377 THYROTOXICOSIS The Present Position By J. W. LINNELL, M.D.(Camb.), F.R.C.P.(Lond.) Consulting Physician Metropolitan Hospital; Honorary Consultant, L.C.C. Thyroid Clinic, New End Hospital, Hampstead and RAYMOND GREENE, M.A., D.M.(Oxon.), M.R.C.P.(Lond.) Physician, Metropolitan Hospital and Royal Northern Hospital; Consulting Physician, L.C.C. Thyroid Clinic. New End Hospital, Hampstead One of the authors of this paper is a physician who, for the last 25 years, has been interested in the subject of thyrotoxicosis. Associated for most of this time with thvroid surgeons, his outlook is chiefly that of a clinician. The other is likewise a physician but, being primarily an endocrinologist, his interest has beehi chiefly in the experimental and theoretical aspect. Now working side by side at the L.C.C. Thyroid Clinic on the practical problems which constantly arise and make thyrotoxicosis such a fascinating study, we venture to put forward our views on its present position with the knowledge that we are merely touching the fringe of a vast region, much of which is still unexplored. Aetiology It must be admitted that we are still very ignorant of the causes of thyrotoxicosis. Two lines of enquiry seem to offer hopes of ultimate solution-the one, a combined geological, genetical, statistical and pathological investiga- tion of the relationship between thyrotoxicosis and either pre-existent thyroid abnormality or familial tendency thereto--the older line of in- vestigation with which the name of McCarrison is most prominently linked; the other, a newer psychological and neurological approach, in which prominence is given to psychological disturbances and their possible repercussions on the hypothalamus, ' the conductor,' as Sir Walter Langdon-Brown put it, ' of the endo- crine orchestra,' but also of the autonomic nervous svstem. Geographical and Geological Clues There is no doubt that thyrotoxicosis occurs more commonly in those areas in which simple endemic goitre is most prevalent. In England there was formerly a ' goitre belt ' extending, in rural areas, from Cornwall, north-eastwards through Somerset into Oxfordshire between the Cotswolds and the Chilterns, through Buckinghamshire to Northamptonshire and thence northwards to Derbyshire and up the Pennine Chain (Stocks, 1928). There are off- shoots from Wiltshire to the Isle of Wight, across Herefordshire, into South Wales and across Cheshire into North Wales. The in- cidence of goitre in this area is less obviously excessive than in years gone by, a change which is usually attributed to the improved distribu- tion of fish, with its high iodine content, and to the betterment of the water supply, for con- taminated water is a bad waster of iodine (McCarrison, I928). Other endemic areas have been described. Of these the most im- portant are, in Europe, the Alps; in Asia, the Himalayas and the Punjab plains, where the older Aravalli rocks penetrate the later alluvial deposits; in Africa, the Sudan, Egypt and Sierra Leone; in America, the basins of the Great Lakes and the St. Lawrence; and in Australasia, the mountainous areas of New Zealand. The cause of the goitrousness of these areas is generally admitted to be, at least in part, iodine deficiency. This may be an absolute deficiency in the soil and therefore in the water, or a relative dficiencv due to contamination of group.bmj.com on April 17, 2018 - Published by http://pmj.bmj.com/ Downloaded from
Transcript
377
THYROTOXICOSISThe Present Position
By J. W. LINNELL, M.D.(Camb.), F.R.C.P.(Lond.)Consulting Physician Metropolitan Hospital; Honorary Consultant, L.C.C. Thyroid Clinic, New End Hospital,
Hampstead
and
RAYMOND GREENE, M.A., D.M.(Oxon.), M.R.C.P.(Lond.)Physician, Metropolitan Hospital and Royal Northern Hospital; Consulting Physician, L.C.C. Thyroid Clinic.
New End Hospital, Hampstead
One of the authors of this paper is aphysician who, for the last 25 years, has beeninterested in the subject of thyrotoxicosis.Associated for most of this time with thvroidsurgeons, his outlook is chiefly that of aclinician. The other is likewise a physicianbut, being primarily an endocrinologist, hisinterest has beehi chiefly in the experimentaland theoretical aspect. Now working side byside at the L.C.C. Thyroid Clinic on thepractical problems which constantly arise andmake thyrotoxicosis such a fascinating study,we venture to put forward our views on itspresent position with the knowledge that weare merely touching the fringe of a vast region,much of which is still unexplored.
AetiologyIt must be admitted that we are still very
ignorant of the causes of thyrotoxicosis. Twolines of enquiry seem to offer hopes of ultimatesolution-the one, a combined geological,genetical, statistical and pathological investiga-tion of the relationship between thyrotoxicosisand either pre-existent thyroid abnormality orfamilial tendency thereto--the older line of in-vestigation with which the name of McCarrisonis most prominently linked; the other, a newerpsychological and neurological approach, inwhich prominence is given to psychologicaldisturbances and their possible repercussionson the hypothalamus, ' the conductor,' as SirWalter Langdon-Brown put it, ' of the endo-crine orchestra,' but also of the autonomicnervous svstem.
Geographical and Geological CluesThere is no doubt that thyrotoxicosis occurs
more commonly in those areas in which simpleendemic goitre is most prevalent. In Englandthere was formerly a ' goitre belt ' extending,in rural areas, from Cornwall, north-eastwardsthrough Somerset into Oxfordshire betweenthe Cotswolds and the Chilterns, throughBuckinghamshire to Northamptonshire andthence northwards to Derbyshire and up thePennine Chain (Stocks, 1928). There are off-shoots from Wiltshire to the Isle of Wight,across Herefordshire, into South Wales andacross Cheshire into North Wales. The in-cidence of goitre in this area is less obviouslyexcessive than in years gone by, a change whichis usually attributed to the improved distribu-tion of fish, with its high iodine content, and tothe betterment of the water supply, for con-taminated water is a bad waster of iodine(McCarrison, I928). Other endemic areashave been described. Of these the most im-portant are, in Europe, the Alps; in Asia, theHimalayas and the Punjab plains, where theolder Aravalli rocks penetrate the later alluvialdeposits; in Africa, the Sudan, Egypt andSierra Leone; in America, the basins of theGreat Lakes and the St. Lawrence; and inAustralasia, the mountainous areas of NewZealand.The cause of the goitrousness of these areas
is generally admitted to be, at least in part,iodine deficiency. This may be an absolutedeficiency in the soil and therefore in the water,or a relative dficiencv due to contamination of
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the water, or to the presence in the soil andtherefore in the water of undue quantities offluorine, which is capable of displacing iodineand may possibly thus induce a physiologicaldeficiency (Wilson, I94I). All such cases ofdeficiency may be overcome by so simple afactor as a weekly call to an isolated village by afishmonger's van (Young, quoted by Wilson).
Given, however, the fact that thyrotoxicosisis often superimposed on a simple goitre, weare left with the question of why some simplegoitres become toxic while others do not. Oneof us is intimately acquainted with the for-merly highly goitrous area where Buckingham-shire borders on Northamptonshire and Bed-fordshire, where recent surveys have shown ahigh incidence of fluorosis. Here the deathscertified as due to thyrotoxicosis in the period19I3-19 were only io to 12 per million (com-pared with 22-24 in West and Central Wales)and, in I936, 40 to 50 per million (comparedwith over 0oo in West and Central Wales).Yet a noticeable proportion of the oldervillagers have enormous and obviously harm-less goitres. Though a large proportion ofsimple goitres eventually become toxic, theydo not all do so, a matter to which we shallrefer again later. Moreover, thyrotoxicosismay be ' primary,' arising not upon the soil ofa simple goitre, but of a gland apparentlynormal. Further clues must be sought.
Genetic CluesHowever clear.may appear to be the relation-
ship between iodine deficiency and goitre, theinfluence of heredity must not be neglected.The railways have brought fish to inlandvillages, but they have also shown the in-habitants that there are other pebbles on thebeach, and have reduced in-breeding. Martinand Fisher (I945) have produced strong evi-dence for a single recessive gene favourable tothe development of primary thyrotoxicosis, thedisease actually appearing in those carriers ofthe gene who are subjected to, perhaps, mentalshock, infection, or endocrine imbalance, as atthe menopause. The evidence for a geneticfactor is less clear-cut in nodular toxic goitre,though affected relations are more commonthan in the general population. There is agrowing tendency among clinicians to minimizethe significance of nodules and it may be that
future genetical research will support theessential unity of the two diseases.Another genetic clue may be found in the
fact that the maps of exophthalmic goitre mor-tality produced by McEwen bear a startling re-lationship to the ethnographical maps whichshow stature and pigmentation. The areas withthe highest death rate from thyrotoxicosis arethe areas of greatest ' brunetteness,' the areas,in fact, in which the former British inhabitantsof these islands have become least mixed withlater blond invaders (Roberts, 1938). We haveourselves been impressed by the remarkablenumber of cases of thyrotoxicosis referred toNew End from one small area in South Wales,though we naturally bear in mind the dis-turbing influence on our figures of the diagnos-tic acumen of the local doctor.
Endocrinological CluesThe thyroid gland is under the direct control
of the anterior pituitary gland, which secretesa so-called thyrotrophic or thyrotropic hor-mone. Both words are unfortunately chosen,for the pituitary hormone neither ' nourishes 'nor '.looks towards' the thyroid but stimulatesit into activity and should, with greaterpropriety, be called ' thyrokinetic.' In theabsence of sufficient thyrokinetic hormone (asin experimental animals subjected to hypophy-sectomy and in human beings with Simmonds'disease and other forms of hypopituitarism)the thyroid atrophies and the symptoms ofhypothyroidism appear. Injections of theappropriate pituitary extract restore the thyroidto normal. Injections of this extract into nor-mal animals cause hypertrophy and hyper-activity of the thyroid and many of the symp-toms of thyrotoxicosis, including exophtha[-mos. Indeed according to some observersexophthalmos in more easily produced bypituitary extract in thyroidectomized than inintact animals, and it can be caused even aftersection of the cervical sympathetic chain. Thehistological changes in the thyroid induced bythe injection of pituitary extract are identicalwith those found in Graves' disease. Thesefacts suggest that the symptoms of Graves'disease are due in part to over-stimulation ofthe thyroid by the anterior pituitary. Twodifficulties in the acceptance of this viewoccur. In the first place experimental work
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has shown that animals develop an immunityto thyrokinetic pituitary- extvracts. It does-notfollow, however, that such an immunity woulddevelop in the naturally occurring disease. Inmost of the experiments heterozoic extractswere used and in such circumstances the pro-duction of immunity would be expected.Moreover it must be remembered that theseextracts are artefacts of a protein nature; thenatural stimulant may have a different chemicalcomposition and may even not be a protein atall. The second difficulty which has arisen inthe acceptance of the hypothesis is the factthat undue amounts of thyrokinetic hormonehave not been demonstrated with certainty inthe blood of thyrotoxic patients, a negativeargument which does not invalidate thehypothesis, but does postpone its acceptance.The relationship of the thyroid to the an-
terior pituitary has become clearer throughrecent experiments with 'goitrogenic' sub-stances such as thiouracil. The administrationof such drugs to animals has been shown tointerfere with the synthesis of thyroxine by thethyroid. The drugs are not antidotes tothyroxin, for they do not interfere with theaction of thyroid in the treatment of myxoede-matous patients. The deficiency of thyroxinein the blood- causes an increase in number ofthe basophil cells of the anterior pituitary witha vacuolation exactly similar to that whichoccurs in experimental animals exposed tocold. So great is the increase in number andactivity of the basophil cells that the acidophilcells are almost crowded out. This effect isonly temporary, and may be inhibited by thesimultaneous administration of thyroxine andthiouracil but not of sodium iodide andthiouracil. The last link in the chain of eventsconnecting the pituitary and thyroid glands isthus forged. The thyroid activity is controlledby the secretion of the basophil cells of theanterior pituitarv, which are themselves con-trolled by the level of circulating thyroxine.The thyroid is intimately linked with other
glands than the pituitary. The islets ofLangerhans may be called upon to deal withthe hyperglycaemia which often accompaniesexcessive thyroid activity. The relationshipbetween the thyroid and the gonads is shownby the enlargement of the former so commonin girls 'at puberty and in women during
pregnancy and the premenstrual phase; men-strual function may be affected in both, hyper-thyroidism and hypothyroidism; and in menmyxoedema is often associated with depressionof the sexual function and of the production ofsperm. In the response of the body to cold thethyroid works in partnership with the adrenalmedulla and there is evidence that its activityis in some circumstances inhibited by theadrenal cortex. The function of the thyroidand the parathyroids are complimentary inrespect of calcium and phosphorus metabolism.None of these interrelationships, other thanthat between the thyroid and the anteriorpituitary appear to be of significance in theaetiology of thyrotoxicosis, unless perhaps themany points common to thyroid crisis andadrenal crisis may point to a relationship ofgreater significance than has hitherto beenthought. Nevertheless they are important inexplaining many symptoms which, escapingthe ' classic' list, escape also adequate treat-ment. There is no disorder in which it is morenecessary for a physician to be a holist* ; toremember that the patient is more than thesum of his parts, and that concentration on histhyroid gland will often leave much of hisillness still untreated.
Neuropsychiatric CluesIt is well known that the beginning of thyro-
toxicosis can often be related to mental dis-turbances. ' The worry and fatigues associatedwith the nursing of a near relative through along illness and the silent struggle withfinancial difficulties are frequent factors. Per-haps the most potent forms of mental distur-bances are those associated with the emotions,the unhappy marriage with its continued irrita-tions and inhibitions, the broken engagement,and the fear of undesired pregnancy' (Fraserand Dunhill, I937).
It is through the hypothalamus and theautonomic nervous system under its controlthat emotions find their somatic expression,and it is therefore relevant to ask what cluesthere may be which link it with thyroid over-activity. Many of the symptoms of thyro-toxicosis-those' of autonomic imbalance-may be produced by electrical stimulation ofthe hypothalamic nuclei or mimicked by en-cephalitis in this region of the brain. Experi-
* Holist: One who believes that the whole may be greater than the sum of the individual parts
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mentally thyroxine in excess has been found toproduce toxic changes in the brain stem.Narcotics acting on the hypothalamus havelittle influence on the B.M.R. of normal peopleor on their reaction to insulin or on their bloodcholesterol, whereas in sufferers from Graves'disease the drop in the B.M.R. may be as greatas 50 per cent. and the insulin resistance andblood cholesterol show greater changes (Fenz,quoted by Boon, I938). Such results might bedue to a narcotic effect on hypothalamic centresthought to control thyroxine production or toa reduction of the sensitivity of these centres tothyroxine. It is certainly within the bounds ofprobability that thyroxine acts on the hypo-thalamus as well as on the peripheral nervoussystem. Boon (I938) has suggested that inthyrotoxicosis a hypersensitive hypothalamus,reacting to a normal blood-thvroxine, causes,via the carotid plexus and the pituitary, a stillgreater output of thyroxine, thus initiating avicious circle. On this hypothesis it is easy toexplain both the influence of mental strain ininitiating the disease and the occasional curesproduced in early primary cases by rest,psychiatric methods or thiouracil. It is, onthis hypothesis, improbable that a permanentcure could be produced in long-standing casesby any known means other than thyroidectomy.
SymptomatologyTo discuss in full the symptoms and signs of
thyrotoxicosis hardly comes within the scopeof this paper. They have been described onmany occasions by first-rate authorities, andcomparatively recently an excellent paper deal-ing with the heart in toxic goitre by Papp(I945) was published in this journal. We shfalltherefore content ourselves with drawingattention to the increasing importance which isbeing attached, both in America and thiscountry, to the large group of patients withnodular goitres so little toxic that they areaccounted by the profession in general asnon-toxic. In this country their importancehas been particularly stressed by workers atthe L.C.C. Thyroid Clinic, and in America byseveral well-known workers at different clinics,whose views have been admirably summarizedby Cole, Slaughter and Rossiter (I945). Formany years there has been a. strong belief atthe L.C.C. Thyroid Clinic that not only do
the great majority of all such goitres eventuallybecome toxic but that by the time early middlelife is reached goitre, without some evidence oftoxicity, is comparatively uncommon. Theevidence, however, is, as a rule, only to beobtained through most careful observationsince it may amount to no more than a few ofthe following symptoms and signs; a constantfeeling of lassitude, occasional attacks of pal-pitations, a certain degree of unwantedemotional instability, irritability, and nervous-ness, generally noticed by relatives and friendsrather than by the patient herself, loss ofweight, irregular sweatings and feelings of heat,a slight, sustained increase of the resting or,better, sleeping pulse-rate, a fine tremor of thefingers, moist palms, and the suspicion of astare due to retraction of the upper eyelids.The fact that their onset is generally insidiousand that they are liable to phases of remissionas well as exacerbation does not aid their dis-covery. 'It may well be thought that whensuch a goitre patient is the subject of neuro-circulatory asthenia or an anxiety state, or hasarrived at the climacteric, it must be a matterof the greatest difficulty to tell whether she isthyrotoxic. This cannot be denied, yet'thoughdiagnostic mistakes are bound to occur, theybecome progressively fewer with increasingexperience. When any reasonable doubtexists, help may be found in coming to adecision in the improvement or lack of im-provement resulting from a three weeks' courseof thiouracil judiciously administered. It maybe argued that all that is needed is an estima-tion of the'basal metabolic rate. Unfortunately,the fact of the matter is that the estimation ofthe basal metabolic rate is a highly fallible pro-cedure. Not only is it inaccurate in manyhands, but'even when the value given is a trueone it can give no indication of the level beforethe beginning of the disease. The increase inoxygen consumption represented by a rise' of20 per cent. is significant, but if this rise isfrom -20 per cent. to normal, the significancewill be missed. In the slightly toxic patientwhom we are considering, the rise, which mustin every case be present, may be even less thanthis and its estimation is thus of little value. Inview of a growing belief that all nodulargoitres should be removed without unduedelay, irrespective of their being toxic or not
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on account of their possessing potentialities forevil in several directions, mistakes may proveless harmful in the future than they have donein the past.By the terms of reference imposed on us by
the title of this paper we are precluded fromconsidering possible complications other thanthose which are thyrotoxic in origin. Theseare, however, of sufficient importance. Wehave every reason to believe that it is still farfrom generally known that after acute rheuma-tism, toxic goitre is the most fruitful cause ofauricular fibrillation; that many cases socaused derive from goitres so slightly toxic .thatthey are apt to be looked on as non-toxic ismuch less widely appreciated; that auricularfibrillation can occasionally be the first detect-able sign of toxic change is probably known tofew. Fibrillation caused by thyrotoxicosis isnearly always paroxysmal at first and only laterbecomes established, which is fortunate sinceestablished fibrillation, in the absence of treat-ment of the causal thyrotoxicosis, leads on in-evitably to congestive failure. It is well worthremembering that a slightly toxic nodulargoitre, the presence of which is often un-recognized, can be responsible for, or share inthe development of fibrillation in a patient whois suffering from rheumatic heart disease, orwho is the subject of hypertension. Instead offibrillation, auricular flutter or auricular par-oxysmal tachycardia can be caused by themildly toxic as well as the frankly toxic goitre,but these are, in our experience, rare com-plications.
If we are pressed to supply proof of thetruth of our assertions in regard to the dange'rof goitres generally considered harmless, ourreply is that the proof lies in the dramatic im-provement brought about by subtotal thyroid-ectomy; in literally scores of patients we haveseen not only do all symptoms of ill-health dis-appear, but also auricular fibrillation-- es-pecially if it is still paroxysmal.
TreatmentThere are some patients-in our experience
they constitute a small minority-the subjectsof primary toxic goitre, who will recover eitherwith no treatment at all or with rest andsedatives and the removal of mental stress.Unfortunately, when faced with an individual
patient, one' has no- means o'f knowing if' shebelongs to either of these classes, and, again,there is no doubt that a number df such patientsso ''cured' relapse later under conditions ofstress, during pregnancy or the puerperium,at the menopause, as a result of an infectiveillness, or, occasionally, for no discoverablereason. Previous to the advent of thiouracil itwas considered wise to watch the effects of afew months' rest and sedatives on any patientwith primary toxic goitre, in whom thesymptoms were of recent origin, before goingfurther, but today such a course is probablyseldom'followed. Deep X-ray therapy, onceso strongly advocated, has gradually fallen intodisfavour as being useless in nodular and, atbest, very undependable in primary toxicgoitre. In spite of article after r article byauthorities insisting that iodine does not curebut only brings about a temporary ameliorationof the symptoms and signs of thyrotoxicosis, so,firm is the belief in its'curative'virtues that itis comparatively rare even now to see a thyro-toxic patient for the first time who has notbeen taking it on medical advice for weeks,months, or even years. That it has had, andstill has, an important' ptace in treatment im-mediately before, and possibly 'immediatelyafter, operation, there is no doubt, and its useshould, 'in our opinion, be restricted to thesetwo periods. At the present moment for allpractical purposes choice of treatment liesbetween thiouracil and surgery. 'Thiouracil,which was introduced by Astwood (I943) wasgreeted by the profession in general withalmost unbridled enthusiasm as providing asafe means of cure, some well-known physiciansdeclaring exultantly that thenceforth operationwould be unnecessary save to relieve pressuresymptoms, or for cosmetic reasons. Ere long,however, voices were raised in many quartersboth in America and this country contestingthe extreme claims made for it and insistingthat not' only was there no convincing evidencethat it cured but that'it was by no means en-tirely harmless, since various complications'attended its use in a not unimportant propor-tion of patients treated with it. The list ofpossible complications grew rapidly with'in--creasing experience of the new drug, headache,nausea, vomiting, diarrhoea, -pyrexia, splenicenlargement, various rashes, adenitis, swelling
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of the salivary glands, jaundice, pains in thejoints, purpura, anaemia, leucopenia,'thrombo-cytopenia, agranulocytosis, myxoedema (whichis reversible) and even heart-block beingdescribed by different workers. There is littledoubt now that at first excessive dosage wasthe rule and that many of these complicationswere directly due to this, but judging by re-ports in the current literature, it would seemthat even with the far smaller dosage in usetoday'adverse reactions are to be expected inat least io per cent. of all cases treated. Mostof these are, fortunately, of little importance,but some, for instance agranulocytosis, highfever, severe pains in the joints, jaundice,purpura and severe anaemia, and persistentvomiting, call for a cessation of administrationof the drug. By far the most serious of the.complications is agranulocytosis, which is saidto occur in about 2.5 per cent. of patientstreated' and carries a death-rate of 25-30 percent. Usually, but by no means always, itdevelops in the early weeks of treatment,appears to have little or no relation to dosage,and may come with alarming suddenness. Atfirst it was believed that its approach could bepredicted by means of frequent white bloodcounts, but now it is recognized that this isnot the case since a certain degree of leucopeniais the commonest of findings in patientstreated with thiouracil. It may be said at thispoint that there is general agreement that themortality rate of agranulocytosis can bematerially reduced by the administration ofmassive doses of penicillin, e.g., 500,000 unitsin the day. As regards' results it can now bedefinitely said that good results are to be ex-.pected at first in nearly all cases treated, thesymptoms and signs of thyrotoxicosis generallydiminishing dramatitcally within a few weeksunless the patient has been given a course ofiodine a short time previously, when theeffect of the thiouracil will be much delayed.,A very few patients are, in our experie'nce,completely recalcitrant, and a few improve onlyup to a point and then either remain stationaryor deteriorate. As regards later results,numbers of patients are enabled to resume andmaintain their normal activities as long astreatment is continued. When it is discon-tinued most patients relapse sooner or later,and usually sooner rather than later. Re-
missions, lasting for months, however, arepossible in a considerable proportion of caseswhere treatment is maintained for six or moremonths prior to its discontinuance, and thereis no doubt that in a certain number of patientswhere perhaps in any case a spontaneous curewould have resulted, thyrotoxic symptoms andsigns' have been kept in abeyance till it hasoccurred. It is even possible, should thehypothesis of the vicious circle described in anearlier part of the paper prove true, that anoccasional patient may, by prolonged inducedhypothyroidism, be given an opportunity toescape from the circle; but of this we have sofar seen no evidence.As regards the effect of thiouracil on the size
of the goitre this, in the case of a nodular toxicgoitre, is practically nil; a primary toxic goitremay likewise be unaffected or it may decrease,sometimes to the point of disappearing, or itmay increase, sometimes with alarmingrapidity. Exophthalmos may remain station-ary, decrease or increase. Auricular fibrillationdisappears in a certain number of cases,especially if the treatment be persisted with.As regards the prospect of permanent cure, amatter' to which we have already referred, inspite of the optimism of Meulengracht (I946)and others, the general opinion in expertcircles is that thus far there is no convincingevidence that it occurs. Even the Lancet(1946), a confirmed adherent to thiouracil,considers that it is still too soon to dogmatizeor to speak of a permanent cure. The durationof the treatment necessary to keep a patient inreasonable health is, therefore, unpredictable.Nor is this the whole story, for throughout thecourse the patient must, ideally, keep in closecontact with her doctor, since not only agranu-locytosis, but some other complication mayappear without warning, at any stage, even ifthey usually appear-when they do appear-in the first few weeks of treatment. Especiallyshould she be instructed to cease taking thedrug and report at once to her doctor, shoulda sore throat, fever or a rash develop.So much we believe can be said in all fair-
ness of thiouracil' in treatment, whether withthe idea of cure or of remission -of symptoms..Those who are still enthusiastic-and they aremany-should, we think, read the report tothe Council on Pharmacy and Chemistry made
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by Van Winkle Jr. and his associates (I946),before making up their minds finally about it.It is the- result of a survey of no less than5,745 patients treated with thiouracil forvarious periods, and its conclusion is that onthe basis of the available information it canonly be recommended for use in pre-operativetreatment and where operation is contra-indicated. To this conclusion we had our-selves come before the publication of this re-port. Not only had we had in mind thedanger of complications, the uncertainty whichprevails as to the length of treatment necessaryand the improbability of cure, but the expenseand tedium it causes the patient and the worryand anxiety the doctor, especially if the patientbe careless or ignorant. Finally we had beeninfluenced by the fact that a number ofpatients come to us not only with auricularfibrillation but congestive failure, that thentime is often of supreme importance, andthiouracil too slow and uncertain in its action.Thus, in spite of our being physicians, it hadnot been long before we were convinced thatsurgery still held pride, of place in the treat-ment of thyrotoxicosis. That thiouracil hadan important place, too, we did not doubt, butgenerally speaking, only in preparation forsafer operation, and not as a method of cure.As a matter of fact there is no need for its usein the preparation of the large majority ofthyrotoxic patients, iodine being quite sufficient,but there are a considerable number of patientsso toxic that they cannot be renderedsufficiently safe for operation by iodine andfor whom operation by stages-a burden onpatient and surgeon alike-would have beenaccounted necessary a short time ago; now,however, by the judicious use of thiouracil thelarge majority of them can achieve such adegree of pre-operative improvement that theycan be operated on with little danger. In thisconnection it is well to remember that its effecton the gland substance is to make it extremelyvascular and friable so that the operationbecomes most difficult and trying unless iodineis given during the last two or three weeks todevascularize it to some extent. It is also ourexperience that thiouracil causes adhesions toform between the capsule of the gland andthe surrounding tissues. In view of thesefacts, contrary to the practice that obtains in
many of the well-known American Clinics, wetend more and more to discontinue thiouracilonce the gross thyrotoxic symptoms are con-trolled, switch over to iodine for a fortnight orso, and then operate. Thus far we have hadno reason to regret our adoption of thisprocedure.Coming more closely to the important sub-
ject of surgery, the best results can, in ouropinion, only be obtained through teamwork.What is needed is a surgeon who is not only atechnical expert as regards the operation buthas made as deep a study of thyrotoxicosis asthe physician' with whom he should beassociated. It is almost unnecessary to say thatthe latter in addition to being an experiencedgeneral physician should be a competentcardiologist. The anaesthetist too plays a veryimportant role, for there is no operation insurgery for which there is greater need' ofspecial experience on the part of the an-aesthetist than subtotal thyroidectomy. Theth'eatre staff should be' specially trained andthe ward nurses not only qualified to deal withthe many difficulties and octasional dangerswhich may almost suddenly arise before and'after operation, but possess sympathy and con-sideration of a high degree and have the abilityto inspire their charges with all possible con-fidence. When the margin of safety is oftennarrow, the smallest detail may make thedifference between life and death. The com-mon belief among surgeons that any com-petent general surgeon without special trainingin thyroid surgery is technically fit to performan operation in which a small, but still im-portant, proportion of cases presents greatdifficulties to the expert, we think ill-founded.That without special knowledge of the subjectof toxic goitre and cardiology, he should con-sider himself competent to take medical, aswell as surgical, charge of the patient beforeand after operation, we cannot allow. It is, webelieve, the occasional thyroid surgeon who ischiefly responsible for the ill repute which isstill attached to the operation. Apart from thetragically high mortality rate which oftenattends his well-meant efforts, such undesirableresults as insufficient removal of. gland tissue,severance of one or both laryngeal nerves, orchronic tetany are too common. -Nor is helikely to realize the immense. importance a
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woman, even if she be of an age at which onewould think that appearances* matter little,attaches to the cosmetic effect. Over and overagain it has been our lot to be accusedby general practitioners of encouragingmassacre ' when we have publicly advocated
surgery. This attitude is understandable. Ananalysis of the Registrar General's returns for1936 shows that of the deaths from thyro-toxicosis i(1 the whole of England and Wales,over i6 per cent. were operative deaths, andwe have no reason to believe that it has greatlyfallen since. This figure assumes that alldeath certificates issued mentioned operationas a contributory cause. It is probable thatdoctors did not always mention it if they con-sidered that death took place despite and notbecause of surgery. Our attitude is that agood method of treatment ought never to bedamned for a lack of skill on the part of thosewho use it, provided always that there areample opportunities for such a state of affairsto be remedied. And these there are inabundance. We fully appreciate the fact thatthere are far too many thyrotoxic patients inthe country for more than a fraction of them tobe treated at existing goitre clinics, but, asLinnell, Keynes and Piercy (1946) haverecently suggested, teams can easily be built upat most hospitals of standing on the lines wehave indicated by surgeons who have madethemselves competent to do thyroid surgery bywatching experts and studying the manyaspects of the disease. There should be, andwe believe, need be no second-best in thvroidsurgery. And in good hands there is no moresatisfactory operation in the whole realm ofsurgery, the vast majority of patients beingable to live approximately normal lives thence-forward. There must be occasionally cases ofregrowth of the gland with a recurrence of toxicsymptoms but, generally speaking, not only isthe tumour removed once and for all, togetherwith the anxiety its mere presence so oftencauses, but with it the danger of such com-plications as pressure, haemorrhage into itssubstance and carcinomatous change. In the*great majority of patients thyrotoxic symptomsdisappear rapidly, to recur no more; the riskof the onset of auricular fibrillation is practicallyabolished; where it is present there is a good
prospect of a quick return to normal rhythm,either as a direct result of the operation or ofthe administration of quinidine. Where it stillpersists the ventricular rate can almost alwaysbe satisfactorily controlled by digitalis and-amost important point, especially today-con-valescence is relatively brief. As regards mor-tality, this is at the present time in the regionof i per cent. in practically all the well-kno\wnclinics of the world, and this in spite of patientsof all ages, of every degree of thyrotoxicosis,with and without auricular fibrillation, withand without congestive failure on admission tohospital, being accepted as candidates foroperation. With the judicious use of thiouracilin the preparation of very toxic cases this mor-tality rate should fall still further, though it isunreasonable to suppose that it will ever reacha vanishing point; toxic crises can occasionallyfollow operation, and not every patient mori-bund through he-art failure can be saved by it.It has been said that so great is the risk ofoperation in elderly patients with auricularfibrillation that it should not be attempted.This is not our experience. The patient who'frightens us is the frightened girl.
We are not suggesting that by any method oftreatment the patient is always completelycured, even though her hyperthyroidism maybe perfectly controlled. One cannot make' asilk purse out of a sow's ear, and the thyro-toxic patient is often, from the beginning,' poor stuff '. Moreover, in preventing, whetherby medical or by surgical means, the excessiveproduction of thyroid hormone, we are leavinglargely unaffected the cause of this excess. Thepsychological maladjustment or autonomic im-balance remain.
We cannot leave the subject of treatmentwithout calling attention to the fact thatrecently a new remedy has been tried out inAmerica with, apparently, considerable success.Hertz and Roberts (1946) and Chapman andEvans (1946) have published reports on theeffects of freshly prepared radio-active iodineadministered orally in a number of cases oftoxic goitre. One dose of the liquid, which ispractically tasteless, has in several patientsproved sufficient to effect a ' cure.' It is im-possible for us to express any opinion whatever
384 August I1947
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Augusf 1947 LINNELL AND GREENE: Thyrotoxicosis 385
regarding the value of the treatment, since wehave had no experience of it, but if the claimsof these workers are corroborated, in the near
future it may take the place of surgery to aconsiderable extent and oust thiouracil fromthe place it now occupies. -
BIBLIOGRAPHY
ASTWOOD, E. B. (I943), 7. Amer. MedL Ass., 122, 78.BOON, A. A. (I938), Acta Psychiat. et Neturolog., Supp. I8.CHAPMAN, E. M., and EVANS, R. D. (1946), 3. Amer. Med. Ass.,
131, 2, 86.COLE, W. H., SLAUGHTER, D. O., and ROSSITER, L. J.
(1945), 7. Amer. Med. Ass., 127, 883.FRASER, F. R., and DUNHILL, T. (Ig37), 'Brit. Enryclop. of
Med. Pract.' London.HERTZ, S., and ROBERTS, A. (1946), 3. Amer. Med. Ass., 13r,
2, 8i.LANCET, I946, ii, 207.LINNELL, J. W., KEYNES, G., and PIERCY, J. E. (I946),
B.M.J., ii, 449.
McCARRISON, R. (I928), 'The Simple Goitres,' London.McEWEN, P. (1938), B.M.J., i, 1037.MEULENGRACHT, E., KJERULF-JENSEN, KAI SCHMITH.
Paper read at 2oth Scandinavian Congress for InternalMedicine, Gotenberg, Sweden, June 27-29, 1946, as sum-marized in Lancet, 1946, ii, 207.
PAPP, C. (I945), Post-grad. Med. J., 21. 45-ROBERTS, J. A. F. (1938), B.M.J., i, 1174.STOCKS, P. (1928), Quart. J. Med., 2I, 223.VAN WINKLE JR., W., et al. (1946), .A.M.A., 130, 343.WILSON, D. C. (I94I), Lancet, 1, 2I1.
CORRESPONDENCE
THE DOCTOR AND THE NURSESIR,
I have read with interest your Editorial for theJuly number of the Journal. My personal ex-perience of surgeons does not incline me to agreewith your observations as to their meekness, or toaccept as realistic your account of the conversationbetween sister and surgeon which you allege is adaily occurrence. Be that as it may, you havecertainly raised an extremely important practicalpoint in regard to the training of the student nurse,viz., the failure on the part of the vast majority ofdoctors on a hospital staff to realize their obligationsin this vital matter. Medical men in general, andsurgeons in particular have been accustomed formany years to a privileged position, in virtue ofwhich they receive the slavish attention of theirvarious technical assistants in ward or theatre, tosay nothing of the adulation of a public brought upin the tradition of the sacrosanctity of the MedicalProfession. They have accepted this, like so manvof the privileged classes, as an inalienable right, andat the same time (again like so many of the privilegedclasses), they have failed to shoulder the responsi-bilities upon which alone the title to privilege shouldrest.There are other points in your Editorial which
give opportunity for discussion, but I hesitate totrespass upon your valuable space. The duty ofthe doctors in playing their part in the youngnurses' education is one of primary importance andyou, Sir, do well to call attention to it. I hope thatothers may be stimulated to contribute to thiscorrespondence and to make some effort to jolt theHonorary Members of Hospital Staffs out of theirattitude of complacent self-satisfaction.
I enclose my card, and remain, Sir,Yours faithfully,
ATHANASIUS, M.D.
THE NURSE AND THE DOCTORSIR,
I have been given a copy of your Journal so thatI may read the Editorial: as I work in the theatreI wonder if you would be interested in my views.I agree that it is most unsatisfactory when changesare made in the theatre staff during a ' list ', butthe nurse usually regrets this more than the surgeon,and we, of course, obey sister's orders. I think itis true that sister usually has our best interests atheart and cannot afford to have us going sick, thatis why she avoids any individual overworking ifpossible. But sisters like surgeons have their likesand dislikes.As regards the medical staff teaching the nurses,
I couldn't agree more. We always enjoyed lecturesfrom the doctors and one distinguished surgeonwho used to visit us was more than popular. It isinteresting, too, that he was one of those whodidn't ignore us in the wards, even in our proba-tionary days and always had time to give a reasonfor his demands.
Finally, whilst agreeing that the nurses' curri-culum needs improving I have long wanted to makean addition to the doctor's education. Just as webenefit from the doctors' teaching I think that theywould benefit from ours. Every time a newlyqualified house surgeon appears for the first timein the theatre or wards, I am amazed at his (or her)ignorance of the ordinary routine of hospitalpractice. Could not something be done to remedythis ?
Yours,'S.R.N.'
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