contributed by the plasma. The cholesterol content of the corpuscles remained unchanged ( table S) .
In contrast to the normal dogs which had been given thyroxine, the thyroidectomized dogs lost considerable weight following such treatment (table 1) Dogs So treated had a tremendous increase in physical activity, but no apparent increase in appetite.
When thyroxine treatments were discontinued, the plasma hypercholesteremia returned, but this was a very slow process as compared with its original appearance. The first evidence of an increase in plasma cholesterol was obtained in dogs 5, 7 and 9 three weeks after the last thyroxine feeding;
it was 9 weeks, however, before any of the dogs had a plasma cholesterol content equal to that of the pretreatment period ( table 3) .

DISCUSSION
Experimental hyperthyroidism of the severity produced in our dogs was not associated with a hypercholesterolemia. This is in accord with the observations of Simonds and Helpler (7), but does not agree with those of Blinoff ( 8) and Parhon and Derevici ( 9) , Who concluded that ingestion of thyroid gland by normal dogs led to a hypocholesterolemia. This apparent discrepancy is due to the fact that the changes in cholesterol ascribed by Blinoff and Parhon
to thyroid stimulation fall within the limits of normal variation for our dogs.
Epstein and Lande (10), Mason, Hunt and Hurxthal (11) and Hurxthal ( 12) found a hypocholesterolemia in cases of exophthalmic goiter, and concluded that in this disorder the blood cholesterol varies inversely with the B.M.R. Our experimental results, as well as numerous clinical observations ( 13 to 16) , make it seem improbable that there is a definite relation between thyroid activity and blood cholesterol in either experimental or clinical hyperthyroidism. It appears more probable that, when a hypocholesterolemia is found in clinical hyperthyroidism, it is due to prolonged malnutrition ( 17) or to the so-called 'toxic' condition rather than to a specific effect of the thyroid on sterol metabolism. Experimental hypothyroidism in the dog is associated with a hyper

482

cholesterolemia just as is clinical myxedema. The ingestion of thyroxine abolishes this hypercholesterolemia just as it abolishes that of clinical hypo- thyroidism ( 13, 18) .It is readily apparent that these changes in plasma cholesterol are too large to be entirely due to changes in plasma volume. The observations of Thompson ( 19) suggested that a significant portion of hese variations might be due to hemoconcentration and hemodilution, but such was not the case in our experiments ( table 2) .

At the present time there is no satisfactory explanation for the hyper-cholesterolemia associated with hypothyroidism. The increases in blood cholesterol following thyroidectomy, and the subsequent decreases following thyroxine treatment were confined entirely to the plasma, agreeing with the clinical observations of Gardner and Gainsborough ( 13) and Boyd ( 20) . This indicates the improbability of a general increase in tissue cholesterol. The increase in plasma cholesterol may be due to disturbances in the rate at which this substance is synthesized, destroyed or excreted, or it may merely ref!ect the rate at

which transported fatty acids are oxidized or stored. But whereas the latter explanation might account for the increase in esterified cholesterol, it does not explain the simultaneous increase in free cholesterol.

SUMMARY
Experimental hyperthyroidism in dogs does not produce significant changes in the free and total cholesterol content of either whole blood or plasma. Thyroidectomy produces a marked hypercholesterolemia which reaches a peak 4 to 5 weeks after operation, and appears to be confined entirely to the plasma. This hypercholesterolemia is made up of equal increases in the amounts of free and esterified cholesterol, so that there is no significant change in the per cent of plasma cholesterol existing in the free form. Administration of thyroxine to thyroidectomized dogS abolishes this hypercholesterolemia without disturbing the normal ratio of free to total cholesterol; such treatment does not produce a hypocholesterolemia. These observations are in agreement with the clinical findings in cases of myxedema, and they suggest that the hypocholesterolemia sometimes found in clinical hyperthyroidism is du.e to factors other than the increased thyroid activity.

REFERENCES
1. Whippie, G. H., and F. S. Robscheit-Robbins: Am. J. Physiol. 72:395. 1925.
2. Bord, E. M.: ]. Bioi. CheIl1. 114:223. 1936.
3. Bioor, W. R.: ]. Bioi. CheIl1. 24:227. 1916.
4. Yasuda, M.: ]. Bioi. CbeIl1. 92:303. 1931.
5. Bioor, W R.: ]. Bioi. Cbem. 103:699. 1933.
6. Kunde, M. M.: Am. ]. Phrsioi. 82: 195. 1927.
7. Simonds, ]. P., and 0. E. Helpler: ].A.M.A. 98:283. 1932.
8. Biinoff, A.: Compt. rend. Soc. de bioI. 103:188. 1930.
9. Parhon, C. I., and H. Derevici: Compt. rend. Soc. de biol. 107: 388. 1931.
10. Epstein, A. A., and H. Iande. Arch. Int. Med. 30:563. 1922.
11. Mason, R. I., H. Hunt and I. M. Hurxtbai: New England ]. }.;fed. 203:1273. 1930.
12. Hurxthal, I. M.: Arcb. Int. Med. 51:22. 1933.
13. Gardner, ]. B., and H. Gainsborough: Brit. M. ]. 2:935. 1928.
14. Wade, P. A.: Am. ]. M. Sc. 177:790.1929.
15. Hinton, ]. W.: Am. ]. M. Sc. 180:681. 1930.
16. Bonilla, E., and A. Mora: Endokrinologie 9:171. 1931.
17. Man, E. B., and E. F. Gildea: ]. Oin. Investigation 15:203. 1936.
18. Giliigan, D. R., M. C. Volk, D. Davis and H. I. Blumgart: Arch. Int. Med. 54:746,1934. 19. Tbompson, W. A.; ]. Clin. Investigation 2:477. 1925.
20. Bord, E. M., and W. F. Connell: Quart. ]. Med. 5:455.1936.

1944 LOSS OF WEIGHT IN OBESE PATIENTS ON SUB-MAINTENANCE DIETS AND THE EFFECT OF VARIATION IN THE RATIO OF CARBOHYDRATE TO FAT IN THE DIET BY A. B. ANDERSON (From the Biochemical Laboratory, Department of Pathology of the University and Royal Infirmary, Glasgow) Quarterly Journal Medicine, 13:27-36, 1944

p 34
....Discussion
From the results given in the first section, it is clear that the finding by previous workers that, with diets of the same calorific value, the low carbohydrate diets produced the greatest loss of weight, can be explained by a higher salt content in the high- carbohydrate diets. The failure to lose weight rapidly on a high-carbohydrate diet of ordinary salt content is probably due to retention of water and salt in the tissues. Water and salt retention in the obese is a well recognized phenomenon, and has been studied extensively by Newburgh and Johnston (1930), who showed that obese patients, despite a large calorie deficit, might not lose any weight for as long as nine days, and then undergo a rapid loss to the expected level. Newburgh and Johnston found that departures from the predicted weight were always accounted for by storage or loss of water.
That many obese patients show a retention of water in the Volhard water excretion test has been reported by Zondek (1925) and Wohl and Ettelson (1935) ; the latter, in a series of 36 overweight patients, found 19 with some degree of water retention. Rowntree and Brunsting (1933) have described two obese patients with extreme water retention, in whom simple dehydration produced by the administration of ammonium salts and mercurial diuretics was followed by a reduction in weight to practically a normal level.
p 35
Water retention on diets of normal salt content is of practical importance in the treatment of obesity, as patients tend to become discouraged if dieting is not followed by obvious loss of weight. That a normal man who is being underfed may show a similar retention of water to that occurring in the obese has been found by a careful study of the water balance by Wiley and Newburgh (1931).
In considering calorie deficit and weight-loss, it must be remarked that the relationship found in the observations described here holds only for the region covered by the observations, namely a calorie deficit of 500 to 1,300 calories. It is not justifiable to extend the line outside these limits; this would, for example, give no loss of weight with a calorie deficit standing at 273. It can be concluded from the close correlation found within these limits that the various 'types' of obese

patient react in the same way to undernutrition, and that, provided a low-salt diet is being taken, the weight-loss can be approximately predicted.
Summary
(1) In obese subjects on low calorie diets, the greater weight-loss on high fat diets as compared with that on high- carbohydrate diets of equal calorific value was due to the higher salt content of the high-carbohydrate diets, leading to retention of water and salt.

(2) When the salt content of the high-carbohydrate diet was reduced to that of the high-fat diet, the loss of weight was the same on both diets.
(3) In 24 patients of various clinical 'types' of obesity, all on the same low-salt diet of 867 calories, a close correlation was found between the loss of weight and the calorie deficit, obtained by subtracting the calories supplied by the diet from the daily basal requirement found by determination of the basal metabolism.

1945 THE INTEGRATION OF MEDICINE BY F. M. R. WALSHE, M.D., D.Sc., F.R.C.P. (Being an abridgement of the Annual Oration of the Medical Society of London, May, 1945) BMJ MAY 26, 1945 Vol. I p 723 - 727
p723
In the course of discussion upon the future and development of medicine two themes recur with melancholy iteration - namely, that specialism is an evil, and that it is inevitable.

p724
....As has been aptly said, once we seek to go beyond the basic elements of medicine as we know it, we tend to know more and more of less and less. thus it happens that those responsible for the training of our successors too often find themselves imparting unrelated categories of information and partial and often conflicting generalizations culled from different fields of medicine, and it is becoming nobody's business, and seems less and less within anyone's capacity, to teach medicine as a whole, or to build into a coherent body of knowledge the several contributions of the specialists.
It is therefore because ours is a useful rather than a liberal profession that we have been forced to face the situation created by the accumulation around us of more, and more diverse information than we can digest and assimilate. Hughlings Jackson was clearly aware of this, over 50 years ago, when he said that "we have multitudes of facts, but we require, as they accumulate, organizations of them into higher knowledge ; we require generalizations and working hypotheses. The man who puts two old facts into new and more realistic order deserves praise as certainly as does the man who discovers a new one. There is an originality of method." But in this, as in much else, Jackson was before his own time and ours ; ....Nevertheless, by whatever channel this awareness of the disorderly state of our science has reached us, we are at least generally agreed that we cannot indefinitely go on as we are, and that something must be done to bind the broken foundations of modern medicine and to make it something more than a congeries of ingenious techniques and unrelated fragments of knowledge. This, at any rate, however gained, is something gained.
Integration Keeps Pace With Differentiation
The thought that I am trying to develop will be familiar to many of you. It is summed up in the aphorism so familiar to neurophysiologist, "Integration keeps pace with differentiation." This is a fundamental principle in the evolution of the nervous system, and I cite it because I believe it to have a vital meaning for us in my present connexion. We owe its original formulation to the now disregarded genius of Herbert Spencer, from whom it was taken and so fruitfully employed by Hughlings Jackson. Derived anew from this latter source, it became a guiding inspiration in Sherrington's monumental contributions to experimental physiology, and its influence may be seen in the title he gave in his classic work of 1906, The Integrative Action of the Nervous System. Yet it is not so much with integrative action of the nervous system in respect to the organism as a whole that I am now concerned as with the development within that system, as it becomes progressively more differentiated, of structures and functions designed to control and to unify the several parts and to make them into a harmonious whole. In short, integration does, as an observed fact, keep pace with differentiation in the evolution of that system.
....Let us now replace the term "differentiation" by "observation" and the term "integration/" by "interpretation and synthesis." Observation leads to the increase and differentiation of information, while interpretation and synthesis are its integration into ordered knowledge, and I suggest that in the process of scientific thinking interpretation and synthesis must keep pace with observation if a coherent body of knowledge is to be forged. From this we pass easily and naturally to the notion that there is a rhythm in scientific thought, the two elements observation and interpretation alternating.
p725
I sometimes doubt whether one is justified in recording in print a new observation unless one also seeks to indicate what it holds, and to apply the inductive process to it. One should not fling a raw fact on to paper in public, as a keeper flings a chunk of raw meat to a tiger. I believe that in medicine we have a unique advantage in this respect over the purely experimental scientist, in that medicine, while becoming increasingly an experimental, has long been and must continue largely to be an observational science. In its observational aspect it deals with a supremely difficult material under conditions that make constant demands upon intuition and judgement. Nature is not interested in scientific method, and the experiments she provides for us in the guise of disease and injury we have to take as we find them ; we cannot subject them to the necessary but artificial simplification that is the essence of a good experiment. We are therefore forced to think, to synthesize, and to interpret our evidence to a point rarely necessary in the designed laboratory experiment. While, therefore, we must welcome the increasing role of experiment in the study of medicine, we must be on our guard not to be infected by the distrust of ideas characteristic of much experimental work, but continue to use the intellectual assets which experience of

clinical observation gives every good doctor.
p727
In short, what I am proposing is that a humane education is an invaluable asset to any youth embarking upon the study of medicine. I am aware that I raises the banner of a forsaken cause wen I say this ; but nevertheless, twenty-five years of clinical teaching have fully persuaded me that wen I find a clinical clerk who can stand up and read at a ward visit a case history that is a well-ordered, lucid, and fluently expressed account of the patient and his situation, that student will almost invariably be found to have had a sound education, and not a mere course of instruction of the polytechnic order, a utility education.
....Conclusion
What I have had to say is somewhat remote the medicine that presents itself to us in our daily lives. Yet as we grow older the urge to lift our eyes from the details of the little plot in which each of us labours becomes ever stronger, and we are impelled to look round upon the wider field of natural knowledge as a whole. Some may even feel the pull towards some philosophy of knowledge, towards those common truths to which all science must be obedient. Man does not live by facts alone, but craves also for generalizations, and the desire for some philosophy of knowledge burns, if with varying intensity, in all of us. Looked at in this spirit, how untidy and in places how overgrown the field of medicine seems to be ; in other places how bare, how precariously balanced the whole upon the uncertain
p727
foundations of biological knowledge! So it must remain until we develop a wider and deeper consciousness of what constitutes ordered knowledge, and by what cycle of thought it is to be achieved.
Yet to feel some discontent with medicine as we find it does not imply any lack of pride in its achievements, nor any diminished sense of privilege in seeking to serve it. If one is a critic, it is, I trust, in the spirit expressed by Milton when he says, "For he who freely magnifies what hath been nobly done, and fears not to declare as freely what might be done better, gives ye the best covenant of his fidelity."

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

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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.
p 1398
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
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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.

1945 SERUM IODINE IN HYPOTHYROIDISM BEFORE AND DURING THYROID THERAPY BY ALEXANDER W. WINKLER, DOUGLAS S. RIGGS, and EVELYN B. MAN J. Clin. Invest. 24: 732 - 741, 1945 (from the Departments of Internal Medicine and Psychiatry of Yale University, School of Medicine and the Medical Service of New Haven Hospital and Dispensary, New Haven, Connecticut; and the Laboratory of the Fairfield State Hospital, Newtown, Connecticut

(Received for publication March 10, 1946)

p 732
Many investigations have established the value of serum iodine concentration as a quantitative index of thyroid activity (1 to 7). Most previous reports have been concerned primarily with the increase in serum iodine which occurs in hyperthyroidism. The present study deals with the decrease in serum iodine characteristic of untreated hypothyroidism, and with the effect of thyroid therapy on the level of serum iodine of hypothyroid patients.

MATERIAL
Data are presented on 29 patients with spontaneous hypothyroidism and 1 patient (84883) with hypothyroidism following

total thyroidectomy. Most of the patients were ambulatory.
....In order to keep the group as homogeneous as possible, no patients have been included in whom the diagnosis of hypothyroidism was questionable or who developed hypothyroidism following subtotal thyroidectomy. In most of the patients included here the diagnosis of hypothyroidism was confirmed by striking improvement in signs and symptoms after a few weeks of thyroid therapy. In the few patients who remained untreated, or who were inadequately treated, the diagnosis rested on the presence of the clinical manifestations of hypothyroidism. Most of the patients did not present the extreme clinical picture usually described as typical of full-blown classical myxedema. For example, generalized non-pitting edema was extremely rare. While most patients at some time during the course of their disease did exhibit some puffiness of the face, in a few even this slight degree of edema was never observed. It is reasonable to suppose, therefore, that many of the patients probably had small remnants of functional thyroid tissue which prevented them from developing full-blown myxedema.
....Since the amount of iodine in the serum of myxedematous patients is exceedingly small, some discussion of the accuracy of serum iodine determinations is necessary if the results are to be evaluated correctly. When duplicate 6 ml. aliquots of serum have been analyzed, the duplicates have usually checked within 0.5 gamma per cent. If the duplicates differed by more than 0.9 gamma per cent, the analysis was considered unsatisfactory and, if possible, was repeated. It is evident that if the concentration of serum iodine is below normal the possible analytical error represents a large proportion of the determined value. Hence, small differences in the results of determinations on the same patient at different times
p 733
are of no significance, unless such differences are found consistently and repeatedly.
The basal metabolic rates were determined with the Benedict-Roth apparatus under the standard conditions describe by Benedict, DuBois and others.
p 736

DISCUSSION
....Most of the early workers on blood iodine levels in hypothyroidism, employed inadequate analytical techniques and their

results are not considered here. Since the advent of more reliable methods for iodine estimation, a few reports of serum iodine in untreated hypothyroidism have appeared (Table III), but none of these have included any discussion of the effects of thyroid
p 737
therapy on the level of serum iodine. With the exception of Turner and co-workers (15), all of these investigators have found that serum iodine values in untreated hypothyroidism are uniformly subnormal. This conclusion is abundantly confirmed by the series reported here (Table I). The 1 exception (25270) was a patient who had been on thyroid for 17 years and whose treatment was allowed to lapse in order to confirm the original diagnosis of hypothyroidism. After nearly 2 months without thyroid the patient experienced such a marked exacerbation of her symptoms as to necessitate resumption of therapy. At this time, however, the laboratory data were not in good accord with the clinical picture. The basal metabolic rate was only -14 per cent. The bound magnesium was 21 per cent of the serum total magnesium, well within normal limits (16). There was a

slight hypercholesterolemia. In view of these findings it seems possible that the patient, fully aware of the efficacy of thyroid, may have resumed treatment herself a few days before her visit to the clinic. This would explain the normal iodine of 4.3 gamma per cent. An alternative explanation might be contamination of the blood sample with adventitious iodine before or during analysis, since the determination was not on the precipitated proteins. In any event, this single exception does not seriously challenge the conclusion that in untreated hypothyroidism, serum iodine is characteristically subnormal, just as it is characteristically above normal in hyperthyroidism. Failure to find a low serum iodine in a patient suspected of having hypothyroidism strongly suggests that the patient's symptoms are not due to thyroid deficiency.
It should be emphasized that a single subnormal serum iodine value is not diagnostic of hypothyroidism. Equally small concentrations of iodine have been found in the blood of euthyroid subjects who have recently stopped taking large amounts of desiccated thyroid (11), and of hyperthyroid patients following subtotal thyroidectomy (12). By itself, therefore a low serum iodine simply indicates undersecretion by the thyroid gland when the blood sample was collected, and it must be interpreted in the light of the patient's symptoms and previous history.
It has already been suggested that few of the patients reported here were completely devoid of functional thyroid tissue. However in 1 patient (84883) known to have had a total thyroidectomy, serum iodine values not significantly greater than 0 were observed. Furthermore, treatment of hyperthyroid patients with thiouracil or thiourea in amounts sufficient to occasion symptoms of hypothyroidism may lower the concentration of serum precipitable iodine to the vanishing point (18). Total lack of thyroid secretion for a sufficient period of time would therefore appear to imply
p 738
virtual absence of circulating thyroid hormone, and grave doubt is cast on the existence in man of significant extrathyroidal manufacture of thyroid hormone. Of 17 patients in the present series who had been untreated for 1 year or more, 9 had serum iodine concentrations above 1.0 gamma per cent, i.e. significantly greater than 0. The appearance of symptoms of hypothyroidism, therefore, does not necessarily imply complete absence of thyroid function.
The rise in serum iodine to normal levels when hypothyroid patients were treated with adequate doses of desiccated thyroid is in accordance with the well-established fact that relatively small daily doses of thyroid are sufficient to maintain subjects without thyroid tissue in normal thyroid balance. It also agrees with the hypothesis that, baring unusual sources of exogenous iodine, serum iodine is a reliable measure of the concentration of circulating thyroid hormone. Moreover, since the serum iodine level in adequately treated patients with hypothyroidism are no higher than in euthyroid individuals, the circulating hormone derived from substitution therapy with desiccated thyroid must be quantitatively as effective as the hormone produced by the normally active thyroid gland. It seems legitimate to conclude that the maintenance dose of thyroid required by any patient with hypothyroidism is that amount which will restore the serum iodine to normal.
The effect of serum iodine of administration of various amounts of desiccated thyroid has already been noted (Table II and Figure 1). Since the figures for increase in serum iodine per grain of desiccated thyroid were calculated from the difference between 2 iodine values, they were subject to twice the possible error of a single determination. In view of the large possible analytical error, the constancy of the increase in serum iodine per grain of desiccated thyroid is particularly remarkable. In obtaining the average value of 2.0 gamma per cent of iodine per grain of thyroid, the data of patient 25270 were omitted. As stated previously, there was reason to doubt the normal value obtained on this patient when she was supposedly receiving no thyroid.
The amount of hormone supplied by the normally-functioning thyroid gland has usually been considered as equivalent to the maintenance dose of desiccated thyroid for hypothyroid patients. This hypothesis involves 3 assumptions : that all the dried thyroid is absorbed from the alimentary tract ; that it is quantitatively as effective as the natural hormone ; and lastly, that the hypothyroid patient's own gland contributes no hormone. Although complete intestinal absorption has been proved directly, it is strongly suggested b the fact that in the treatment of human hypothyroidism, desiccated thyroid is even more effective than intravenous thyroxine in iodoequivalent amounts (19). The validity of the second assumption has already been discussed. The third assumption is not always justified since a patient with outspoken clinical hypothyroidism may have a serum iodine concentration of 1.0 to 2.0 gamma per cent. However, since each grain of dried thyroid causes an increase in serum iodine averaging 2.0 gamma per cent, a value close to the average normal level. The production of hormone by the normal thyroid gland may therefore be regarded as approximately equivalent, in terms of iodine content, to 3 grains of U.S.P desiccated thyroid.
If each additional grain of thyroid administered to a hypothyroid subject causes a rise in serum iodine of about 2.0 gamma per cent, it is easy to understand why such patients are unable to tolerate more than 3 grains of thyroid daily without developing definite symptoms of thyroid excess such as nervousness, tremor, and tachycardia. If the initial serum iodine of thyroid were 1.3 gamma per cent (the average for this series of patients), and 4 grains of thyroid per day were administered, the serum iodine would presumably rise to about 9.3 gamma per cent, a value distinctly above the normal range. This calculation involves the unproven assumption that the linear relationship between dose and serum iodine would hold for doses greater than 2 grains per day. Nevertheless, the result of the calculation agrees with clinical observation than slight over-doses of thyroid are prone to induce high serum iodine levels and unpleasant symptoms of hyperthyroidism in previously hypothyroid subjects.
The average relationship between serum iodine and basal metabolic rate may be roughly evaluated. The effect of varying thyroid dose on the basal
p 739
metabolic rate in hypothyroidism was analyzed and these workers (20) concluded that, for the range of 0 to 2 grains daily, he true dose-response cure was probably much closer to a straight line than to the curvilinear relationship suggested by other

investigators (21). The former found that the basal metabolism increases about 12 to 16 per cent per grain of desiccated thyroid. Comparison with the slope of the average line of Figure 1 yields a value for the increase in basal metabolic rate of 6 to 8 per cant per gamma per cent increase in serum iodine. The relationship holds only for values obtained after a given dosage had been maintained for several weeks without change. The metabolic rate responds much more slowly to alterations in thyroid status than does the serum iodine. In support of this statement, Figure 2 presents in detail the laboratory data on a hyperthyroid patient who developed hypothyroidism following total thyroidectomy. It is apparent that in this case the decrease in serum iodine following total extirpation of the thyroid gland was out of all proportion to the change in basal metabolism. In several additional cases the
p 740
basal metabolic rate has remained relatively high despite a definitely subnormal concentration of iodine in the blood serum. For example patient A94667, when first seen, had a basal metabolic rate of -34 per cent and a serum iodine of 2.0 gamma per cent. After more than a year of satisfactory treatment with thyroid, medication was discontinued for 251 days. During this time the basal metabolism never fell below -15 per cent, and after the 251 days without treatment was only -6 per cent. Yet serum iodine values of 2.8 gamma per cent and 2.6 gamma per cent were found 77 and 251 days after thyroid therapy was stopped. These values were almost as low as the initial one when the metabolic rate was frankly subnormal. Indeed, in the entire series of patients at the time of the initial iodine determination metabolic rates as low as -30 per cent or lower need not appear unless the patient had remained untreated for several years (Table 1, columns 8 and 9), Yet in at least 3 instances, (A43024, A62475, and A49144) the serum iodine fell to low concentrations when thyroid had been omitted for less than 2 months. Similar dissociation between metabolic rate and blood iodine has been observed after subtotal thyroidectomy (12) and following discontinuance of thyroid medication in euthyroid subjects (17). It is not possible to state from our data exactly how rapidly the serum iodine decreases after thyroid has been stopped but it is clear that the decrease may take place weeks or even months before there is any marked change in the basal metabolism. Whether this lag is due to retention of active hormone in the tissues, or whether the fall in metabolism in dependent on slowly-occurring changes which are secondary to the diminished amount of active hormone in the body, cannot be stated until more is known concerning the mode of action of the thyroid hormone. In any event, it would appear that fluctuation in the level of serum iodine in hypothyroidism corresponds more nearly to the need of thyroid therapy than does the basal metabolic rate.
The previous reports in which some earlier articles were cited have emphasized the constancy of hypercholesterolemia in untreated hypothyroidism (13, 22). In the present series the incidence of normal or subnormal serum cholesterol values, in patients untreated for a reasonably long period of time, as unusually high (24 per cent). Of the 6 patients who did not develop hypercholesterolemia (B12566, 88453, F.S.H. 4774, B55424, B56968, and 73340), 3 were suffering from severe malnutrition, 1 died soon afterwards with advanced hepatic insufficiency, 1 had active pulmonary tuberculosis, and 1 was without obvious complications. Both malnutrition and advanced hepatic insufficiency are known to be associated with depression of the serum cholesterol (23, 23, 25). Hypercholesterolemia is not, therefore, and obligatory accompaniment of hypothyroidism, and, in the presence of nutritional deficiency or advanced liver disease, the serum cholesterol level may be normal or even exceedingly low (733400.

SUMMARY AND CONCLUSIONS
1. In untreated hypothyroidism serum iodine is characteristically subnormal. In many hypothyroid patients, however, it is

significantlyu greater than 0, indicating the presence of functional thyroid tissue in such patients.
2. Desiccated thyroid in amounts sufficient to relieve the symptoms of hypothyroidism causes a return of serum iodine to normal levels.
3. On the average, a 1-grain increase in the daily dose of thyroid administered to hypothyroid subjects occasions an increase in serum iodine of 2.0 gamma per cent. The relationship between serum iodine and thyroid dose appears to be linear within the limits of 0 and 2 grains per day.
4. The basal metabolic rate responds much more slowly to alterations in thyroid status than does the serum iodine.
5. Evidence is presented in support of the hypothesis hat, in terms of iodine content, the daily production of hormone by the normally functioning thyroid gland is roughly equivalent to 3 grains of U.S.P desiccated thyroid.
6. It is concluded that serum iodine is not only a valuable aid in the diagnosis of hypothyroidism but is also a useful criterion of the adequacy of treatment with thyroid substance.

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.

1951 THE EFFECT ON ENDOGENOUS THYROID ACTIVITY OF FEEDING DESICCATED THYROID TO NORMAL HUMAN SUBJECTS* MONTE A. GREER, M.D. BOSTON The New England Journal of Medicine Volume 244 MARCH 15, 1951 Number 11

388
IT HAS been known for many years that a reciprocal relation appears to exist between the levels of circulating thyroxin and thyrotrophin in the vertebrate species so far investigated, Until recently, however, direct tests of thyroid actiyity in man have not been feasible. Within the last few years, radioactive iodine has provided a new method .for the study of thyroid function, permitting observations that would otherwise be impossible.
Using shielded G-M counters, it is possible to follow directly the accumulation of radioiodine in the thyroid gland. Studies in several clinics have indicated that this method is an accurate index of thyroid function.
In view of the widespread therapeutic use of thyroid medication, it was of interest to determine whether the administration of physiologic amounts of the hormone to man would produce the same compensatory depression of the thyroid gland as that observed in laboratory animals. Previous investigators, using other measures of thyroid function, have observed that the thyroid gland is depressed by thyroid feeding. Farquharson and Squiresl found that the administration of moderate doses of desiccated thyroid to apparently euthyroid "hypometabolic" subjects produced no appreciable elevation of the initially low basal metabolic rate. On the contrary, when thyroid medication was stopped, the basal metabolic rate fell rapidly below the pretreatment level and remained depressed for several weeks before gradually rising up the initial level. Riggs and his co- workers2 administered gradually increasing amounts of thyroid up to 20 to 25 gr. dally to euthyroid subjects. It was found that both the basal metabolic rate and the serum-precipitable iodine remained relatively constant until daily doses in excess of 3 to 5 gr. were given, when both. indices of thyroid activity began to rise co-comltantly. When the admmlstratlon of thyroId was abruptly stopped, the basal metabolic rate and serum-precipitable iodine fell abruptly, but transiently, to abnorncally low levels, indicating an inhibition of endogenous hormone production and a delayed return to normal thyroid function.
The present investigation was designed primarily to determine how rapidly depression of the normal human thyroid gland occurs after the institution of daily physiologic doses of thyroid hormone, how much hormone is required daily to produce complete depression of the thyroid and how rapidly recovery of thyroid activity occurs after the cessation of therapy.

MATERIALS AND METHODS

Fortv-seven normal human volunteers, consisting chiefly of laboratory technicians, physicians and nurses, were employed. They were between 17 and 67 years of age, and all but three were women. All were clinically euthyroid so far as could be determined, although basal metabolic rates were obtained in only a few instances. About one fourth of the subjects had taken thyroid previously at one time or another; three had stopped the hormone only a few weeks before beginning the. experiment. Four had been taking 3 or more grams daily for several years, the initial study of all but one of these being made while they were still taking the hormone.

Studies with radioactive iodine were made wIth a modification of the technic devIsed by Astwood and Stanley.3 The isotope with an eight day half-life, I131, was used. Following the admistratlon of a 50-microcurie tracer dose of I13l, serIal counts were made over the thyroid gland by means of an externally placed shieided gamma counter. Since the 24-hour uptake had been found to be as relIable as any index of thyroid function determined by eans of I131 only this measurement was used. The Il31 was obtained from Oak RIdge; the standardization made at that laboratory before shipment was accepted. An amount of radic:active iodine approximating 50 microcuries. was pipetted into a 50-cc. Erlenmeyer flask and diluted wIth 15 to 20 ml. of tap water. The flask was then placed in front of the shielded gamma counter, and the absolute quantity of radioactivity determined. The distance of the flask from the end of the gamma tube was measured by a ruled steel slide, at the edge of the shielding, which was connected to a thin

389

thyroid function, although without clinical evidence of hypothyroidism, was associated with normal levels of circulating thyroxin.
It is interesting that subjects who had been taking desiccated thyroid for several years showed as rapid a return of thyroid function as did those subjects who had been taking the drug only a few days. This strongly indicates that chronic depression

of the thyroid gland produces no permanent injury. One other interesting feature is that a "rebound" phenomenon seems concomitant with the return of the depressed thyroid glands to normal. This was especially evident in the continuously treated subjects,; two had uptakes higher than 50 per cent in the first swing of recovery, which subsequently dropped below this level. Uptakes of from 50 to 75 per cent have been observed in 5 other patients after withdrawal of thyroid hormone, which they had been taking for several years, but these were not included in the present study because only a single determination of their thyroid function was made. This rebound is presumably due to a lag in the adjustment of pituitary thyrotrophin production.

The depressed pituitary may be stimulated to increased secretion of thyrotrophin as the level of circulating thyroxin falls upon cessation of therapy. However, there is perhaps a certain lag before the pituitary again becomes inhibited by increased endogenous thyroid secretion, the thyroid gland thus becoming overstimulated. This same type of delayed readjustment is probably responsible for the fall in basal metabolic rate and serum-precipitable iodine seen after the withdrawal of exogenous thyroid. It is possible that the occasional case of thyrotoxicosis seen to develop upon the withdrawal of thyroid medication from euthyroid patients may be partially explained on this basis.
....

The data presented indicate that the administration of exogenous thyroid hormone results in a corresponding depression of endogenous thyroid function, whatever the mechanism by which this is produced. Since it has been found that the serum- precipitable iodine and the basal metabolic rate do not rise in normal subjects unless thyroid in excess of 3 to 5 grains daily is given, it seems reasonable to assume that astable euthyroid level of circulating thyroxin is maintained by a depression of endogenous hormone formation equivalent to the amount administered. This stable level is probably maintained through pituitary regulation.

The administration of small doses of thyroid to normal patients for the control of obesity, menstrual disturbances, "fatigue" and so forth would thus seem to be without reason or promise of therapeutic effect, since excessive amounts would be required before any elevation of the levels of circulating thyroxin and basal metabolic rate could be produced. The doses commonly administered for these disorders are certainly below what would be considered toxic levels, and the only effect to be expected would be a compensatory depression of endogenous thyroid activity. The disappointing experiences of clinicians in their attempts to treat apparently euthyroid patients for such disorders are thus readily explained. The occasional patient who complains of symptoms of hyperthyroidism while taking only 3 to 4 grains of thyroid daily may represent those persons whose thyroid glands become markedly depressed by the exhibition of 1 gr. or less of hormone daily. Three grains would thus be

390
three times their daily requirements; this might possibly give rise to symptoms of overdosage.
It is of interest to consider the "increased sensitivity" of myxedematous patients to exogenous thyroid hormone. This supposition seems to have existed since the days of the first successful treatment with thyroid extract of patients with Gull's Disease. So far as the author is aware, no evidence has been published that establishes any difference in the tissue susceptibility to thyroid hormone of euthyroid subjects from that of myxedematous subjects.
It is frequently stated that myxedematous patients show signs and symptoms of "toxicity" at lower dosage levels than do those with normal thyroid glands, but adequate data supporting this statement have never been presented. There is no question that small doses of hormone have a much greater effect in raising the basal metabolic rate and relieving the evidences of hypothyroidism in myxedematous than in euthyroid-patients. This is readily explained by the necessity for first equaling endogenous hormone production before any elevation of the basal metabolic rate can be produced in normal subjects. Riggs and his co-workers2 seem to be correct in assuming that the failure of the serum-precipitable iodine to rise until 3 to 5 grains of thyroid were administered daily to normal subjects was due to the necessity of first depressing endogenous thyroid activity. However, they stated that this did not adequately explain the differences between the two groups, since hypothyroid patients became "toxic" on such low doses that they could not obtain data equivalent to that on euthyroid patients who took large doses. They suggested that the thyroid gland in intact patients is capable of "breaking down" thyroid hormone, an explanation that seems unlikely in view of the evidence of Leblond and Sue7 that the thyroid gland is incapable of concentrating organically bound, iodine and that it is only when the element is available as inorganic iodide that accumulation is possible.
Certainly the evidence presented by Riggs2. 8 indicated little difference in the responses of subjects with and without thyroid glands, since the basal metabolic rate increased as much for an equivalent rise in serum-precipitable iodine in normal persons as in those with myxedema.
As gradually increasing doses of thyroid are given to patients with myxedema, there is a progressively diminishing augmentation of the basal metabolic rate as it approaches normal. Thus, 1 grain of thyroid taken daily will produce a much greater increment in the basal metabolic rate of an untreated myxedematous patient with a basal metabolic rate of -30 per cent than it will in a myxedematous patient already being treated with 1 grain daily who has a basal metabolic rate of -10 per cent. If the basal metabolic rate is plotted against the dose of thyroid given in myxedematous patients, a curve is seen that approaches a plateau as the metabolism returns to normal.9 It seens quite possible that if this curve were extended and thyroid given in doses equivalent to the 5 to 25 gr. administered by Riggs to normal subjects, no difference would be found between subjects with and those without thyroid glands. It would be expeeted that much larger doses of thyroid would be required to produce an equivalent rise of the metabolic rate if the subject were near the euthyroid level before treatment was

begun. Such has in fact been found to be the case in investigations of intact subjects. SUMMARY

The effect of exogenous thyroid hormone on the endogenous thyroid function of 47 normal human subjects has been investigated with the use of radio-active iodine. Marked depression of the subject's thyroid gland could be produced within one week by the administration of adequate daily physiologic doses of hormone. The daily amount of hormone required to produce marked thyroid depression was between land 3 grains in 93 per cent of those studied, although one girl required 9 grains. After the withdrawal of therapy, thyroid function returned to normal in most subjects within two weeks, although a few subjects showed depression for six to eleven weeks. Thyroid function returned as rapidly in those subjects whose glands had been depressed by several years of thyroid medication as it did in those whose glands had been depressed for only a few days. Thus no permanent injury to the thyroid gland seems to be produced by long-continued hormone administration. It is felt that the reduction in endogenous thyroid function was brought about through a depression of pituitary thyrotrophin secretion. It is suggested that no important difference in sensitivity to thyroid hormone exists between athyreotic and intact subjects.

REFERENCES

I. Farquharson, R. F., and Squires. A. H. Inhibition of secretion of thyroid gland by continued ingestion of thyroid substance. Tr. Am. Physicians 56:87-97, 1941.
2. Riggs, D. S.. Man, E. B., and Winkier, A. W. Serum iodine of euthyraid subjects treated with desiccated thyroid. j. Clin. lnvestigalion 24:722-731, 1945.

3. Astwood. E. B., and Stanley, M. M. Use of radioactive iodine a study of thyroid function in man. West. j. Surg. 55:625- 639. 1947.
4. Cortell. R., and Rawson, R. W. Effect of thyroxin On response of thyroid gland to thy,otropic hormone. Endocrina/ogy 35:488-498. 1944.

5. Stanley, M. M.. and Astwood, E. B. Response of thyroid gland in normal human subjects to administration of thyrotropin, as shown by Studies with II". Endocrinology 44:49-60. 1949.
6. Stanley, M. M. Direct estimation of rate of thyroid ho,mone formation in man: effect of iodide ion on thyroid iodine utilization. j. C/in Endocrino/. 9:941-954, 1949.

7. Le blond, C. P., and Siie, P. Iodine fluctation in thyroid as influenced by hypophysis and ulher factors. Am. j. Physiol. 134:549-561, 1941.
8. Winkier, A. W., Riggs, D. S., and Man. E. B. Serum iodine in hypothyroidism before and during thyroid therapy. J. Clin. lnvestigalion 24:732-741.1945.
9. Means, ]. H., and Lerman, ]. Symptomatology of my:tedema: its relation to metabolic levels. time intervals and rations of thyroid. Arch. lnt. Med. 55:1-6, 1935.

1955 CONVERSION OF THYROXINE TO 3-5-3'-TRIIODOTHYRONINE IN VIVO ROSALIND PITT-RIVERS, PH.D., JOHN B. STANBURY, M.D. AND BETTY RAPP The Department of Medicine of the Harvard Medical School and the Medical Service of the Massachusetts General Hospital, Boston, Massachusetts Journal Clinical Endocrinology Vol. 15, 1955 p616 - 620

p616
THE principal iodinated compound of the blood is thyroxine (1, 2, 3). In addition, small amounts of triiodothyronine have been found in the blood of clinically euthyroid subjects and of patients with hyperthyroidism (4). Both thyroxine and triiodothyronine have been identified in the normal rat and ox thyroid gland (5). However, it has not been shown whether the triiodothyronine which is present in the peripheral blood is secreted directly by the thyroid gland, or whether it is derived from degradation of previously secreted thyroxine.
The present study demonstrates that triiodothyronine can be formed in the human subject from thyroxine in the absence of the thyroid gland, and confirms in man the finding of Gross and Leblond (6) that "unknown 1" later shown to be triiodothyronine) can be formed in certain peripheral tissues in the thyroidectomized animal.
p619
....COMMENT
Hypothyroid patients were chosen for this study. All but 1 were rendered nearly or completely euthyroid, in order that any possible remaining functioning thyroid tissue would be completely depressed. Further, the patients were treated with pure thyroxine rather than desiccated thyroid, in order to preclude the possibility of exchange between I131 from the labelled thyroxine and I127 from triiodothyronine in desiccated thyroid.
The rise in serum concentration of labeled triiodothyronine cannot be attributed to simple exchange. No stable triiodothyronine was given to these patients. The increase in labeled triiodothyronine in the serum of the patient who received no stable thyroxine was entirely similar to that in the other patients; this suggests that the administered labeled thyroxine did not exchange with triiodothyronine previously formed in vivo from the administered thyroxine.
It may be seen from Table 1 that the amounts of triiodothyronine found in the serum of athyreotic patients are small, and it may well be that considerably greater amounts could have been found in other organs or tissues. In their study on

thyroidectomized mice, Gross and Leblond (6) were unable to detect "unknown 1" (triiodothyronine) in the sera of the animals by autoradiographic methods, although they found detectable amounts in other tissues.
It appears, therefore, that the thyroid gland is not essential for the formation of triiodothyronine, and that some other organ is able to perform the partial deiodination of thyroxine. In this connection the recent experiments of Albright et al. are worthy of comment. These authors have reported that kidney slices in vitro are able to effect this conversion. Roche et al. (10), however, were unable to find triiodothyronine in the rat after injection of labeled thyroxine.
The concentration of labeled iodine in the serum of these patients was remarkably uniform. It is not clear why the slope of the thyroxine decay curve was distinctly less than the variable slopes of the triiodothyronine decay curves. Although the finding does not suggest a simple precursor-product relationship, fluctuations in the serum concentrations of stable thyroxine and triiodothyronine may have occurred and obscured the expected relationship between the slopes of the curves. SUMMARY
Small amounts of triiodothyronine have been detected in the blood of 6 athyreotic humans after administration of I131 labeled thyroxine.

1954 THE INFLUENCE OF THE THYROID IN MALIGNANT DISEASE J. G. C. SPENCER. From the Department of Pathology, Frenchay Hospital, Bristol. BRITISH JOURNAL OF CANCER 8:393-411, 1954 P 393
REGIONAL AND LOCAL DIFFERENCES IN CANCER DEATH RATES.

REFERENCES to the table of incidence of malignant disease in various countries (Table I) tends to confirm the work of earlier workers in the field of the demography of cancer. These figures, recently published by World Health Organisation (1952a), are fully standardised, i.e., corrected for age and sex differences in the population of each country, and so are as comparable one with another as it is possible to make them. All investigations on these lines during the past half century have pointed to the same conclusion : that the incidence of malignant disease is largely conditioned by local factors, and Stocks (1947), after a lifetime of work on this problem, can do no better than quote Hoffman's (1915) statement made 40 years ago, that "the local variations in cancer frequency throughout the world are primarily conditioned by local causes and not by faulty methods of diagnosis or defective methods of death registration."

p 395
....(2) United Kingdom.
Variations of goitre and cancer within the United Kingdom are striking. A recent survey (Stocks, 1950) of the incidence of carcinoma of the stomach in 83 county boroughs over a period of 18 years showed notable differences "which cannot be explained by chance variation or by differing accuracy of certification of cause of death". These variations were shown to correspond to variations in the hardness of the water supply : those with a moderate hardness tended to have
p 396
a lower incidence of cancer than towns with soft or very hard water. The Medical Research Council Goitre Survey of the United Kingdom (Murray, Ryle, Simpson and Wilson, 1948) showed that moderate hardness of drinking water is associated with less goitre than places with either soft or very hard water.
p 397
....Comparing these two maps a striking correlation is at once apparent. Outstanding are the heavy incidences of goitre and cancer in mid-Wales, Westmoreland
p 398
and the Fen district and neighbouring counties, and by contrast the light incidence in Yorkshire, Lincolnshire, Herefordshire and Pembrokeshire. Gradations of correspondence of both maps are evident in comparing Norfolk, Suffolk and Essex ; Kent and Sussex ; Cornwall and Carmarthen.
p 401
....(9) United States of America.
The large goitre belt in the U.S.A. across most of the northern states and running south along much of Pacific Coast (Fig. 6), first came to the public notice during the Great War, when of nearly 12,000 men turned down for military service on account of goitre, some 3,600 were unable to button the military tunic around their necks on account of the size of their goitres (McClendon, 1939). If the forty large towns and cities of the U.S.A. are arranged in descending order
p 402
of their crude death rates for cancer as given by Hoffman (1915) it will be found that eight of the first ten lie in known goitrous areas, and that eight of the last ten (showing the lowest cancer rates) lie in the non-goitrous areas.
p 403
....CLINICAL OBSERVATIONS.
A self evident association between cancer and goitre or impaired thyroid function from the clinical aspect is unlikely to have remained undetected till now.
....There are, however, a number of observations that, while not fully conclusive, may provide pointers sufficiently circumstantial to warrant further clinical investigation on the lines outlined here.
(1) The metabolic rate in man decreases progressively with increasing age, and the incidence of malignant disease increases progressively with age. The incidence of malignnat <as typed> disease thus seems to be correlated with the decrease in metabolic rate. As metabolic rate is in general a rough indication of thyroid activity, there would appear to be some relationship between malignant disease and thyroid dysfunction. Thus, the lowered metabolic rate often seen in diabetes

mellitus (Joslin, 1946) may be considered with the increased liability of diabetics to develop carcinoma in any site or organ as compared with non-diabetics (Joslin, 1946). In the same way the lowered metabolic rate commonly found in patients with all types of peptic ulcers (Kolmer, 1949) may be considered with the incidence of carcinoma of the stomach - still one of the commonest neoplasms of man.
(2) It has long been observed that puberty and pregnancy are periods when goitres may appear (Marine and Lenhart, 1909) ; Marine, 1935), and may disappear when the period of excessive demand ceases or when iodine is given. These are also the periods when melanomata tend to increase in size and may, not infrequently, become malignant.
....Then end of pregnancy is also the period when chorionic carcinoma and lactation carcinoma of the breast occur - perhaps the most rapidly growing class of cancer known.
(3) Administration of thyroid has been found to improve the action of oestrogens in the treatment of carcinoma of the prostate, permitting the effective use of smaller doses of oestrogen and delaying the onset of insensibility to oestrogen (Winsbury White, 1948). In support of this clinical experience a paper in endocrinological research is quoted (Chu and You, 1945), but the final conclusions of these workers was that the simultaneous administration of oestrogen and thyroid was the same as that obtained by thyroid feeding alone.
(4) Reduction of keloid formation can often be brought about by administration of thyroid. A series of such cases is given by Updetraff (1933), all in his
p 404
series showing a low metabolic rate. Although keloids are not neoplasms in the strict sense of the word, they tend to recur after adequate excision, and partly ulcerated keloids are prone to undergo carcinomatous change after a period of time.
(5) Weights of the thyroid of children coming to autopsy between the ages of 6 and 10 were observed in three European towns, and the cancer incidence of those noted (Bayard, 1919).

(6) The iodine content of the thyroid has been shown to reach its maximum in the adult and remains fairly constant until the age of about 50, after which there is a gradual decline (Rundle, 1951). The age for the start of the decline in iodine contant of the thyroid coincides in general with the age at which malignant disease in man becomes a prominent feature.
(7)

....Since January other patients have been seen in the wards of the hospital with coexistent carcinoma and goitre. It is relevant to note that the area from which this hospital draws its material, Gloucester, Somerset and Cornwall, is not one in which goitre is frequent.
(8) The association of goitre and malignant disease in the post-mortem room was strikingly illustrated by analysis of 1000 post mortems at the Middlesex hospital (Stocks, 1924), when anomalies of the thyroid were found in 13.3 per cent of males and 21.2 per cent of females of 500 persons dying of cancer ; whereas only 2.0 per cent of males and 6.5 per cent of females dying of non-cancerous conditions showed anomalies of the thyroid. Professor Barlow excluded from these anomalies secondary invasion of the thyroid by cancer, and the anomalies most frequently found were simple parenchymatous enlargement and adenomatosis, while calcified nodules, cystic changes, atrophy and fibrosis were frequent. The final result of the survey showed that thyroid anomalies occurred in 18.7 per cent of 500 persons dying of cancer and only in 3.9 per cent of 500 persons dying of conditions other than cancer.
....The majority of hypo-functioning thyroid glands are small and virtually impossible to detect on palpation and indistinguishable clinically from normally functioning glands, and it is common clinical experience that moderately enlarged thyroids are easily missed even when they are not retrosternal, especially when no symptoms direct attention to that area of the neck.
p 405
....ANIMAL EXPERIMENTS.
The influence of thyroid activity on malignant growths in animals is demonstrated in the review of experimental work quoted here, in which both administration and deprivation have been used to show its important effect on dependent neoplasms.
(1) The incidence of successful takes of grafts of granulosa cell tumours, luteomas, and tubular adenomas made into the spleen of mice was noted under varying conditions.

(Miller and Gardner, 1950)

Comment.- The presence of excess of thyroxine in the tissues appears to be prejudicial to the successful grafting of tumours from one mouse to another.

p 406
....Comment.- Wheat, yeast and casein are all proteins with moderately high content of tyrosine, thyroxine being derived by stages from tyrosine and iodine, tyrosine deficiency being a recognised cause of hypothyroidism.
....PHYSIOLOGICAL AND PATHOLOGICAL DATA.
Under normal conditions the thyroid is closely associated with (a) Tissue Oxidation, (b) Growth, (c) Development. These three functions are conveniently compared with conditions that exist in malignant neoplasms.

Tissue Oxidation. Thyroid stimulates metabolism by increasing oxygen consumption, probably by catalysing the enzyme systems which are responsible for tissue oxidation processes. Growth Thyroid promotes normal growth under normal physiological conditions.
Development. Thyroid brings about development and differentiation of tissue.

Malignant tissues, in comparison with normal tissues and benign tumours, are characterised not only by having the lowest concentration of Cytochrome C, but also by having the greatest disparity between the old components of the oxidase - cytochrome system.
Malignant tissues also show very low amounts of catalase and of the flavin enzymes and co-enzymes (Greenstein, 1947) Most carcinogenic substances, in particular the potent hydrocarbons but also those of the urethane group, have been shown to have a considerable growth restraining influence (Haddow, 1938).

Histologically, malignant disease tends to show a dedifferentiation or reversion towards anaplastic tissue pattern that is often compared to embryonic or foetal type of cell.
p 408
....Furthermore, the presence of thyroxine in the tissues, as has already been amply demonstrated in the animal experiments detailed above, brings about a tissue environment that is unfavourable to tumour growth and development, at least as long as tumours remain in the dependent phase.

In an attempt to explain how this change in tissue is effective we are left with several possibilities :
(a) That thyroxine encourages normal physiological tissue respiration rather than the so-called anaerobic type which appears to be the one demonstrable biochemical difference between normal and neoplastic tissue (Greenstein, 1947).
(b) That thyroxine in adequate amounts may reverse the process of dedifferentiation or drift towards anaplastic growth that characterises most neoplastic tissue - the more malignant, the more anaplastic - that is, it may bring about the process of differentiation and development that it certainly does promote in the embryonic stages and early years of life.
(c) That thyroxine, by raising the metabolic rate or by maintaining it at a
p 409
proper level, brings about some degree of katabolism and/or an increased rate of excretion of the carcinogen.
(d) That thyroxine brings about some depression of pituitary activity. In this connection, the depolymerisation of connective tissue which seems to be brought about by excess of thyrotropic hormone (Robb-Smith, 1954) is particularly relevant in view of the importance which some attach to changes in connective tissue in the genesis of malignant disease, for thyroid medication is capable of reversing the process and of bringing about polymerisation of the mucopolysaccharides and so a return to a more normal structure of connective tissue.
(e) That the favourable effect of thyroxine in these experiments is due to a combination of some or all of these factors.
At a recent Imperial Cancer Research Fund lecture at the Royal College of Surgeons, Professor Hadfield said : "It is my firm belief that for many years we have been so anxious to discover all we possibly can about the structure of the growth and its metastases that we have almost forgotten the soil in which it grows." (Hadfield, 1954).
In coming to any conclusion regarding the possible association between malignant disease and thyroid function, it cannot be too strongly stressed that a low metabolic rate or an insufficiency of thyroid substance can in no way be considered as a primary cause of cancer. Thyroid and related substances cannot therefore be considered as a cure for cancer. It is, however, suggested that thyroid function (or dysfunction) may be associated with the susceptibility or immunity to cancer. As such, thyroid might well be used as a therapeutic weapon, ancillary only to accepted surgical treatment, much as antiserum is a valuable ancillary in the treatment of tetanus or gas gangrene, but in itself is no substitute for radical surgery in either condition, even though it may rightly be regarded as the factor which takes suitable surgical toilet out of the realm of debatable value to the sphere of accepted success under reasonable conditions.
In the wider and perhaps more important field of preventive medicine, the possibility that an increased susceptibility to cancer occurs in those with a poor thyroid function leads for the first time to a real chance of adopting prophylactic measures against cancer on a wide scale. The measures adopted would be in the main those already available against goitre in the young and in adolescents, with the idea of building up healthy active thyroid glands during their period of development ; and in adult life steps would be taken to maintain a good level of thyroid activity by ensuring that iodine is available in suitable quantities in food and drink, especially when middle life is reached and there is a natural tendency for the iodine level to fall (Rundle, 1951). Only in some such way can an immunity be built up against the many carcinogenic substances which it is virtually impossible to avoid, largely due toe the widespread use of coal and oil. In addition, it must be recalled that there are substances such as cholesterol, vitamin D and the sex hormones and even sunshine itself, which are all part of a normal and healthy existence in spite of their proved capacities to cause cancer, even if they are not finally shown to be the primary causes of the commonly occurring, non-industrial neoplasms that form the bulk of the problem of malignant disease. SUMMARY
Data from fifteen countries in four continents give support to the importance of local factors to account for the known local

variations of cancer incidence.
p 410
Iodine availability, traced by goitre incidence, appears to be one of such factors. Closer scrutiny of some of these countries corroborates these conclusions.
Clinical findings and a review of some of the experimental work available lend further emphasis to these observations. The apparent relationship of thyroid insufficiency and the liability to develop cancer is discussed in connection with such other hormonal influences over cancer as are already known, particularly in respect of the pituitary.
Lines of investigation and clinical trials have been started, but results of any value cannot be expected for several years.
A non-specific organ immunity or susceptibility seems to be the simplest explanation of the facts presented, and the possibilities, preventive and perhaps therapeutic, that are opened up by this line of research are briefly discussed.

1958 ABSTRACTS OF THE 31ST SCIENTIFIC SESSIONS Campbell Moses, Thaddeus S. Danowski, Pittsburgh, Pa., and Herman I. Switkes, Aspinwall, Pa., Circulation, 18:761, 1958
....While maintaining a normal protein-bond iodine level, statistically significant decreases in total cholesterol and b - lipoprotein cholesterols were found in the great majority of subjects. While there was considerable variation in the persistence of the hypocholesterolemic effect, the data indicate that even in subjects euthyroid by the usual indices, a thyroid deficit exerting considerable effect on the cholesterol-lipoprotein partition may be present.

1960 One Factor in Increase of Bronchial Carcinoma Broda O. Barnes, Ph.D., Denver, and Max Ratzenhofer, M.D., Graz, Austria JAMA 174: 2229-2230, 1960
p 2229
IT IS WELL established by clinical studies and by postmortem findings that the incidence of bronchial carcinoma has increased sharply in recent years. Many theories have been advanced to account for this increase. Doll summarized possible etiological factors in 1953 of England, which included atmospheric pollution, after-effects of influenza, and smoking. Burney has recently enlarged on the subjected influance of smoking. The relative merits of any of the theories being discussed in this paper are only to present some data from autopsies during the last 15 years from the Pathological Institution of the University of Graz. About 2,000 autopsies are done each year from the province of Steirmark, population about 1,500,000. All ages and classes of people are represented, and likewise, all diseases.

The data were taken from 26,546 autopsies done from 1944 through 1958. The same increase in lung cancer was found as reported from other areas. In 1944, 22 cases of bronchial carcinoma
were found in 1,820 post mortem examinations, while in 1959 83 cases were found in 2,249 autopsies. The largest number occurred in 1956, when 91 cases were revealed in 2,229 autopsies. The number of bronchial carcinomas for each year is represented in the figure.

During the interval of 15 years, mortality from tuberculosis also showed some remarkable changes. In 1944 the 1,820 autopsies included 236 deaths from tuberculosis, as illustrated by the broken line in the figure. The rapid decrease during the war years was due to death removing the susceptible population as a result of war conditions. A more gradual decrease occurred from 1948 to 1955, probably as a result of improved methods of treatment. Hence, in 1955, out of 1,965 autopsies, tuberculosis caused only 58 deaths. In this same year, for the first time more deaths were recorded from cancer of the lung than from tuberculosis. The same was
p2230
true for succeeding years. This does not necessarily mean, however, that more deaths occur from cancer of the lung than from tuberculosis, as persons with tuberculosis might not be hospitalized and, hence, would not come to autopsy. The figure shows that a great reduction in tuberculosis is occurring in Graz, as elsewhere. Two other important changes took place during the 15-year interval. First of all, the average age of patients who died from tuberculosis was increasing. In 1944 the average age at death was 38 years, while in 1957 it was 54 years. In other words, the tubercular patient was approaching the "cancer age" before death. The second change was the frequent association of tuberculosis with a malignancy. For many years it has been known that malignancies are not common in patients with tuberculosis. In 1946, for the first time, tuberculosis appeared in 7 of 52 patients with bronchial carcinoma. In each year thereafter, the two diseases were associated. Figures are not available for all the years, but in 1948 apparently the peak was reached, when 21% of the patients with bronchiogenic carcinomas had associated tuberculosis. Apparently, as the incidence of tuberculosis decreases, there is less likelihood of the association of the two diseases.
The question immediately arises whether there has been an association of other malignancies with tuberculosis, as the tubercular age rose. Our data did not bear this out. Cancer of the stomach was more frequent than any malignancy over the 15-year period studied. In 1947 only two cases of tuberculosis were found in 68 patients with cancer of the stomach, an occurrence of 3%. During the peak years of tuberculosis, one finds an occasional case of malignancy from various organs, but they are unusual. This is not due to a lack of age in the tubercular group, since several malignancies such as leukemia and cancer of the uterus are frequent at early ages.
If other institutions with a large number of autopsies can confirm out observation, it appears that there are two diseases competing for the same person: tuberculosis at an early age and bronchogenic carcinoma as he grow older. At least three factors seem important in the detection of the association: (1) a high incidence of tuberculosis at a relatively advanced age, (2) a high incidence of bronchogenic carcinoma, and (3) routine autopsy on a large population. It should be expected that countries with a high incidence of tuberculosis would have a low incidence of bronchogenic carcinoma and vie versa, unless

other factors are present.
Our data indicate that a large increase in bronchogenic cancer can be expected as the death rate from tuberculosis decreases. At the turn of the century, the United States had about 200 deaths per 100,000 from tuberculosis. If the same proportion of the population is susceptible to tuberculosis today, and if 20% of this same population is susceptible to bronchogenic carcinoma, then 40 per 100,000 might succumb to lung cancer when tuberculosis is eradicated. This, of course, is conjecture, but it illustrates that a further increase in bronchogenic carcinoma may be expected. In order to make this preliminary report brief and to the point, details of observations on the 868 cases of bronchogenic carcinoma and further discussion will be presented in a later publication.
Summary
A review of 2,546 autopsies revealed 868 cases of bronchogenic carcinoma. Since the advent of chemotherapy, patients with tuberculosis are living long enough to develop cancer. Apparently cancer of the lung is far more prevalent than other malignancies in deaths from tuberculosis. The data suggest that one factor in the increase of bronchogenic carcinoma is that persons who previously would have died from tuberculosis are alive today.
Addendum
After this paper was completed for publication Dr. Alf Westergren found 100 cases of primary pulmonary cancer in which one-third of the patients had an associated pulmonary tuberculosis.
References
1, Doll, R: Bronchial Carcinoma: Incidence and Etiology, Brit. M.J. 2:521-527 (Sept 5) 1953
2. Burney, L. E. Smoking and Lung Cancer. J.A.M.A. 171:1829-1836 (Nov. 28) 1959
3. Westergren, A: One Hundred Cases of Pulmonary Carcinoma, Analyzed with Reference to Tuberculosis, Acta chir. scandinav., supp. 245, pp. 131-141, 1959.

1960 THE DEVELOPMENT OF BRONCHOGENIC CARCINOMA IN PATIENTS WITH PULMONARY TUBERCULOSIS Roger E. Campbell, M.D., and Felix A. Hughes, Jr., M.D., Memphis, Tenn. Journal Thoracic and Cardiovascular Surgery 40:98-101, 1960
p98

THERE has been considerable discussion in the past concerning the simultaneous occurrence of pulmonary tuberculosis and bronchogenic carcinoma. Recent interest in this problem reflects the presumption that the incidence of bronchogenic carcinoma may be higher in patients with pulmonary tuberculosis than in the general population. This led us to review and analyze the 11,000 cases of pulmonary tuberculosis and 650 cases of bronchogenic carcinoma seen at Kennedy Hospital between the years 1947 and 1958.

During this 10-year period, 24 patients with proved pulmonary tuberculosis and bronchogenic carcinoma were seen. Active pulmonary tuberculosis unquestionably existed prior to the onset of the carcinoma in 10 patients, while active pulmonary tuberculosis was present when the carcinoma was discovered in 14 patients. Activity is considered real when two or more positive cultures for acid-fast bacilli are established.

p 100
....Some of the following clinical and radiologic findings should make one suspicious of a possible coexistent neoplasm in tuberculosis patients: (1) if, after a reasonable trial of antituberculosis chemotherapy, there is no improvement of the patient's general and radiologic status, (2) enlargement of the hilar area, especially if unilateral, (3) atalectasis of a lobe or segment of the lung, (4) solitary nodular density, especially if it is in the lower lobes and has a fuzzy border, and (5) cavities with a thick, irregular wall and a poorly visualized, eccentrically placed, radiolucent central area.
SUMMARY
1. A study of case histories of 11,000 patients with tuberculosis and 650 patients with bronchogenic carcinoma was made in an attempt to establish the relative incidence of the coexistence of these two disease processes in the same patient.
2. The findings indicate that this combination of diseases occurs 20 times more frequently in the patient with tuberculosis than in the patient from the general population.
3. The study suggests that this incidence may increase as the age of the tuberculous patient becomes older.
4. All male patients with tuberculosis over the age of 45 should be studied frequently by clinical and radiologic examinations in the quest for location of the malignant lesion, in addition to the infection. Any suspicion should then invoke a complete investigation to prove the existence or nonexistence of the two lesions.

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.

1967 A New Synthetic Thyroid Hormone Combination for Clinical Therapy HERBERT A. SELENKOW, M.D., F.A.C.P., and MARV1N S. WOOL, M.D. Boston, Massachusetts Ann Int Med 67: 90, 1967
90

THYROID HORMONE PREPARATI0NS of animal origin have been used extensively for over three quarters of a century. Their striking metabolic effects in correcting human thyroid insufficiency are well-known to physicians, and their therapeutic use in suppression of goiter as well as in non-thyroidal metabolic disorders is common practice. Less appreciated, however, are the variations in potency and hormonal constitution that may occur among preparations derived from the same or from different animal species or that are a consequence of a particular method of processing (1-9). Widely varying or even impotent preparations of commercially available thyroid (3, 4,6, 10-12) can still conform to U. S. Pharmacopeia (USP) specifications. This results directly from inadequacies in the current method of standardization. In recent years, several large manufacturers of animal thyroid have supplemented chemical standardization with bioassay and have thus improved the quality and uniformity of their product.

In view of pharmaceutical problems associated with desiccated thyroid USP and in view of the ready availability of synthetic l-thyroxine (l- T 4) and l-triiodothyronine (l- T 3)' it seemed logical to develop a combination of these hormones of comparable composition as in thyroglobulin. Such a preparation would have the advantage of containing quantitatively exact amounts of synthetically pure l- T 4 and l- T 3 formulated to simulate the metabolic actions of endogenous thyroid gland secretions (7). This report presents further observations supporting the clinical efficacy of such a synthetic thyroid hormone combination.

METHODS AND MATERIALS
A group of 57 patients with primary myxeedema of various etiologies and 6 patients with pituitary myxedema were treated on an outpatient basis. Their ages varied between 14 and 80 years (mean 47 years). In addition, other treatment groups included patients with nontoxic goiter, normal and goitrous pregnancy, and hyperthyroidism treated with a conlbination of antithyroid drugs and thyroid.
.....
95
.....

DISCUSSION
Problems concerned with variations in the hormonal content of natural thyroid preparations have recently undergone extensive re examination (1-9, 30). Variations in hormonal potency of commercial thyroid preparations due to seasonal and geographic factors, species differences, methods of processing, or other factors have been apparent for some time (4, 8, 9, 3l, 32). Sporadic reports have appeared concerning impotent or weakly potent preparations despite conformance with requirements of the USP (3, 4, 6, 10-12). In addition, there has been considerable controversy as to hormonal stability upon prolonged storage (33-36). Recent reports of analyses of the hormonal contents of various desiccated thyroid and thyroglobulin preparations conforming to the organic iodine requirement of the USP are presented in Table 2. Despite some differences in analytical technique, the marked variations in contents of 1- T 4 and 1- T 3 are readily noted.
The crux of this problem relates directly to the now untenable premise upon which the USP standardization is based; that is, that the hormonal potency of animal thyroid is related directly to its organic iodine content (37). It is now known that approxmately 80 to 85% of the organic iodine of thyroglobulin is c
composed, for the most part, of monoiodotyrosine (MIT) and diiodotyrosine (DIT) and the remaining 15 to 20%, of l- T 4 and l- T 3. Since the former amino acids are calorigenically inert, the total hormonal activity of thyroglobulin is dependent upon the content of l- T 4 and l- T 3. Since 1- T 3 is approximately four times as effective orally as l- T 4 in maintaining euthyroidism, small variations in the quan

96
tity of this potent iodoth)'ronine will account for relatively large changes in hormonal activity. In addition, the serum PBI level on replacement doses of thyroid is dependent upon the quantity of l- T 4 present, since physiologic doses of l- T 3 do not appreciably elevate the serum PBI of athyrotic patients. Recent reports have shown that some hormonally active preparations of animal thyroid (thyroglobulin) contain proportionately less l- T 4 than l- T 3 with
resultant PBI levels disproportionately low compared with the patient's metabolic status (31, 32). In contrast, some clinically inactive preparations of desiccated thyroid conforming to USP specifications have been shown to be almost devoid of l- T 3 (3, 4, 6). The difficulties associated with chemical
standardization of the hormonal content of thyroid preparations have been reviewed (1-8, 30).
Synthetically prepared l- T 4 and l- T 3 have been available commercially for over a decade. Each has achieved widespread acceptance, and both are in daily use throughout the world. Neither alone, however, simulates all the metabolic characteristics of endogenous thyroid gland secretions. l- T 4 has a slow, gradual onset of action, is incompletely absorbed by mouth, and produces levels of serum PBI that are disproportionately elevated compared with metabolic status. On the other handl [- T 3 has a brisk, short-lived action, is well-absorbed by mouth, but fails to raise serum PBI levels in physiologic replacement dosages. It seems logical, therefore, in view of the inadequacies of standardization of animal thyroid, that an appropriate blend of synthetic l- T 4 and l,- T 3 would be desirable. A mixture containing 90% l- T 4 and 10% l- T 3 was suggested by Taylor (38) and has been available in Great Britain. However, this preparation would give disproportionately high levels of serum PBI because of its high l- T 4 content.
During the past 5 years, studies in this laboratory using various blends of l- T 4 and l- T 3 as their monosodium salts have indicated that an appropriate ratio for therapeutic use of these hormones in combination is about 4 to 1 by weight. This mixture contains somewhat more l- T 4 than is present in calorigenically comparable quantities of desiccated porcine thyroid or thyroglobulin (Table 2), probably necessary because of the less complete absorption of l- T 4 than l- T 3 (39). Results of the present investigation confirm and extend previous findings (7) that this particular formulation
[1] simulates the metabolic effects of endogenous thyroid hormone secretion as judged by clinical responses in myxedematous patients, [2] produces levels of serum PBI and other thyroid parameters representative of the patient's metabolic status, and [3] is well-tolerated within a wide therapeutic
dosage range. It is noteworthy that the PBI-response curve (Figure 1) for this synthetic combination differs from that of the lots of desiccated thyroid USP tested in that the slope of the PBI rise of the synthetic mixture is steeper and reaches higher levels than that of the PBI rise with comparable calorigenic doses of the animal preparations. It is not clear at this time whether this results from the slightly higher l- T4 content, from differences in absorption ancl
degradation, or, perhaps, from the finding that the PBI in patients on animal thyroid may result, at least in part, from small, hormonally active peptides of high l- T 3 content (40). It is also possible that some thyroxine in thyroglobulin is deiodinated to l- T 3 before absorption. Further investigation of the phannacology of these homonal products is required before this observation can be clarified. Despite the modest differences in levels of PBI, it was not possible on clinical grounds to differentiate between patients on comparable equal calorigenic doses of the natural or synthetic preparations.

The data presented in Table 3 concerning parameters of thyroid function in pregnant women and their infants at term are 97

They indicate that the concentrations of free thyroid hormones in the maternal and fetal circulations at term are equal as measured by the "free thyroxine index" (17) and by the more Jirect "free thyroxine" (16) obtained by equilibrium dialysis. Despite rather conflicting and contradictory evidence in older
rublications, these results support the concept that the unbound fraction of thyroxine passes freely between the maternal and fetal circulations at term. This finding confirms more recent reports that levels of maternal and fetal "free thyroxine" are equal despite Jistinct differences in protein-bound thyroxine and the thyroxine-binding proteins (27-29). It would thus seem clear that exogenous thyroxine given to women during pregnancy could contribute significantly to fetal thyroxine levels and would thus provide adequate replacement for any inadequacies of fetal thyroid secretion.

As has been emphasized previously, the ultimate determination of clinical "euthyroidism" rests upon the patient's subjective evaluation of "well-being" as well as the physician's experience in making this appraisal. Neither the basal metabolic rate nor the more objective laboratory parameters of thyroid function (PBI, resin- T 3' "free thyroxine") are of sufficient specificity or reliability to be used without reservation to assess the full effectiveness of thyroid hormone therapy. At best, they are useful guides for assisting the physician in determining achievement of clinical eu-thyroidism. The correlations between PB1 levels and thyroid dosage presented in this study must therefore be considered as pharmacologic observations and do not necessarily indicate a direct measure o£ the desired clinical effects. Good judgment must still be exercised in interpreting normal PBI and resin- T 3 values as indicative

of "euthyroidism." However, it can be stated that these thyroid function tests appear to be more consistently indicative of clinical thyroid status with the synthetic ombination than with wynthetic hormones used alone or with some animal thyroid preparqtions. For comparative purposes, averag3e maintenance doages for commonly used thyroid preparations are given in Table 4.

It has been our experience that this syntheetic combination can be used for clinical purposes in the same manner as

comparable dosages of desiccated thyroid. The same precautions concerning its use in the elderly, in patients with adrenocortical insufficiency, and in patients with known or potential cardiovascular diseases apply equally to all thyroid hormone preparations. Undesirable side effects are fortunatly remarkably uncommon with all thyroid preparations used within the prescribed limits of dosage and applied judiciously,. No significant toxicity has been noted with any of the preparations in this study. From numerous studies of synthetic thyroid hormones used separately and from the restults of this report, it seems justified to concluede that the comnbination of the

TABLE 4. Average Dosages of Thyroid Honnone Preparations for Maintenance of Euthyroidism

* PBI = protein-bound iodine. 98

sodium salts of l- T 4 and l- T 3 in a ratio of 4 to 1 by weight is an effective hormonal preparation for clinical usage. It has the advantages of chemical purity, obviating the need for either analytic or biologic standardizations and, in addition, simulates the clinical and metabolic actions of endogenous thyroid gland secretions. It should find a useful place in the treatment of all thyroid disorders requiring hormonal therapy.

SUMMARY
A new combination of synthetic l-thyroxine and l-triiodothyronine has been formulated to simulate the metabolic and biochemical characteristics of natural thyroid gland secretions. This hormonal combination has been used in a large group of patients with hypothyroidism or various other thyroid disorders. It produces metabolic effects indistinguishable from comparable doses of potent preparations of desiccated thyroid, U. S. Pharmacopeia, and has the advantages of not requiring standardization and of producing levels of serum protein-bound iodine and resin-tri-iodothyronine representative of the patient's metabolic status. This preparation can be used advantageously in clinical therapy wherever thyroid hormone replacement is indicated.

REFERENCES
(I have only checked the numbers on the references - not the text.)

1. DEVL1N, W. F., STEPHENSON, N. R.: The chemical determination of liothyronine and thyroxine in enzymic hydrolysates of pork thyroid. I. Pharm. Pharmacol. 14: 597, 1962.
2. WIBERG, G. S., DEVL1N, W. F., STEPHENSON, N. R., CARTER, J. R., BAYNE, A. J.: A comparison of the thyroxine:triiodothyronine content and biological activity of thyroid from various species. Ibid., p. 773.

3. P1LEGG1, V. J., GOLUB, 0. J., LEE, N. D.: Determination of thyroxine and triiodothyronine in commercial preparations of desiccated thyroid and thyroid extract. I. Clin. Endocr. 25: 949, 1965.
4. DEVL1N, "-1. F., ,,-TATANABE, H.: Th)'roxin-tri-iodothyronine concentrations in thyroid powders. I. Pharm. Sci. 55: 390, 1966.

5. LEM1EUX, R., TALMAGE, J. M.: The determinatiO11 of liothyronine and th)'roxine in thyroid preparations. I. Pharm. Pharmacol. 18: 94,1966.
6. KOLOGLU, S., SCHWARTZ, H. L., CARTER, A. C.: Quantitative determination of the thyroxine, triiodolh)'ronine, monoiodotyrosine and di-iodot)'rosine content of desiccated thyroid. Endocrinology 78: 231, 1966.

7. WCOL, M. S., SELENKOW, H. A.: Physiologic combinations of synthetic thyroid hormones in myxedema. Clin. Pharmacol. Ther. 6: 710, 1965.
8. MACGREGOR, A. G.: Why does anybody use thyroid B.P.? Lancet 1: 329, 1961.
9. ST~\SILLI, N. R., KROC, R. L.: Biologic activity of pork and beef thyroid preparations. I. C/in. Endocr. 16: 1595, 1956. 10. CATZ, B., GINSBURG, E., SALENGER, S.: Clinically inactive thyroid U .S.P .A preliminary report. Ncw Eng. I. Med. 266: 136, 1962.

11. "-TILLIAMS, A. D., MEISTER, L., FLORSHEIM, W. H.: Chemical identification of defective thyroid preparations. I. Pharm. Sci. 52: 833, 1963.
12. ,,-TILLIAMS, A. D., MEISTER, L., FA1RCLOTH, M., FLORSHEI~I, \1\1. H.: Significance of phosphorous-nitrogen ratio in U .S.P .thyroid. I. Pharm. Sci. 53: 1415, 1964.

13. ZAK, B., "-'lLLARD, H. H., MYERS, G., BOyLE, A. J .: Chloric acid method for determination of protein bound iodine. Anal. Chem. 24. 1345,1952.

14. SCHOENHEIMER, R., SPERRY, W. M.: Micromethod for the determination of free and combined cholesterol. I. Bioi. Chem. 106: 745, 1934.
15. MITCHELL, M. L., HARDEN, A. B., O.RoURKE, M. E.: The in vitro resin sponge uptake of triiodoth)'ronine 1-131 from serum in thyroid disease and in pregnancy. I. Clin. Endocr. 20: 1474, 1960.

16. STERLING, K., BRENNER, M. A.: Free thyroxine in human serum: simplified measurement with the aid of magnesium precipitation. I. Clin. Invest. 45: 155, 1966.
17. CLARK, F., HORN, D. B.: Assessment of thyroid function by the combined use of the serum protein-bound iodine and resin uptake of 131-1 triiodothyronine. I. Clin. Endocr. 25: 39, 1965.

18. SELENKOW, H. A., ASPER, S. P., JR.: The ef[ec-tiveness of L-triiodothyronine or L-thyroxinc: administered orally in treatment of myx-edema. I. Clin. Endocr. 15: 285, 1955.
19. TAPLEY, D. F.: Pharmacology treatment, in The Thyroid, 2nd ed., edited by WERNER, S. C. Harper & Row, Publishers, New York, 1962, p. 817.

20. SELENKOW, H, A., 1NGBAR, S. H.: Diseases of the thyroid, in Principles of Internal Medicine, edited by HARRISON, T. H., ADAMS, R. D., BENNE1T, 1. L., JR., RESNIK, W. H., THORN, G. W., WINTROBE, M. M. McGraw-Hill BooK Co., New York, 1965, p. 421.

99

WILLljAMfS, R. H., BLAKKE, J. L.: The thyroid, in Textbook of Endocrinology, 3rd ed., edited by WILLIAMIS, R. H. W. B. Saunders Co., Philadelphia, 1962, p. 96.
22. WISWELL, J. G: The diagnosis and treatment of primary and secondary hypothyroidism. in Current Concepts in Hypothyroidism, edited by CRISPELL, K. R. The Macmillan Co., New York, 1963, p. 117.

23. ASTWOOD, E. B.: Thyroid and antithyroid drugs, in The Pharmacological Basis of Therapeutics, 3rd ed., edited by GOODMAN, L. S., GILMAN, A. The Macmillan Co, New York, 1965, p. 1466.
24. SELENKOW, H. A., HOLLANDER, C. S.: Physiologic, pharmacologic and therapeu tic considera tions in surgery for hyperthyroidism. Anes-thesiology 24: 425, 1963.

25. HERBST, A. L., SELENKOW, H. A.: Hyperthyroid-ism during pregnancy. New Eng. J. Med. 273: 627,1965.
26. DANOWSKI, T. S., LIMIAYE, N. R., SUNDER, J. H., COHN, R. E., MOSES, C.: Hydrocortisone and/ or desiccated thyroid in physiologic dosage.
XVII. Major and minor thyroidal indices during therapy with large doses of desic-cated thyroid. Metabolism 14: 950, 1965. 27. CESANO, L., DE MARTINIS, C., DOGLIO, R., LAURO, R., Russo, P.: [Distribution of the thyroid hormone between the maternal and fetal compartments] (Ital.). Boll. Soc. Ital. Biol. SPer. 42: 210, 1966.
28. DENAYER, P-, MALVAUX, P., VAN DEN H. G., BECKERS, C., DEVISSCHER, thyroxine in maternal and cord Clin. Endocr. 26: 233, 1966.
29. MARKS, J. F., HAMLIN, M, ZACK. P.: Neonatal thyroid function. II. Free thyroxine in in fancy. J. Pediat. 68: 559, 1966.
30. SELENKOW, H. A" WOOL, M. S.: Thyroid hor-mones, in Topics in Medicinal Chemistry, edited by RABINOWITZ, J., MYERSON, R. M. John Wiley, Philadelphia, 1967.
31. BRAVERMAN, L. E., INGBAR, S. H.: Anomalous effects of certain preparations of desiccated thyroid on serum protein-bound iodine. New Eng. J. VIed. 270: 439, 1964.
32. LAVIETES, P. H., EpSTEIN, F. H.: Thyroid ther-apy of myxedema: a comparison of various agents with a note on the composition of thyroid secretion in man. Ann. Intern. VIed. 60: 79, 1964.
33. WERMIER, P. L.: Thyroid gland preparations (correspondence). JAMA 166: 401, 1958.
34. HUBATA, J. A.: Thyroid stability demonstrated (correspondence) .I dem. 35. Editorial: Thyroid outdated. Pharm. J. 186: 131, 1961.
36. FRIEND, D. G.: Suggestions for improving drug therapy. Clin. Pharmacal. Ther. 7: 276, 1966.
37. HUNT, R., SEIDELL, A.: Commercial thyroid preparations and suggestions as to the standardization of thyroid. JAMA 51: 1385, 1908.
38. T A YLOR, S.: A new thyroid preparation (letter to the editor). Lancet 1: 341, 1961.
39 ODDIE, T. H., FISHER, D. A., EpPERSON, D.: Effect of exogenous thyroxine on thyroid accumulation and secretion in euthyroid sub-jects. J. Clin. Endacr. 25: 1196, 1965.
40. WYNN, J. 0.: Components of the serum protein-bound iodine following administration of I-131-labelled hog thyroglobulin. J. Clin. Endocr. 21: 1572, 1961.

1973 Thyrotrophin-releasing hormone BMJ 1971;1:62
Work on mechanisms controlling release of thyroid hormones started in the 1930s. By 1955 enough convincing evidence had accumulated for the conclusion to be drawn that the hypothalamus dominated the functions of the anterior pituitary, and that this control was exerted by way of some substances released into the blood stream. In 1970 R. Burgus and his colleagues in Houston reported the isolation of 1 mg of highly purified thyrotrophin-releasing hormone from the brains of 270,000 sheep, and its structure, like that of the porcine hormone, was identified. Although no assay methods for thyrotrophin-releasing hormones are yet available, data on its role in health and disease have accumulated owing to sensitive assays for thyroid-stimulating hormone. Thyrotrophin-releasing hormone has been suggested as a cause of hyperthyroidism

in some patients with clinical Graves's disease, and a recent report from the University of Pennsylvania is of special interest. ....The relative roles of the hypothalamus and pituitary in the genesis of thyroid disease are undergoing a reappraisal. As in so many other fields, the ability to make accurate measurements of small concentrations of active biological substances is a necessity for this type of work to advance. Immunoassay techniques have already shown that most patients with Graves's disease have low serum levels of thyroid-stimulating hormone and raised levels of thyroxin. With special assay methods triiodothyronine (T-3-thyrotoxicosis has been detected. The efforts now being expended in attempts to measure thyrotrophin-releasing hormone in the plasma may open up yet another channel in the elucidation of thyroid disease.

1973 LETTER: Discriminant Value of Thyroid Function Tests J. VESTERDAL JØRGENSEN BMJ 1973, 3, 170
....During the past two years in this laboratory we have used the combination of total thyroxine concentration in serum (T-4) and T-3 uptake (Triosorb) as the screening procedure for dysthyroidism. Besides giving the actual results for each test, the report forms display them as a point in a system of co-ordinates (see figure). The two curved boundary lines in our graph have a location corresponding to the straight lines calculated by Dr. Barnett's group, but our lines represent upper and lower limits for a free thyroxine index calculated as: F.T.I.=(T-3 uptake x T-4) ÷ k.
From table II in the authors' paper it can be seen that linear discriminant analysis of serum protein-bound iodine and T-3 uptake correctly identified 176 patients out of 191. by the free thyroxine index, however, only 168 out of 191 patients were correctly allocated. 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

1973 LETTER: Grades of Hypothyroidism R. L. HIMSWORTH, P. M. FRASER, BMJ 1973, 3, 295
SIR, - We have read the recent article by Dr. D. C. Evered and his colleagues (19 March, p. 657) with great interest. The key group of patients in the series describe was that said by the authors to be suffering from "subclinical hypothyroidism." Most of these patients had circulating antibodies to thyroid tissue and were distinguished from other patients with antibodies solely on the basis of a raised serum thyroid-stimulating hormone (TSH) concentration. Nowhere in their paper do the authors give the absolute upper limit of serum TSH concentration measured by their assay in the normal population. Without this information patients with "subclinical hypothyroidism" cannot, by definition, be categorized. In the discussion reference is made to an earlier paper in which "the range of serum TSH concentrations in normal subjects has been defined." In fact a range is not given in the paper to which reference is made but only the arithmetic mean values for two relatively small groups of men and women. The "95% confidence limits" (sic) for these means are given but they have been calculated on the incorrect assumption that the data are normally distributed. Inspection of fig. 6 of the present paper shows that the authors themselves have ignored the upper calculated confidence limit to which they refer (2.8 lU/ml) and have fixed on one nearer to 4 lU/ml. This latter figure approximates to the highest value (4.2 lU/ml) in a group of 29 normal patients described by the same workers in an earlier publication. As the lower normal values are below the limit of sensitivity of the assay employed and the data are therefore truncated, it is very difficult to predict the true distribution without a very much larger sample. It is possible that if a large population were to be samples values in excess of 4.2 lU/ml would be encountered in some normal subjects.
The authors have therefore not provided a sound basis for their division of patients with autoimmune thyroid disease into those with and those without "subclinical hypothyroidism." furthermore this arbituary division into two groups may serve to conceal a determinant of TSH secretion which is active in some patients. It is apparent from the data in this paper, and from the work of others, that in some euthyroid patients with damage to the thyroid gland the TSH concentration may be abnormally elevated by any criteria. If the plasma concentrations and effects of thyroxine and triiodothyronine are indeed normal in such patients, then the raised TSH must be sustained by a factor operating independently of the physiological negative feedback of the thyroid hormones on the hypothalamus and the pituitary. This factor could be related either to a reduction in the mass of thyroid tissue capable of synthesizing hormone or to something released by the damaged gland.
The classification that Dr. Evered and his colleagues have proposed does not, therefore, seem to us to be either valid or useful. Indeed the use of the term "subclinical hypothyroidism" is inappropriate as the patients, on the evidence presented, are neither subclinical not hypothyroid. - We are, etc.,
R. L. HIMSWORTH, Division of Clinical Investigation, P. M. FRASER, Division of Computing and Statistics, Clinical Research Centre, Harrow, Middlesex
1. Ormston, B. J., Garry, R., Cryer, R. J., Besser, G. M, and Hall, R., Lancet, 1971, 2, 1
2. Hall, R., Amos, J., and Ormston, B. J., British Medical Journal, 1971, 1, 582

1974 Evidence for Circulating Immune Complexes in Thyroid Disease ELIZABETH A. CALDER, W. J. PENHALE, E. W. BARNES, W. J. IRVINE BMJ, 1974, 2, 30-31
p 30
....Introduction

Previous reports (Calder et al., 1973 a, b) have suggested that circulating immune complexes may play a part in the

pathogenesis of certain thyroid diseases. This was based on the finding, firstly, that the lymphoid cell dependent cytotoxic activity of serum from patients with Hashimoto thyroiditis is an IgG antibody localized in both the first and second Sephadex G-200 elution peaks and, secondly, that incubation of lymphoid cells from normal donors with Hashimoto serum rendered them cytotoxic to thyroglobulin-coated target cells. Several methods are currently available for the in vitro detection of circulating immune complexes. One is an anti-complementary assay based on the binding of C1 to circulating immune complexes after heat inactivation of the C1 bound in the blood, with a subsequent back titration of added guinea-pig complement. the method has been used successfully to detect immune complexes in patients with dermatitis herpetiformis (Mowbray et al., 1973).

We here report the use of this test to detect the possible presence of circulating immune complexes in patients with Hashimoto thyroiditis, primary hypothyroidism, and thyrotoxicosis.
p31
....Discussion

The results show that anti-complementary activity is present in the serum of a significant proportion of patients with Hashimoto thyroiditis, primary hypothyroidism, or thyrotoxicosis, the greatest frequency being detected in serum from patients with Hashimoto thyroiditis.
....It is possible that the anti-complementary activity of Hashimoto serum is due to complex formation with other antigens, in particular to thyroid microsomal antigen and the complement-fixing thyroid microsomal antibody.

The difference in frequency of anti-complementary activity in the three clinical groups of thyroid disease indicate that circulating immune complexes of the optimum size for binding complement are more common in the serum of patients with Hashimoto thyroiditis. This could reflect variations in the degree and type of tissue damage occurring in these different disease states resulting in the release of thyroglobulin, its sub-components, or other thyroid antigens.

1974 Scottish Automated Follow-up Register for Thyroid Disease: Four Years' Experience in Glasgow CHARLES MURRAY BOYLE BMJ, 1974, 2, 490-392
P 490
Summary

Four years of experience in Glasgow with an automated follow-up system for thyroid disease developed initially in a low-density population area has confirmed that the approach is a successful, practical, and exportable method of sharing long-term patient management between general practitioners and a hospital specialist clinic.
Introduction

The Scottish Automated Follow-up Register for thyroid disease (SAFUR) has been operating at the Western Infirmary, Glasgow, for four years. The system was developed as a joint venture between general practitioners and hospital thyroid clinics in a low-density and dispersed population area in the North of Scotland for the long-term care of patients who had received radioiodine or surgical or drug therapy for thyrotoxicosis. Computer and laboratory facilities are sited in Aberdeen and are available to other centres in Scotland. When regular follow-up is considered necessary the patient is entered on to the register. at regular intervals (usually yearly) he attends his general practitioner, who is supplied with a kit containing a needle, syringe, and bottle for the collection of blood for protein bound iodine and serum cholesterol estimation and a tick- off clinical index for evaluating metabolic status. The results are processed centrally and sent to the relevant hospital, where a decision is made whether to call the patient to the clinic. Normal results are sent to the practitioner, who in turn communicates with the patient. Some results of the first four years of experience with the system (October 1969 to September 1973) in the urban environment of Glasgow are presented here.

p 491
....Discussion
....A large proportion of doctors (35 out of 436) are unwilling to co-operate, and the most-quoted reason is lack of time. The time taken to take the blood sample and fill out the questionnaire at each patient visit is estimated to be no more than five minutes. On average the practitioner can expect two such visits a year. This figure also holds for those practitioners who are unwilling to co-operate. It is therefore likely that the SAFUR organization is failing to communicate effectively with certain general practitioners and that this problem should be resolved by better explanation, presentation, and advertising of the usefulness of the system in providing a shared management programme.

1974 Plasma TSH and Serum T-4 Levels in Long-term Follow-up of Patients Treated with 131I for Thyrotoxicosis A. D. TOFT, W. J. IRVINE, W. M. HUNTER, J. SETH BMJ, 1974, 3, 152-153
p 152
....Introduction

The incidence of hypothyroidism after 131I treatment of thyrotoxicosis is greatest in the first year (7-22%) and continues at 2-4% a year (Hagen, 1968 ). Toft et al., (1974) found a low serum thyroxine (T-4) level to be a sensitive index of developing hypothyroidism in the early months after radioiodine therapy but it has not yet proved possible, using conventional tests of thyroid function, to predict when or in whom hypothyroidism will occur in later years. This results in the follow-up of large numbers of patients. A high plasma thyrotrophin (TSH) level is considered to be a good index of thyroid failure but it is not uncommon after 131I treatment of thyrotoxicosis and may persist in euthyroid patients for many months (Slingerland et al., 1972; Toft et al., 1973). The present paper reports the clinical and biochemical

p 153

progress over two years of a group of euthyroid patients with high plasma TSH levels and of a group of euthyroid patients with normal plasma TSH levels who were treated with 131I for thyrotoxicosis between 1954 and 1966. On the basis of the plasma TSH level a rational follow-up policy is suggested for the ever-increasing number of patients who are being treated with radioiodine.

....Discussion

The high incidence of hypothyroidism after 131I treatment of thyrotoxicosis necessitates the follow-up of large numbers of patients. In most centres patients are seen frequently in the first post-therapy year, when the incidence of hypothyroidism is highest, and at intervals if six to 12 months thereafter on a lifelong basis or until hypothyroidism develops. Though a low serum T-4 is a good index of impending hypothyroidism in the early months after radioiodine treatment (Toft et al., 1974) it has not proved possible to predict the onset of hypothyroidism in patients treated in earlier years. A low serum T-4 does not have the same significance in such patients as it may persist indefinitely while the euthyroid state is maintained by high or normal levels of circulating triidothyronine (Sterling et al., 1971; Bellabara et al., 19 72). Over half (58%) of the patients treated with 131I treatment for thyrotoxicosis between 1954 and 1966 had high plasma TSH levels in February 1972 when euthyroid. These high levels, considered to be a sensitive index of thyroid failure, remained unchanged over 24 months in most of the patients but hypothyroidism occurred at a rate of 5% a year. On the other hand, no patient in whom a normal plasma TSH level was found in February 1972, six to 18 years after radioiodine treatment, developed hypothyroidism over the same 24-month period.

It is suggested that in long-term follow-up of patients treated with 131I for thyrotoxicosis those with a high plasma TSH level should be examined at yearly intervals as they are at risk of developing hypothyroidism, whereas those with a low plasma TSH level should be seen at intervals of two years or longer.
One possible interpretation of the significantly lower mean serum T-4 levels in the euthyroid patients with high plasma TSH levels compared with the euthyroid patients with normal plasma TSH levels after 131I therapy is that the serum T-4 levels in the former group were suboptimal. Any increase in morbidity, such as ischaemic heart disease, in these patients will become apparent only in future years, and at present no thyroxine replacement therapy has been instituted.

whole letter typed:
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. The reference to these patients in table I of their article as "euthyroid (all criteria except TSH level)" reflects the authors' feeling, also expressed in the discussion of their observations, that the significance of the elevated TSH level is as yet not sufficiently clear.
May I suggest that if, on describing the thyroid state of these patients, one referred to the physiology of the entire thyroid axis these patients could be assigned a definite and clinically more helpful diagnosis - the elevated TSH, the pattern of the thyroid-releasing hormone (TRH) response (in the patients so tested), and the return of the TSH to normal on thyroid substitution are all consistent with the diagnosis of hypothyroidism. Because the choice of a particular diagnostic term tends to determine one's further approach to a given problem, I feel that the use of the term "euthyroid" in relation to these patients, with whatever qualifications, is undesirable.
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. I find "compensated hypothyroidism" actually preferable; it expresses both the thyroid pathology and the mechanism whereby it is corrected, quite possibly only temporarily. By emphasizing the presence of a thyroid abnormality rather than that the effects of this abnormality are, for the present, clinically not recognized (quite possibly for lack of obtaining the relevant information) both the interests of the patient and progress towards an understanding of their condition would be better served.
In a subsequent article by Dr. A. D. Toft and others (20 July, p. 152) 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 LETTER: Tests of Thyroid Function W. J. IRVINE A. D. TOFT BMJ, 1974, 4, 291
SIR, -We were interested to read the paper by Dr. C. W. Havard and Miss Margot Boss (14 September, p. 678) in which it was stated that similar information to that provided by the thyroid-stimulating hormone (TSH) stimulation test may be obtained by the measurement of serum TSH levels before and after the injection of thyrotrophin-releasing hormone (TRH). 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. In our experience, in the investigation of suspected hypothyroidism no additional information is gained by estimating the TSH response to TRH unless to attempt to differentiate between pituitary and hypothalamic hypothyroidism.
In the following issue (21 September, p. 708) Dr. E. G. M. D'Haene and his colleagues did not find as good a correlation between the effective thyroxine ratio (E.T.R.) and the free thyroxine index F.T.I. as previously reported. They did not, however, assess the diagnostic accuracy of either test on the grounds that an objective measurement would be compared with a subjective clinical impression. They therefore have no basis for assuming that the F.T.I. is the better clinical test. In a recent report we could find no difference in diagnostic accuracy between the E.T.R. and the F.T.I. measured in 100 consecutive patients referred to the thyroid clinic. The thyroid status in these patients was determined not only by subjective clinical means but also by other in vivo and in vitro tests of thyroid function such as plasma TSH estimations and radioiodine uptakes with triiodothyronine (T-3) suppression and TSH stimulation if required. ..... We are, etc., W. J. IRVINE A. D. TOFT Department of Endocrinology, Royal Infirmary and University Department of Therapeutics, Edinburgh

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