No. 1761.

MAY 30, 1857.

Troonian Lectures,DELIVERED BEFORE THE ROYAL COLLEGE OF

PHYSICIANS, 1857,

BY G. OWEN REES, M.D., F.R.S.,PHYSICIAN TO, AND LECTURER ON THE PRACTICE OF MEDICINE AT,

GUY’S HOSPITAL.

LECTURE III.

Diatheses: Uric, Oxalic, Saccharine. Diabetic Sugar NOT thesame as the Sugar produced in the Liver in Health. Theories.

MR. PRESIDENT,—I am now desirous of making a few remarkson the subject of diathesis as connected with what have beencalled by way of distinction, "urinary diseases."

It should be remembered that the urine can only be regardedas an indicator of the general state of system, when we have itas it is secreted from the kidneys, and that any changes whichmay be effected in it after it is secreted, are more or less theresults of local actions occurring in the tubes and receptaclesthrough which it has to pass before it is evacuated by the ure-thra. It is not too much to say that this point has been sadlyoverlooked. We find searcely any notice taken of it, exceptin diseases characterized by the escape of large quantities ofvery obvious substances from the bladder as the result of severeor long continued irritation. Now it is of paramount import-ance to determine the nature of the changes occurring after thesecreted urine is received into the channels destined to conductit out of the system, before the question of diathesis can besatisfactorily considered. The consequence of our havingneglected this part of the subject is that we have become fixedin error, and habituated to the use of a jargon having little orno meaning in its application to disease. Every abnormal con-stituent discovered either as a deposit or in solution in theurine has been eagerly caught at as the index of some generalcondition or diathesis, and urinary pathology has been workedup into a state of confusion indicating in itself that some graveerror has lain at the root of the system. It is especially withrespect to deposits that this dire confusion has prevailed, and Iwould now wish to attempt the simplification of the subject,by reverting to views which I have at different times promul-gated, but have not until now ventured to put in any very de-cided form.In the lectures I had the honour to deliver last year in

this theatre, I made the statement, that, were it not for theuric acid diathesis, urinary calculus would be as rare a diseaseas tetanus, and I traced the existence of oxalate of lime and ofthe earthy phosphates in the urine, or as constituents of calculi,to changes effected after secretion. I showed how urine con-

taining the urates was convertible, out of the body (by the ap-plication of an increased temperature), into urine containing adeposit of oxalate of lime, and I adduced facts and argumentsshowing that the presence either of uric acid or the oxalateof lime in the urinary canals would lead to inflammationof the mucous surfaces and the consequent effusion of an alka-line fluid, and that this would cause a precipitation of the earthyphosphates. All these evils were regarded as dependant, sofar as the secreted urine was concerned, on the presence of an excessive quantity of uric acid or of an urate in the blood, andtherefore on the uric diathesis, notwithstanding that the urine,as evacuated, and after passing over the mucous surfaces, mightdeposit oxalate of lime or earthy phosphates. The oxalic andthe phosphatic diatheses were ignored, the uric acid diathesisbeing the only one recognised.

It is obvious that if the above be true, an entirely new viewof treatment must be taken. The kidney, in fact, must beregarded as always secreting an acid urine, unless irigesta(in the form of food or medicine) be given to change its cha-racter...

An utter neglect of the pathology of the urinary mucousmembran’J has led to all the perplexity in which the questionof phosphatic disease has become involved. The experiment Imade in the case of a patient with deficient anterior abdominalparietes, as detailed in former lectures, showed how easily thesecreted urine had its acidity neutralized, as it flowed from theureter over an inflamed mucous surface. The crucial experi-ment also detailed, of causing a patient who was passing alka-line urine, to pass urine of acid reaction, by administering alka-lies, is, again, quite conclusive as to the mucous surfaces beingin fault, and as to their possessing the power of changing acidurine to alkalinity when in an inflamed state. Let us followthis change, and describe the therapeutical action of alkalinetreatment. We will suppose we have (as I have often had) apatient afliicted with the uric acid diathesis. He tells you hishistory : how he passed red sand in quantity, and perhaps asmall calculus escaped from his kidney and found its waythrough the urethra. This state of things, after a time, he maysay, changed. He began occasionally to pass alkaline urineand the phosphates. Sometimes during the same day he willtell you he has passed both red sand and the phosphates. Oldsufferers have more than once brought me specimens of suchdeposits. He may tell you his urine next became. almost con-stantly alkaline : that acids in every form were administered,in order to obviate this, but that he has gone on from bad toworse. The bladder you will find is now involved, and if hehave no calculus there, it is not the fault of those who haveprescribed acid treatment.Now here we have a man passing an alkaline urine; there is

phosphatic deposit, and two views may be taken of his casethe one, that long disease has caused the phosphatic diathesisto appear, and that the urine is secreted alkaline by the kidney;the other view being, that the uric acid diathesis is still pre-sent, and that the mucous surfaces have become inflamed, andare neutralizing, by their secretion, every drop of urine, andthus the phosphates are precipitated. According to the firstview, an acid plan of treatment might be beneficial; accordingto the second, alkalies are indicated. ,

Let us put the case to proof. We give small doses of citrateof potash. These are to be carefully administered, and as thecase improves, the dose is to be lessened. During this treat-ment, the urine still continues alkaline, but the earthy phos-phates appear in less quantity. They are gradually being heldin solution by the bi-carbonate of potash which exists in theurine, owing to the destruction of the citrate in the system.The urine is now secreted of alkaline reaction, and the inflamedmucous surfaces being no longer irritated by an acid fluid, gra-dually recover themselves, and eventually cease to pour outtheir alkaline liquor, and we obtain from the urethra thehealthy and acid secretion of the kidney. There is no conceiv-able theory bearing reference to the phosphatic diathesis ofProut and his followers which can explain this result.The existence of an uric acid diathesis is a matter now proved

- that is to say, we have satisfactorily established the presenceof a state of system in which uric acid and its combinationsappear in the blood in abnormal quantity. This, which waslong matter of belief, has been clearly demonstrated by the ex-periments of Dr. Garrod; and to the presence of uric acid inthe blood I believe we may trace nearly all the evils to whichcalculous subjects are liable, for those constitutents of urinarycalculi and of urinary deposits, which do not admit of beingtraced up to its presence, are extremely rare-viz., cystine,silica, uric oxide, &c. Regarding diathesis as expressive of a.power or force predisposing the organism to some especial formof disease, I propose next to consider a state of urine which hasbeen considered indicative of a diathesis, but which, I believe,bears no relation whatever to an especial disease, but is pro-duced by many. In every case, however, it has reference toone and the same action taking place in the organism-viz.,emaciation. Writers have described the excretion of an excessof urea as an urinary disease, as an affection not necessarilyconnected with any organ or organs of the body, but havingreference to a peculiar state of system not of necessity engraftedon any organic affection capable of detection by physical exami-nation or by symptomatology. According to this view, in fact,the urine containing an excess of urea is the disease, and thetherapeutical considerations are to follow without further in-

quiry. Such has been the practice in these cases, and thepatient has had the gratification of knowing he suffers fromazoturia, or excess of nitrogenous matter in the urine. Withthis he of course connects no idea whatever, nor is it desirablehe should; but the misfortune is, that the profession have hadquite as little acquaintance with the subject as the patients,which is also not very desirable.

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It is now some years since I first had my attention directed of symptoms favouring the position I have taken. They speakto these cases. By degrees I learned how extremely rare this of pains of a severe character in various parts of the body, anddiseased’state of urine was in anything like an excessive form. these are in many instances accompanied by other indicationsThe cases I saw, it is true, yielded an urine of high specific highly suggestive of important latent disease.gravity, and very rich in urea; and I found a state of debility When speaking on the subject of diathesis, I cannot refrainwhich might or might not be removed by remedies, and in the from introducing some remarks having reference to the subjectone case that the urine improved, and in the other it did not. so ably treated in the Gulstonian Lectures of this season. The

Lengthened observation showed me, that many of these cases old classification placing diabetes amongst urinary diseases hasdid badly; symptoms of grave disease occurring, and phthisis so completely held sway np to the present time, that the sub-or other organic mischief showing itself at the close. ject of the saccharine diathesis naturally suggests itself in

It naturally occurred to me, under these circumstances, to this place. Those who have studied the works of Prout will

suspect that this azoturia was nothing more than a symptom, be familiar with the idea that chemist connected with the termnot of any especial form of disease, nor of any diathesis, but "saccharine diathesis," and cannot fail to observe how com-of a condition common to many diseases. When emaciation pletely all the opinions he advanced regarding it, appear sub-occurs, then, from any cause whatever, we may expect to find verted by the interesting discoveries of M. Bernard. From thethis azoturia present. The advantage of detecting it is great, moment those discoveries were published, our views, of neces-if it be regarded in its proper bearings; but if it be looked sity, underwent a change, and however far we may be evenupon as a disease in itself, the practitioner had better far be now from a full and correct interpretation of the phenomena ofwithout the discriminating power on which he may pride hi’n- saccharine diabetes, we still feel perfect confidence that weself, inasmuch as, content with his discovery, he may cease to have made a step in advance.inquire into the case as he would do were his attention less It is not my intention to enter upon the etiology of diabetesfixed on the urine, mellitus further than to remind you that the views of M. Ber.

It has several times happened, that I have seen patients who nard, ably enuncia-ted by your Gulstonian lecturer, have shownwere described as suffering from azoturia. The urine has been that the liver, contributing, as it does, to the formation of sugarobserved carefully, the quantity passed during twenty-four in the normal state of the organism, may be regarded, underhours, and the specific gravity, noted daily, and tne cause of certain diseased conditions, as the producer of the diabeticthe disease considered to consist in the prevalence of a peculiar state. That in point of fact, according to Bernard, we havediathesis. The patients have presented all the peculiarities not now to determine how a substance, foreign to the healthywhich systematic writers describe as indicative of this drain on constitution of the blood, becomes engendered in the system,the system. On inquiring into such cases, however, I have but merely to inquire into the causes producing, on the onenearly always been able to discover some more or less localised hand, an over-activity in the sugar-forming action of the liver,disease to which all the symptoms might be traced-some dis- or, on the other, the diminution of the destructive power ap-ease attended with emaciation, and therefore, as a consequerce, parently possessed by the blood in health over that sugarproductive of the highly-animalised urine. It is not very long when it has mingled with the circulating fluid.ago that the symptom of azoturia so engrossed the attention of Now all this is clear enough, were the sugar secreted by thean examiner of the urine, and so entirely connected itself in liver, and that produced by injuring the base of the fourth ven-his mind with a peculiar diathesis, that advanced, and eventu- tricle, identical with that existing in the urine of true dia-ally fatal phthisis was entirely overlooked. This occurred in betes. This, however, is not the case, and we are not, there-the case of a gentleman, pursuing professional avocations with fore, so nearly about to unravel the difficulty as we might atgreat zeal, and who, observing his muscular power gradually first be inclined to believe.on the decrease, became anxious as to his condition. The urine About two years ago I took the opportunity of obtainingwas examined, and declared to indicate azoturia; unfortu- blood from the hepatic veins of a dog, in order to determine the;nately, that discovery was considered, as it has been constantly presence of sugar; for, like many others, I was at first a littleconsidered, and is still considered, sufficient guide to treatment. incredulous. By the assistance of my friend, Mr. Hilton, thisIn consequence of this, physical examination of the great cavi- was effected without much difficulty.ties of the body had, I found, never been carefully made. On examining the blood obtained in this way, I found, it isHere, then, the indications of phthisis, so important to detect true, that it yielded me sugar ; but there was a peculiarity inat an early period of the disease, altogether escaped notice. the reaction of the tests, which led me to suspect I was notAs consumption advanced, the azoturia became aggravated, dealing with the same sugar as that contained in the urine ofand I was eventually called in merely to condemn the case as diabetes. It was quite impossible for me at the time to under-hopeless. take a chemical investigation of the subject, and I was notThe emaciation sometimes occurring during chronic disease sufficiently satisfied with my results to venture on publication.

of the brain, is also attended with this discharge of an addi- Some months ago I mentioned my suspicions to my friend, Dr.tional quantity of solid matter; and if the state of the urine Pavy, who has thrown much light on this interesting subject,distract attention from the true seat of disease, great mischief and he told me that the same doubt had occurred to him somemay be done, as the remedies in vogue for the relief of azoturia time since, and he immediately showed me from his note-books-viz.., opiates and other narcotics, are such as often greatly that he had worked the question out very satisfactorily, thoughaggravate the cerebral affection. In certain neuralgic cases he had not published on the point. Having Dr. Pavy’s permis-also, this urine indicative of wasting is met with. Here, how- sion to do so, I will now detail the results of his inv estigations.ever, the error does not lead to much evil; the patient may be It appears that the principal point of difference between thesetreated according to the rules prescribed for azoturia with ad- sugars consists in the greater facility possessed by the hepaticvantage, and if the neuralgia (as is very likely) be relieved by sugar, and by the sugar of artificial diabetes, of undergoing de-opiates, the theory of diathesis, perhaps, may be considered struction by contact with animal tissue. This has been shownsupported by the results obtained, and the neuralgia thought by an experiment made on the sugar of artificia.l diabetes, com-to have depended on azoturia. I saw a case of this kind paring the result with that obtained by similarly treating grapelately, which is now going on well enough, under the treat- sugar and true diabetic sugar. The experiments were con-ment which was adopted in order to remove the tendency to a ducted as follows:- Three vessels were taken. In the first, alarge excretion of urea. The neuralgia and the azoturia will, quantity of pounded liver, obtained from a healthy dog, wasI fear, however, in this case, eventually be shown to have de- placed with a solution of the urine of artificial diabetes; thepended on some obscure internal disease, which physical exa- specific gravity of the solution was 1045. In the second vesselmination is at present unable to detect. was placed pounded liver with a solution of common grapeWhen examining the specific gravity of urine, I would cau- sugar, of specific gravity 1040. In the third was placed

tion observers not to conclude that healthy urine is never pounded liver with t solution of extract of true diabetic urine,passed much above the specific gravity of 1022, and that any- of specific gravity 1040. The pounded liver was used (as anything above 1026 or 7 must necessarily be regarded with sns- other animal matter might have been) merely to induce changespicion. Nearly all healthy men pass, at some period of the in the elements of these saccharine principles by its presence.day, an urine above the highest point just mentioned, and very The three mixtures were now set aside for nine days. At theoften, shortly after a full meal, the specific gravity rises to end of that time, on submitting them to examination by Barres.1030 and 32. This, too, will occur in persons of great mental will’s solution, it was found that the artificial diabetic sugarand physical activity, and when in the enjoyment of the highest had entirely disappeared, while the reactions were obtained in.health. all their completeness from the two other solutions. Experi-

I must not omit to direct attention to the cases which have ments made with the same solutions, substituting blood forbeen quoted at different times as illustrative of azoturia. They I pounded liver, led to the same results, showing a power of reoall, as far as I have been able to discover, contain a narration sisting decomposition on the part of grape sugar and true dia-

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betic sugar, far exceeding that existing in sugar obtained bythe production of diabetes artificially.

Thare seems little doubt that the sugar of diabetes is a higherquality of the principle, and that it can preserve its atomicarrangement with far greater force than the hepatic variety. IA power, however, seems to reside in the blood, which after80me length of time eventually destroys, not only hepatic sugarand that of diabetes artificially produced, but even that of truediabetes mellitus. Thus Dr. Pavy’s experiments show that ifthe blood taken from a diabetic be allowed to coagulate, andthe serum then be separated from the crassamentum, we candetect scarcely any evidence from the latter after a very longexposure. In the serum, however, it can be detected in quan-tity till decomposition is thoroughly set in. For some con- Isiderable time both crassamentum and serum give full evidence,however, which contrasts strongly with the reaction of bloodtaken fresh from the right ventricle in health, and which con-tains hepatic sugar, for here the sugar disappears almost imme-diately the separation into serum and clot is completed. It isalmost certain that when we produce the artificial diabeticstate by operation, we obtain in the urine the hepatic sugar ofthe liver. It is also proved that this sugar of artificial diabetesis not the same as the sugar of true diabetes.Now, of course, were these sugars identical, we might con-sider true saccharine diabetes as a disease in which the sugar-forming property of the liver became abnormally active; or, onthe other hand, a disease in which normal sugar was formed inthe liver in usual quantity, but that the blood had lost thepower of destroying it when so formed, and that it thereforeappeared in the urine.The results I have detailed place us, however, in a very

different position. We know now that true diabetic sugar isdestructible only with great difficulty, and that it is not thesame as ordinary hepatic sugar. The question will then arise-Are we to regard the sugar of diabetic urine as a modificationof that poured into the blood by the hepatic veins in health,or, on the other hand, as a product of disease bearing no rela-tion whatever to the sugar of the liver ?To those who have studied the subject of sugar in its chemical

relations, who are acquainted with its varieties and the facilitywith which these are convertible into each other by the mostsimple processes, there will be no difficulty in believing thatthe sugar of diabetes may be easily derived from that producedin the liver in health. Late experimenters oa the sugars ob-tained from the vegetable kingdom have shown how easilytransmutations are thus effected, and chemical properties de-veloped or abstracted by simple contact with materials’ appa-rently possessing anything but chemical activity. No one canfail to be struck,, fox instance, with the curious fact, that thesugar contained in fruits possesses a certain action on light,influencing polarization, which action is precisely reversed inthe sugar obtained 5y o’MtZcttM, from the very same source.Thus, the gummy kind of sugar obtained from grapes possessesthe property of lift-handed circular polarization; but if weallow this sugar to lie exposed, a kind of imperfect crystalliza-tion occurs throughout the mass; and if we collect the granularcrystals so formed, we find we have in these a sugar differingmaterially from that originally extracted from the fruit. Itschemical constitution is not the same. Its constitution is

012 HJ4 O14, instead of 012 HJ2 0,,; and when examinedoptically, it is found to possess the property of right-handedcircular polarization. The change appears to be effected hereby some constituent of the vegetable juice exercising its influ-ence as crystallization goes on-probably the acids play an im-portant part. Now, the liver, owing to some diseased action,may be supposed, in diabetes, to produce a-,sugar differing fromthat of health-a sugar which cannot be destroyed by thechanges taking place naturally in the blood-changes rapidlyaffecting and destroying healthy hepatic sugar.The phenomena of diabetes mellitus are, then, not quite sosimple as the experiments and discoveries of Bernard would atà first view make them appear; and we have yet to determinethe causes in action for the formation of this abnormal sugar.Does the presence of a different ferment interfere -even as weobserve catalysis productive of varying results out of the body-may not an analogous action be going on in the liver ? and,if so, what may be the nature of the ferment productive of dis-ease, and whence is it derived ? Are we to look to the portalblood for the ferment, or controlling influence which forms thisless destructible suar ? And is it owing to this diseased stateof blood that the liver, even though unaffected, is unable tocause the changes occurring in health ’!But we iieel not have recourse to the theory -of a ferment.

The portal bloocl may present such principles to the liver as

are only convertible into the true diabetic sugar. So far aswe can yet determine, then, the whole phenomena of diabeticdisease may eventually be traced to an abnormal state of thebile, gastric juice, and pancreatic secretion, any one or all ofwhich may interfere with the formation of healthy products inthe portal blood, and so overpower a healthy liver in the dis-charge of its office. Analogy would certainly, however, ratherdirect us to conclude that in diabetes the function of the liverbecomes altered under the influence of some cause as yet un-known. Bernard has proved that the organ in health has avery strong transformative action on grape sugar; and so

powerful is this, that we should almost be entitled to conclude,even in the event of the portal blood bringing diabetic sngar,ready prepared, into the hepatic circulation, that it Would bemetamorphosed by the liver into normal hepatic sugar beforeit could reach the cava through the hepatic veins.

These results, then, taken together, render it probable thatwe are to look for the cause of diabetes mellitus in a disturbedstate of the hepatic function, not in an increase of naturalaction, but in an action varying in kind. We see that in healththe liver would reduce proximate animal principles to a normalhepatic sugar, and in the perversion of force occurring in dia-betes mellitus, we have a product given us approaching in cha.racter, it is true, to the normal sugar, but by no means idéfi’ótical with it. There is great facility for theorising with respectto the agencies in operation in effecting this change of action.,As vegetable juices contain principles which, by simple contactcan alter the chemical and optical qualities of the sugar firstgenerated in the fruit, how easy to believe that the elaboratefluids contained in the several parts of the circulatory system £of the liver may do the same. We know that acids are activein the vegetable kingdom -we know that the liver-substance isacid-may not an over acid state cause the production of thisabnormal sugar ? or may not even a too slow circulation throughthe organ (by allowing too long contact with acid matter) brinabout disease ? These are questions requiring much consider-ration.

.

In reflecting on the phenomena of this important disease, weare naturally led to consider the anatomical relations of theorgans most obviously concerned in its causation; and thestomach and liver must more especially present themselves toour notice. The position of these organs-situate as they artin the immediate vicinity of the central masses of the sympa-thetic, the semilunar ganglia, and the splanchnic nerves, andsupplied also with branches having immediate connexion withthe cerebro-spinal system,-is in itself suggestive of the highimportance of the offices discharged by them, of their sympa-thies and close relation. In this part, then, of the living and.moving organism, a most intimate union is effected betweenthe sympathetic and cerebro-spinal systems-systems present-ing a curious and doubtless intentionally-different arrangementas regards their chemical relations, and one which has been, asfar as I can ascertain, entirely overlooked by physiologists; anarrangement having most certainly a deep meaning, and onewhich I fully believe is to throw light on many obscure pro-blems in medical science. I allude to the distribution of theultimate fibrillse of the sympathetic and cerebro-spinal systemlJ,Thus the ultimate extremities of the sympathetic are almost en-tirely spread over parts possessing an alkaline reaction, whileprecisely the opposite is the case with the ’fibril1ae .of thecerebro-spinal system. The former lie in mucous and seroussurfaces, and in the bloodvessels bathed with alkaline nuid;the latter lie in muscular fibre and in the cutis as cutaneousnerves, and in both cases are bathed in strongly acid secretion.Now there is no part of the organism to which we can point inwhich these chemical opposites are so freely interwoven as inthe neighbourhood of the liver and stomach; and here againwe are attracted by the peculiar nature of the secretions pouredout by these organs. They seem to be exceptions to thegeneral rule-to be the parts, as it were, acted upon by theelectro-chemical arrangement, and parts to which it is sub-servient.My object in taking this notice of the nervous relations of

the stomach and liver is merely preliminary to making a sug-gestion to my fellow-labourers in this important field, to lookcarefully to the state of what I shall presume to call the greatnervous centre of the sympathetic in diabetic cases, wheneveropportunity may occur. In this terrible malady, we may per-haps there find the origin of evil in some diseased conditiongiving rise, not to the increased activity of glycogenesis, butto a diseased state of the hepatic function, productive of thesugar we find in true diabetes,-a sugar difficultly destructible,and therefore not hepatic sugar, nor the sugar produced in theurine by puncture of the base of the fourth ventricle.