m CORNELL UNIVERSITY LIBRARY 3 1924 087 318 535 Cornell University Library The original of this book is in the Cornell University Library. There are no known copyright restrictions in the United States on the use of the text. http://www.archive.org/details/cu31924087318535 aouT ITS PATHOLOGY AND TREATMENT Founded on the GouUtonian Lectures on " The Chemistry and Pathology of Gout," delivered iy the author before the Royal College of Physicians of London in 1897 ; with the addition of some recent investigations concernitig the Treatment- of Gout, and a detailed account of the Treatment of the various forms of Gout AETHUE P. LUFF M.D. LoND., B.Sc, F.R.C.P. PHYSICIAN IN CHARGE OF OUT-PATIENTS, AND LECT0EER ON FORENSIC MEDICINE AT ST. MARY'S HOSPITAL CASSELL AND COMPANY, Limited LONDON, PARIS, NEW YORK ct MELBOURNE 1899 ALL RIGHTS RESERVED First Edition October 1898. Beprinted 1899. P E E F A E . Part I. of this book is mainly a reproduction of the Goulstonian Lectures on " The Chemistry and Pathology of Gout," delivered in 1897 before the Royal College of Physicians of London. Part IL deals with the causation of gout, its various forms and its diagnosis and prognosis. Part III. includes a series of investigations undertaken with the objects of ascertaining the various conditions affecting the formation and removal of gouty deposits, the influence of alcoholic drinks on the gouty process, the solvent effect of the mineral constituents of various vegetables on gouty de- posits, and the value of certain drugs in effecting the removal of such deposits. Part lY. deals with the treatment of gout and of gouty conditions, especially in the light of the knowledge gained by recent investigations. The subject of diet has been carefully dealt with, and a classification of the various mineral waters is given according to their therapeutic value in the treatment of the various forms of gout. ARTHUR P. LUFF. 31, Weymouth Street, Cavendish Square, W. October, 1898. COI^TENTS. PART I. THE PATHOLO&Y OF GOUT. CHAPTER I. PASE Uric acid and its compouuds — Discussion of the various theories as to the causation of gout — View that excess of some compound or compounds of uric acid constitutes the primary cause- of gout — View that alloxur hases con- stitute the poison of gout — View that morbid changes in the structure of tissues constitute the primaiy cause of gout — View that nervous disturbance constitutes the primary cause of gout 1 CHAPTER II. Cause of the presence of uric acid in the blood of gout — Deficient excretion of uric acid in gouty subjects — Estimation of uric acid in the urine — Detection and estimation of uric acid in blood . ... ... 25 CHAPTER III. Seat or seats of formation of uric acid — Uric acid not a normal constituent of the blood — Pathological conditions under which uric acid appears in the blood 36 CHAPTER IV. The renal origin of gout — Association of kidney affections with gout — Association of renal disease with the presence of uric acid in the blood — Nature of the kidney affection which causes gout 52 CHAPTER V. Origin of uric acid — Formation of uric acid from urea in the kidneys — Uric acid fonnation and liver disease — Forma- tion of uric acid from nuclein — Different modes of formation of uric acid in health and in blood disorders , 64 vi Gout. CHAPTEE VI. PAGE Composition of the amoi-phous urate deposit of urine— Causes of uratio deposition— Formation of the gouty deposit- Time occupied in the conversion of sodium quadriurate into biurate— Seats of uratio deposition in gout . . 83 CHAPTER VII. Causes affecting the deposition of sodium biurate— Eeasous for the special selection of the great toe and ear as seats of gouty deposits — Cause of the inflammation accompanying the gouty paroxysm 92 PART II. ETIOLOGY OF GOUT— THE VAEIOUS FOEMS OF GOUT AND THEIR CLINICAL FEATUEES — DIAGNOSIS AND PEOGNOSIS. CHAPTER VIII. jEtiology of gout — Predisposing causes of gout — Exciting causes of gout — Acute gout— Chronic gout — Saturnine or lead gout — Irregular or abarticular gout 105 CHAPTER IX. Irregular gout affecting the alimentary tract— Irregular gout affecting the air-passages and lungs — Irregular gout aifecting the heart and vessels— IiTegular gout affecting the nervous system — Irregular gout affecting the genito- urinary system— Irregular gout affecting the skin — Gouty glycosuria and diabetes — Gouty hepatic congestion — Gouty affections of the eye and ear — Retrooedent or metastatic gout — Diagnosis and prognosis of gout . . 116 PART III. THE AUTHOR'S INVESTIGATIONS OF CERTAIN POINTS CONNECTED WITH THE TREATMENT OF GOUT. CHAPTER X. Experimental investigation of certain conditions and factors affecting the solubility and the precipitation of sodium quadriurate and sodium biurate 128 Contents. vii CHAPTEE XI. PAGE Experimental investigation of the influence exerted by the mineral constituents of meat, milk, and vegetables re- spectively on the solubility of sodium biurate— The in- fluence of alcoholic beverages on the gouty process . . 140 CHAPTEE XII. Experimental investigation of the relative effects exerted by the mineral constituents of various vegetables on the solubility of sodium biurate — Experimental investigation of the influence exerted by the mineral constituents of various vegetables in retarding the conversion of sodium quadriurate into sodium biurate — The vegetables most beneficial to gouty subjects 160 CHAPTEE XIII. Beasons for believing the treatment of gout by alkalies to be erroneous— Experimental investigation of the value of the treatment of gout by the various alkalies, by piperazine and by lysidine— Eeasons for believing the treatment of gout by salicylates to be erroneous — Experimental iu- vestigation of the value of the treatment of gout by salicylates— General conclusions 176 PART lY. THE TREATMENT OF GOUT AND OF GOUTY CONDITIONS. CHAPTEE XIV. The general principles on which the treatment of gout is based — Examination of the urine —Treatment of acute gout — Diet in acute gout — The action of colohicum — Treatment of subacute and chronic gout — Means of checking the excessive formation of uric acid — Means of promoting the elimination of uric acid — Local treatment of gouty joints 199 CHAPTEE XV. Treatment of retrocedent or metastatic gout— Treatment of the various forms of irregular gout — ^Treatment of gouty glycosuria and diabetes— Preventive treatment of gout — Diet in gout— Alcohol in gout 213 viii Gout. CHAPTER XVI. PAGE The uses of mineral waters in the treatment of gout — The mineral waters heat suited for the removal of gouty deposits— Classification of the mineral waters used in the treatment of gout— The simple waters, or waters comparatively free from sodium salts — Simple alkaline waters — AlkaUne sulphated waters— Alkaline muriated waters — Common salt or muriated waters — Sulphur waters— Hot and cold mineral waters — Classification of mineral waters according to their therapeutic value in the treatment of the various forms of gout .... 226 Index . . . ... ... 243 lart I. THE PATHOLOGY OF GOUT. CHAPTER I. Uric acid and its compounds — Discussion of the various theories as to the causation of gout — View that ex- cess of some compound or compounds of uric acid constitutes the primary cause of gout — View tliat alloxur bases constitute the poison of gout — View that m,orbid changes in the structure of tissues constitute the primary cause of gout — View that nervous disturbance constitutes the primary cause of gout. Gout is the manifestation of a number of morbid tendencies, some of which may be inherited and some acquired, and which result in the different diseases associated with the arthritic diathesis. If the joints are affected, articular or regular gout results ; if other organs or tissues are affected, then irregular gout is produced. Gout is associated with the presence of an excess of uric acid in the blood, and the questions that will be first dealt with mainly resolve them- selves^ into the mode or modes by which the uric acid is produced and introduced into the blood, the source or sources of its production, the relation- ship that it bears to the gouty paroxysm and 2 The Pathology of Gout. to the other manifestations of gout, and the factors or conditions which influence its formation and its injurious action. URIC ACID AND ITS COMPOUNDS. Uric acid is a bibasic acid, the formula of which is H2(C5H3N403). This acid forms the following three classes of salts: — (1) Tob neutral urates, in ^hich a metal takes the place of all the displace- able hydrogen, such as Na^CjHsN^Og, the neutral sodium urate. (2) The biurates, in which a metal takes the place of half the displaceable hydrogen, such, as NaHCsHjN^Oj, the sodium biurate. The biurates, although acid salts in constitution, are not acid to test paper. (3) The quadriurates, in which a metal takes the place of one-fourth of the dis- placeable hydrogen of two molecules of uric acid, such as NaHCjHjN^Os, HjCgH^N^Og, the sodium quadriurate. Of these three classes of salts the neutral urates cannot exist in the living organism, and therefore take no part in the pathology of gout. It is also important to understand that uric acid does not and cannot exist in the blood in the ffee state under any conditions whatsoever. The sodium quadriurate is the soluble uric acid compound which is originally contained in the blood of gouty subjects, and this substance, as just mentioned, is a derivative of two molecules of uric acid in which sodium is substituted for one-fourth of the displaceable hydrogen, or, in other words, it is a molecular combination of sodium biurate with uric acid. This sodium quadriurate is, Formation op Sodium Biueate. 3 however, an unstable body, and after a certain time it unites with some of the sodium carbonate of the blood to form sodium biurate, which, if produced in larger quantities than the fluids of the body can retain in solution, becomes deposited in various structures in the crystalline form. This conversion of sodium quadriurate into the biurate by the sodium carbonate of the blood is shown in the following equation : — 2 maHCjHjN^Og, H2C5H3N^03\ + Na^COg = , ^ Sodium Quadriurate ^ Sodium Carbonate 4 NaHCsHgN^Og + GO, + H^O Sodium Biurate The sodium quadriurate is, therefore, to bo regarded as a comparatively soluble but very un- stable compound, whilst the sodium biurate is comparatively insoluble but very stable. Murexide test for uric acid. — If two or three drops of strong nitric acid are added to a fragment of uric acid in a porcelain dish, and heat gently applied until all the nitric acid is driven off, a reddish-coloured residue (alloxan) will be left. If, when the dish is cold, a few drops of solution of ammonia are added to this, a beautiful crimson- purple colour is developed, due to the production of murexide by the action of the ammonia on alloxan. This is an extremely delicate test, and the one-hundredth part of a milHgramme of uric acid may be detected by this reaction. THEORIES AS TO THE CAUSATION OF GOUT. Of- the various theories to account for the production of "gout the humoral theories have 4 The Pathology of Gout. been to the front for many centuries at various periods in the history of the disease. Galen was one of the first to teach that tophi arose from the desiccation of collected and pathologically altered humours. CuUen, who was the great opponent of the ancient humoral theory of gout in the latter half of the last century, admitted, however, that in some instances a peculiar matter appears in gouty patients, but he considered that it was the effect and not the cause of the malady. Uric acid was discovered in the urine by Scheele in 1775, and in 1787 Wollaston demonstrated its presence in gouty concretions. These discoveries did not, however, bring to light the important part played by uric acid in gout. It was in 1847 that Sir Alfred Garrod first found uric acid in the blood of gouty subjects in the form of a sodium salt. The dis- covery of uric acid in the blood of gouty patients eventually led to the much-discussed question as to whether it was the cause or the result of gout. Those who held the former view were in their turn divided as to whether the uric acid compound only exerted its baneful effects when it had crystallised out of the blood and had become deposited in the affected tissues, or whether, while still circulating in the blood, it exercised a true toxic influence. The various views held as to the primary cause of gout may be classified into the three following groups : — (1) Excess of uric acid regarded as the primary cause ; (2) morbid changes in the structure of tissues regarded as the primary The Causation of Gout. 5 cause ; and (3) nervous disturbance regarded as the primary cause. The following is a brief review of the various opinions held as to the primary causation of gout, adopting the classification just given : — I. — Excess of uric aced regarded as the PRIMARY CAUSE OF GOUT. This group may be divided into two sections accordingly as the uric acid compound is regarded as exerting its baneful effect in the crystalline state or in the dissolved state. 1. The uric acid compound regarded as acting passively and physically while in the crystalline state.— Sir Alfred Garrod and Sir William Roberts are the two principal exponents of this view, which regards gout — in so far as its phenomena depend on uric acid — as a disease the manifestations of which are proximately due to mechanical injury. Sir Alfred Garrod holds that every paroxysm of gout is attended by a crystalline deposit of sodium biurate, and that this deposit exercises chiefly a mechanical effect. He explains, in connection with articular gout, that Avhen the blood, for some reason or other, is incapable of holding the uric acid compound in solution, it is deposited in an articular cartilage which is specially predisposed for its reception. Such predisposition is generally caused by its being the seat of former injury or disease. The crystallisation of the biurate within, the interstices of the cartilage then provokes the inflammatory changes, so that the deposition is the 6 The Pathology of Gout. cause of the inflammation. Sir William Roberts is of opinion that uric acid probably does not possess any inherent poisonous quality, and that as long as it remains in solution it produces no harmful results. The mischief that it is capable of producing only results from its precipitation or crystallisation as sodium biurate in the tissues or fluids of the body. He considers that the inflammation, pain, swelling, and the remoter secondary degenerative changes of regular gout are quite explicable by regarding the crystalline biurate which is precipitated in the cartilaginous and fibrous structures of the joints as exerting a mechanical action as a foreign body. Cornil and Ranvier also favour the idea that the crystal- line uratic deposit in cartilages produces inflamma- tory changes by its mechanical irritation. POSSIBLE CAUSE OF IRREGULAR GOUT. Sir AVilliam Roberts even considers that the manifestations of irregular gout may be due, like the arthritic manifestations, to uratic deposition — that is, to actual precipitation of crystals of sodium biurate into the connective and fibrous structures of the implicated organs, whether the liver, heart, lungs, or brain, or into the fibrous sheaths of the nerves controlling the functions of the affected viscera. He is further of opinion that the presence in the blood of scattered needles of sodium biurate might constitute foci around which clotting might take place, and that the thromboses not unfrequently observed in gouty cases might Causation of Irregular Gout. 7 thus be accounted for. The various localities in the body, apart from the joints, in which uratic deposits have been found, will be referred to later (see p. 90), but as regards the possible de- position of sodium biurate in nervous structures constituting the exciting cause of some of the pains and aflections of different viscera peculiar to irregular gout, it may be of interest to mention here the following facts : — (Crystals of sodium biurate have been found by Watson, Gairdner, and Dafour on the cerebral meninges ; by Schroeder van der Kolk in the neurilemma of peripheral nerves ; and by Cornil in the cerebro-spinal fluid. With regard to the manifestations of irregular gout being due to uratic deposits in the affected viscera, it is true that observations on the subject are very limited in number. But, in the first place, it should be remembered that such irregular uratic deposits are extremely likely to escape observation in the post-mortem room, unless very carefully looked for by the aid of the microscope ; and, in the second place, it is highly probable that such deposits would become dissolved during life as the attack of irregular gout passes off. AMORPHOUS QUADRIURATES NOT IRRITANTS. The question might be raised that if the crystal- line biurate always acts as an irritant, why should not the semi-solid urinary excrement of birds and serpents set up kidney mischief by acting as an irritant to the kidneys during its excretion ? The reason is that the urinary excrement of birds 8 The Pathology of Gout. and serpents is composed of an amorphous quadri- urate, and that in the amorphous condition it is incapable of acting as an irritant. Moreover, it is possible, as Sir William Roberts has suggested, that the uratic excrement passes through the tubules of the kidneys of birds and reptiles in the gelatinous form, which could not produce the mechanical irritation that a crystalline deposit would be liable to cause. 2. The uric acid compound regarded as acting as a poison or irritant while in the dissolved state. — This view, while holding that the uric acid compound is the primary cause of gout, regards it as producing morbid changes in the structure of tissues while remaining in the dis- solved state. Many writers and observers have supported the view that, apart from the local trouble in the joints caused by the deposited sodium biurate acting as an irritant, the soluble uric acid compound which is circulating in the fluids of the body acts as a poison, the toxic effects of which are responsible for a number of the symptoms associated with the gouty state. Pfeilfer holds the somewhat peculiar view that a compound of uric acid is deposited in both healthy and diseased portions of the body — apparently without producing any marked symptoms — and that an acute attack of gout is caused by the blood re- dissolving this deposited uric acid compound, owing to a temporary increase in the alkalinity of the blood, and that dissolved in the blood in this concentrated form the uric Uric Acid not a Poison. 9 acid compound acts as a chemical poison. That this view is untenable is evident when it is remembered that uric acid is deposited as the sodium biurate, and, as will be shown later (see pp. 137 — 139), the solubility of this body in a fluid medium is not heightened by an increased alkalinity of that medium. URIC ACID NOT A POISON. Sir William Roberts* argues that the accept- ance of the theory that uric acid possesses a toxic action is difficult for the following two reasons : — (1) That there is no direct experimental proof that uric acid is a toxic agent ; and (2) that although the fluids of the body of a gouty man, on the eve of an outbreak of acute gout, are impregnated with sodium biurate to saturation, yet such a person does not show any signs of poisoning, but enjoys complete immunity from toxic symptoms until the sudden advent of the arthritic attack. Another fact which is strongly opposed to the view that uric acid is a toxic agent is that in cases ot leucocythsemia and severe ansemia the blood is frequently highly charged with uric acid in the form of sodium quadriurate without the production of any toxic symptoms that could be referred to the uric acid compound. ALLOXUB BASES REGARDED AS THE POISON OF GOUT. Kolischf considers that some antecedents or allies of uric acid are responsible for the toxic * Croonian Lectures ; " Uric Acid Gravel and Gout," 1892. t Wiener Tdinisohe Tfochensehrift, 1895, p. 787. lo The Pathology of Gout. effect which he believes constitutes the primary cause of gout. His view is that the graver mani- festations of gout only make their appearance when the functions of the kidneys become im- paired from any cause, and since he finds that in the urine of the gouty there is an increase of alloxuric substances, and also that alloxur bases cause changes in the kidneys resembling parenchy- matous degeneration, he infers that these bases are concerned in the production of the kidney affection which precedes the development of gout. His theory is that during normal action of the kidneys the greater part of the alloxur bases is excreted as uric acid ; but when the structures which form uric acid are enfeebled there is an increased excretion of alloxur bases, with con- comitant toxic effects. Kolisch's views have re- ceived some confirmation by Weintrand, * who has also found an excessive excretion of alloxuric substances in the urine of gouty patients. On the other hand, they are controverted by the observa- tions of Schmoll,t His, J Laquer,§ and Mafatti,|| who failed to find any increased excretion of alloxuric substances in the urines of gouty patients. II. — Morbid changes in the structure of TISSUES REGARDED AS THE PRIMARY CAUSE OF GOUT. This group may be divided into two sections * Charite Annalen, 1895, xx., p. 215. t Zeilaehrifi fiir klinische Median, 1896, xxix., p. 610. % Berliner klinisehe Wochensehrift, 1896, xxxiii., p. 70. § Verhandlungen des Cong. f. innere Med., 1896, xiv., p. 33. II Wiener klinisehe Woohensehrift, 1896, ix., p, 723. Ebst bin's Views. ii accordingly as the morbid changes are produced by the presence of a soluble urate or not. 1. Necrotic changes in the affected tissues regarded as the primary catise of gout, the necrosis being due to the presence of dissolved urates. — Ebstein * who has devoted a considerable amount of time to the experimental study of the causation of gout, is the great exponent of this view. His theory is that a destructive or, as he terms it, a necrotising process is produced in the cartilages or other implicated tissues by uric acid in one form of combination, and that, following this, the uric acid in another form of combination is deposited in the necrosed areas. In other words, that a destructive process always prfeeedes the process of deposition, both processes being due to uric acid, but in different states of combination. Ebstein maintains that uratic crystals only form in necrotic tissues, never in healthy tissues. He regards the necrosis of tissue and the subsequent uratic deposits as together constituting the characteristic ensemble of the gouty process. His theory assumes that the irritant, is the neutral sodium urate in the dissolved state, and that the first step in the gouty process consists in a stasis of the lymph stream, followed by the infiltration of the tissue in circumscribed areas by the lymph containing the dissolved neutral urate. The neutral urate, according to his view, acts as a chemical irritant, and sets up a necrotising process in the implicated tissues, * " Die Natur und Behandlung der aicht," 1882. 12 The' Pathology of Gout. and finally produces complete necrosis of the tissues in the affected areas. The necrotising and necrotic portions of the tissues provoke irritation of the surrounding parts, and so produce the in- flammatory phenomena of gout. Ebstein assumes that the process of necrosis generates a free acid, which converts the neutral urate present in the fluids of the body into the acid urate, which sub- stance is then deposited in the crystalline form in the fully necrosed areas. No mention is made of the nature or name of this hypothetical acid. ebstein's experiments. To support this theory Ebstein relies upon two different classes of experiments conducted by him. One class consists of his examination of the organs and tissues of birds that he considered he had rendered gouty, by preventing the elimination of their urinary secretion. The other class of experiment consists of observations on the irritant effect of a solution of a sodium urate on the delicate corneal tissue of the eye. As I venture to differ from the deductions that Ebstein has drawn from his experiments and observations, I propose to describe his methods of experimentation, and briefly to criticise his deductions therefrom. ebstein's experiments on birds. Ebstein's first series of experiments consisted in an endeavour to induce in cocks a condition which, from the anatomical point of view, he considered was analogous to the gouty state in man. This Ebs vein's Experiments. 13 he effected by preventing the elimination of their urinary uratic secretion in two ways — (a) by hga- turing the two ureters, and so damming back upon the circulation the urates which would otherwise have passed away; and (6) by administering to the cocks small and repeated subcutaneous in- jections of the neutral potassium chromate, which Ebstein considers inhibits the passage of uric acid through the kidneys by its action on the renal parenchyma, and so causes a damming back upon the circulation of a portion of the urates, which normally are excreted in their entirety by the kidneys. In the bodies of the birds experimented on uratic deposits were found in the articulations, in the tendon-sheaths, in the liver, and in the muscular tissues. Ebstein found that the deposi- tion of urates was much more copious and more widely spread in the cocks experimented on by injection of potassium chromate than in those whose ureters were ligatured. This difference he referred to the fact that he could keep the birds alive for a long time while subjecting them to the action of potassium chromate, whereas after ligaturing both ureters they, as a rule, only lived for about twenty-four hours. As the result of these experiments Ebstein came to the following conclusions : — (1) That necrosing and necrotic processes are developed in various organs as the result of some irritant ; (2) that uratic deposits form in the necrotic areas which in appearance resemble the gouty deposits of man ; (3) that a reactive inflammation, with infiltration of small 14 The Pathology of Gout. cells, is set up in the neighbourhood of these necrotic areas. CRITICISM OF EBSTEIN'S EXPERIMENTS ON BIRDS. This class of experiments therefore consisted of observations of the uratic deposits formed in fowls when the elimination of their uric acid is prevented either by ligaturing the ureters, or by the pro- gressive disablement of the kidneys by repeated subcutaneous injections of potassium chromate. 1 do not think that the morbid processes occurring under these conditions in fowls can be considered as, in any sense, comparable with those occurring in connection with gout in man. Ebstein found uratic deposits in the liver and muscular tissues of the birds experimented on, localities where they are not found, at all events to any appreciable extent, in human gout. From this one may fairly conclude that the two processes cannot be con- sidered as comparable. Moreover, since the fowl produces and eliminates by the kidneys so large a quantity of urates, the more or less sudden stoppage of kidney excretion must necessarily result in the damming back of it and the rapid accumulation of it in the blood and tissues, where, as Sir William Roberts* suggests, it would probably first collect in a state of solution as the quadriurate, which would then bo precipitated in the tissues as the gelatinous biurate, and this in its turn would be changed into the crystalline biurate. * Cioonian Lectures : " Uric Acid Graval and Gout," 1892, p. 118. Ebste/n's Experiments. 15 ebstein's experiments with urates. It is on the second class of experiments that Ebstein depends for proof of his assumption that the neutral sodium urate is capable of acting as a chemical irritant to the tissues, and of pro- ducing in them the necrotising changes which subsequently lead to complete necrosis of the affected areas of the implicated tissues. In order to show that a combination of uric acid with sodium acted as an irritant, Ebstein took a saturated solution, prepared at 100° F., of uric acid in a 5 per cent, solution of sodium phosphate, and injected it into the peritoneal cavity, into the kidney, into the anterior chamber of the eye, into the cartilage of the ear, and into the cornea of a rabbit. Powdered uric acid was also introduced by insufflation into the conjunctival fold of one eye. Very appreciable changes were produced in the cornea only, and it was in this structure that Ebstein studied what he considers were the irritant or toxic effects of uric acid. He found that these injections produced a modified form of inflammation in the tissues of the cornea. As a control experiment he injected into the cornea of the other eye a simple solution of sodium phos- phate, or water containing calcined magnesia in suspension, neither of which produced any inflam- matory changes. He therefore inferred that the inflammatory changes were set up in the cornea Viy the urate in solution acting as a chemical irritant. i6 The Pathology of Gout. CRITICISM OF EBSTEIN'S EXPERIMENTS WITH URATES. The objection to this method of experimenta- tion is that, in the first place, the sohition of uric acid in sodium phosphate does not contain the neutral sodium urate, which is the body on which Ebstein relies for the production of the initial irritant effects leading on to the necrotising process. The solution would contain the sodium quadriurate or the biurate, or a mixture of the two. Moreover, as Sir William Roberts has pointed out, such a saturated solution would soon begin to deposit its urate in the form of the gelatinous biurate, which, infiltrating the affected area of the corneal tissue, would act as a mechanical irritant. It is, there- fore, clear that all the corneal changes observed by Ebstein can be accounted for by the assumption that they are caused by a mechanical irritant. The ex- periments of Neubauer are opposed to the view that a soluble urate circulating in the blood can act as a poison or irritant and start necrosis. He found that the administration of large quantities of uric acid to rabbits (as much as twelve grammes in some cases) did not seem to cause any incon- venience. Moreover, is it likely that solutions of urates should act as irritants, when their passage through the kidneys is part of the natural elimina- tion of nitrogen in man ? If solutions of the urates are to be regarded as irritants, then the kidneys would never escape damage. Another important argument which militates against the acceptance Criticism of Ebstein's Experiments. 17 of Ebstein's theory is that, not only is there no proof that the neutral sodium urate, upon which he depends for the starting of the gouty changes, ever exists in the human body, but, on the other hand, there is strong evidence to show that it never can exist in the human body. The neutral sodium urate is an extremely caustic and unstable compound, and is decomposed in the presence of - carbonates, so that it is impossible for it to exist in the blood. The first factor upon which Ebstein relies for his theory of the causation of gout there- fore disappears. Moreover, the responsibility for the assumed necrotic changes cannot be transferred from the neutral sodium urate to the biurate, since Pfeiffer has shown, by means of subcutaneous injections of a solution of a biurate, that although it can produce pain and irritation, yet it cannot cause necrosis, especially when in so weak a solu- tion as must occur in the human body. The assumption by Ebstein that the process of necrosis generates an acid which is supposed by him to convert the neutral urate into the acid urate is based on an imperfect acquaintance with the chemistry of the urates. Sir William Roberts has shown that uric acid is primarily taken up by the blood and lymph as a quadriurate — not as a neutral urate — and he has also proved that the formation and deposition of the crystalline biurate are not favoured by the intervention of an acid. Moreover, in connection with leucocythsemia severe anaemia, and other diseases, to which reference will be made later, we know that a considerable 1 8 The Pathology of Gout. quantity of uric acid may be present in the blood in the form of sodium quadriurate without giving rise to necrosis of tissues anywhere. ebstein's views as to necrotic changes in GOUT. Ebstein considers that, by dissolving out the crystalline urates from tissues in which they are deposited, he is able to demonstrate the existence of necrosis in the sites previously occupied by the uratic deposit, and insists that the crystalline urates are only deposited in tissues that have undergone necrotising and necrotic changes. This, however, is opposed to the experience of such competent observers as Sir Alfred Garrod, Sir William Roberts, Sir Dyce Duckworth, and Comil and Ranvier. I have also frequently examined sections of cartilages containing uratic deposits which have not shown any ncciosis at the sites of the deposits, and in which the cartilage appeared to be practically uninjured. The changes that maj' be seen in cartilages containing a dense deposit of sodium biurate are quite intelligible on the assumption that they are caused in part by the mechanical pressure of the crystals, and in part by the inflammation and subsequent degeneration set up by the presence of the crystalline deposit. If the sodium biurate is only formed and deposited in necrosed areas, how is it that crystals of sodium biurate are occasionally found free in the synovial fluid of a gouty joint ? As Sir William Roberts* * Croonian Leitares: " TJiic Acid Gravel and Gout," 1892, p. 117. The Causation of Gout. 19 remarks : " it will scarcely be contended that necro- tising and necrotic processes can take place in synovia!" Sir Dyce Duckworth* in a modified sense believes that a soluble urate may act as an irritant. Although he considers that gout is primarily due to a disorder of the nervous system, he entertains the additional view that the urate in solution may set up degeneration and necrotic changes in tissues. This view is expressed as follows : " It can hardly be doubted that lesions result from the action of uric ac!d in solution in the tissues, and that thus both acute and chronic inflammatory changes may be set up without the direct influence of uratic deposit as an alleged irritant in joints and in certain viscera, notably in the kidneys. Degenerative changes and necrosis also appear to be thus induced." 2. Inflammatory or degenerative changes in the affected tissues regarded as the primary cause of gout, such initial changes not being caused by urates. — Dr. Ord in 1872 considered that gout was due to a special form of degeneration in some of the fibroid tissues, resulting in an excessive formation of sodium urate, which is then discharged into the blood, and is subsequently deposited in those parts least freely supplied with vascular and lymphatic structures. Dr. Ord, whose views, in this particular, have been supported by Dr. Norman Moore and Mr. Bo^vlby, also considers that uratic deposits only occur in tissues which * -'A Treatise on Gout," 1889, p. 53. 20 The Pathology of Gout. have previously begun to degenerate. Dr. Berkart * considers that the severity of the local symptoms attending an attack of acute gout are inconsistent with the assumption that they are produced by a primary chondritis, due to irritation set up by the deposition of sodium biurate in the articular carti- lages. He considers that the r6le of the uric acid is one of a humbler kind than that which has hitherto been attributed to it. In his opinion the uratic deposits are most frequently connected with a form of panarthritis, or a general inflammatory affection of the joints, which chiefly affects the smaller joints of the extremities. Without assum- ing any identity between arthritis deformans and gout, he considers that in both instances the disease probably originates in some kind of atrophy of the substance of the bone, that the degenerative process then attacks the cartilages and fibrous tissues of the joints, and that following on this there occurs a necrosis of the tissues close to or within the joint. This necrosis, he considers, is the primary cause of the pain, hypersemia, collateral oedema, and de- squamation of the skin of the affected joint. The degeneration and necrosis of the tissues are the result of a profound disturbance of nutrition. Dr. Berkart attributes the presence of the urates in the blood in part to leucocytosis, and in part to the formation of uric acid from the disintegration of the tissues ; so that he reg^irds the uratic deposits as an epiphenomenon, and not as the cause of the gouty paroxysm. • Brit. Med. Journ., 1895, vol. i., p. 243. The Causation of Gout. 21 III. — Nervous disturbance regarded as the PRIMARY CAUSE OF GOUT. The view that gout is intimately connected with disturbances of the nervous system has many supporters. CuUen, the great opponent of the humoral theory in the latter half of the last century, considered that gout mainly depended on an affection of the nervous centres. Sir Dyce Duckworth * while accepting the view, as previously mentioned, that uric acid has some connection with gout, considers that gout is primarily depen- dent on a functional disorder of a definite tract of the nervous system, and that the part specially involved is possibly situated in the medulla oblongata, where it may be that there is a trophic centre for the joints. One reason that Sir Dyce Duckworth gives for considering this possible is the relationship of gout to diabetes, the consider- ation of which has led him to the belief that the portions of the nervous system involved in the two diseases cannot be far apart from one another. In consequence of this disorder of the neurotrophic system defects of nutrition arise which not only cause undue formation of uric acid, but also inhibit the normal destruction of that body in the tissues ; at the same time the renal excre- tory power for uric acid appears to be tempo- rarily inhibited as part of the process of the gouty paroxysm. Sir Pyce Duckworth, therefore, regards gout as * •• A Treatise on Gout," 1889. 2!2 The Pathology of Gout. belonging to the class of neuro-humoral diseases, but he does not at present insist on the localisation of the primary disturbance in a limited portion of the cerebro-spinal axis. He draws the following dis- tinction between inherited and acquired gout. In primary or inherited gout the toxsemia is dapen- dent on the inherited gouty neurosis. In second- ary or acquired gout the toxaemia arises from the digestive and excretory organs becoming over- loaded, and then, if with this toxaemia there is depression and exhaustion of the nervous system, the gouty neurosis may be established by the morbid blood condition affecting the nutrition of the nervous system. Sir Dyce Duckworth claims that the suddenness with which an acute attack of gout comes on, preceded as it is usually by a sense of well-being in the patient, is indicative of the nervous origin of the outbreak, and that it is to the instability and undue sensitiveness of the nervous system in the gouty that the manifesta- tions of the paroxysm are due. Dr. Edward Liveing* considers that there is much to be said in support of the view that gout is the manifestation of a disorder which has its primary seat in the nervous -system. He remarks that the view that uric acid exerts a toxic influence upon the nervous centres, and that the particular character of the disorder is determined by the territory involved, is one that presents real obstacles, on account of the limited operation attributed to a cause so general in its nature^ * " On Megrim-and Sick Headache," 1873, pp. 404-5. Nervous System and Gout. 23 Dr. P. W. Latham* regards some change in the nervous system as the most important factor in the etiology of gout. He thinks that such change is localised in the medulla oblongata, or in the spinal cord, or in both, and that this nervous disorder may be either hereditary or acquired. He argues that if a portion of the medulla oblongata involving some of the roots of the vagus be the part affected, the metabolism of the liver may be interfered with, and so lead to the formation of uric acid. He also considers that if, from any cause, uric acid is cir- culating in the blood, it would act as a poison upon any weak spot in the nervous system, and that it is intelligible that it might act upon portions of the spinal cord which control the nutrition of the joints, and so cause nutritive changes or inflam- mation in the joints connected with that portion of the cord. In consequence of the inflammation or nutritive changes in the joints, sodium biurate becomes deposited in them, or in the tissues around the affected joint. Dr. Latham explains the phe- nomena of a gouty paroxysm by direct stimulation of sensory nerves by uric acid. He considers that the gout associated with chronic ' lead poisoning may be explained by the lead acting in such cases more particularly on those portions of the spinal cord which are concerned in gout. Dr. Ralfe held the view that the accumulation of uric acid in the blood in gout was due to non- conversion into urea of the uric acid normally formed in the tissues, and he considered that the * " Crooniau Lectures," 1S86. 24 The Pathology of Gout. conditions which prevent the normal destruction of uric acid in the tissues depend probably on disturbance of innervation. THE author's view AS TO THE PRIMARY CAUSE OF GOUT. From a careful consideration of these various views as to the primary cause of gout, I am of opinion that the greatest mass of evidence is in favour of the view that a salt of uric acid is the materies morbi. The details of various experiments that support this view will be given later. CHAPTER II. Cause of the presence of uric acid in the blood of gout — Deficient excretion of uric acid in gouty subjects — - Estimation of uric acid in urine — Detection and estimation of uric acid in blood. CAUSE OF THE PRESENCE OF URIC ACID IN THE BLOOD OF GOUT. The next question to consider is whether the excess of uric acid present as quadriurate and biurate in the blood in gout is the result of de- ficient excretion, of over-production, or of deficient destruction. All observers are agreed that an abnormal quantity of uric acid in the form of one or other of its salts is found in the blood in gout. This overcharging of the blood with uric acid must be due to one or more of the following causes: — (1) . Normal production and deficient excretion of uric acid; (2) over-production and normal excre- tion of uric acid ; and (3) diminished destruction of uric acid by imperfect oxidation, or by some other means. This last theory may be dismissed at once. There is no proof that the process of oxidation destroys uric acid ; on the contrary, there is proof that uric acid is produced by a process of oxidation. Moreover, not only is there no proof that uric acid is produced during health in the organs and tissues of the body generally, and that it subse- quently undergoes more or less destruction, but 26 The Pathology of Gout. there are good reasons for believing that uric acid is, in health, only formed in the kidneys, and never appears in the general circulation except under pathological conditions. With regard to the second theory of over- production and normal excretion of uric acid, there is abundant experimental proof to show that an increased production of uric acid does not lead to gout, so long as the kidneys remain in a normal condition. For instance, in connection with diseases such as leucocythssmia and severe anaemia there is an over-production of uric acid, but no development of gout. In these diseases the excessive quantity of uric acid produced is readily excreted by the kidneys, as is shown by the large amount of uric acid that may be found in the urine. In addition, gout is essentially a disease of middle age, and is only very excep- tionally met with in childhood and in j'^outh, although the formation of uric acid is greatest in early life, and apparently diminishes with the advance of age. VIEW THAT DEFICIENT EXCRETION OF URIC ACID IS CONNECTED WITH GOUT. There are nlany facts to support the view that gout is due to deficient elimination of the uric acid normally produced, and to subsequent absorption of this uric acid from the kidneys in consequence of that deficient excretion. That there is a deficient excretion of uric acid in gout is, I think, justified by the following facts. Judging as far as is possible Uric Acid Excretion. 27 by averages, recent accurate estimations of the excretion of uric acid show that in gouty subjects there is a decrease in its daily excretion as com- pared with healthy indiTiduals. Pfeififer * compares the quantities of uric acid contained in the urine of gouty patients at various ages, in whom the complaint had not yet become chronic, with the quantities contained in the urines of healthy subjects at the same age. For purposes of com- parison the quantities of uric acid found by him were calculated in grammes per 100 kilogrammes of the body-weight. His results are given- in the' following' table : — Age. Gouty subject. Healthy subject. 30 to 40 40 to 50 50 to 60 60 to 70 0-885 grm. 0-818- „ 0-701 „ 0-661 „ 0-965 grm. 0-882 „ 0-752 „ This table indicates that the amounts of uric acid excreted by gouty subjects were always rather lower than the quantities excreted by healthy persons of tiie same age. Dr. John Fawcettf also found as the result of several careful determinations of the uric acid elimination of various gouty patients that, in the majority of cases, the amounts excreted were distinctly below the average uric acid excretion of a healthy man on similar diet. In the following table (Table I.) are the results * Berliner kliaiaehe Wochemchrift, 1892, p. 413. t " Guy's Hospital Reports," 1895. 28 The Pathology of Gour. of the daily determinations that I made for eight successive days respectively of the total uric acid excretion in the urine of three persons, viz. : — (a) A male patient suffering from an attack of subacute gout supervening on chronic gout ; (6) a male patient suffering from chronic gout and lead-poisoning, with recent pain in the right metatarso-phalangeal joint, and in both ankle joints; (c) a healthy man. The quantities of uric acid in the three cases are given in gramme^, and are calculated per 100 kilogrammes of the • body-weight. All the individuals were between forty and fifty years of age,, TABLE I. Showing the daily elimination of uric acid in {a) a case of subacute gout ; (b) a case of chronic gout and plumbism ; («) a healthy person. Quantities of uric acid given in grammes per 1 00 kilo- grammes of the tody-weight. All the individuals between forty and fifty years of age. Subacute gout. Chronic gout. , Healthy subject. 0-260 grm. 0-578 grm. 1-105 grm. 0-263 „ 0-617 1-027 „ 0-315 „ 0-665 1-020 „ 0-350 „ 0-715 1-376 „ 0-442 „ 0-443 1175 „ 0.556 „ 0-372 1030 „ 0-506 „ 0-593 1-252 „ 0-494 „ 0-694 1-203 „ 0-398 „ 0-.'i72 1-148 „ (average) (average) (average) These results probably justify the view that deficient excretion of uric acid occurs in connec- tion with gout. Later the probable rdle taken by Estimation of Uric Acid. 29 the kidneys in the production of uric acid and in the development of gout will be dealt with in detail ESTIMATION OF URIC ACID IN UEINE. One of the lines of investigation that I have pur- sued required that a very large number of estima- tions of the total amount of uric acid excreted in the urine per diem should be made. The process that I have employed throughout is the Gowland- Hopkins method, which is a very accurate and reliable process. I have had a very considerable practical experience of the various methods that have been employed for the estimation of uric acid in the urine, including Heintze's process, Haycraft's process, Fokker's process, Salkowski's process, and Ludvvig's modification of Salkowski's process. In connection with all these processes there are faults or objections from which the Gowland-Hopkins process is free. This process depends upon the fact that when urine is saturated with ammonium chloride all the uric acid is precipitated as an ammonium urate. From the ammonium urate the uric acid is set free, and the amount of it is determined by titration with a standard solution of potassium permanganate. One' great advantage of this process is that there is no danger of the reduction of the ammonium urate as there is of the silver urate produced in some of the other processes; moreover, the ammonium urate is easy to filter, and permits of the liberation of its uric acid with great 30 The Pathology of Gout. readiness. Another great advantage of the pro- cess is that although xanthin is at first precipitated along with the ammonium urate, yet the subse- quent treatment with hydrochloric acid entirely removes it, so that finally it is not estimated along with the uric acid. THE GOWLAND-HOPKINS METHOD FOR THE ESTIMATION OF URIC ACID IN URINE. To 100 c.c. of the urine powdered ammonium chloride is added till practical saturation is ob- tained ; about 30 grammes of ammonium chloride as a rule are required. When a small quantity remains undissolved, after brisk stirring for a few minutes, saturation is sufficiently complete. The urine is then allowed to stand for two hours, during which time, if possible, it is occasion- ally stirred to promote subsidence, and is then filtered through thin filter-paper, and- washed three or four times with a saturated solution of ammonium chloride. The filtrate should remain perfectly clear and bright. The precipitated ammonium urate is then washed off the filter into a small beaker with a jet of hot distilled water, and is heated just to boiling with an excess of hydro- chloric acid. The beaker and its contents are allowed to stand in the cold for two hours, when the uric acid separates out completely, and is then collected on a filter and washed with cold distilled water. The filtrate should be measured before the washing is begun, and one milligramme added to the final result for each 15 c.c. of filtrate present — Estimation of Uric Acid. 31 this need never be more than 20 — 30 c.c. The uric acid is then washed off the filter with hot water, warmed with sodium carbonate till dissolved, and made up with water to 100 c.c. The liquid is then transferred to a flask, 20 c.c. of strong pure sulphuric acid are added, and the mixture is then imme- diately and while warm titrated with one-twentieth normal potassium permanganate solution. The latter should be added slowly towards the end of the reaction, the close of which is marked by the first appearance of a pink colour, which is per- manent for an appreciable interval. Previously the disappearance of the colour is instantaneous. The permanganate solution is niade by dissolving 1-578 gramme of pure potassium permanganate in a litre of distilled water. 1 c.c. = -00375 gramme of uric acid. ESTIMATION OF URIC ACID IN BLOOD. Another line of investigation that I have pursued has involved the examination of the blood of man and of several of the lower animals lor the presence of uric acid. Quantitative determinations of uric acid in blood have been made within the last few years by Salkowski and Leube, von Jaksch, and Klemperer. Salkowski and Leube* slowly added the fluid blood to ten times its volume of boiling water, boiled for ten minutes, allowed to subside, filtered, and evaporated down to the volume of the original blood used. The uric acid was then deter- mined in this liquid by the Salkowski method. * " Die Leliio von H irn," p. 94. 32 The Pathology of Gout. Von Jaksch* diluted the blood (using from 100—300 C.C.) with from three to four times its volume of water on the water-bath, and when coagulation commenced acetic acid was added so as to produce weak acidity ; the mixture was then heated on the water-bath for 15 — 20 minutes till the albumen settled, and was then filtered, and the sediment extracted and washed with hot water. The filtrate was further acidified with acetic acid, boiled, cooled, filtered, and sodium phosphate added. The Salkowski-Ludwig method for the estimation of uric acid was then employed. Klempererf diluted the blood with from six to eight times its volume of water, removed the albu- men by Von Seegen's method, and then estimated the uri(^.aoid by the Salkowski-Ludwig process. In order to test the accuracy of the different methods for the estimation of uric acid in blood, a quantity of fresh bullock's blood — which I proved to be free from uric acid by the murexide test — was taken, and to it a known percentage of uric acid was added. I then experimentally tried on different batches of this blood the various methods that have just been described. I obtained, how- ever, such very erroneous and discordant results that I was forced to the conclusion that no reliable process had as yet been devised for the estimation of uric acid in blood. I therefore endeavoured to devise a process that would yield rehable results. * " Ueber die klinjsohe Bedeutung ; Vou Harnsaure unj Xanthinbasen im Blut," 1891. t Deutsche medic initche Wochenachrift, 1896, xxi., p. 6o5. Estimation of Uric Acid. 33 After performing a very large number of experi- ments, into the details of which it is unnecessary to go, I arrived at the following process, which constitutes the most reliable one for the estimation of uric acid in blood with which I am acquainted. PROCESS FOR THE ESTIMATION OF URIC ACID IN BLOOD. The fresh blood is allowed to flow direct into its own volume of rectified spirit, with which it is thoroughly agitated ; the mixture is then evaporated on the water-bath until the mass can be reduced to a coarse powder, which is dried in the water-oven and afterwards finely powdered. The admixture of the blood with the spirit pre- cipitates the albuminous matters in a granular form, so that when dried the blood can be reduced with ease to a fine powder. Eor the experimental work one part of the dried blood is taken as being equal to five parts of liquid blood. For the ex- traction and estimation of uric acid in blood from 50 — 100 grammes of the powdered blood should, if possible, be taken. In all my analyses of the blood of animals and birds I employed 100 grammes of the dried blood, and in my analyses of human blood I used 50 grammes of dried blood. The method employed was to mix 100 grammes of the powdered blood with a litre of boiling distilled water, and to allow the mixture to boil for half an hour, during which time it was frequently agitated. It was then filtered firstly through glass-wool, and afterwards through filter paper, and evaporated 34 The Pathology of Gout. down to 50 c.c. ; this liquid was filtered, allowed to cool, and then submitted to the Gowland-Hopkins process for the estimation of uric acid. On adding known quantities of uric acid to different specimens of blood — which I had previously proved to be free from uric acid by the murexide test — and then submitting them to this process, I was able to extract from 80-87 per cent, of the uric acid, but the whole of I he uric acid could never be extracted from the blood residue. Various solvents were tried in place of the distilled water, such as dilute solutions of sodium acetate, potassium acetate, sodium phosphate, borax, sodium carbonate, etc., in the hope of being able to extract all the uric acid from the blood, but I was unable to find any solvent that acted better than the distilled water. This process that has just been described is the one that I employed, in conjunction with the murexide test, in all the examinations of the various kinds of blood for uric acid, which will be subsequently referred to. THE SOUKCES OF URIC ACID. Admitting then an excess of uric acid in the blood in the form of quadriurate or biurate, and that its deposition therefrom as the sodium biurate in cartilages and other tissues is the direct exciting cause of a gouty paroxysm, the two questions that naturally arise are : (1) Where is the uric acid formed ? (2) How is the uric acid foi med ? I believe that nric acid is formed in connection with some diseases, notably blood Sources of Ukic Acid. 35 diseases accompanied by leucocytosis, in a different manner to that in which it is produced in health, and also that in connection with such diseases it is formed in different organs to those in which it is produced in health. I also hold the opinion that the source of the uric acid contained in the blood in gout is the same as that from which the uric acid eliminated in the urine in health is derived. It will be well, therefore, first to consider the various views as to the seat or seats of formation of uric acid in health and in gout. 3^ CHAPTER III. Seat or seats of formation of uric acid — TJric acid not a normal constituent of the hlood — Pathological con- ditions under which uric acid appears in the hlood. VIEW THAT THE KIDNEYS FORM AS WELL AS EXCRETE URIC ACID. Until 1847 it was supposed that uric acid was formed in the kidneys themselves, as up to that time none had ever been detected in the blood. In that year Sir Alfred - Garrod demon- strated the presence of uric acid in the blood of gouty subjects, which discovery led to the con- clusion that uric acid was Jormed in certain other organs and tissues of the body, and was merely eliminated by the kidneys. The view that then arose was that the uric acid eliminated in the urine originated in the system by the metabolism of the nitrjgenised tissues, and was then thrown out by the kidneys. Sir Alfred Garrod* originally held this view, but in later years he came to the con- clusion that uric acid is produced by the direct action of the kidneys from urea and other nitro- genised bodies contained in the blood and con- veyed to the kidneys. From the experimental evidence that he has put forward, Sir Alfred * " Transactions of the Koyal MediciilandChirurgicalSociely," 1848, p. 93. The Kidneys and Uric Acid. 37 Garrod * concludes that the presence of the salt of uric acid in the blood of gouty subjects, provided it is not introduced via ihe alimentary canal, must be accounted for by absorption into the blood from the kidneys after its formation in these organs, the salt being changed by the blood from ammonium quadriurate, which is the form in which uric acid is mainly present in the kidneys, to sodium quadri- urate, which is the form in which uric acid first appears in the blood. He therefore concludes that uric acid is normally formed in the kidneys, and that when present in the blood it is a result of its having been absorbed after forma- tion in those organs. Kolischf regards the kidneys as the most important of the uric acid- forming organs. Dr. Latham considers that the final formation of uric acid takes place in the kidneys, where it is produced by the conjugation of substances manufactured in the liver, and conveyed in the blood to the kidneys. The following experijnental evidence has been put forward in support of the view that uric acid is formed in the kidneys. Zalesky experimented on serpents, who eliminate all their urinary nitrogen as uric acid. He found that after re- moval of the kidneys of serpents they lived about as long a time as when the ureters were tied, and that after death no uratic deposits were found in any of the tissues. As he found after ligaturing the ureters of other serpents that * " Proceedings of the Eoyal Society," 1893, pp. 482—484. f Wiener klinische Wochenschrift, 1895, viii., p. 787. 38 The Pathology of Gour. uratic deposits were to be seen after death in most of the organs and tissues, he concluded that the kidnsys were the producers as well as the elimi- nators of uric acid. The following experiments also are strongly opposed to the view that the kidneys, with regard to uric acid, merely act as filters, which separate the uric acid brought to them in the blood. Sir Alfred Garrod* gave from fifteen to thirty grains of potassium urate daily, and similar daily doses of sodium urate, without producing any increase of uric acid in the urine. Wbhler and Frerichs found that the administration of potas- ■ sium and sodium urates increased the amount of urea, but did not augment the quantity of uric acid in the urine. Neubauer found that the adminis- tration of large quantities of uric acid to rabbits, either by the stomach or by injection into the veins, was followed by a corresponding increase in the excretion of urea, but no uric acid was discovered in the urine. VIEW THAT THE LIVER AND SPLEEN PRODUCE URIC ACID. The view that the liver was the seat of pro- duction of uric acid probably originated in the knowledge that the excretion of uric acid in the urine is most abundant during digestion, when the liver is most active. This view is, however, equally compatible with the idea that the liver merely produces the antecedents of uric acid, which sub- sequently become conjugated in the kidneys. The * "Lumleiaa Leiituros," 1883. The Liver and Uric Acid. 39 investigations of Schroder and Minkowski ap- parently were strongly in favour of the view that uric acid was formed in the liver. Schroder * states that the liver of birds contains a high per- centage of uric acid, and that after removal of the kidneys uric acid continues to be formed, and accumulates in the liver and blood. The last- mentioned statement is utterly opposed to the results of Zalesky's experiments on the extirpation of the kidneys of serpents. Moreover, if the liver of birds contained uric acid, and if it passed thence to the kidneys, it must be present in the blood. As will be shown by and by, the blood of birds is quite free from uric acid. Minkowski f succeeded in keeping geese alive from six to twenty hours after extirpation of the liver ; after the opera- tion, their urinary excrement contained only 2 to 3 per cent, of uric acid, instead of the normal 60 or 70 per cent. This diminished excretion of uric acid after extirpation of the liver is, however, no proof that the liver is the seat of formation of uric acid. The results are equally compatible with the view that the liver is the seat of production of the antecedents of uric acid only. Dr. Murchison regarded the liver as the seat of production of uric acid, and considered that the pre- sence of the latter in the blood or tissues was due to functional derangement of the liver, in consequence of which the metabolism of some of the albumen became arrested at the stage of uric acid formation, * Ludwig's Festschrift, 1887, p. 89. t Arch. Exp. Path. u. Tharmak,, xxi. 40 The Pathology of Govt. instead of going on to the complete stage of urea formation. Charcot regarded the liver as the principal seat of production of uric acid. He considered that a functional derangemient. of the liver caused the production of excessive quantities of uric acid, and its consequent accumulation in the blood. Meissner regards the liver of fowls in the normal condition as the principal source of uric acid, but considers that the spleen and the nervous tissues share in the formation. Ranke was of opinion that his experiments led to the conclusion that the spleen was the principal organ concerned in the production of uric acid. It has, however, never been possible to show that the spleen takes any active part in developing gout. On the con- trary, the large amount of uric acid found in the blood of cases of leucocythsemia and severe anaemia show that an exaggerated production of uric acid does not by itself exert any influence on the origin • of gout. VIEWS THAT URIC ACID IS PRODUCED IN VARIOUS TISSUES. Ebstein, who attributes in cases ot gout the main production of uric acid to the muscles and bone-marrow of the affected extremities, admits, however, that the kidneys may take a part, not only in the secretion, but also in the manufacture of uric acid. Robins was the first to formulate the view that uric acid is formed in connective tissues generally, and that the patho- logical condition is merely an exaggeration of the Connective Tissues and Gout. 41 physiological one. This view therefore regards normal fibrous tissues as the seat of production of uric acid, and considers that in gout this production is increased. Chrzonsczewsky also concludes that uric acid arises in connective tissue, and that it is conducted thence through the lymphatic vessels. Cantani considers that the connective tissues take an active part in the formation of uric acid, and that in cases of gout it is especially produced in the cartilages and peri-articular tissues (ligaments, tendons, etc.). Senator also inclines to the opinion that at least part of the uric acid is formed in cartilaginous tissue. Most writers and observers on the subject, however, consider that it is only certain that uric acid, deposits in substances of the connective- tissue class, and that there is no proof that uric acid is formed in connective tissue. Dr. Haig claims that, in addition to the forma- tion of uric acid in the animal economy, the gradual introduction of small quantities of uric acid in the food leads to its gradual accumulation, and that consequently very large amounts may be stored in the body without any excessive formation having taken place. Dr. Haig, however, does not produce any proof that uric acid is stored up in the system apart from gout. The contrary is proved by the fact that in diseases such as leuco- cythseraia, severe anaemia, etc., although large quantities of uric acid are formed, yet they are readily eliminated without storage in the system occurring. 42 The Pathology of Gout. is uric acid a normal constituent of the blood? It will be evident that if the various views as to the formation of uric acid in the liver, spleen, connective tissues, muscles, and bone- marrow be correct, then it must be conveyed in the blood in order to be excreted by the kidneys. We know that some 400-500 grains of urea are normally excreted in the urine, and that this urea is conveyed in the blood from various organs to the kidneys, where it is excreted. But, in addition, from eight to ten grains of uric acid are daily excreted in the urine of man. The question is, Does this uric acid come as such to the kidneys ? In other words, is it produced in any of the organs or tissues of the body generally and conveyed in the blood to the kidneys, to be by them excreted, or is it produced in the kidneys and then turned into the urine ? The answers to these questions will depend very much upon our ascertaining whether uric acid exists in the blood of man in health, and whether it exists in the blood of those animals, such as birds, the whole of whose nitro- genous urinary excrement consists of a compound of uric acid. For it follows that if uric acid be not formed in the kidneys, it must be conveyed in the blood to those organs. If such be the case, its detection in the blood, provided careful search for it be made, ought to be a fairly easy matter, considering that in the murexide reaction we have such an extremely delicate test for the The Blood in Health. 43 identification of uric acid. Here it is well to bear in mind that statements as to the presence of uric acid in the blood and viscera are valueless unless the substance is proved to be uric acid by the murexide test. Dr. Haig, who asserts that uric acid is always present in the blood and tissues, bases his statements solely on the application of Haycraft's process to water-extracts of the blood and tissues, and the subsequent calculation of the silver precipitate so obtained in terms of uric acid. As far as can be ascertained from Dr. Haig's writings, he has never identified by the murexide test this uric acid reported to be present in the blood and tissxies. URIC ACID NOT PRESENT IN THE BLOOD OF MAN IN HEALTH. . Sir Alfred Garrod* as the result of his investigations, declares that in absolute health the uric acid in the blood is inappreciable, that in gout the blood is very rich in it, and that uric acid is found in smaller but appreciable quantities in individuals who are developing a gouty condition, or v/ho are under the poisonous influence of lead. Yon Jaksch t examined the blood of several healthy individuals, but found no uric acid present. Klemperer \ also was unable to find any uric acid in the blood of healthy persons. I have also carefully examined the blood of healthy subjects by the process previously * " Lumleian Lectures," 1883. t Deutsche medicinische Wochtnschrift, 1890, xxxiii., p. 711. J Leutache medicinische IJ'ocheiisc/irift, 1895, xxi., p. G.55. 44 The Pathology of Gout. described, and have been unable to find any uric acid present. On the other hand, urea was found in every sample of blood examined. URIC ACID NOT PRESENT IN THE BLOOD OF MAMMALS OTHER THAN MAN. Sir Alfred Garrod* examined the blood of the ox, sheep, and pig by the uric acid thread test, but could never find a trace of uric acid present. I have also examined the blood of the ox and sheep, working on very large quantities of blood by the process I have described, but I have never found any uric acid present. On the other hand, urea was found in every sample of, blood examined. URIC ACID NOT PRESENT IN THE BLOOD OF BIRDS AND REPTILES. The examination of the blood of birds and reptiles has a very important bearing on the discovery of the normal seat of formation of uric acid. As is well known, the semi-solid urinary excrement of birds consists, apart from the small quantity of water present, entirely of uric acid compounds, so that the nitrogen excreted by the kidneys of birds is eliminated entirely in the form of uric acid and none of it in the form of urea. This white mortar-like urinary excrement of birds has been shown by Sir William Roberts to consist of the quadriurates of ammonium, • "Liimleian Lectures," 1883. The Blood of Birds. 45 potassium, and sodium. Consequently birds excrete in proportion to their body-weight an enormous amount of uric acid as compared with the uric acid output of mammals. If this large quantity of uric acid be produced in the organs and tissues generally it must be conveyed in the blood to the kidneys, and it therefore would be easy of detection in the blood of birds. Now it can be demonstrated that the blood of birds is abso- lutely free from uric acid. Sir Alfred Garrod examined the blood of the turke}', fowl, pigeon and duck by the uric acid thread test, but never found a trace of uric acid present. I considered that these observations of Sir Alfred Garrod as to the absence of uric acid from the blood of birds were of so great importance — in view of the opinion which I strongly entertain that uric acid in health is only formed in the kidneys — that I thought it desirable to re-examine the blood of birds. I accordingly worked on very .large quantities of the blood of the turkey, goose, duck and fowl. After the most careful examination, I have never been able to detect any uric acid in the blood of these birds, and I therefore confirm Garrod's observations. I am also able to confirm his observations as to the presence of urea in the blood of birds. I found urea present in the blood of all the birds that I examined, viz. the turkey, goose, duck and fowl Dr. John Davy examined the blood of two snakes (fi^jer communis) for uric acid, but failed to detect any. 46 The Pathology of Gout. The objection has been raised to the above- mentioned experiments that the quantity of uric acid present in the blood requisite to produce u daily excretion of eight to ten grains might be so minute as to escape detection. This objec- tion, I think, is disposed of by the fact that I have worked on pints of mammalian blood at a time, and have not been able to extract the least trace of uric acid, although urea was always found. That the process was a reliable one was shown by the fact that when I purposely added small quantities of uric acid to either mammalian blood or birds' blood I could always easily extract it and detect its presence. Moreover, the objection as to the supposed difficulty of detecting small quantities of uric acid, if such were normally present in blood, is not a valid one, considering that in the murexide test for uric acid we have a test of extreme delicacy. It can be demon- strated (see p. 3) that the one-hundredth part of a milligramme of uric acid gives a very evident murexide reaction. However, the objection that has been raised could not possibly apply to the examination of the blood of birds. The urinary excrement of birds consists almost entirely of compounds of uric acid and contains no urea, and if such uric acid is conveyed by the blood to the kidneys, then it must be capable of easy detection in that medium. Yet, as previously mentioned, no uric acid can be detected in the blood of birds. This mass of experimental evidence, which Sources of Utnc Acid. 47 shows that uric acid is never present in the blood of human beings and of other mammals in health, and also that it is never present in the blood of birds and serpents, although their urinary excre- tion is almost entirely composed of a compound of uric acid, conclusively supports the view that uric acid is normally produced in the kidneys. How is it possible in all these cases that uric acid could be absent from the blood, if the view be correct that uric acid is formed in the system generally, and is conveyed in the blood to the kidneys, which play, as it were, merely the part of a filter in the removal of the uric acid from the blood ? I consider that the evidence brought forward renders such a view impossible. THE SOURCES AND FORMATION OF URIC ACID IN PATHOLOGICAL' CONDITIONS, OTHER THAN GOUT, IN WHICH IT APPEARS IN THE BLOOD. Although I hold the opinion that in health uric acid is only formed in the kidneys, and that the uric acid found in the blood in gout is absorbed from the kidneys after formation in these organs, yet it must be borne in mind that there are other diseases, besides gout, in which uric acid appears in the blood, and in connection with which it has most probably not been absorbed from the kidneys, but has been formed elsewhere in the system. It will, therefore, be well briefly to consider what these pathological conditions are, and what are the probable sources of the uric acid in such conditions. The investi- 4 8 The Pathology of Gout. gations of Von Jaksch, Klemperer, and others have conchisively established that the presence of uric acid in the blood is not a pathognomonic sign of gout, and also that uric acid may appear in quantities in the blood, and be eliminated without causing gout. BLOOD DISORDERS ACCOMPANIED BY THE PRESENCE OF URIC ACID IN THE BLOOD. Von Jaksch* found uric acid in the blood of cases of both primary and secondary ana?niia, pernicious anaemia, and splenic tumour. He also found it in the blood in conditions in- ducing dyspnoea, notably in heart disease, pleurisy with eflFusion, pulmonary catarrh, pneumonia, and emphysema. Klemperer t has recently confirmed the results of Von Jaksch and others as to the presence of uric acid in the blood of leuco- cythsemia, and many observations have been made of the increased excretion of uric acid that accompanies this disease. Laache % found a daily excretion of 37 grammes (nearly six times the average normal amount) in a patient sufllering from this disease. Bartels § observed a daily excretion of 4 grammes (more than six times the average normal amount). Stadthagen || found a daily excretion of 2 grammes (three times the average normal amount). Bohland and • Deutsche medieiniiche Wochen'chrift, 1890, xxxiii., p. 741. t Deutsche mediciniscTie Woehenschrift, 1895, xxi.,p. 655. + " Klinische Urinanalyse," 1C92, p. 31. § Deutsche Archiv fiir klinische Mediciti, Band i"., p. 13. II J'irchotc's Archir, Band cix., p. 390. Sources of Uric Acid. 49 Scherz* found a daily excretion of 1'4 gramme (twice the average normal amount). Von Jaksch f concluded that the occurrence of iiric acid in the blood was due to diminution of the oxidising activity of the red corpuscles, and to consequent storing up in. the blood of the uric acid formed in the body, which, according to his view, is normally oxidised and destroyed. Horbaczewski's view, which will be considered later, that the formation of uric acid is due to the disintegration of leucocytes would equally apply, since in all the diseases in which Von Jaksch found uric acid in the blood, leucocytosis was present. More- over, there is no experimental proof to support the view that uric acid is oxidised and destroyed by oxygenated blood. On the contrary, there is experimental proof that the process of oxy- genation can, in the presence of nuclein, produce uric acid instead of destroying it. EENAL DISEASES ACCOMPANIED BY THE PRESENCE OF URIC ACID IN THE BLOOD. Von Jaksch t found uric acid in the blood of all the cases of renal disease that he examined, the proportions being especially large in cases of granular kidney disease and uraemia. Von Jaksch's results were confirmed by Klemperer,§ who ex- amined the blood of cases of contracted kidney, and * Pfliiger's Arehiv, Band xlvii., p. 13. f " Ueber die klinisohe Bedeutimg. Von Harnsaure und Xanthinbasen im Blut," 1890. J liOC. oit. § Loc. cit. E 50 The Pathology of Gout. found uric acid always present. Obviously this fur- nishes a further proof as to the renal origin of uric acid, when it can be shown that in such cases of kidney disease (not associated with gout) in which the uric acid excretion is diminished, uric acid makes its appearance in the blood. LEAD POISONING ACCOMPANIED BY THE PRESENCE OF URIC ACID IN THE BLOOD. Sir Alfred Garrod * examined the blood of nine patients suffering from plumbism, who had never suffered from gout, and found ap- preciable quantities of uric acid in the blood of seven out of the nine. Dr. Oliver f refers to the early stage at which anaemia becomes a prominent symptom of lead poisoning. Although no doubt the kidney mischief which occurs in connection with plumbism is responsible- for the appearance of most of the uric acid in the blood, by interfering with its excretion by the kidney cejls, yet it is possible that a small amount of the uric acid may result from the slight leucocytosis accompanying the anaemia of plumbism. PEVERS AND ABSENCE OF UUIC ACID FROM THE BLOOD. Von Jaksch found no uric acid in the blood of patients suffering from typhoid fever, intermittent fever, and acute rheumatism, nor in connection with diseases of the liver, stomach, and intestines, when unaccompanied by anaemia. His observations * •• A Treatise on Gout," 1876, p. 241. t Goulstonian Lectures on " Lead Poisoning," 1891. Sources of Uric Acid. 51 seem undoubtedly to prove that the presence ot uric acid in the blood is not a factor in the pro- duction of the so-called uric acid intoxication of fever. Fever, indeed, appears to influence un- favourably the production of uric acid. FOllMATION OF URIC ACII) DIFFERENT IN GOUT AND IN BLOOD DISEASES. It is evident that in connection with certain diseases, especially those in which leucocytosis occurs, uric acid in the form of sodium quad- riurate may be present in quantities in the blood, and yet not give rise to gout. The reason, in my opinion, is that in such diseases the kidneys being in a sound condition can readily eliminate the quadriurate. I believe that the seat or site of formation of uric acid is a different one in gout to what it is in these blood disorders, in which uric acid occurs in the blood without the development of gout. In gout I believe that all the uric acid present in the blood is absorbed from the kidneys, owing to some affection of those organs which interferes with the proper excre- tion of the uric acid formed in the kidneys. In cases of contracted granular kidney disease, and in cases of plumbism, the uric acid present in the blood is, I believe, derived from the same source, viz. from the damaged kidneys. In blood diseases and disorders the uric acid present in the blood i.s probably derived from the nuclein of the leucocytes and as the kidneys are in a sound condition it is readily excreted by them. CHAPTEK IV The renal origin of gout — Association of kidney affections with gout — Association of renal disease with the presence of uric acid in the blood — Nature of the kidney affection which causes gout. ASSOCIATION OF KIDNEY AFFECTIONS WITH GOUT. An interesting point to consider is whether gout ever occurs without preceding kidaey mischief of some kind or other. That is, whether, if the kidneys remain sound, it is possible for such an accumulation of uric acid to occur in the system as to produce an attack of gout. We will first ascer- tain whether there is any evidence that an affection of the kidneys (functional or organic) is associated with or precedes gout. In the first place it is time that the old idea should be abandoned that the healthy kidneys can only eliminate a certain amount of uric acid. That the healthy kidneys are capable of separating from the blood and ex- creting large quantities of uric acid is shown by the observations, previously referred to, of Laache, Bartels, Stadthagen, and Bohland and Scherz, on the excretion of uric acid in cases of leucocythsemia. In this disease the blood is laden with uric acid, and all these observers found a greatly increased daily excretion of uric acid, varying from twice to over six times the normal amount. This large O excretion of uric acid by the kidneys shows that Gour AND Kidney Affections. 53 urates do not themselves cause damage to the uric acid-secreting cells of the kidneys VIEWS AS TO THE ASSOCIATION OF GOUT AND KIDNEY DISEASE. Sir Alfred Garrod, Sir William Roberts, and Levison all attribute the accumulation of uric acid in the blood of gouty persons to deficient excretion rather than to increased production. Sir Alfred Garrod' holds the view that among the causes exciting a gouty fit is a functional failure of eliminating power for uric acid on the part of the kidneys. He also considers that this early func- tional failure is followed in cases of chronic gout by structural kidney disease. His view is that the uric acid present in the blood of gout is formed in the kidneys, and is absorbed from them into the blood. This view is quite compatible with the theory that a defective capacity of the kidneys for the excretion of uric acid is the primary patho- logical cause of gout. Levison * states that gout is not accompanied by leucocytosis, and therefore the nuclein of leucocytes is not available for the production of uric acid. He considers that gout cannot be developed unless a primary renal lesion is present, and that this is almost invariably of the nature of an interstitial change. Vogel t estimated, in three cases of chronic gout, the intake of nitrogen by analysis of the food and the output of nitrogen in the urine and faeces. He found that there was * "The TJrio Acid Diathesis," 1894. ' t Zeitsohrift fur klinische Medicin, xxiv., p. 512. 54 The Pathology of Gout. a nitrogen retention greatly in excess of what could be attributed to a retention of uric acid. Yogel states that his patients behaved, in this respect, like sufferers from renal disease, although the clinical signs ot' granular kidney mischief were wanting in all the cases. In connection with this, ■ it must be borne in mind that the absence of the clinical signs of disease of the kidneys does not necessarily imply integrity of those organs. ASSOCIATION OF KENAL DISEASE WITH THE PHE- SENCE OF URIC ACID IN THE BLOOD, AND WITH UKATIC DEPOSITS IN THE JOINTS. As previously mentioned, Von Jaksch found considerable quantities of uric acid in the blood of all the cases of diseases of the kidneys that he examined, and his results were confirmed by Klemperer. It is well known that uratic incrustation of articular cartilages is not un- commonly found at the post-mortem examina- tions of subjects who have never been known to suff'er from ostensible gout during life. Drs. Ord and Greenfield* examined a number of bodies in the post-mortem room for the existence of uratic deposits in the joints, and the presence of kidney disease. Among 96 cases presenting lesions of the kidneys, uratic deposits were found in the joints of 18. Dr.' Norman Moore, f Avho bases his observations on the results of a large number of post-mortern examinations, states that * " Tianeaotiona of the International Medical Congress at London, 1881," vol. 11., p. 107. \ '• St. Baitholomew's Hospital Reports, 1887," vol. xxiii. Gout and Kidney Disease. 55 chronic interstitial nephritis is found in a large proportion of those bodies in which sodium urate is to be seen in the joints. He found that chronic interstitial nephritis is not invariably accompanied by the presence of sodium urate in the articular cartilages, though it is usually accompanied by some traces of degeneration in some of the articular cartilages. He examined the following number of cases, all of which, as far as could be ascertained, had never suffered frem ostensible gout. Kidney disease. No. of cases. Uratie deposit in joint or joints. Chronic interstitial nephritis Chronic parenchymatous ne- phritis 53 U 25 2 Levison * is a strong supporter of the view that there is always some degree of antecedent renal disease connected with gout. In reply to criticisms of this view he points out that the post-mortem examinations of gouty patients have generally shown renal lesions, and that the few exceptional cases are open to criticism. He states that all the post-mortem examinations of patients dying of granular kidney disease at the Communal Hospital, Copenhagen, during a period of fourteen months, showed uratie deposits in one or other of the joints, although most of the patients were not known to have had any definite gouty attack I thought that it would be a matter of interest to ascertain the proportion of cases of uratie deposition in the joints occurring in subjects in * Zeiischrift fiir kliuische Medicin, 1894, xx^i., p. 293. S6 The Pathology of Gout. whom granular disease of the kidneys was found at the post-mortem examination, and in connection with whom the previous history as to the occur- rence or not of gout was known. For this purpose I obtained the help of some of the pathologists at the London hospitals, who have kindly examined the joints in such cases whenever they were able to do so. I have collected altogether the results of 77 such examinations, for which I am indebted to the kindness of Dr. Cyril Ogle, Dr. F. J. Smith, Dr. Hebb, and Mr. Jackson Clarke. These 77 cases were all cases of granular kidney disease, and in 41 cases uratic deposits were found in one or more of the joints. The distribution of uratic deposits among the gouty and non-gouty cases is shown in the following table. TABLE II. Showing the reiulCs of the examinations of the joints of 77 cases of granular kidney disease. No. of cases. Uratic deposit in joint or joints. Known to have had gout „ . Never known to have had gout 10 67 10 31 Totals 77 41 In the 10 cases known to have had gout, uratic deposits were found in one or more of the joints of all, and the kidney condition was in every case described as " markedly granular " or " fairly granular." Among the 67 cases of granular kidney disease Gout and Kidney Disease. 57 not known to have suffered from previous gouty attacks, uratic deposits were found in one or more of the joints of 31— rthat is, in 46 per cent, of the cases, which closely agrees with the 47 per cent, found under similar conditions by Dr. Norman Moore. In these 67 cases are included all cases which showed the existence of any granular kidney disease, but several of the cases in which no uratic deposits were found were described as only " slightly granular " or " faintly granular." If from the 67 cases a selection is made of those described as "markedly granular," or as " typical granular kidneys," then the proportion of cases in which uratic deposits were found in the joints appears as follows : — No. of cases. Uratic deposit in joint or joints. Marked granular kidney 1 disease ... ... ... j 26 20 Thus it is seen that among the cases of marked granular disease of the kidneys occurring in persons who were never known to have suffered from ostensible gout during life, uratic deposits were found in the joints of 77 per cent, of the cases. These results, taken in conjunction with those of Dr. Norman Moore and of Levisbn, show that kidney disease exercises a powerful influence in causing an accumulation of uric acid in the blood, and consequently in producing uratic deposits in the joints. 58 The Pathology of Gout. gouty affections of the kidneys not always kevealed clinically. It has been urged that if kidney disease, with the consequent diminished excretion of uric acid, be the primary factor in the causation of gout, signs of kidney mischief would always manifest themselves prior to an attack of gout, and that very few such cases have ever been recorded. But, in the first place, it must be remembered that such signs are not usually looked for, and, in the second place, they need not necessarily reveal themselves clinically. It is well known that contracted granular kidney is not always evidenced either by the occurrence of albuminuria or of dropsy. The contention that if organic renal failure existed the urea excretion would probably be equally afi'ected together with that of uric acid does not hold good, if the view is adopted that uric acid is produced in the kidneys, while urea is only eliminated by them. It is well known that in gouty subjects the kidneys have been found at the post mortem examination in a diseased condition, when there have been no external manifestations during life of the existence of such renal mischief. That uratic deposits are frequently found in the kidneys of gouty subjects is a matter of common experience, but in the absence of such deposits the kidneys may still be afi'ected. Sir Dyce Duckworth believes that changes occur in the kidneys of gouty subjects quite independently of uratic deposits in these Gout and Plumbism. 59 organs. It has been urged that the renal theory is difficult to harmonise with the hereditary character' of gout. It is quite possible, however, that there may be in gouty subjects an hereditary tendency to the renal affection,, since both Dr. Dickinson and Eichorst have shown that there is an hereditary tendency to granular kidney. KIDNEY DISEASE AND GOUT ALIKE CAUSED BY CERTAIN TOXIC AGENTS. Certain toxic 'agents, which predispose to or which excite kidney disease, are also known to produce gout. Lead gives rise to both chronic kidney disease and gout. In chronic lead-poison- ing proliferation of the epithelium of the urinary tubules first occurs, followed by granular atrophy and excessive formation of interstitial tissue. In numerous cases of chronic lead-poisoning gout has developed. Very similar changes occur in the gouty kidney, and it seems reasonable to assume that the changes in that organ in both chronic lead-poisoning and in gout so affect the excreting apparatus of the kidneys as seriously to diminish their power of eliminating uric acid. That lead-poisoning gives rise to the accumula- tion of uric acid in the blood has been shown by Sir Alfred Garrod. Gout subsequently de- veloped in two cases of plumbism in which the blood was found by him to be rich in uric acid. He also determined the excretion of uric acid in the urine of two patients to whom acetate of lead had been medicinally administered. In both 6o The Pathology ob Gout. patients a well-marked diminution of uric acid in the urine occurred. It was also noticed that after the lead had been given for a day or two, the excretion of the uric acid in the urine was suddenly diminished to a very small amount — a condition which usually lasted for a day or two. This points to the fact that lead exercises a marked inhibitory effect on the cells of the kidneys concerned in the excretion of uric acid. The action of the lead is not due to inhibition of the formation of uric acid, since in cases of plumbism the blood becomes charged with uric acid. Alcohol is another body which in excessive quantities gives rise to kidney mischief, and which may also give rise to gout. REASONS FOR BELIEF IN THE RENAL ORIGIN OF GOUT, There is abundant evidence to show the connection between kidney mischief and gout for the following reasons : — (1) Uric acid has, in every case in which it has been specially searched for, been found in the blood of cases of renal disease ; (2) uratic deposits are fairly frequently found in the joints of persons who have suffered from renal disease, but who have never been known to have had ostensible gout; (3) kidney mischief is fre- quently met with at the post-mortem examinations of gouty subjects ; and (4) certain toxic agents predispose to both kidney disease and gout. The statement has been made that the absence of ostensible gout in those cases of kidney disease Re.val Ok/gin of Gout. 6i in which uric acid has been found during life in the blood, and in which uratic deposits have been found in the joints after death, would rather point to the conclusion that something more than the presence of uric acid in the blood and the deposition of biurate in the joints is necessary in order to produce gout, and that therefore uric acid may be merely a by-product in that condition of the system called gout- This statement is based on an imperfect acquaintance with the different modes of deposition of sodium biurate. In my opinion, the reason why deposits of sodium biurate are so frequently found at post-mortem examina- tions in the joints of persons who have suffered from granular kidney disease, but who have never been known to suffer from ostensible gout during life, or to complain of pain in the joints in which the deposits are subsequently found, is that in such cases the deposition of the biurate into the j I lints has been very slow and gradual and has never become excessive, whereas a some- what sudden and copious deposit is required to produce an attack of acute or subacute gout, and a considerable ajnount must be present in the joints to produce the deformities of chronic gout. Moreover, the fact that uric acid is found in smaller proportions in the blood of cases of granular kidney disease than in cases of gout explains why, in connection with the former affection, the de- position of the biurate into the joints may be so slow and gradual as not to produce the symp- toms of ostensible gout. 62 The Pathology of Gout. nature and anatomical seat of the kidney affection causing gout. The next question to consider is — What is the renal lesion which, by interfering with the proper excretion of uric acid by the kidneys, allows absorption of it to take place from those organs into the general circulation, and so starts the gouty state? In my opinion the kidney affection may be either a functional one or an organic one. My belief is that a functional affec- tion of the kidneys always precedes any gouty manifestations, and that this functional affection may subside, if the exciting cause of it be removed or it may pass on to a structural lesion. It is the liability to this functional affection of the kidneys which, in my opinion, constitutes the hereditary factor of gout. Such functional affection may however, be started by various agents and causes among which are excessive indulgence in nitro- genous foods, wines and beers, the toxic effect ox lead, and the influence of nervous impulses, such as mental shocks, severe accidents, etc. The ana- tomical seat of the presumed kidney affection giving rise to the development of gout is probably in the epithelium of the convoluted tubes, as that has been shown by Levison * to be the primary seat ot disease in granular kidney, and by Oliver to be the seat of the kidney affection associated with lead poisoning. The increase of interstitial tissue is probably a secondary change. * Zeitachrift fur klinische Medicin, 1894, xxvi., p. 293. Gout and Kidney Affections. 63 If this renal view be correct, it is obvious that the kidney condition must always be considered in the treatment of gout, and that, given diseased organs incapable of eliminating the normal amount of uric acid, either some other channel for its elimination raust be secured or its formation must be limited to the diminished outpiit, so that absorption of it into the general circulation may be avoided. The retention ( f uric acid in certain cells of the kidney, and its subsequent absorption into the blood, is analogous, as Sir Alfred Garrod has pointed out, to an attack of jaundice. When no obstruction exists to the exit of bile from the biliary passages, no appreciable amount of its colouring matter is found in the blood, but when its free elimination is checked, then absorption of it into the blood speedily takes place. 64 CHAPTER Y. Or it/in of uric acid — Formation of uric acid from urea in tlhe kidneys — Uric acid formation and liver disease — Formation of uric acid from nuclein — Different modes of formation of uric acid in health and in blood disorders. VIEW THAT URIC ACID IS THE RESULT OP DIMINISHED OXIDATION. A COMMONLY received notion as to the origin of uric acid is tliat it results from a less perfect oxidation of the nitrogenous constituents of the tissues than occurs when urea is formed. Ac- cording to this view urea is the ultimate product of the metabolism of nitrogenised tissues in mam- mals, whereas the formation of uric acid is con- sidered as occupying an intermediate stage in the metabolism of nitrogenised tissues. In birds and serpents it has been supposed that the nitrogen is eliminated in the form of ammonium quadriurate without having undergone the further change into urea. This notion is mainly based on the observa- tion of the two following facts : (1) That uric acid by means of oxidising agents can be split up into urea and other substances ; (2) that in certain reptiles whose respiration is languid, and whose temperature is low, the kidneys excrete uric acid to the entire exclusion of urea. The inference that the production of the uric acid in such repitiles Diet and Uric Acid. 65 is the result of imperfect oxidation is, however, disproved by the well-known fact that birds, whose respiration is rapid, and whose temperature is higher than that of mammals, also, like reptiles, excrete uric acid to the exclusion of urea. So that, although uric acid is a less highly oxidised product than urea, it is very doubtful whether it can be considered as an antecedent in the formation of urea VIEW THAT EXCESS OF URIC ACID IS THE RESULT OF AN ANIMAL DIET. Another commonly received notion is that gout is accompanied by an excessive formation of uric acid, which is usually attributed to the ingestion of a too highly nitrogenised diet, and especially to an animal one. Virchow,* however, considers that a too highly nitrogenised diet is not necessarily the cause of gout, because he has often observed gout in poorly-fed convicts. Gout is certainly not incompatible with a vegetable diet, as, amongst certain birds kept in captivity and living exclusively on grain, uratic deposits have been observed around the joints. On the other hand, animal food does not necessarily produce uric acid in a healthy system, as is shown by its absence from the urine of some of the carnivora. It is true that the ingestion of very large quantities of proteid matter is followed by an increased production of uric acid, and, vice versd, but ap- parently it makes little, if any, difference whether the proteid matter is of animal or of vegetable * Berliner kliniache TFochentehri/t, 1884. 66 The Pathology of Gout. origin. The only reason that a vegetable diet is less productive of uric acid than an animal diet, is in the fact that the former is poorer in proteid material, and therefore to consume in the vegetable diet as much proteid matter as is ordinarily con- sumed in an animal diet would require the in- gestion of very large bulks of vegetable food. Therefore the assumption is not altogether correct that the total daily excretion of uric acid is greater on an animal than on a vegetable diet. With the same intake of nitrogen in the two diets, there is practically no difference in the uric acid output. This is shown by the experiments of Bleibtreu,* who examined his urine after three days' flesh diet and after three days' vegetable diet. Although after the flesh diet there was a considerable rise in the amount of urea excreted, there was very little difference in the uric acid excretion. After the three days' flesh diet the uric acid excreted in twenty-four hours was 0'859 gramme, while after the three days' vegetable diet it was 0'791 gramme. Similar results were obtained by Hirschfeld,+ who found that on a diet very poor in nitrogen he excreted daily 0'417 gramme of uric acid; on one rich in albumen 0386 gramme ; and on a highly albuminous diet 0492 gramme. That the production of uric acid is not depen- dent, at all events to any great extent, on diet is also shown by the fact that the same diet which in one class of animals will produce uric acid will in * Pfliiger's Archiv, Baud xlv., p. 401. f Virchow'a Archiv, Band cxvii., p. 301. Renal Excretion. 6y another class produce urea. Thus, in the urine of the carnivorous lion and tiger there is a quantity of urea and but very little uric acid ; on the other hand, the carnivorous python and boa excrete uric acid and no urea. Graminivorous birds excrete uric acid and no urea, whilst herbivorous mammals ex- crete quantities of urea and but little or no uric acid. Sir William Roberts,* comparing the functions of the kidneys of birds and serpents with those of mammals, considers that an immense functional evolution has taken place in the mammalian kidney ; that the evolution of mammalian urine has probably turned mainly on the point that the mammalian plan required that the renal excretion should be voided not in the solid or semi-solid form, but as a watery solution. This modification would require the discarding of the sparingly soluble uric acid as a medium for the elimination of nitrogen, and the substitution of a nitrogenous substance readily soluble in water, such as urea. He considers it possible that the reason why this substitution has not been completely effected is that in that particular the mammalian type has not yet reached its ideal perfection, and that the residuum of uric acid in mammalian urine may be something in the nature of a vestigial feature. VIEW THAT URIC ACID IS FORMED FROM UREA IN THE KIDNEYS. In mammalia, including man, and in birds uric acid is absent from the blood in health, * Croonian Lectures on " Uiic Acid Gravel and Gout," 1892, p. 33. 68 The Pathology of Gout. while urea is always present in the blood. The blood of the renal artery is much richer in urea than the blood of the renal vein : according to Picard in the proportion of about two to one, according to Sir Alfred Garrod in the proportion of about three to one. From his most recent observations, Sir Alfred Garrod * concludes that in birds and other uric acid-excreting animals the metabolism of the nitrogenised tissues is exactly the same as in mammals. He believes that urea is the ultimate product of this metabolism, and that the uric acid is a subsequent product of the union of urea with some other principle or prin- ciples, glycocine probably being one of them. He regards the kidney as the organ whose function it is to manufacture uric acid from the nitrogenised matters brought to it in the blood, and considers it possible that the kidney contains different cells — some for the formation of urea, and some for the formation of uric acid — and that the ratio between the two may vary in different classes of animals. One very strong argument against the forma- tion of uric acid in the liver, spleen, connective tissues, etc., is that it is never present in the blood of mammals (including man) and of birds in health. If it were formed in such organs or tissues, it must be conveyed in the blood to the kidneys. Since, according to Sir Alfred Garrod 's and my own investigations, urea, and not uric acid, is found in the blood of birds, and since uric acid, and not urea, is found in the urinary excrement of birds, it * ''Proceedings of the Eoyal Society," 1893. Formation of Uric Acid. 6g seems highly probable that urea is at least one of the sources of formation of uric acid, and that the conversion of urea into uric, acid is effected in the kidneys. Dr. P. W. Latham's * explanation of the formation of uric acid in the animal economy is that the amido-bodies, glycocine, taurine, leucine, and tyrosine, are normally converted in the liver into urea, but if from any cause the metabolism of glycocine be interrupted, there would then be present in the liver glycocine and urea, which would produce hydantoic acid, and then hydantoin, and the latter, which is freely soluble, would then pass on in the circulation to unite in the kidneys with urea or with biuret to form an ammonium salt of uric acid. Therefore, according to this view, the imperfect metabolism of glycocine is the primary and essential defect in connection with the abnormal formation of uric acid in the human system. According to Dr. Latham the synthesis of uric acid from urea and glycocine takes place in the following steps : — 1. The urea and glycocine produce hydantoic acid — ' CH4N2O + CaHjCNHjjO.OH = C3H5N2O3 + NH3. Urea Glycocine Hydantoic acid 2. The hydantoic acid becomes dehydrated and forms hydantoin — C3H6N2O3 = C3H4NA + H^O. Hydantoic acid Hydantoin 3. From more of the urea biuret is produced — 2 CH^NjO = CjHsNjOa + NH3. Urea Biuret * " Croonian Lectures," 1886. 70 The Pathology of Gout. 4. By combination of hydantoin and biuret uric acid is produced — C3H4NJO2 + CjHsNaO^ = C5H4N4O3 + NH3 + H^O. Hydantoiu Biui'et Uric acid The production of uric acid from urea and glycocine may be shown in a single equation as follows — 3 CH4N2O + C2H2(NH2)O.OH = C5H4N4O3 + 3 NH3 + 2 HjO. Urea Glycocine Uric acid FACTS SUPPORTING THE VIEW THAT URIC ACID IS FORMED FROM UREA AND GLYCOCINE. There are several reasons for believing that uric acid may be formed from urea and glycocine in the living organism. Horbaczewski produced uric acid by the interaction of urea and glycocine, and this result was confirmed by Dr. Latham. Glycocine is certainly formed in the human body, and prob- ably is one of the antecedents of urea, for in man, glycocholic acid, a compound of glycocine and cholic acid, passes in the bile into the intestine, and having served its purpose, and its constituents having been set free, the glycocine, together with the other amido-bodies, taurine, leucine, and tyrosine, pass in the portal blood to the liver, and probably in the hepatic cells are converted, or mainly con- verted, into urea. That glycocine is concerned in the production of uric acid is somewhat probable from the fact that in the carnivora, whose urine contains little or no uric acid, the bile contains no glycocholie but only taurocholic acid, and therefore yields no Formation of Uric Acid. yi glycocine. The experiments of Hahn, Massen, Nencki, and Pawlow also support the view that glycocine is concerned in the formation of uric acid. They shut the livers of dogs almost com- pletely off from the general circulation by diverting the portal circulation into thei inferior vena cava, and so caused an increased amount of glycocine to be sent to the kidneys, by preventing its conversion into urea in the liver. They found that, although the dogs passed less urea (the nitrogen being mainly eliminated as ammonium carbamate), the urid acid voided was considerably increased. Dr. Latham* believes that if an excessive amount of nitrogenous material is introduced into the portal circulation, the portion which is least readily acted upon is the glycocine, the presence of which promotes the formation of uric acid. He considers that the primary defect in gout consists in the imperfect metabolism of glycocine. We may therefore conclude that the conversion of urea into uric acid by the agency of certain of the kidney cells is at least possible, and that this conversion is eftected by the conjugation of urea and glycocine. URIC ACID FORMATION AND LIVER DISEASE. If uric acid be formed in the kidneys from urea and glycocine brought from the liver, it can be readily understood that alterations in the meta- bolism of the liver must necessarily affect the forma- tion and excretion of uric acid. This would explain why liver trouble of some kind or another is so * Loo. cit. 72 The Pathology of Gout. commonly associated with gouty dyspepsia, and also renders intelligible the fact that several observers have been unable to dissociate the connection between liver troubles and gout, and have therefore attributed the formation of uric acid to the liver. For instance, Dr. Murchison considered that gout is a hereditary disease by virtue of the transmission by parents to their offspring of a defective power of the liver, in consequence of which its functions are deranged with unusual facility ; as a result of this derangement of the liver the metabolism of the albumen is to a great extent arrested at the stage of uric acid formation, instead of going on to the final stage of urea formation. Dr. George Harley considered that a strong relationship existed be- tween gout and hepatic derangements. Sir Dyce Duckworth* is of opinion that "the liver is the organ in which in health uric acid is chiefly formed, and it is probably to derangement of function in this gland that we must look for over-production of this substance." All these views are rendered equally, if not more, intelligible by regarding the liver as the seat of production of the antecedents of uric acid (urea and glycocine), the final conjugation of those bodies taking place in the kidneys. VIEW THAT URIC ACID IS FOllMED FROM NUCLEIN. Horbaozewski | has shown that uric acid, as well as xanthin and hypoxanthin, can be prepared from • "A Treatise on Gout," 1889. t " Beitriige zur Kentnisae der Bildung der Harneaure und der Xanthinbasen." Sitzungsbericht der K. Aoad. d. Wiss in Wien. C, ill,, 1891, Formation of Uric Acid. 73 spleen pulp. The close relationship of these three bodies to one another is shown by a comparison of their formulae — C5H4N4O3 TJric acid. C5H4N4O2 Xanthin. C5H4N4O Hj-poxanthin. By digesting fresh spleen pulp with hot water till changes set up by bacterial agency are started, he found that the fluid, when freed from albuminous bodies, contained xanthin and hypoxanthin, but no uric acid. By treating this fluid with arterial blood and keeping the mixture at 40° to 50° C, uric acid forms in it after several hours. A similar result is produced by using as the oxidising agent either a dilute solution of hydrogen peroxide, or an abundant supply of atmospheric air. Horbaczewski found that the nitrogen contained in the uric acid so formed was about equal in amount to the nitrogen contained in the xanthin and hypoxanthin (xanthin bases). So that there exist in the spleen nitrogenous substances which can be transformed, at all events in part, into xanthin bases or into uric acid. The xanthin bases when once formed cannot be further oxidised into uric acid. Horbaczewski brings forward proof that the substance which yields xanthin bases and uric acid is the nuclein ot the spleen cells. It was found that when pure nuclein, prepared from spleen pulp, was dissolved in very weak alkali, and digested with blood at 40° C, uric acid was formed. Sadowenj and For- manck have shown that uric acid can be prepared in a similar manner from almost all the tissues and 74 The Pathology of Gout. organs of the body, and conclude that the nuclein contained in the cells is the mother-substance. It having thus been shown that uric acid could be prepared from nuclein outside the system, an attempt was next made to ascertain whether a similar decomposition could also occur in living human beings. Horbaczewski found that the excretion of uric acid can be increased either by the administration of nuclein with food, or by the subcutaneous injection of a solution of it. Umber * found that the administration of a large amount (500 grammes per diem) of food like thymus, which contains a considerable quantity of nuclein, increases the excretion of uric acid as compared with its excretion when a similar amount of flesh is given. The same amount of liver given to one person caused an effect similar to that caused by thymus, but in others its action was less marked. Kidney and brain administered as food yielded nearly the same amount of uric acid as flesh. From his experiments Horbaczewski concludes that uric acid is formed in health by the dis- integration of nuclein, and that sudden variations in uric acid production may be due to the breaking up of leucocytes and conversion of their nuclein into uric acid or xanthin bases within the system. It has been shown by many observers that a temporary or permanent leucocytosis is always accompanied by an increased excretion of uric acid. A relationship between the number of * Zeitsehrift fUr Idiniaehe Medicin, 1896, xxix., pp. 174-189. FonMATioN OF Uric Ac/d. 75 leucocytes in the blood and the excretion of uric acid is observable in human beings during fasting and after taking food. During fasting the number of leucocytes diminishes, and the amount of uric acid excreted falls ; after taking food the number of leucocytes increases, and the amount of uric acid excreted rises. The increase in the number of leucocytes in the blood after a meal appears to be due, at all events in part, according to Hofmeister, * to the rapid increase of lymph cells in the adenoid tissue of the stomach and intestines during digestion, whence they are discharged into the lymph stream, and finally into the blood. Gamprecht t — who uses the term '■ alloxur bodies " in Kossel and Kruger's sense as meaning those bodies which have an alloxan and urea nucleus, and therefore as including, besides uric acid, xanthin, guanin, hypoxanthin, adenin, and their derivatives — found that in the exceptional cases of leucocythsemia in which the uric acid excretion is normal or diminished, the alloxur bases are increased, and that their amount varies directly with the amount of leucocytosis. He gives one case of his own in which this is shown very clearly, and points out that it forms an additional support to Horbaczewski's view that uric acid comes from degeneration of leucocytes, and is formed from their nuclein. From a consideration of all the work that * ArcMv fiir Sxper. Pathologle und Fharmakologie, Band xxii., p. 306. •f Centralblatt fiir allgemeine Pathologie und pathologischen Anatomic, 1896, vol. vii., p. 820. "jS The Pathology of Gout. has been done in connection with leucocytosis and the excretion of uric acid, it is clear that there is no constant ratio between the number of leucocytes and the amount of uric acid excreted, for there may be leucocytosis without increase of uric acid, as there may be an increase of uric acid without leucocytosis. I think that in cases of leucocythsemia, severe anaemia, etc., where uric acid is present in the blood, it is probably derived from the nuclein of leucocytes or other cells. It is, however, in my opinion, wrong to draw the further inference that the source of the uric acid excreted in health is the nuclein derived from leucocytes throughout the body. If such irere the case, uric acid would be found in the blood in health ; but, as previously shown, it is not. Moreover, in birds there is no special leucocytosis to account for the large formation and excretion of uric acid that occurs. In connection with leucocythaemia, anaemia, etc., the excretion of uric acid in the urine may rise to six times the normal amoimt, and yet no signs of gout appear. The reason lor this non- development of the symptoms of gout in connec- tion with these diseases is that the kidneys remain in a sound condition, and therefore the v/ric acid (which in these diseases is probably derived from nuclein) is readily and rapidly excreted by them. This knowledge of the derivation of uric acid from nuclein in connection with diseases associated with leucocytosis has, in my opinion, proved a stumbling-block to many writers and Diet and Uric Acid. 77 observers in their conception of the pathogenesis of gout. For it by no means follows that because in diseases associated with leucocytosis the uric acid which appears in the blood is derived from nuclein, therefore such must be its source in gout. The simple fact is that gout is not a disease associated with leucocytosis, and therefore the uric acid of gout cannot be derived from nuclein. VIEW THAT PART OF THE URIC ACID IS INTRO- DUCED READY-FORMED IN FOOD. Dr. Haig, who in my opinion wrongly ascribes to uric acid an almost universal role in the causa- tion of disease, claims that the uric acid excreted in the urine comes from two sources: — (1) The uric acid which is formed in the body out of nitrogenous food ; (2) the uric acid introduced into the body ready-formed in certain articles of diet, such as meat, meat extracts, soup, tea, coffee, etc. He considers that flesh diet increases both the introduction and the formation of uric acid, a view which is opposed to the previously quoted ex- perimental results obtained by Bleibtreu and by Hirschfeld. Dr. Haig * gives the quantities of uric acid which a man may introduce into his system with an ordinary dinner as follows : — grain. 8 oz. soup . . containing 0"02 per cent, uric acid = 0-70 2 oz. fish . . „ 003 „ „ = 0-26 3oz. meat . . ,, 0-04 „ ,, =0-52 i drachm meat extract „ 080 ,, ,, = 0'24 1-72 * Brit. Med. Journ., 18 0-0.5 „ „ 0-72 0-02 „ „ 0-90 0-01 „ „ 0-94 i} 144 Author's Investigations. From the foregoing table it is seen that the mineral constituents of milk in all proportions diminish the . solvency of sodium biurate. The effect is most marked when O'l per cent, of milk ash is present. It is extremely unlikely that such a proportion could be present in the blood unless a person were exclusively fed for some time on milk. To introduce 01 per cent, of the mineral constituents of milk into the blood would require that all the mineral constituents of about twenty- two ounces of milk should be introduced at one moment into the blood of an adult of average weight. These experiments therefore seem to indicate that the mineral constituents of milk can exercise no appreciable influence in hastening or maturing an attack of gout. TABLE XIV. Showing the influence of the mineral constituents of vegetables (potatoes, spinach, and beans) on the solubility of sodium biurate at 100° F. Solvent. Sodium biurate dissolved. Water 110 per 1,000 Water containing : — 1-0 per cent, of vegetable ash 215 )} 0-5 „ „ 1-70 M 0-2 „ „ 1-35 »» 0-1 „ „ 1-15 )) 0'05 „ „ 1-10 002 „ „ 1-10 jj 001 „ „ 1-10 JI From Table XIV. it is seen that the mineral constituents of vegetables in quantities Alcoholic Beverages and Gout. 145 of 01 per cent, and above very appreciably increase the solvency of sodium biurate. In quantities below 01 per cent, the solutions exercise the same solvent power on the biurate as distilled water. These experiments indicate that the mineral constituents of vegetables, if taken in sufficient quantities, would delay the advent of an attack of gout by their increasing the solvency of sodium biurate, and would also exert a solvent effect on gouty deposits, INFLUENCE OF ALCOHOLIC DEINKS ON THE GOUTY PROCESS. It is well known that certain alcoholic drinks injuriously affect the gouty process, whilst others exert a less injurious influence. Alcoholic drinks which have been obtained by fermentation, but which have not been submitted to distillation, such as wines and beers, appear to exercise a more harmful influence than if the same amount of alcohol be consuined in the form of one of the distilled spirits, such as whisky, brandy, etc. Garrod considers that the reason for the prevalence of gout in the south of England and its rarity in Scotland is chiefly due to the different beverages drunk in the two countries. Distilled spirits contain little or no acid, whilst wines and beers are distinctly acid, and to the acids contained in these drinks many physicians have attributed, and still do attribute, their gout- inducing properties. The acids present are tartaric, 146 Author's Investigations. succinic, malic, acetic, formic, propionic, butyric and cenantliic. The acidity of wines is mainly due to tartaric, malic and succinic acids. The amount of free acid in sound wine, reckoned as tartaric acid, varies between 0'3 and 07 per cent. I found the acidity of some 1847 port, reckoned as tartaric acid, to be 6 per cent. Cider owes its acidity mainly to malic acid. Its total acidity is usually 01 per cent. If we arrange the various wines in (a) their order of acidity and (6) the order of their gout-inducing power, we find that the most acid wines are not those which most predispose to gout. The arrangement of wines and beers in the order of acidity, beginning with the most acid, is that given by Dr. Bence Jones, while the arrangement in order of their gout-inducing power is that given by Sir Alfred Garrod : — • TABLE XV. Wines and been arranged in order of acidity and gout-inducing power. (a) Acidity {beginning with the . (V) Gout-inducing power (beginning most acid). with the most powerful). Moselle Port Ehine wines Sherry Burgundy Other stronger wines Madeira Champagne Claret Stout and porter Champagne Strong ales Port Claret Sherry- Hock Malt liquors Moselle Weaker kinds of ales Claret, hock, moselle and the weaker kinds of ales have comparatively little gout-inducing power. Alcoholic Beverages and Govt. 147 gout-inducing properties of certain wines and beers not due to acids or sugar. Sir Alfred Garrod considers that acidity ot alcoholic liquors cannot have much influence in determining an attack of gout, as port, sherry and malt liquors, which are the most powerful pre- disposing agents, are amongst the least acid, whilst the more acid wines, such as clarets, are com- paratively harmless in this respect. This opinion is entirely borne out by the experiments I have described, which show that a diminution of the alkalinity of blood serum does not hasten the con- version of sodium quadriurate into biurate, does not diminish the solubility of sodium biurate, and therefore cannot promote deposition of sodium biurate, and so be a determining cause of an attack of gout. The question is — to what constituent or constituents of wines and beers are their gout- inducing properties due ? They are not due to the alcohol alone, for in countries such as Scotland, Norway, Sweden, and Poland, where distilled spirits are, or were, "freely consumed, gout is almost un- known. Moreover, several experiments that I have made indicate that alcohol, in such quantities as are ever likely to be present in the blood, has no effect either upon the conversion of sodium quadriurate into biurate or on the solubility of the latter. The gout-inducing properties are most probably not due to the acids of the wines and beers, for the reasons which have already been given. They are also most probably not due to the 148 Author's Investigations. sugar. The late Dr. George Harley experimentally investigated the subject, and stated that the popular notion as to the pernicious effects of sugar in cases of gout is open to grave criticism, seeing that not only can no reliable facts be adduced in favour of the statement, but no reliable authority for the assertion can be cited even by its believers. I have myself found experimentally that sugar has no appreciable effect either on the decomposition of sodium quadriurate, or' on the solubility of sodium biurate. PROBABLE CAUSE OF THE GOUT-INDUCING PROPERTIES OF CERTAIN WINES AND BEERS. The gout-inducing properties are certainly not directly due to the cenanthic ether and other ethereal salts of wines exerting any effect either on the rate of decomposition of the sodium quadriurate or on the solubility of the biurate. To demonstrate these points I have extracted from old port wines the ethereal salts to which the bouquet of the wines is due, and have experimented with these ethereal compounds on the quadriurates and biurates. Using quantities far in excess of those likely to be present in the blood after the moderate, or even immoderate, consumption of such wine, I find that none of these volatile constituents exercise the slightest effect either in hastening the decomposi- tion of the sodium quadriurate or in diminishing the solubility or hastening the precipitation of sodium biurate. As to the modus operandi of certain wines, such as port, etc., in hastening an Wines and Gout. 149 attack of gout, I incline to the opinion that the influence of wines on the development of gout is in great part due to the effect they exercise on the metabolism of the liver, and the consequent in- creased amount of glycocine that passes on to the kidneys. This increased amount of glycocine would then cause an increased production of uric acid in the kidneys, and provided there be deficient elimination of it from those organs, absorption of the surplus uric acid would take place into the genera;l circulation. At the same time, it must be remembered that those accustomed to drink wine are also able to indulge in other luxuries of the table which greatly favour the development of gout. ISO CHAPTER XII. , Experimental investigation of the relative effects exerted hy the mineral constituents of various vegetables on the solubility of sodium biurate — Experimental investigation of tlie influence exerted hy the mineral constituents of various vegetables in retarding the conversion of sodium, quadriurate into biurate — The vegetables most beneficial to gouty subjects. From the results of tlie preliminary experi- ments described on p. 144, it appears probable that if the mineral constituents of vegetables were present in sufficient quantities in the fluids of a gouty person, they would not only delay the advent of an attack of gout by increasing the solubility of the sodium biurate present in these fluids, but would also, by their increased solvent effects on uratic deposits, facilitate the removal of the latter. I have therefore carried out a long series of ex- periments with the mineral constituents of all the vegetables in ordinary use, in order to elucidate the two following points : (1) the relative effects exerted by the mineral constituents of various vegetables on the solubility of sodium- biurate at the temperature of the human body, and therefore presumably on uratic deposits ; and (2) the in- fluence, if any, exerted by these constituents in retarding the conversion of the sodium quadri- urate, which is present in the fluids of the body in gout, into the sodium biurate. Obviously the Experiments with Vegetable Ashes. 151 elucidation of these points would have a material bearing on the treatment of gout.* EXPERIMENTAL INQUIRY TO ASCERTAIN THE SOLVENT EFFECTS EXERTED BY THE MINERAL CONSTITUENTS OF VARIOUS VEGETABLES ON SODIUM BIURATE. The method of carrying out these experiments was similar to that described on p. 142. I oper- ated separately on the mineral constituents of the following vegetables: — Spinach, Brussels sprouts, potato, asparagus, Savoy cabbage, French beans, lettuce, beetroot, winter cabbage, celery, turnip tops, turnip, carrot, cauliflower, seakale, and green peas. The results obtained are shown in the fol- lowing sixteen tables, which are arranged in the order of the average solvent effect exerted by the mineral constituents of the various vegetables, com- mencing with those exercising the greatest influence. The solubility of sodium biurate in distilled water is placed at the head of each table for comparison. TABLE XVI. Showing the influenoe of the mineral constituents of spinach on the soluiiliti/ of sodium biurate at 100° F. Solvent. Sodium biurate dissolved. Water MO per 1.000 "Water containing : — • 1-0 per cent, of spinach ash 3-36 )t 0-5 „ 2-76 0-2 „ „ 2-12 0-1 „ 1-90 0-05 „ 1-52 0-02 „ 1-21 J) o-oi „ „ 1-18 )» * The results of these experiments were first oommuniojited to the Royal Medical and Chirurgical Society of London in a paper read on June 14th, 1898. 152 A UTHOR 's Inves tig a tions. TABLE XVII. Showing the influence of the mineral constituents of Brussels sprouts on the solubility of sodium biurale at 100° F. Solvent. Water Water containing : — I'D per cent, of Bruasels sprouts ash 0-5 0-2 01 005 0-02 001 Sodium biurate dissolved, 110 per 1,000 306 „ 2-21 1-68 „ 1-62 1-52 1-30 1-23 TABLE XVIIL Shoioing the influence of the mineral constituents of potato on the solubility of sodium biurate at 100° F. Solvent. Sodium biurate dissolved. Water 110 per 1,000 Water containing : — 1-0 per cent, of potato ash 2-49 , 0-5 „ „ 2-17 J 0-2 „ „ 1-92 0-1 „ „ 1-47 005 „ 1-36 0-02 „ „ 1-12 001 „ „ 1-10 TABLE XIX. Showing the influence of the mineral constituents of asparagus on the solubility of sodium littrate at 100° F. Solvent. Sodium biurate dissolved. Water Water containing : — 10 per cent, of asparagus ash O-.'i 1-10 per 1,000 0-5 0-2 0-1 0-05 0-02 001 2-77 2-09 1-58 1-45 1-33 112 1-10 Experiments with Vegetable Ashes. 153 TABLE XX. Showing the influence of the mineral constituents of Savoy cabbage on the solubility of sodium biurate at 100° F. Solvent. Sodium biurate dissolved. Water... 1-10 per 1,000 Water containing ; — I'D per cent, of Savoy catbage ash 2-32 0-5 1-92 0-2 1-77 0-1 1-57 0-05 1-34 0-02 1-13 0-01 110 )» TABLE XXI. Showing the influence of the mineral constituents of French beans on the solubility of soUium biurate at 100° F. Solvent. Sodium biurate dissolved. Water MO per 1,000 Water containing : — 10 per cent, of French beans ash 2-48 0-5 1-87 0-2 1-68 01 1-56 005 1-28 jj 002 1-16 jj 001 110 »> TABLE XXII. Showing the influence of the mineral constituents of lettuce on the solubility of sodium biurate at 100° F. Solvent. Sodium biurate dissolved. Water I-IO per 1,000 Water containing : — 1-0 per cent, of lettuce ash 2-72 0-5 ,, „ 1-92 02 „ „ 1-57 0-1 1-53 0-05 1-21 0-02 ,, ,, 1-10 001 „ „ 1-09 » 1 54 A UTHOR 's Investiga tions. TABLE XXIII. Showing the influence of the mineral constituents of beetroot on the soluhility of sodium biurate at 100° F. Solvent. Sodium biurate dissolved. Water 1-10 pel 1,000 Water containing : — 1-0 per cent, of teetroot ash .-. 2-46 0-5 1-82 0-2 „ „ 1-60 01 „ 1-45 0-05 „ „ 1-34 0-02 „ 115 0-01 „ „ 1-10 TABLE XXIV. Showing the influence of the mineral constituents of winter cabbage on the solubility of sodium biurate at 100° F. Solvent. Sodium biurate dissolved. Water ; 1-10 per 1,000 Water containing : — 1-0 per cent, of cabbage ash 2-30 0-5 „ 214 0-2 „ „ 1-63 J» 0-1 1-31 005 „ „ 1-23 )f 0-02 „ „ MO 0-01 „ MO TABLE XXV. Showing the influence of the mineral constituents of celery on the solubility of sodium biurate at 100° F. Solvent, Sodium biurate dissolved. Water 110 per 1,000 Water containing : — 1-0 per cent, of celery ash 0-5 „ „ 0-2 2-20 1-84 1-53 01 „ 0-05 „ „ 1-44 1-30 jj 0-02 „ „ 0-01 „ 110 1-06 Experiments with Vegetable Ashes. 155 TABLE XXVI. Showing the influence of the mineral constituents of turnip tops on the solubility of sodimn biurate at 100° F. Solvent. Sodium biiirate dissolved. Water 1-10 per 1,000 Water containing : — 1 per cent, of turnip tops ash 2-16 0-5 „ „ 1-82 0-2 „ „ 1-58 0-1 „ „ 1-42 0-05 „ „ 1-20 002 „ „ 1-13 0-01 „ „ 1-11 TABLE XXVII. Showing the influence of the mineral constituents of turnips on the solubility of sodium biurate at 100° F. Solvent. Sodium biurate dissolved. Water 1-10 per 1,000 Water containing : — 10 per cent, of- turnip ash 2-04 )} 0-5 „ „ 1-78 0-2 „ „ 1-50 0-1 „ „ 1-42 0-05 1-32 0-02 „ „ 1-14 0-01 „ 1-10 >) TABLE XXVIII. Showing the influence of the mineral constituents of carrot on the solubility of sodium biurate at 100° F. Solvent. Water Water containiag 10 per cent, of carrot ash 05 0-2 0-1 005 002 0-01 Sodium biurate dissolved. 110 per 1,000 1-63 1-53 1-47 1-4S 1-33 113 111 156 Author's Investigations. TABLE XXIX. Showing the influence of the mineral constituents of cauliflower on the soluhility of sodium biurate at 100° F. Solvent. Sodium biurate dissolved. Water Water containing : — 1-0 per cent, of cauliflower aah 0-5 0-2 0-1 0-05 0-02 001 1-10 per 1,000 1-52 1-50 1-42 1-34 1-28 1-09 1-09 TABLE XXX. Showing the infltience of the mineral constituents of seakale on the solubility/ of sodium biurate at 100° F. Solvent. Water Water containing : — 1 -0 per cent, of seakale ash ... 0-5 „ 0-2 „ 01 0-06 0-02 „ 0-01 „ Sodinm biurate dissolved. 110 per 1,000 1-49 1-47 1-35 1-23 110 110 MO TABLE XXXI. Showing the influence of the mineral constituents of green peas on the solubility of sodium biurate at 100° F. Sodium biurate Solvent. dissolved. Water 1-10 per 1,000 Water containing : — 1-0 per cent, of green peas ash 0-99 0-5 „ „ 101 0-2 „ „ 1-04 0-1 „ „ 1-10 0-05 „ „ 1-10 002 „ „ 1-10 0-01 „ „ MO Experiments with Vegetable Ashes. 157 From tlie results detailed in these tables it is , evident that 0'05 per cent, and over of the mineral constituents of nearly all the vegetables very appreciably increases the solubility of sodium bi- urate. The solitary exception is in the case of the mineral constituents of green peas, which practically exert no influence whatever on the solubility of the biurate. As I considered that these solvent effects of the mineral constituents of most vegetables on the biurate might have an important bearing on the treatment of gout, I next endeavoured to ascertain whether these effects were due to the alkalinity of the vegetable ashes, or whether they could be referred to any one saline constituent of the vegetables. EXPERIMENTAL PROOF THAT THE SOLVENT EFFECTS OF THE MINERAL CONSTITUENTS OF VEGETABLES ON SODIUM BIURATE ARE NOT DUE TO THEIR DEGREE OF ALKALINITY. That the solvent effect exerted respectively by the mineral constituents of each vegetable on the sodium biurate was not proportional to the alka- linity of the ash was very easily determined. I made estimations of the alkalinities of the different vegetable ashes, and calculated the percentages of alkalinity in terms of sodium carbonate. The alkalinity of the ashes was due to potassium and sodium carbonates ; none of the ashes contained either potassium or sodium hydrate. The follow- ing table shows a comparison of the solubility 158 Author's Investigations. exerted by the mineral constituents of vegetables on sodium biurate, and the alkalinity of those con- stituents. TABLE XXXII. Showing that the solvent effect on sodium iiurate of the mineral constituents of vegetables is not dependent on the alkalinity of those constituents. Vegetables arraBged in order of solvent effect of their Vegetables arranged in order of tht alkalinity mineral constituents on of their aiihes, and showipR percentages of sodium biurate. Com- alkalinity reckoned as sodium carbonate. mencing with those exert- Commencing with the most alkaline. ing the greatest effect. Spinach Spinach .. 2600 Brussels sprouts Celery .. 20-80 Potato Turnip .. 20-80 Asparagus Potato .. 17-55 Savoy cabtage Beetroot .. 15-60 French beans Cauliflower .. 13-20 Lettuce Carrot 13-00 Beetroot Brussels sprouts .. 12-35 Cahbage French beans .. 12-35 Celery Turnip tops .. 11-70 Turnip tops Lettuce .. 11-05 Turnip Asparagus .. 8-45 Carrot Cabbage. ., 5-85 Cauliflower Green peas ;. 5-20 Seakale Savoy cabbage 4-55 Green peas Seakale .. 1-95 It is evident from a glance at this table that the solvent effect of a vegetable ash on sodium biurate, with the exception of spinach ash, bears no relationship, either of a direct or an inverse ratio, to the alkalinity of the ash. For instance, it can be seen that the solvent effect on the biurate of the ash of Brussels sprouts is high, while its alkahnity is low ; on the other hand, the solvent effect on the biurate of the ash of celery is low, while its alka- linity is high. In other words, it is evident that the order in which the vegetables are arranged as Experiments with Vegetable Ashes. 159 regards the solvent effect of the mineral con- stituents on the biurate is neither the order nor the inverse order of their relative alkalinities. These results support the conclusions I arrived at from some experiments made with blood serum, and described in the " Goulstonian Lectures " of 1897. I then showed that a diminution in the alkalinity of blood serum did not cause a diminu- tion in the solvent power of the serum for biurate, and, conversely, that an increase in the alkahnity of the serum did not increase its solvent power for the biurate. EXPERIMENTAL PROOF THAT THE SOLVENT EFFECTS OF THE MINERAL CONSTITUENTS OF VEGETABLES ON SODIUM BIURATE ARE NOT DUE TO ANY SINGLE CONSTITUENT. The next problem to solve was whether the effect exerted by the mineral constituents of vegetables in increasing the solubility of sodium biurate is due to any one constituent. With regard to this point, it appeared probable before hand that such would not prove to be the case, since Sir William Roberts has shown that sodium, calcium, and magnesium salts diminish the solvent power of water on sodium biurate, and that potassium salts exercise no influence, one way or the other, on the solubility of the biurate. Now it can easily be demonstrated that the solvent effect is not due to the potassium salts. The following table contains a comparison of the solvent powers exerted by the mineral constituents of i6o Author's Investigations. vegetables on sodium biurate, and the proportions of potassium salts present. TABLE XXXIII. Showing that the solvent effect on sodium biurate of the mineral constituents of vegetables is not dependent on the amounts of potassium salts present. Vegetables arranged in order Vegetables arranged in order of the proportions of solvent cflfect of their of potassium salts present, and showing the mineral constituents on percentages of potassium salts present in sodium biurate. Com- the ashes, reckoned as potassium oxide. mencing with those exert- Commencing with those richest in potassium ing the gi-eatest elfect. salts. Spinach Potato . 56-03 Brussels sprouts Turnip . 64-05 Potato Carrot . 63-36 Asparagus Lettuce . 48-01 Savoy catbage i* rench beans . . . , 46-50 French beans Asparagus . 39-21 Lettuce Green peas . 38-96 Beetroot Beetroot . 38-33 Cabbage Cabbage . 37-71 Celery- Brussels sprouts . 35-00 Turnip tops Celery . 33-14 Turnip Turnip tops . 30-55 Carrot Savoy cabbage , . . . 26-82 Cauliflower Cauliflower . 23-46 Seakale Spinach . 23-43 Green peas Seakale ... . 2-59 It is also evident from this table that the solvent effect of the mineral constituents of vegetables on sodium biurate bears no relationship, either of a direct or an inverse ratio, to the proportions of potassium salts present. For instance, it can be seen that the solvent effect on the biurate of the ash of spinach is high, while the proportion of potassium salts is low ; on the other hand, the solvr ent effect on the biurate of the ash of turnips is low, while the proportion of potassium salts is high. It can also be demonstrated that the increased Sodium Salts in Vegetables. i6i solubility of the biurate effected by the mineral constituents of vegetables is not due to the sodium salts. The following table contains a comparison of the solvent powers exerted by the mineral con- stituents of vegetables on sodium biurate, and the proportions of sodium salts present. TABLE XXXIV. Showing that the solvent effect on sodium biin-ate of /he mineral (oni/itumts of vegetables is not dependent on the amounts of sodium salts present. Vegetables an-anged iu oi-aer Vegetables arranged in order of the proportions Ul aUiVcllL (jlieUL UI LHcIl niinei-al con.stitueuts on sodium biurate. Com- mencing with those exert- ing the greatest effect. of sodium salts present and showing the percentages of sodium salts present in the ashes, recl, asparagus ,, 1-45 „ „ celery „ 1-44 „ „ ,, turnip „ 1-42 „ „ ,, turnip tops ,, 1-42 „ „ „ cauliflower „ 1'34 „ „ „ cabbagre „ 1-31 „ „ , seakale ,, 1-23 „ „ „ green peas „ 1-10 „ Use of Vegetables. 175 This table shows the great advantage that the mineral constituents of vegetables possess over common salt as regards their solvent effect on sodium biurate. I have been able to calculate that with the moderately free use of vegetables, espe- cially if supplemented by the use of a table salt prepared from vegetables, it is quite possible to introduce "more than Ol per cent, of the mineral constituents of vegetables into the fluids of the body. 176 CHAPTER XIII. Reasons- for believing the treatment of gout hy alkalies to he erroneous — Experimental investigation of the value of the treatment of gout hy the various alkalies, hy piperazine, and by lysidine — Reasons for believing the treatment of gout hy salicylates to he erroneous — Experimental investigation of the value of the treatment of gout hy salicylates — General conclusions. For a considerable period of time two methods of treatment which have for their professed object the ehmination of uric acid from the system have been more or less employed by medical men. They are the treatment of gout by means of alkalies, and by means of salicylates. These two methods of treatment I consider owe their popu- larity to the entirely erroneous supposition that uric acid is present as such in the fluids and deposits of gouty patients, whereas the uric acid is always present as sodium quadriurate or biurate, and the chemical and phj'sical behaviour of these substances is entirely different from that of uric acid. As I have for some time believed that both these methods of treatment are wrong in principle and action I thought it expedient to submit the matter to experimental investigation. Experiments with Alkalies. 177 reasons for believing the treatment of gout by alkalies to be erroneous. The plea fpr the treatment of gout by means of alkalies is mainly based on the following assump- tions: (1) That uric acid is present in the blood and tissues, and is rendered soluble by the ad- ministration of alkalies; (2) that the biurate de- posited in joints is rendered soluble by means of alkalies, and (3) that there is a general acidity of the system which is neutralised and removed by alkalies. It will be seen that these assump^ tions do not stand the test of experimental inquiry. With regard to the first assumption, it is now well known that in gouty subjects uric acid is never present as such in the blood and tissues, but is always combined with sodium as the quadriurate or biurate. The only way in which alkalies could beneficially affect the quad- riurate would be to delay its conversion into the biurate. In order to test this point, I conducted a series of experiments so as to ascertain the effect of artificial blood serum, to which different alkalies had been added, on the decomposition of sodium quadriurate. In all the experiments the artificial blood serum employed was Sir WilHam Roberts's standard solution (see p. 87). This was employed instead of blood serum in order to obviate the objections that have been raised to the use of blood serum in such experiments, viz., the tendency to variation in its alkalinity. Moreover, as shown M 178 Author's Investigations. by Sir William Roberts, this standard solution reacts with uric acid and with the quadriurates and biurates in the same manner as blood serum itself. OBJECTS OF CONDUCTING THE EXPERIMENTS WITH SODIUM QUADRIURATE. These experiments were undertaken in order to ascertain whether any of the drugs, ordinarily em- ployed in the alkaline treatment of gout, possess any power, when introduced into the circulation, of restraining the precipitation of sodium biurate from the quadriurate contained in the blood. Such ex- periments would show whether any such drugs would be of use either in delaying or partially arresting an attack of gout, or in lessening the formation of gouty deposits. When sodium quadriurate is mixed with water it is decomposed into a uric acid moiety and a sodium biurate moiety, the uric acid appearing, immediately it is set free, in the form of ovoid or spindle-shaped crystals. These crystals appear in a very short time after the contact of the quadri- urate with water — generally in from one to five minutes — whilst the sodium biurate passes into the gelatinous form, which, if sufficient water be pre- sent, is dissolved. If, instead of water, an alkaline medium be employed to decompose the quadriurate, such as blood serum, or artificial blood serum, at the temperature of the human body, then as long as free alkaline carbonate is present the uric acid moiety of the quadriurate, instead of crystallising Experiments with Alkalies. 179 out as uric acid, unites with the sodium carbonate to form sodium biurate, which first assumes the amorphous form. After a time this amorphous biurate becomes gradually converted into the needles of the crystalline biurate. The time, therefore, that elapses between the saturation of the blood serum with sodium quadriurate, and the first appearance of needle-shaped crystals^ of sodium biurate represents the inhibitory influence of the medium on the crystalline precipitation of sodium biurate. The experiments to ascertain the effect of drugs employed in the alkaline treatment of gout were conducted in the following manner. METHOD OF CONDUCTING THE EXPERIMENTS WITH SODIUM QUADRIUEATE. Ten milligrammes of sodium quadriurate were well rubbed with ten drops of a 01 per cent, solu- tion of the drug in artificial blood serum, and the mixture was then placed in a small corked tube and kept at a 100° F. Every half-hour a small quantity of the mixture was removed and examined under a high power of the microscope, and the time at which crystals of the sodium biurate first appeared was noted. A similar experiment, for purposes of comparison, was made with the quadri- urate and artificial blood serum alone. I experi- mented separately in this way with potassium bicarbonate, potassium citrate, lithium carbonate, lithium citrate, sodium bicarbonate, sodium phos- phate, piperazine, and lysidine. The results are shown in the following table : — i8o A UTHOR 's In ves tig a tions. TABLE XLIV. Showing the iiijluence exerted on the decomposition of sodium quadri- urate by artificial blood serum alone, and by artificial blood serum containing O'l per cent, vf various drugs in solution. Solvent. Sodiam biurate crys- tals appeared after the lapse of — Artificial blood serum 2 hours „ „ containing 0-1 per cent, of potassium bicarbonate „ „ containing 0-1 per cent, of potassium citrate „ „ containing O'l percent, of lithium carbonate ... j» „ „ containing 0-1 percent, of lithium citrate „ „ containing 0-1 percent, of sodium bicarbonate . . . „ „ containing 0-1 per cent, of sodium phosphate .. „ „ containing 0- 1 per cent, of " piperazme „ „ containing O'l percent, of lysidine These results show that none of the drugs men- tioned in the table exercise the slightest efi'ect in delaying the conversion of the quadriurate into the biurate, even when present in far larger proportions than could possibly be introduced into the blood by the medicinal administration of the drugs.* Therefore it appears that the treatment of gout by alkalies and salts of the alkalies does not delay the conversion of the quadriurate into the biurate. DOES THE TREATMENT OF GOUT BY ALKALIES INCREASE THE SOLUBILITY OF SODIUM BIURATE ? With regard to the second assumption, that the administration of alkalies increases the solubiUty of * In order to have O'l per cent, of any drug in the, blood, it ■would be necessary to introduce 100 grains of that drug at once into the circulation of an adult man of average weight. Experiments with Alkalies. i8[ the biurate deposited ia the joints and tissues, Sir William Roberts* has shown that sodium bi- carbonate and sodium phosphate diminish the solubility of sodium biurate, while potassium bi- carbonate exercises no influence whatever on its solubility. He fails to find any direct object in the administration of alkalies for gout, and he has seen gouty attacks reeur with full severity when the urine has been for a long time maintained persistently alkaline by the administration of bicarbonate and citrate of potassium. That the administration of alkalies might increase the solu- bility of the biurate appeared at one time to be probable from the results of some experiments performed by Sir Alfred Garrod. He immersed small pieces of cartilage infiltrated with sodium biurate for forty-eight hours in aqueous solutions of the carbonates of lithium, potassium, and sodium respectively. At the end of that time he found that the cartilage immersed in the lithium solution was restored to its natural condition ; that in the potassium solution was much acted upon, while that in the sodium solution appeared to be un- altered. These results are somewhat in opposition to those of Sir William Roberts, and as neither the experiments of Sir Alfred Garrod nor those of Sir William Roberts represent the conditions under which alkalies, when introduced into the circula- tion, would act on sodium biurate, I thought it desirable to re-investigate the subject, as far as possible under such conditions. * The Croonian Lectures, 1892. 1 82 AuTHOs's Investigations. INVESTIGATION OF THE EFFECTS OF VARIOUS ALKALINE DRUGS ON THE SOLUBILITY OF SODIUM BIURATE. These experiments were undertaken in order to compare the solubility at 100° F. of sodium biurate in artificial blood serum, and in artificial blood serum containing different proportions of the various drugs. The experiments were carried out in a similar manner to that described on pp. 137, 138. I experimented separately with the following drugs — potassium bicarbonate, potassium citrate, lithium carbonate, lithium citrate, sodium bicar- bonate, sodium phosphate, piperazine, and lysidine. Much greater proportions of the drugs were em- ployed than could possibly be introduced into the blood by medicinal administration. The results are shown in the following tables :- — TABLE XLV. Showing the solabiUty at 100° F. of sodium biurate.in artificial blood serum alone, and in artificial blood serum contavttUig different proportions of potassium bicarbonate. Sodium biurate dissolved. Artifici al Mood serum Artificial blood serum containing 001 per cent, of potassium bicarbonate Artificial blood serum containing 010 per cent, of potassium bicarbonate ... Artificial blood serum containing 0'20 per cent, of potassium bicarbonate ... 0-11 per 1,000 0-10 „ 0-10 0-11 These results show that potassium bicarbonate Experiments with Alkalies. 183 ■would not in ' the slightest degree increase the solvent power of the blood for gouty deposits. TABLE XLVI. Showing the mluhilUy at 100° F. of sodium binrate in artificial blood serum alone, and in artificial blood serum containing different proportions of potassium citrate. Artificial blood serum Artificial blood serum containing O'Ol per cent, of potassium citrate . Artificial blood serum containing 0-10 per cent, of potassium citrate.. Artificial blood serum containing 0-20 per cent, of potassium citrate Sodium biurate dissolved. 0-11 per 1,000 010 „ 0-10 „ Oil These results show that potassium citrate would not in the slightest degree increase the solvent power of the blood for gouty deposits. TABLE XLVII. Showing the solithility at 100° F. of sodium liurate in artificial blood serum alone, and in artificial blood serum containing different proportions of lithium carbonate. Solvent. Sodinin liiurate difisolved. Artificial blood serum Artificial blood serum containing 0-005 per cent, of lithium carbonate Artificial blood serum containing O'Ol per cent, of lithium carbonate Artificial blood serum containing 0-10 per cent, of lithium carbonate O-U per 1,000 Oil „ O'U 015 These results show that lithium carbonate would not in the slightest degree increase the solvent power of the blood for gouty deposits, even when present in far larger proportions than could be 1 84 A VTHOK 'a Inves tig a tions. introduced into the blood by medicinal adminis- tration. Lithium salts are usually given in doses of one to five grains three times a day, whereas to get 001 per cent, of a lithium salt into the blood it would be necessary to introduce 10 grains of the salt at once into the circulation of an adult man of average weight. TABLE XLVIir. Showing the solubility at 100° F. of sodium binrate in artificial blood serum alone, and in artificial blood serum containing different proportions of lithium citrate. Solvent. Sodium biurate dissolved. Artificial blood serum 0-11 per 1,000 Artificial blood serum containing 0-005 per cent, of lithium citrate 0-11 Artificial blood serum containing 0-01 per cent, of lithium citrate .. • 0-11 Artificial blood serum containing 10 per cent, of lithium citrate 0-11 „ These results show that lithium citrate would not in the slightest degree increase the solvent power of the blood for gouty deposits. TABLE XLIX. Showing the solubility at 100° F. of sodium biurate in artificial blood serum alone, and in artificial blood sentm containing different proportions of sodium bicarbonate. Solvent. Artiflciil blood serum Artificial blood serum containing 0-01 per cent, of sodium bicarbonate Artificial blood serum containing 010 per cent of sodium bicarbonate Artificial blood serum conttiining 0-20 per cent, of sodium bicarbonate Sodium biurate dissolved. Oil per 1,000 0-10 „ 009 0-OS „ ExFElilMENTS WITH PlPERAZISE. 185 These results show that sodium bicarbonate would slightly decrease the solvent power of the blood for gouty deposits. TABLE I. Showing the solubility at 100° F. of sodium biurate in artijieial blood serum alone, and in artijieial. blood serum containing different proportions of sodium phosphate. Solvent. Artificial Wood serum Artificial blood serum containing O-Ql per cent, of sodium phosphate ArtiKcial blood serum containing 0-10 per cent, of sodium phosphate Artificial blood serum containing 0'20 per cent, of sodium phosphate Sodium biurate dissolved. 0-11 pe r 1,000 o-ii J> 0-11 n U These results show that sodium phosphate would not in the slightest degree increase the solvent power of the blood for gouty deposits. TABLE LI. Showing the solubility at 100° F. of sodium liurate in artificial blood serum alone, and in artificial blood serum containing different propjrtions ofpiperazine. Solveut. Sodium biurate dissolved. Artificial blood serum 0-11 per 1,000 Artificial blood serum containing O'Ol per cent, of piperazine ... 0-09 „ Artifij;ial blood serum containing O'lO per cent, of piperazine 0-11 „ Artificial blood serum containing 0-20 per cent, of piperazine 0-13 „ These results show that piperazine would not i86 Author's Investigations. in tlie slightest degree increase the solvent power of the blood for gouty deposits, even when present in far larger portions than could be introduced into the blood by medicinal administration. Piper- azine is usually given in doses of five grains three times a day, whereas to get 0"10 per cent, of piper- azine into the blood it would be necessary to in- troduce 100 grains of the drug at once into the circulation of an adult man of average weight. TABLE LII. Shovnng the solubility at 100° F. of sodium iiurate in artificial blood serum alone, and in artificial blood serum containing different proportions of lysidine. Solvent. Sodium biurate dissolved. Artificial blood serum Artificial Wood serum containing 0-01 per cent, of lysidine Artificial blood serum containing 0-10 per cent, of lysidine Artificial blood serum containing 0-20 per cent, of lysidine 0-n per 1,000 009 „ 0-10 „ 0-10 „ These results show that lysidine would not in the slightest degree increase the solvent power of the blood for gouty deposits, even when present in far larger proportions than could be introduced into the blood by medicinal administration. Lysidine is given in doses of from 30 to 120 grains three times a day, whereas to get 0'20 per cent, of lysidine into the blood it would be necessary to introduce 200 grains of the drug at once into the circulation of an adult man of average weight. Experiments with Gouty Deposits. 187 further experiments as to the influence of potassium and lithium salts on the solv- ency of gouty deposits. As it appeared to me that the experiments of Sir Alfred Garrod, previously referred to [see p. 181), as to the solvent effect of potassium bicarbonate and lithium carbonate on gouty deposits, were scarcely comparable with what occurs when those drugs are acting vid the blood and other fluids of the body, I thought it desirable to repeat the experiments under different conditions. I there- fore investigated the solvent action on gouty deposits of artificial blood serum impregnated with quantities of potassium bicarbonate and lithium carbonate respectively; the quantities of the drugs used were as nearly as possible equal to those which would be present in the fluids of the human body when full doses are being admin- istered. The artificial blood serum impregnated with potassium bicarbonate contained O'Ol per cent, of that drug. The artificial blood serum impregnated with lithium carbonate contained 00015 per cent, of that drug. The experiments were carried out in the following manner. METHOD OF ASCERTAINING THE SOLVENT EFFECTS OF POTASSIUM BICARBONATE AND LITHIUM CAR- BONATE ON GOUTY DEPOSITS. A piece of cartilage well and uniformly infil- trated with sodium biurate, which had been 1 88 Author's Investigations. removed from a gouty joint at a post-mortem examination, was divided into three equal pieces. One piece was suspended in a bottle containing 100 c.c. of artificial blood serum, the second piece in a bottle containing 100 c.c. of artificial blood serum impregnated with potassium bicarbonate- and the third piece in a bottle containing 100 c.c of artificial blood serum impregnated with lithium carbonate. The bottles with their contents were kept throughout the experiments at the blood heat, and every twenty-four hours fresh supplies of fluid were introduced, so that the first piece of cartilage was constantly bathed in artificial blood serum at the blood heat, the second piece in artificial blood serum impregnated with potassium bicarbonate, and the third piece in artificial blood serum im- pregnated with lithium carbonate. By this method of procedure it was considered, as regards any solvent effect that the drugs might exert on the gouty deposit, that the results would be fairly comparable with what occurs when potassium or lithium salts are medicinally administered. The pieces of cartilage were removed every twenty-four hours and examined by means of a lens, and the experiments were continued until all the sodium biurate was dissolved out of the cartilage. The solution of the sodium biurate from the cartilage proceeded at the same pace in the three pieces, and was in no way accelerated by the presence of the potassium bicarbonate or the lithium carbonate. The sodium biurate was completely dissolved from the three pieces of cartilage on the fifteenth day. Alkalies and Gout. 189 These experiments indicate that the quantities of potassium bicarbonate and lithium carbonate that could, by ordinary dosage, be introduced into the fluids of the body can exercise no influence on the solvency of gouty deposits, and the results obtained support the view of Sir William Roberts that potassium bicarbonate and lithium carbonate exercise no influence on the solubility of sodium biurate. The net result of all these experiments is that the treatment of gout by alkalies or by piperazine or lysidine does not increase the solu- bility of the biurate deposited in the joints and tissues. Levison* holds very similar opinions with regard to the alkaline treatment of gout. He considers that the administration of the ordinary akalies, of lithium salts, or of piperazine with the object of either dissolving sodium biurate or of preventing its deposition is decidedly useless. He also found that the administration of piperazine exerts no influence upon the amount of uric acid excreted. Sir William Roberts t does not find any direct object in the administration of alkalies for gout; he has seen gouty attacks recur with full severity when the urine has been for a long time maintained persistently alkaline by the adminis- tration of potassium bicarbonate and citrate. Dr. J. Fawcett,i as the result of his investigations on the treatment of gout by piperazine, arrives at an unfavourable conclusion as to its efficacy in * " The Uric Acid Diathe&ia," 1894. t The Croonian Lectures, 1892. X Guy's Hospital Reports, 1895. igo Author's Investigations. gout. He found tliat in acute cases it did not relieve the pain, nor was there any constant in- crease in the excretion of uric acid under its use. Mordhorst* also considers that piperazine and lysidine are useless in the treatment of gout. A GENERAL ACIDITY OF THE SYSTEM XOT ASSOCIATED WITH GOUT. ■ The third assumption (see p. 177), that in con- nection with gout there is a general acidity of the system which, causes a diminished alkalinity of the blood, is opposed to the results of recent in- vestigations on the subject. The experiments of Klemperer and my own experiments (see p. 130) show that the alkalinity of the blood of gout is but very httle, if at all, diminished, and that corre- sponding variations in the alkalinity of the blood may frequently be met with in healthy individuals. Moreover, the experiments described on pp. 131-139 demonstrate that a diminution in the alkalinity of blood serum containing uric acid in solution does not facilitate the deposition of sodium biurate from it, nor does a diminution in the alkalinity of blood serum diminish its solvent power for sodium biurate. It appears therefore that there is no ground whatever for the assumption that the treatment of gout by alkalies tends to neutralise a so-caUed general acidity of the system, and so renders the blood a ])etter solvent of gouty deposits. * TUrap. Uomts., %., 1896. Alkalinjty of Blood. 191 no eelatkjnship between the acidity of the urine and the akalinity of the blood. The idea that a general acidity of the system is associated with gout has, in my opinion, arisen from observations of the fact that the urine of gouty patients is acid. These observations are generally made on small samples of the urine, although when the total acidity of the urine for the twenty-four hours is determined, it is frequently found to be below that of the normal acid output in the urine for that period of time. It is certain that the erroneous assumption has been made by some writers that variations in the acidity of the urine can be taken as a gauge of corresponding variations in the alkalinity of the blood, and that therefore a fall of acidity in the urine means an increased alkalinity of the blood, and vice. versA. That this assumption is quite wrong is shown by reference to the following table (Table LIII.), in which are. arranged side by side the determinations that I made on the same days of the alkalinity of the blood and of the total acidity of the urine for each twenty-four hours of an adult patient suffering from subacute gout. The total acidity of the urine was determined by collecting the whole of the urine for the twenty-four hours, and then titrating a portion of the urine by the process described by Lepinois.* The estimations were made mostly on alternate days throughout the duration of the attack. * /. Pharm., 1896 (6), iii., 8—16. 192 Author's Investigations. TABLE Liir. Showing the absence of any constant relationship hetween the alkalinity of the blood and the acidity of the urine of a patient during an attach of sttbacute gotti. Dates of determinations. Alkalinity represented as percentage of anhydrous sodium carbonate present in the blood. Acidity of total urine for the 24 hours reckoned as grammes of hydroeliloric acid. Feb. 4th. 0-167 1-392 6th. 0167 0-953 8th. 0-167 1096 10th. 0156 1-374 1 2 th. 0-167 1-583 15th. 0-158 . 1-.529 17th. O-loS 1-629 19th. 0-167 1-581 22nd. 0-180 1-602 24th. 173 Alkaline 2Gth. 0-161 Alkaline 28th. 0179 0-608. Mar 2nd. 0167 0-622 This table shows that no constant relationship existed in this case of gout -between the alkalinity A A s^ / ^ ^/1 /^ -«> / ^ V r V, y B ^/ ■-• ""*' ■" \ 1 ^ •"" 1 1 \ i — 1 1 1 A, rut. ■ah ^ of ^ Tie ^ 1 ^^ ^ ^x Diagram showing the absence of any constant relationship between ■ the alkalinity of the blood and the acidity of the urine of a patient during an attack of subacute gout. A, Alkalinity of blood B, acidity of urine. Salicylates and Gout. 193 of ttie blood and the acidity of the urine, and moreover that on those days when, owing to treatment with citrate of potassium which was administered from February 19th to 28th, the urine remained alkaline, there was no corresponding rise in the alkalinity of the blood. These determinations of the alkalinity of the blood and the acidity of the urine of this case. of subacute gout are shown in curves in the diagram on p. 192, a glance at which at once demonstrates that no constant relationship existed between the alka- lin'ity of the blood and the acidity of the urine. EEASiONS FOR BELIEVING THE TREATMENT OF GOUT BY SALICYLATES TO BE ERRONEOUS. Just as the treatment of gout by means of alkalies is based on the entirely erroneous supposi- tion that uric acid is present as such in the fluids and deposits of gouty patients, so the main reason for giving a salicylate in gout is based on the assumption that it unites with uric acid throughout the system, and so effects its removal from the system and its elimination in the urine. That sodium salicylate does cause an increased elimina- tion of uric acid in the urine, at all events in the early stages of its administration, is undoubted. This is shown by the following daily deter- minations that I made of the total uric acid excretion of a healthy man be/ore, during, and after treatment with sodium salicylate. The diet was of the same nature throughout the experiment. 194 Author's Investigations. TABLE LIV. Shoming the daily excretion on successive days of uric add by a healthy man before, daring, and after treatment with sodium s.ilicylate. Daily excretii)n of uiic add in grammes. ( 0-547 Before taking salicylate \ 0o89 ( 0-731 Average ... ... ... ... 0-622 . 0-852 ■ Fifteen grains of sodium salicylate taken \ 942 three times a day.. j 0-826 \ 0-784 0-851 Salicylate left off Average ... ... ... ... 0-565 That this increased elimination of uric acid is due, however, to the removal of ready-formed uric acid stored in the system is, in my opinion, in- correct. In the first place it must be remembered that any uric acid deposited in any of the organs or tissues of gouty subjects is deposited in the form of sodium biurate, and the results of the following experiments show that artificial blood serum con- taining sodium salicylate, in much greater pro- portions than could be introduced into the blood by the medicinal administration of the drug, has not the slightest increased solvent effect on the biurate. Salicylates and Gout. 195 TABLE LV. Showing the soluUlity at 100° F. of sodium bitiraie in artificial blood serum alone, and in artificial blood scrum containing different proportions of sodium salicylate. Solvent. Sodium biurate dissolved. Artificial tlood serum Artificial blood serum containing 0-003 per cent, of sodium aalioylate Artificial blood serum containing 006 per cent, of sodium salicylate Artificial blood serum containing 0-01 per cent, of sodium salicylate Artificial blood serum containing 0-10 per cent, of sodium salicylate 0-11 per 1,000 0-11 „ 0-11 „ Oil Oil „ These results show that sodium salicylate would not in the slightest degree increase the solvent power of the blood for gouty deposits, even when present in far larger proportions than could be introduced into the blood by medicinal administra- tion. Sodium salicylate is usually given, in the treatment of gout, in doses of fifteen to twenty grains three times a day, whereas to get 0\ per cent, of sodium salicylate into the blood it would be necessary to introduce 100 grains of the drug at once into the circulation of an adult man of average .weight. Dr. J. Fawcett,* who likewise finds that sodium salicylate produces an increased uric acid excretion, considers it improbable that the increase can be explained by a mere clearing out of retained uric acid. I also find that artificial blood serum contaming sodium salicylate in far larger proportions than could be introduced into the blood by medicinal * Guy's Hospital Eeports, 1895. 196 Author's Int^estigations. administration has no effect whatever in delaying the conversion of sodium quadriurate into the biurate, as is shown in the following table: — , TABLE LVI. Showing the influence exerted on the decomposition of sodium quad- riurate by artijicial blood sertun, and by artijieial blood serum containing O'l per cent, of sodium salicylate in solution. Solvent. Sodium binrate crystals appeared after tlie lapse of— Artificial blood serum Artificial blood serum containing O'l per cent, of sodium salicylate 2 hours 2 hours It therefore appears from the results of the experiments given- in Tables LV. and LVI. that sodium sahcylate has no direct action either in delaying the decomposition of sodium quadriurate or in effecting a solvent action on deposits of sodium biurate. The erroneous supposition as to salicylates possessing a solvent pojver on gouty deposits probably arose from the faulty deduction that increased elimination of uric acid in the urine after the administration of a salicylate was neces- sarily due to the solvent effect of the salicylate on uratic deposits. The correct explanation of this increased elimination of uric acid is, I believe, to be found in the known fact that salicylic acid unites readily with glycocine to form salicyluric acid, and that it thus brings an increased amount of glycocine to the kidneys, where by the com- bination of that body with urea an increased amount of uric acid is necessarily formed. Since, General Conclusions. 197 therefore, I believe that the effect of a salicylate is to increase the production of uric acid in the kidneys by bringing additional glycocine to those organs, I am of opinion that salicylates are contra- indicated in gout, as increased production of uric acid in kidneys which are already incapable of eliminating the normal amount of uric acid would lead to increased absorption of uric acid into the general circulation, and, consequently, to intensifi- cation of the gouty condition. GENERAL CONCLUSIONS DRAWN FROM THE INVESTIGATIONS. 1. The alkalinity of the blood is apparently not appreciably diminished during a gouty attack. 2. The solubility of uric acid in the blood is not affected by a diminished alkalinity of the blood produced by the addition of organic acids. 3. The deposition of sodium biurate is not accelerated by a diminution of the alkalinity of the blood. 4. An increased alkalinity of the blood does not increase the solubility of deposits of sodium biurate. 5. The gout-inducing properties of certain wines are not due to their acidity. Probably they owe their gout-inducing action to the effect they exercise on the metabolism of the liver. 6. The solubility of sodium biurate is markedly increased by the presence of the mineral con- stituents of most vegetables. 7. The solubility of sodium biurate is dimin- 198 Author's Investigations. ished by the presence of the mineral constituents of meat. 8. The mineral constituents of cert.iin vege- tables delay the conversion of sodium quadriurate into the biurate. 9. The vegetables most useful to gouty sub- jects are spinach, Brussels sprouts, French beans, winter cabbage, Savoy cabbage, turnip tops, turnips, and celery. 10. The administration of the ordinary alkalies, of lithium salts, of piperazine, and of lysidine, with the object of removing gouty deposits, appears to be useless. 11. No general acidity of the system is asso- ciated with gout. 12. No relationship exists between the acidity of the urine and the alkalinity of the blood. 13. The administration of salicylates with the object of removing gouty deposits appears to be useless, and their employment in the treatment of gout is contra-indicated. 199 lart IV. THE TREATMENT OF GOUT AND OF GOUTY CONDITIONS. CHAPTER XIV. The general principles on vihich the treatment of gout is based — ■ Examination of the urine — Treatment of acute gout — Diet in acute gout — The action of colchinum — Treatm,ent of subacute and chronic gout — Means of checlcing the excessive formation of uric acid — Means of promoting the elimination of uric acid — Local treatment of gouty joints. THE GENERAL PRINCIPLES ON WHICH THE TREAT- MENT OF GOUT IS BASED. In the first pkce it should be borne in mind that no routine treatment can be adopted which is suitable to all cases. The nutritional condition of the patient, his habits, surroundings, and mode of life, constitute factors that must necessarily modify the treatment of individual cases, and with gout, as with so many other diseases, it will be found that each individual case requires separate study, and frequently special treatment. The treatment of gout should have for its aim the following objects : (1) the treatment of the gouty paroxysm in cases of acute gout, and the relief of the pain as speedily as possible ; (2) the treatment 200 The Treatment of Gout. of the subacute or chronic condition and the pre- vention of the recurrence of an attack, which may be effected by the promotion of the- ehmination of uric acid, by checking any e cessive formation of uric acid that occurs in some subjects, and by care- ful attention to diet and general hygiene ; and (3) the treatment of the affected joint or joints, with the object of removing the uratic deposits, and of preventing permanent deformity. . EXAMINATION OF THE URINE. In all cases of gout a very careful examination of the urine should be made, and it is especially important to endeavour to ascertain whether the kidney affection is in the functional or organic stage. The indications that the gouty affection of the kidney is passing from the functional into the organic condition are the existence of a certain amoimt of polyuria, a low specific gravity of the urine — usually from 1007 to 1016 — the presence of a small quantity of albumen, which, however, may disappear for some time and then reappear, the presence of a few granular casts if a careful micro- scopical examination is made after centrifuging the urine, and a diminished daily excretion of uric acid and generally of urea. It is most impor- tant carefully to examine the urine for traces of albumen, and for the presence of casts. For the latter purpose the centrifugal machine should be used, as the casts, when present, are usually present in but small numbers, and are otherwise very slow to settle. Estimation of Uric Acid. 201 It is desirable before commencing treatment, and from time to time during treatment, to know the amount of uric acid that is being daily elimin- ated in proportion to the body- weight of , the patient. This determination of the amount of uric acid eliminated must be made on a sample of the mixed urines of twenty-four hours. The process that I always employ for such determinations is the Go wland- Hopkins process (.see p. 30), which is a very accurate method for the estimation of uric acid in urine. The mere determination of the percentage of uric acid in a sample of the urine is useless, as it constitutes no guide to the actual amount of uric acid that is being excreted. It is absolutely necessary^ to determine the total uric acid elimination for the twenty-four hours, and that can only be done by examining a sample of the mixed. urines of that period. Similarly the determination of the percentage of urea in a sample of the urine is no guide to the amount of nitrogenous elimination that is taking place from the kidneys. To ascertain that factor the total output of urea for the twfenty-four hours must also be determined. THE TREATMENT OF ACUTE GOUT. For the treatment of the gouty paroxysm the limb should be placed in the horizontal position, or slightly elevated above the level of the body, and a cradle arranged so as to take the weight of the bed clothes off the affected part. To alleviate the severe pain felt in the affected joint warm packs 202 The Treatment of Gout. should be arranged round it, consisting of cotton- wool saturated with a soothing lotion, and then lightly covered with oil-silk. I have found the following lotion most useful in relieving the local pain : — Sodae carb • •■ 5"i- Linim. belladonnse ... . ... sij. Tinct. opii ••• SJ- Aq. ad ... 5V11J, A small portion of the lotion should be mixed with an equal quantity of hot water, and then poured on cotton-wool previously arranged round the joint. The pack should be changed every eight or twelve hours. In connection with the acute paroxysm no attempt at local depletion — such as the application of leeches to the inflamed joint, blistering, or incisions — should on any account be made, owing to the great liability of thereby extending the inflammatory condition, and so producing subsequent ankylosis or deformity. For the internal treatment of acute gout col- ohicum is one of the most valuable drugs that we possess. It should be especially used for acute gout, and for subacute attacks supervening on chronic gout. If used continuously, tolerance is apt to be acquired, and then the drug ceases to act. At the commencement a large dose of thirty to forty minims of colchicuni wine should be given, followed by a mixture containing in each dose ten to twenty minims of the wine with from forty, to sixty grains of citrate of potassium, which should be administered three times a day. The citrate of potassium, which is given for its combined properties PURGA TI VF.S. 203 of acting as a diuretic and. of diminishing the acidity of the urine, may, if desired, be given as an eifervescing mixture,- using thirty grains of potassium bicarbonate to twenty grains of citric acid. Colchicum reduces the gouty inflammation, reheves the pain, and shortens the attack. It should only be taken under medical advice, and should never be given in such doses as to produce extreme depression : after the inflammation of an acute attack has subsided the doses of colchicum should be gradually diminished until it is left off. Sir Alfred Garrod regards acute gout and the acut« exacerbations of chronic gout as the chief indica- tions for employing colchicum. From three to four grains of blue pill should be given the first night, followed by a dose of Epsom salts in the morning. Mercury should be given only in sufficient doses to produce its cholagogue effect, as owing to the defective action of the kidneys the mercury absorbed into the general system may be eliminated with great difficulty. In my opinion it is advisable in the treatment of gouty patients in the acute or subacute stages to avoid the use of saline purgatives owing their efficacy to salts of sodium, on account of the un- doubted power possessed by all sodium salts of diminisbing the solubility of sodium biurate. In the employment of purgatives for gouty patients the great object is not to produce powerful purgation, but to relieve portal congestion, since a congested condition of the liver means that an excessive quantity of glycocine is transmitted to 204 The Treatment of Gout. the kidneys, where an excessive quantity of uric acid is consequently produced. A pill containing either two grains of euonymin or a quarter of a grain of podophyllin combined with a grain of extract of hyoscyamus and a grain and a half of the compound extract of colocynth will, in many cases, be found to be very useful. If the pain of an acute attack of gout is so severe as to prevent sleep, chloral, sulphonal, or trional may be given, or a full dose of extract of hyoscyamus given with blue pill at night will, in some cases, act as a very useful anodyne. The administration of opium or morphine should, if possible, be avoided owing to the risk of its deficient elimination on account of the kidney affection, and also on account of its diminishing the amount o"^ urine, and its tendency to derange digestion and to check hepatic metabolism. DIET IN ACUTE GOUT. During an attack of acute gout a diet must be given which, in the first place, shall be non- irritating to the affected kidneys, and, in the second place, shall be one that does not produce an ex- cessive quantity of uric acid. For the first day or two of an acute attack the patient should be- restricted to a milk diet, which may consist of milk, arrowroot and milk, bread and milk, milk puddings made with rice, sago, or tapioca, and tea made with boiling milk instead of with water. Weak tea with cold toast thinly buttered may also be taken. The free drinking of hot or cold water. The Treatment of Gout. 205 of salutaris water, or of some mineral water free from sodium salts (for list of such waters, see, p. 230) should be encouraged. The milk diet should be continued untD. the acute inflammation is sub- siding, which stage is indicated by the lessening of the pain, and by the pitting on pressure of the affected parts. No alcohol in any form should be given during this stage, unless there are strong reasons for its administration, such as a weak action of the heart and a feeble, irregular pulse, when a little well-matured whisky diluted with salutaris water will prove the best form of alcohol Beef tea and any of the meat extracts or essences should be avoided at all times by gouty patients owing to the tendency they have to irritate the kidneys, and so to interfere with the elimination of uric acid. With the subsidence of the acute attack the patient may return to a more hberal diet, but care should be taken to avoid anything indigestible. For the dietary suitable for gouty subjects after the acute attack has subsided,- see pp. 222 — 225. THE ACTION OF COLCHICUM. Although no satisfactory explanation of the beneficial action of colchicum in gout has hitherto been put forward, I beUeve that its beneficial effect is mainly due to its diminishing the uric acid pro- duction, thereby arresting the absorption of uric acid from the kidneys, and so preventing the further deposition of biurate in the affected parts. Colchicum is a powerful direct cholagogue, and it is probably owing to its action on the liver that its 2o6 The Treatment of Gout. eiEcacy in mitigating the severity of the pain and relieving an attack of gout is due. If, as a chola- gogue, it inhibits the formation of glycocine, then the amount of uric acid formed in the kidneys must be diminished, and if the uric acid formation is lowered to the quantity that can be eliminated by the affected kidneys, then the absorption of quadriurates from the kidneys into the general circulation is prevented, and so the formation of further gouty deposits is arrested. This view renders- intelligible the efficacy of colchicum not only in connection with articular gout, but also in connection with the various forms of irregular gout. The explanation just given of the mode of action of colchicum is at once supported by the fact recorded by so many observers that the uric acid elimination is always diminished during the period of administration of colchicum, whereas the elimination of urea is practically unaffected by the drug. The following table (Table LVII.) shows the diminished elimination, and, as I believe, the diminished formation of uric acid, that occurred during the administration of colchicum to one of my patients while suffering from an attack of sub- acute gout of both hands and knees. That deficient production of uric acid accompanied the deficient excretion was shown by the fact that the gouty' affection of the joints rapidly improved during the treatment with colchicum, whereas if the formation of uric acid had remained the same, and merely deficient elimination of it had occurred, the articular condition would have become worse. The Action of Colch/cum. 207 TABLE LVII. Shawinff the decreased elimination of uric acid in a case of sub'Ocuie gout during the administration of colchicum. Uric acid in grammes. Daily elimination at the commencement of the attack Average of the daily eliminat'ons for fourteen days while under treatment with colchicum. (Vin. colchici nixxx were given as the first dose, md Ihea m xv three times a day through- out the fourteen days of treatment.) 0-438 0-234 This diminished excretion of uric .acid that occurs during the administration of colchicum is a good sign, since it points, in my opinion, to diminished formation of uric acid. It is in marked contrast to the action of sodium salicylate, which considerably increases the excretion of uric acid by increasing its formation in the kidneys. As previously stated {see pp. 196, 197), the employment of salicylates in the treatment of gout is, in my opinion, contra-indicated. Although colchicum does not directly affect the solution of uratic deposits, yet indirectly it may produce that result, since, by diminishing the formation of uric acid, it allows the kidneys to eliminate the sodium quadriurate circulating in the blood of the gouty patient, and if the blood can be kept free from quadriurate, then the solution of the sodium biurate from the joints and tissues, where it is deposited, will slowly but surely proceed. The mitigation of the pain of an acute gou-ty 2o8 The Treatment of Gout. paroxysm is probably owing to colchicum acting as a cardio-vascular depressant, lowering the tension and frequency of the pulse, and so relieving the pressure and pain felt in the affected joint. THE TREATMENT OF SUBACUTE AND CHRONIC GOUT Means of checking the excessive formation of uric acid. — These consist in careful attention to diet and regimen, the promotion of the metabolism of the liver, so as to check the excessive production of the antecedents of uric acid, and in the relief of congestion of the portal system, which can be effected by keeping the bowels open at least once a day. In addition to colchicum, which may be given in small doses, guaiacum may very usefully be administered as an alterative which stimulates the metabolism of the liver, and also affords relief to the portal system. From five to ten grains of guaiacum resin should be given in cachets two or three times a day, according to the effect on the bowels, since guaiacum generally acts as a laxative. If constipation occur, a sulphur and guaiacum tablet, or a dose of compound liquorice powder, should be taken at night. An occa- sional dose of blue pill and euonymin, followed by a purge of Epsom salts, will be found useful. Sir Alfred Garrod considers that guaiacum relieves gouty inflammation, and that a similar result is produced by the administration of serpentary. If guaiacum is given in too large doses it may produce a papular or urticarial rash accompanied by con- siderable itching. If the patient is suffering from Elimination of Uric Acid. 209 atony and debility of the stomach, nux vomica or strychnine may be given with potassium citrate. Iron preparations are not as a rule well tolerated by the gouty, but if anaemia is present the citrate of iron and ammonium or the carbonate of iron will bo found the best to administer. Means of 'promoting the elimination of uric acid. — The elimination of uric acid may be effected by medicinal treatment, and by diet and regimen. Citrate of potassium should be employed as a diuretic which increases the volume of the urine, and at the same time diminishes its acidity. The use of the citrate of potassium may with advantage be pushed until moderate alkalinity of the urine is produced, as by such means the quadriurates are rendered more soluble and more stable than they are in acid urine, and so the tendency to the deposition of uric acid or sodium biurate in the kidney tissues is removed. Free diuresis should also be encouraged by the drinking of sufficient quantities of water. A patient suffering from gout should avoid, as far as possible, the use of common salt at table, owing to the power it pos- sesses of diminishing the solubility of sodium biurate, and thereby hastening the precipitation of that body. The dietetic treatment of chronic gout is described on pp. 222 — 225. Further treatment of chronic gout. — The en- largement and- tenderness of the gouty joints is due to two causes — the deposition of sodium biurate in the cartilages and fibrous structures, and a chronic inflammatory thickening of the fibrous 2IO The Treatment of Gout. tissues. For tbe reduction of this last-mentioned thickening, as well as for painful gout of the sole of the foot, and for gouty neuralgic affections, iodide of potassium given internally is a useful remedy. This drug should not, however, be regarded as a solvent of gouty deposits, and it is contra-indicated if advanced kidney disease exists. It should be given in doses of five to ten grains three times a day, and may usefully be c6mbined with from five to^ten minims of tincture of iodine. Sir Alfred Garrod advises the administration of guaiacum in those cases where the gouty pains are relieved by the application of warmth, but considers that it is contra-indicated when any marked inflammatory symptoms are present, as shown by the increase of pain when the patient is warm in bed. In such cases potassium iodide is likely to be more bene- ficial than guaiacum. The lithium salts are not, in my opinion, solvents of gouty deposits (see pp. 183, 184, 189), but since they are powerful diuretics they may, on that account, be of some use in the treatment of chronic gout. They should never, however, be given in sufficient quantities to keep the urine alkaline, as their depressing effect in such doses is too great. If the signs of organic renal mischief exist (nee p. 200), then particular attention must be paid to the prevention of an excessive formation of uric acid. This can be accomplished by placing the patient on a suitable diet, by promoting elimination from the kidneys by the administration of suitable diuretics, such as potassium citrate and ammonium Treatment OP Joints. 211 acetate, and by the thorough flushing of the kidneys by a water as free as possible from sodium salts. If marked albuminuria occurs then, in addition to the above-mentioned treatment, vapour baths or Turkish baths may be employed, provided they do not produce debility. THE LOCAL TREATMENT OF GOUTY JOINTS. If much swelling of a joint persists, the limb should be elevated as much as possible, and a light flannel bandage applied to the joint. If the oedema persists, the hot douche followed by sponging with a cold strong solution of common salt will be found serviceable. The application of the so-called solvents of uric acid externally to affected joints is useless, as they are not solvents of sodium biurate. Careful massage and gentle exercise of the stiffened joints should be employed, but only when con- valescence is fairly established ; massage and muscular movement increase the flow of lymph in the lymph channels, and so tend to promote the removal of uratic deposits, and to increase general metabolism. For the stiffness and thickening of joints, careful rubbing with iodide of potassium and soap liniment or with the compound camphor liniment may be resorted to. The thermal baths of Bath, Buxton, Aix-les- Bains, and other spas, and mud baths, are useful in the treatment of cases of chronic articular gout. Treatment by means of baths should, however, be avoided by patients suff"ering from acute gout, by elderly patients, and by those suffering from any 212 The Treatment of Gout. serious cardiac affection. Successful results have been reported from the localised application of very hot dry air, which appears not only to relieve the pain and congestion of the joints, but also to assist in the dispersion of the gouty deposit, probably by increasing the circulation in the various structures of the affected joint. After convalescence as much exercise as possible, short of fatigue and discomfort, should be taken in the open air. Cycling is an excellent exercise for the gouty, since it furnishes good muscular movement in the open air without the gouty joints having to bear the weight of the body. 213 CHAPTER XV. Treatment of retrocedent or vietastatic gout f— Treatment of the various forms of irregular gout — Treatment of gouty glycosv/ria and diabetes — Preventive treat- ment of gout — Diet in gout — AlcoJiol in gout. THE TREATMENT OF RETROCEDENT OR METASTATIC GOUT. Immediate treatment. — If the symptoms are urgent some brandy should be immediately given, and, if necessary, a hypodermic injection of mor- phine should be administered, provided marked albuminuria does not exist. If the metastatic seizure is a severe one, and especially if it affects either the heart or brain, it may be desirable to reinduce an attack of articular gout by placing the feet in a hot mustard-and-water bath, containing a full tablespoonful of flour of mustard to a gallon of water. TreatTTient of the gastro-intestinal form. — A mustard leaf should be applied to the epigastrium, and a mixture containing bismuth subcarbonate, sodium bicarbonate, and hydrocyanic acid should be given. If there is much depression suitable stimulants must be employed. Treatinient of the cardiac form,. — Heart tonics, such as digitalis, convallaria, or strophanthus, and 214 The Treatment of Gout. brandy, should be administered. A mustard leaf may be applied to the epigastrium. If an anginal attack occurs, then, in addition to this treatment, a dose of nitroglycerine should be given at once, or an inhalation of nitrite of amyl employed, and, if necessary, a mustard leaf should be placed over the prsecordial region. For the treatment ot syncopal attacks the patient should be immediately placed in the recumbent position, with the foot of the sofa or bed raised ; some hot brandy and water should be given, warmth and friction applied to the extremities, and a mustard leaf placed over the epigastrium. Treatment of the cerebral form. — If the patient is plethoric, and if the pulse is hard, and stupor or coma supervene, venesection should be performed, and from eight to sixteen ounces of blood with- drawn ; in less urgent cases six leeches may be applied to the mastoid region. Five grains of calomel should afterwards be administered by the mouth, and a turpentine enema given. THE TREATMENT OF THE VAllIOUS FORMS OF IRREGULAR GOUT. Affections of the gastro-intestinal tract and of the air-passages and lungs due to irregular gout require treatment on general principles. For lists of the mineral waters best suited for these forms of irregular gout, see p. 241. Gouty vertigo is generally due to gastric dis- turbance, which then requires suitable treatment. If the vertigo is of central origin, then the ordinary The Gouty Heart. 215 medicinal treatment for acute gout should be employed. The gouty heart is associated with fatty de- generation of the cardiac walls, and is mainly met with among sufferers from irregular gout. The condition is generally evidenced by prsecordial pain or oppression, vertigo, faintness, palpitation, or irregular cardiac action, insomnia, and slight anginal attacks; towards the end of an attack a cold sweat generally breaks out on the surface of the body, and is followed by flatulent eructa- tions, after which the attack subsides. The treat- ment should be rest in the recumbent position, and a small dose of blue pill or calomel, followed by a purge of Epsom salts, should be administered. If the pulse is of low tension a mixture containing corivallaria and strychnine will be suitable. If anginal attacks loccur, nitroglycerine or erythrol tetra-nitrate may be given by the mouth, or in- halations of nitrite of amyl employed. Iodide of potassium is also a very useful drug when there is much pain. The patient must be carefully dieted (see pp. 222 — 225), and graduated exercise, at first of a passive nature, such as the, Schott treatment, and later of an active nature, may be very beneficial. The action of the bowels should be properly regulated, and entire abstention from tobacco smoking, or extreme moderation in its/ use, should be advised. / Angina pectoris. — In anginal attacks in gouty subjects the pulse is generally one of high tension without the existence of any necessary association 2 1 6 The Trea tment of Gout. of atheroma of the vessels. For the immediate relief of the actual attacks nitroglycerine is the best drug to employ, although in rare cases nitrite ol amyl may be found more efficacious. Stimulants and morphine administered hypodermically should also be employed if necessary. For some days after an attack nitroglycerine in doses of one- hundredth of a grain should be given two or three times a day. If organic cardiac mischief exist, the condition must be suitably treated on general prin- ciples. In cases of anginal attacks occurring in gouty subjects, as soon as the severe pain has been relieved by the administration of nitroglycerine, a pill containing one grain of the acetic extract of colchicum and three grains of blue pill should be given at night and should be followed by a dose of Epsom salts in the morning. When the adminis- tration of nitroglycerine is discontinued citrate of potassium and iodide of potassium should be given for some time three times a day. Pseudo- angina pectoris. — For the treatment of this affection a dose of hot brandy and water should be given at once, and a mustard leaf should be applied to the epigastrium. On the subsidence of the severe symptoms a pill containing one grain of the acetic extract of colchicum and three grains of blue pill should be given at night, and should be followed by a dose of Epsom salts in the morning. Gouty phlebitis. — For the treatment of this fairly common form of irregular gout the patient should be kept in the recumbent position, and any sudden movement of the affected limb must be Sciatica and Neuritis. 217 prevented, on account of the danger of detaching a •portion of thrombus and the occurrence of conse- quent embolism of the pulmonary artery. Equal parts -of glycerine and extract of belladonna should be smeared over the affected part, and a linseed poultice with some of the glycerine and extract of belladonna spread on the surface should be applied and renewed every six hours. In addition to this the ordinary treatment of the gouty state must be resorted to. Gouty sciatica. — For the treatment of this painful affection the patient must be kept in the recumbent position, and in severe cases the pain should be relieved by a hypodermic injection of morphine. Ammonium chloride, given in doses of thirty to forty grains three times a day, is a very useful drug in the treatment of this form of iiTegular gout. Two grains of salicylate of quinine should also be given in a pill two or three times a day. In cases of gouty sciatica the ordinary treat- ment of the gouty state must be resorted to. Gouty neuritis. — Blistering along the course of the affected nerve-trunk is the most rapid way of relieving this painful affection. If such a mode of treatment should not be considered desirable, then iodine liniment may be painted along the course of the nerve-trunk, and hot linseed poultices applied as soon as the iodine is dry, and kept in position by a bandage loosely applied. Internally, iodide of potassium and iodine (for the doses see p. 210) combined with small doses of perchloride of mercury should be given. 2i8 The Treatment of Gout. Diseases of the skin associated with gout. — In dealing -with any gouty skin affection the ordinary treatment of the skin disease should be combined with the general treatment of the underlying gouty condition, and careful attention should especially be paid to the diet. Many of the gouty skin affections are considerably benefited by a cdurse of waters and baths at certain spas (a list of these spas is given on pp. 239, 240). The severe itching attending pruritus and urticaria is gener- ally relieved by the application of the following lotion : — Liq. plumbi subaoet. ... "... Sij Tinct. opii 31? Aq. rosEe ad Jviij Rubbing the skin with a menthol cone moistened with water is frequently useful in relieving the irritation. For the treatment of dry skin eruptions Sir William Roberts recommends the skin to be rubbed with a piece of smooth hard parafSn night and morning, so as to leave a delicate coating on the skin, which then probably acts by protecting the cutaneous surface from the air. Renal calculi. — For the treatment of uric acid renal calculi citrate of potassium should be given in full doses, so as to produce a moderate alk,alinity of the urine. By this means the further deposition of free uric acid in the kidneys is prevented, and the alkaline urine, moreover, gradually carries into solution the uric acid already deposited. The free drinking of ordinary water or of one of the mineral waters of the simple kind {see p. 230) should be advised. Glycosuria and Diabetes. 219 Irritable temper. — For the treatment of the irritable temper of gout, Dr. Lauder Brunton recommends the administration of twenty grains of bicarbonate of potassium and ten to twenty grains of bromide of potassium. THE TREATMENT OF GOUTY GLYCOSURIA AND GOUTY DIABETES. Dietetic treatment. — Careful dietetic treatment should be resorted to without, however, restricting the diet too much. An excessively nitrogenous diet is to be avoided as tending to accentuate the gouty condition, but no hard and fast rules as to the amount of diet can be laid down. Each case must be treated by •ascertaining what amount of proteids, fats, and carbohydrates is best borne by the individual. Toasted bread, milk, and milk puddings made with rice, sago, and tapioca are generally permissible in this form of glj'cosuria. The best test of the suitability of the diet is the fact that the weight of the patient is not diminish- ing, while, at the same time, the excretion of sugar is becoming less. The patient should, therefore, be weighed once a week, and the whole of the urine for twenty-four hours 'should be collected once a week, measured, and the quantity of sugar deter- mined in a sample of the mixed urines, so that the total output of sugar for the twenty-four hours may be known. Medicinal treatment. — A pill containing one grain of blue pill, one grain of acetic extract of colchicum, and two grains of euonymin should be 220 The Treatment of Gout. given every other night. A mixture containing thirty grains of ammonium chloride and fifteen minims of dilute nitro-hydrochloric acid in each dose should be taken three times a day ; this mixture acts as a stimulant to hepatic metabolism. Opium and its alkaloids are best avoided. For a list of the mineral waters best suited for the treatment of gouty glycosuria and gouty diabetes, see p. 241. THE PREVENTIVE TREATMENT OF GOUT. If uric acid is manufactured in the kidneys and, in gout, is absorbed therefrom into the general circulation only when the kidneys are incapable of getting rid of the whole of the uric acid, then whatever will promote the elimination of the uric acid, and thereby prevent its absorption into the general circulation, will strike at the origin of the development of gout. This can be efl'ected by (] ) the promotion of increased diuresis, by which means the solution and removal of the quadriurates from the kidneys is encouraged ; (2) by the produc- tion, at all events intermittently, of a moderate degree of alkalinity of the urine, by which means the quadriurates are rendered more soluble and more stable than they are in an acid urine, and so the tendency to the deposition of uric acid or of sodium biurate in the kidney tissues is removed ; and (3) by stimulation of the metabolism of the liver and of the kidney cells engaged in the ex- cretion of uric acid. The preventive treatment of gout consists in the adoption of measures which Preventive Treatment. 221' have for their aim the carrying out of these various points. The first effect can be secured by the patient drinking a sufficient quantity of ordinary water, or of a suitable mineral water. The second effect is attained by the consumption of sufficient quan- tities of vegetable food, and by the occasional administration of citrate of potassium. The third effect is secured by the administration of guaiacum and other suitable cholagogues, such as an occa- sional piU. containing two grains of blue pill and two grains of euonymin given at night, and followed by a dose of Epsom salts in the morning. Sir Alfred Garrod considers that guaiacum taken in the intervals of attacks of gout is a powerful prophylactic, that it does not appear to lose its prophylactic power by long-continued use, and that only in the cases of a few persons does the drug disagree. I have employed guaiacum for some time as a prophylactic, in gout, and can entirely corroborate Sir Alfred Garrod's opinion as to its great utility under such conditions. To prevent, as far as possible, the recurrence of gout the patient should also give careful attention to diet on the lines laid down in pp. 222 — 225. Regular habits of life, with regular and sufficient exercise, should be encour- aged, and constipation should be zealously avoided. Briefly stated, the individual who is subject to gout, and who wishes to prevent a recurrence of the disease, should lead an active and an ab- stemious life. 222 Tub Treatmen-t of Gout. diet in gout. A rational mixed diet is the one best suited for gouty patients, care being taken to avoid excess. The assumption that a purely vegetable diet is best for thfe gouty is erroneous, since the production of uric acid depends on the iiagestion of proteid matter, and it makes no difference whether the proteid matter be of animal or vegetable origin. At the same time it must be borne in mind that since animal food is so much richer in proteids than a vegetable diet, the amount of the former taken by the gouty should be strictly limited. Moreover, the results of the series of investigations summarised on pp. 172 — 175 show that, whereas the mineral constituents of meat exercise a marked eifect in diminishing the solubility of a gouty deposit, the mineral constituents of most vege- tables exercise a marked power in increasing its solubility. The vegetables the mineral constituents of which I find are most efficacious in this respect are spinach, Brussels sprouts, potatoes, cabbage, and French beans. At the same time it must be borne in mind that with certain patients some of these vegetables inay tend to produce some form of dyspepsia, and I cannot too strongly urge that in the dieting of the gouty no hard and fast rules can be laid down, but the idiosyn- crasy of each patient to various articles of diet must be made the subject of careful observation and study. Due consideration should also be given to the patient's experience of what articles of diet Dmr IN Gout. 223 disagree and agree with him. I^ during the treat- ment of gout, an attack of gouty dyspepsia should at any time intervene, then a milk diet should be employed until the dj'speptic symptoms have abated. It is most important that the gouty patient should take a sufficiency of water to drink, so that the various organs are well flushed, the removal of the gouty deposits encouraged, and the specific gravity of the urine kept moderately low. The quantity of fluids taken in the twenty-four hours should not be less than three and a half pints, and may even with advantage reach to four and a half pints. The following plan gives an indication of the diet to be recommended to gouty subjects : — Morning. — Half a pint to a pint of hot water flavoured with a slice of lemon peel should be slowly sipped immediately on rising. Breakfast. — -A selection may be made from the following articles of diet, according to the taste of the patient: — -Porridge and milk, whiting, sole or plaice, fat bacon, eggs cooked in various ways, dry toast thinly buttered, and tea infused for three minutes and then strained from the leaves. Lunch and dinner. — No soup should be taken at either meal. The varieties of fish most suitable to the gouty are whiting, sole, turbot, and plaice. Meat should be taken at only one meal, and then in moderate quantity. Beef, mutton, chicken, turkey, pheasant, and calfs sweetbread are admissible. Salted meat, salted and smoked fish, and shell fish, with the exception of oysters, are best avoided. All articles of food pickled in vinegar should also 224 The Treatment of Gout. be avoided. Two vegetables sbould be taken at both lunch and dinner, and in abundant quantities. The vegetables that, in my opinion, should be avoided by the gouty are asparagus, tomatoes, and green peas. Asparagus is apt to prove irritating to the kidneys of gouty subjects, and also is liable to produce a temporary glycosuria, probably from some irritant effect on the liver. Any of the other ordinary vegetables may be taken, but those that I consider most likely to j)rove beneficial to gouty subjects are, as, indeed, has already been mentioned, spinach, Brussels sprouts, French beans, winter cab- bage. Savoy cabbage, turnip tops, turnips, and celery. Potatoes may also be taken in moderate quantities. Stewed fruits, or baked apples or pears, may with advantage be taken every day at one meal, and a milk pudding made with rice, sago, and tapioca at the other meal. Rhubarb should be avoided owing to the liabiUty of the calcium oxalate contained in it to irritate the kidneys during its excretion. Rich pastry and all rich sweets should be rigorously avoided by the gouty. Night. — A pint of hot water, flavoured with a slice of lemon peel, should be slowly sipped before retiring to bed. Alcohol. — As regards the employment of alcohol, each case must be individually and carefully dealt with. During an attack of acute gout the patient is better without any alcohol. If the gouty person be of robust habit of body, then total abstinence is undoubtedly the best for such a patient. If, how- ever, the cardiac action be weak and failing, then Alcohol in Goun 225 moderate quantities of alcohol should certainly he given. In cases of chronic gout a moderate amount of alcohol may be necessary for the promotion of digestion. The best form of alcohol for the gouty is a tablespoonful of matured whisky freely diluted with salutaris water or with plain water, and taken towards the end of lunch or dinner. If any wine is taken by the gouty, those which are least open to objection are light but sound clarets and hocks. Old wines with a fine bouquet are very provocative of gouty attacks in most persons predisposed to the disease, probably on account of the large quantities of ethereal compounds contained in them powers fully affecting the metabolism of the liver, and so, by causing an increased quantity of glycocine to pass from the liver to the kidneys, leading to an increased production of uric acid in the last- mentioned organs. Ales and stout should also be avoided by the gouty. 226 CHAPTER XVI. The uses of mineral waters in the treatment of gout — The mineral waters best suited for the removal of gouty deposits — Classification of the mineral waters used in the treatment of gout — The simple waters — Simple alkaline waters — Alkaline sulpliated waters — Alka- line muriated waters — Common salt or muriated waters — Sulphur waters — Hot and cold mineral waters — Classification of mineral loaters according to their therapeutic . value in the treatment of the various forms of gout. THE USES OF MINERAL WATERS IN THE TREATMENT OF GOUT. The value of a given mineral water in the treat- ment of gout depends greatly on the main object with which it is taken. For instance, it may be taken to remove gouty deposits, or to stimulate the action of a sluggish liver and to relieve portal congestion, or for the treatraenj; of gouty dyspepsia, or to relieve the bowels in cases of torpor and gastro-intestinal catarrh, or to act on the kidneys, or to relieve gouty affections of the skin. Now it is manifest that any one mineral water is not likely to produce all these effects, and it is also obviously conceivable that a mineral water which might be most useful to effect one of these purposes might C/sEs OF Mineral Waters. 227 prove most injurious if employed to effect another. No doubt considerable error has arisen from in- discriminately sending gouty patients to a particular spa without giving due consideration to the ques- tion as to whether the water of that spa is suitable for the treatment of the specific gouty disorder from which the patient is suffering. • Moreover, it is well to bear in mind that a patient should not be sent to a spa during the acute stage of gout, nor if suffering from marked organic disease of the heart or kidneys. The use of a mineral water, so far as its employment with the object of removing gouty deposits is concerned, lies solely in its watery con- stituent, and does not in any way depend on the mineral constituent dissolved in it. As a matter of fact the salts dissolved in a great many of the iiatural mineral waters are directly harmful in gout both by encouraging deposition of the sodium biurate and by checking solution of the gouty deposits. The flushing of the system, of a gouty patient with abundant quantities of water is un- doubtedly beneficial, since it dilutes the blood for the time, and so tends to prevent uratic precipita- tion, and at the same time promotes diuresis and encourages the elimination of urates. The question, however, naturally arises whether, if the water of a mineral water be its only beneficial constituent for effecting the removal of gouty deposits, the sending of gouty patients to spas for such a purpose pre- sents any advantages over their drinking ordina^rj'^ water at home. If the conditions of the life of the 228 The Treatment of Gout. patient at home and at a spa were the same, there would be no such advantage, but among the special benefits to be derived from residence at a spa must be reckoned the almost undistracted attention that is given by the patient to treatment, the careful dieting that is frequently observed, the change of surroundings, • the absence of business or home worries, and the opportunities for the use of thermal baths for the external treatment of articular gout. It should, however, be carefully borne in mind that, owing to the undoubted fact that sodium salts are directly detrimental to the removal of gouty deposits, those springs should be avoided which owe their activity to those salts, when the removal of the deposits is the main object to be attained. The springs which contain no sodium salts, or traces only, are the ones suitable for such cases^such as the waters of Buxton, Bath, and Strathpeffer in Great Britain; in France the waters of Aix-les-Bains, Contrex6ville, and Vittel; in Switzerland the Pfaefers water ; in Austria the Gastein water; in Bohemia the Teplitz water; in Germany the Wildbad water. I wish it to be clearly understood that I am by no means con- demning the very proper uses to which mineral waters containing sodium salts can be put for the treatment of many gouty affections of the viscera and other structures, but I wi§h to emphasise the point that when the system is flushed with a mineral water with the object of dissolving and removing gouty deposits, then it is undoubtedly advisable to select a water as free as possible from Uses of Mineral Waters. 229 sodium salts. On the other hand, in cases of sluggish action of the liver, of gastro-intestinal catarrh and torpor, of gouty dyspepsia, and of other forms of irregular gout where there are no appreciable uratic deposits in the joints, mineral waters containing sodium salts are undoubtedly beneficial, owing to the action of those salts as hepatic and gastro-intestinal stimulants. The explanations given as to the modus operandi of a particular mineral water must sometimes be received with a certain amount of caution. For instance, the advocates of one mineral water will extol its efficacy in the treatment of gout on account of the lime salts contained in it and its freedom from sodium salts, whilst, on the other hand, the advocates of another mineral water will insist that the large quantities of sodium salts present in it and the absence of lime salts are the potent factors in its usefulness in the treatment of gout. The advantages and disadvantages of sodium salts have already been referred to. With regard to the presence of lime salts, a mineral water con- taining such does not exercise, by virtue of those lime salts, either a deleterious or a beneficial action on the gouty deposits of sodium biurate. The only objection to a" water containing a large quantity of lime salts is the tendency to produce digestive disturbances and to cause constipation. CLASSIFICATION OF MINERAL WATERS. The various mineral waters used in the treat- ment of gout may be classified according to 230 The Treatment of Gout. their chemical composition into the six following groups : — 1. The simple waters, or waters comparatively free from sodium salts. 2. The simple alkaline waters. 3. The alkaline sulphated waters. 4. The alkaline muriated waters. 5. The common salt or muriated waters. 6. The sulphur waters. THE SIMPLE WATERS, OR WATERS COMPARATIVELY FREE FROM SODIUM SALTS. These are the waters that are especially likely to prove useful for the removal of uratic deposits in the joints and tissues. They contain small propor- tions of calcium carbonate and calcium sulphate, but the quantities of" sodium salts present are so small that for all practical purposes they may be neglected. The following table (Table LVIII.) shows the proportions of sodium salts in the respective waters of this class, represented as grains of sodium per gallon : — TABLE LVIII. Showing the proportione of sodittm talts, represented as grains of sodium per gallon, in the principal simple waters. Mineral water. Grains of sodium per feallon. Teplitz 0-20 Strathpeffer... .. 0-4.1 Gontrexeville 0-79 Aix-les-Bains 1-34 Buxton 1-47 Pfaefers ... 1-61 Gastein 5-89 Wildbad ... 7-63 Bath 9-42 Vittel lS-39 The Simple Waters. 231 Teplitz (Bohemia). The waters are hot (83'' to 114° F.). Altitude about 730 feet. Thermal 'baths and peat baths are provided. Open all the year, but the usual season is from May to September. Strathpeffer (Scotland, Ross-shire). The waters are cold. Altitude about 200 feet. Strathpeffer also possesses sulphur springs and a chalybeate spring. Various kinds of baths are provided. The sulphur waters are useful in the treatment of the various skin affections connected with gout. Open all the year, but the usual season is from May to October. Oontrex^ville (France). The waters are cold. Altitude 1,150 feet. Baths are provided. The water, in addition to being almost free from sodium salts, contains magnesium sulphate, so that it is useful not only for the removal of uratic deposits, but also in the treatment of gastro-intestinal and hepatic disorders associated with gout, and for the treat- ment of urinary gravel. The season is from the beginning of June to the end of October. Aix-les-Bains (France). The waters are hot (112° F.). Altitude 870 feet. The waters contain free sulphuretted hydrogen. This spa is especially known for its baths, douches, and douche-massage, all of which methods of treatment are most bene- ficial in the removal of the stiffness and swelling of the joints left after an attack of gout. The waters are also employed in the treatment of cutaneous affections connected with gout. Sir Alfred Garrod especially recommends the treatment at Aix-les- Bains in cases of chronic gout accompanied by 232 The Treatment of Gout. indolent swelling of the previously inflamed part, and by eczema. The spa is open all the year, but the season lasts from April to November. Buxton (England, Derbyshire). The waters are warm (82° F.). Altitude 1,000 feet. Baths, douches, and douche-massage are provided. The water contains a considerable amount of free nitrogen. On account of the very small proportion of sodium salts present it is an extremely beneficial water to employ with the object of removing uratic deposits. The climate is bracing. Open all the year, but the season is from April to September. Pfaefers (Switzerland). The waters are warm (89° to 93° F.). . Altitude about 1,700 feet. Baths are provided. The season is from May to October. Gastein (Austria). The waters are hot (78° to 121=^ F.). Altitude 3,310 feet. Baths are provided. The season is from the beginning of May to the end of September. Wildbad (Germany). The waters are hot (91° to 105° F.). Altitude about 1,320 feet. Baths, douches, and electric baths are provided. The season is from the beginning- of May to the' end of September. Bath (England, Somersetshire). The waters are hot (104° to 120° F.). Altitude 100 feet. Excellent baths, douches, and douche-massage are provided. The water is a very useful one to employ with the object of removing uratic deposits, and chronic affections of the joints can be well treated at Bath by external methods. Open all the year, but the spring and autumn are the favourite seasons. The Simple Alkaline Waters. 233 climate of Bath is mild, and it is therefore a good winter resort. Vittel (France). The waters are cold. Altitude 1,100 feet. The season is from May to September. SIMPLE ALKALINE WATERS. These waters contain sodium bicarbonate. They are useful for gouty patients suffering from hepatic congestion, dyspepsia, and gastro-intestinal catarrh. The principal waters of this class are those of Vichy, Vals, Neuenahr, Salzbrunn, Fachingen, and Bilin. Vichy (France). The waters are hot (89° to 110° F.). Altitude 736 feet. Baths are provided. The waters are especially useful in the treatment of gouty dyspepsia and gastro-intestinal catarrh, in cases of deranged hepatic function, and for plethoric gouty patients suffering from glycosuria or diabetes. Open all the year, but the season is from the middle of May to the end of Sep- tember. In the middle of summer Vichy is- very hot. Vals (France). The waters are cold. Altitude 300 feet. The waters may be used for the same class of gouty cases as mentioned in connection with the Vichy waters, but those springs containing iron should be avoided by gouty patients. The season is from the middle of May to the middle of October. Neuenahr (Germany). The waters are hot (75° to 104° F.). Altitude 760 feet. Baths are provided. The waters may be used for the same class of gouty 234 The Treatment of Gout. cases as mentioned in connection with the Vichy waters. The season is from May to October, but in the middle of the summer Neuenahr is very hot. Salzbrunn (Prussian Silesia). The waters are cold. Altitude 1,320 feet. The waters may be used for the same class of gouty cases as men- tioned in connection with the Vichy waters. The season is from the beginning of May to the end of September. ALKALINE SULtHATED WATERS. These waters contain sodium bicarbonate, sodium sulphate, and generally a moderate pro- portion of sodium chloride. They are useful in the treatment of gout connected with congestion of the liver and portal system, and of gout con- nected with gastro-intestinal catarrh and with some forms of dyspepsia. They may also be em- ployed in the treatment of gouty glycosuria. The principal waters of this class are those of Carls- bad, Marienbad, Tarasp-Schuls, Brides- les-Bains, Cheltenham, Leamington, and Bertrich. Carlsbad (Bohemia). The Carlsbad waters are rich in sodium sulphate and sodium bicarbonate, and also contain a moderate proportion of sodium chloride. The waters are hot (95° to 162° F.). Altitude 1,160 feet. Baths are provided. The waters are best suited for gouty patients suffering from torpor of the hepatic and gastro-intestinal functions, and especially for cases of congestive enlargement of the liver with a tendency to haemorrhoids. They are also of use in the treat- Alkaline Sulphated Waters. 235 ment of gouty glycosuria. The waters are best suited for those of fairly robust constitutions. They are contra-indicated if heart disease is present, or if arterio-sclerotic changes are ad- vanced, or if the kidneys are seriously implicated. The season is from the middle of April to the end of September. A course at Carlsbad may advantageously be succeeded by a stay in Switzer- land at a station situated at a high altitude. Marienbad (Bohemia). The waters are cold. Altitude about 1,980 feet. Baths are provided. The waters are very similar in composition to those of Carlsbad, and are useful for the same class of cases. The season is from May to Sep- tember. A course at Marienbad is also advan- tageously succeeded by a stay at a high altitude. Tarasp-Schuls (Switzerland). The waters are cold. Altitude 3,870 feet. Baths are provided. The waters are useful for the same class of cases as mentioned in connection with the Carlsbad waters. The season is from the middle 'of .Tune to the middle of September. Brides-Ies-Bains (France). The waters are hot (95° F.). Altitude about 1,860 feet. Baths are provided. The waters are useful for the treat- ment of gouty dyspepsia associated with con- stipation.- The season is from the beginning of June to the end of September. Cheltenham (England, Gloucestershire). The waters are cold. The non- chalybeate waters are useful in the treatment of congestive conditions of the liver associated with gout. 236 The Treatment of Gout. Leamington (England, "Warwickshire). The waters are cold. Baths are provided. The waters are useful in the treatment of torpid conditions of the liver and of the gastro-intestinal tract asso- ciated with gout, and also in the treatment of gouty glycosuria. ALKALINE MDRIATED WATERS. These waters contain sodium bicarbonate and sodium chloride. They are useful in the treatment of gouty dyspepsia and of gouty catarrhal affections of the respiratory organs. The principal waters of this class are those of Ems, Koyat, Assmannshausen, and La Bourboule. Ems (Germany). The waters are hot (80° to 120'= F.). Altitude 300 feet. Baths are provided; The waters are especially useful for patients suffer- ing from gouty bronchitis and asthma, for the treatment of which affections the waters can be inhaled in a finely divided condition. They may also be employed in the treatment of gouty dys- pepsia. The climate is a relaxing one, and is best suited to elderly gouty patients. Royat (France). The waters are warm (68° to 95° F.). Altitude 1,480 feet. Baths are provided. The waters are useful for the same class of cases as mentioned in connection with the Ems waters. The season is from the middle of May to the middle of September. Assmannshausen (Prussia). The water is tepid (82° F.), and contains a small proportion of lithium bicarbonate. MuRiATED Waters. 237 La Bourboule (France). The water is hot (130° F.). Altitude 2,780 feet. Baths are provided. The waters are arsenical as well as alkaline muriated, and may be useful in certain cases of chronic gouty skin disorders. The season is from the beginning of June to the end of September. COMMON SALT OR MURIATED WATERS. These waters contain sodium chloride as their principal constituent, and some of them also con- tain a large amount of free carbonic acid gas. They are of use in the treatment of gastro-intestinal and hepatic gout, especially when accompanied by constipation, and in cases of gouty dyspepsia asso- ciated with general atony. They exercise a stimu- lant effect on the gastric glands and on the liver cells. They are not indicated in cases of articular gout, when the removal of the uratic deposits is the main object of treatment. The principal waters of this class are those of Homburg, Wiesbaden, Kis- singen, Baden-Baden, Nauheim, Llandrindod, Wood- hall Spa, Llangammarch Wells, Oeynhausen. Homburg (Germany). The waters are cold. Altitude about 600 feet. Baths, massage, and electrical treatment are provided. The waters produce slight purgation and diuresis, and are useful for the treatment of gouty dyspepsia with a tendency to constipation, and of gouty gastro- intestinal catarrh and hepatic congestion associated with general atony. Wiesbaden (Germany). The waters are hot (100° to 156° F.). Altitude 380 feet. Baths are 238 The Treatment of Gout. provided. The waters are useful for the same class of cases as mentioned in connection with the Homburg waters, but should be avoided in cases of articular gout. Open throughout the year, but in midsummer Wiesbaden is very hot. Kissingen (Bavaria). The waters are cold. Altitude about 600 feet. Baths are provided. The waters are useful for the same class of cases as mentioned in connection with the Homburg waters. The season is from May to the end of September. Baden-Baden (Grand Duchy of Baden). The waters are hot (120° to 150° Fi). Altitude about 650 feet. Baths, douches, and electric baths are provided. The waters are useful in the treatment of gastro-intestinal catarrh and sluggish conditions of the liver. Open all the year, but the sea- son is from the beginning of May to the end of October. During July and the first half of August Baden-Baden is very hot. Nauheim (Germany). The waters are warm (82° to 95° F.). Altitude about 400 feet. This spa is specially known for its baths in connection with the treatment of various affections of the heart. Two of the waters are somewhat similar in com- position to the Homburg water, and may be em- ployed in the treatment of gouty dyspepsia. The season is from May to the end of September. Llandrindod (Wales, Radnorshire). The waters are cold. Altitude 700 feet. Baths are provided. Muriated waters, sulphur waters, and weak chaly- beate waters are found at Llandrindod. The muriated waters are useful in the treatment of Sulphur Waters. 239 gouty gastro-intestinal catarrh and congestion of the hver, and also in the treatment, of gouty glycosuria. The season is from May to October. Woodhall Spa (England, Lincolnshire). This water, in addition to being a highly muriated water, contains bromides and iodides. Llangammarch Wells (Wales, Brecknockshire). Altitude about 600 feet. This water, in addition to being a muriated water,, contains a small quantity of barium chloride. Brine Baths. The brine baths of Droitwich (England, Worcestershire), Kreuznach (Germany), Ischl (Austria), Rheinfelden (Switzerland), Aussee (Styria), Reichenhall (Bavaria), and Bourbonne-les- Bains (France) are useful in the J;reatment of stiff- ness and thickening of the joints in cases of chronic articular gi)ut, but should be avoided if gouty skin affections are present. SULPHUR WATERS. These waters contain sulphur, either in the form of sulphuretted hydrogen only, or, in addition to free sulphuretted hydrogen, some of them contain combined sulphur in the form of the sulphides of calcium, magnesium, and sodium. They are fre- quently very useful in the treatment of gouty skin affections, especially eczema and psoriasis. Sulphur baths are also of benefit for the same purpose. In addition, the Harrogate waters may be employed in the treatment of gouty gastro-intestinal and hepatic affections. The sulphur springs may be classified into the cold and hot springs. 240 The Treatment of Gout. Cold sulphur springs. — The principal waters of this class are those of Harrogate (England, Yorkshire), Strathpeffer (Scotland), Llandrindod (Wales, Radnorshire), Gurnigel (Switzerland), Heustrich (Switzerland), Nenndorf (Prussia), and Weilbach (Germany). Hot sulphur springs. — The principal waters of this class are those of Aix-les-Bains (France), Aix- la-Chapelle (Germany), Baden (Switzerland), Baden (near Vienna), Uriage (France), Bagneres-de-Luchon (France), AUevard (France), Saint-Honor6 (France), and Schinznach (Switzerland). HOT AND COLD MINERAL WATERS. The following table (Table LIX.) shows a classi- fication of the various mineral waters used in the treatment of gout into hot and cold waters : — TABLE LIX. Classification of the various mineral waters used in the treatment ■ of gout into hot and cold waters. Hot. Cold. Aix-les-Bains Cheltenham Aix-la-Chapelle Oontrex6ville Baden Harrogate Baden-Baden Homburg Bath Kissingen Bridea-lea-Bains Leamington Buxton Llandrindod Carlsbad Marienbad Ems Salzbrnnn Gas.tein Strathpeffer La Bourtoule Tarasp-Schuls Nauheim Vala N'euenahr Viohy (some springs) Ragatz-Pfaefers Vittel Royat TepKtz Vichy (some springs) Wiesbaden Wildbad Uses of Mineral Waters. 241 ■THERAPEUTIC USES OF THE VARIOUS MINERAL WATERS FOR THE DIFFERENT FORMS OF GOUT. In the following table (Table LX.) the various mineral waters are classified according to their therapeutic value in the treatment of the various forms of gout. TABLE LX. Classification of the various mineral waters according to their therapeutic value in the treament of the various forms of gout. Object of taking the water. The waters best suited for the purpose. ' Abaorption of gouty- deposits from the joints and tissues. Aix-ies-Bains, Bath, Buxton, Coutrex^ville, Gastein, Pfaefers, Strathpeffer, Teplitz, Vittel, Wildbad. Treatment of gouty dyspepsia. Brides-les-Bains, Carlsbad, Ems, Homhurg, Kissingen, Neuenahr, Eoyat, Vals, Vichy, "Wiesbaden. Treattnent of gouty congestion and torpor of the liver, and of gastro-in- testinal catarrh and torpor. Baden-Baden, Bourbonne, Carlsbad, Chel- tenham, Contrex^ville, Harrogate, Hom- hurg, Kissingen, Leamington, Llan- drindod, Marienbad, Neuenahr, Tarasp- Schuls, Vals, Vichy, Vittel, Wiesbaden. Treatment of gouty affections of the re- spiratory organs. Ems, Eoyat. Treatment of gouty glycosuria and diabetes. Carlsbad, ContrexevUle, Kissingen, Lea- mington, Llandrindod, Marienbad Neuenahr, Vals, Vichy, Vittel. Treatment of gouty skin affections. Sulphur waters and baths {see pp. 239, 240). INDEX. Abarticular gout, 114-124 Acidity and gout, 190-193 Acne, Gouty, 123 Acute gout, 107-110 — i , Clinical features of, 107-110 . , Diet in, 204, 205 , Symptoms of, 108, 109 , Treatment of, 201-205 j;tiology of gout, 105-107 Age and gout, 105 Aix-la-Chapelle waters, 240 Aix-les-Bains waters, 231, 240, 241 Albuminuria, Treatment o^ 210, 211 . Alcoliol and gout, 145-149, 224, 225 Allcalies and gouty deposits, 180-19tf , Treatment of gout by, 176-192 Alkaline muriated waters, 236, 237 ■ — - sulphated waters, 234-236 waters, 233, 234 Alkalinitv of blood of gout, 129-131, 139 Allevard waters, 240 Alloxur bases and gout, 9, 10 Amidobodies and uric acid, 68, 69 Amorphous quadriurates, 7 urate deposit, 84-86 Anaemia, Uric acid in blood of, 48 Angina pectoris. Treatment of, 215, 216 Anginal attacks, Treatment of, 214 Animal diet and uric acid, 65, 66 Asparagus ash, Eft'ect of, 152 Assmannshausen waters, 236 Asthma, Gouty, 118 j Treatment of, 236 Aussee baths, 239 Baden-Baden waters, 238, 241 BfideQ waters, 240 B;ignferes-de-Luchon waters, 240 Bath waters, 232, 241 Baths, Thermal, 211 Beers, Acidity of, 146 Beers and gout, 145-149 Gout-inducing power of, 14e', 148, 149 Beetroot ash. Effect of, 154 BiMs, Urinary excrement of, 83, 84 Biurate, Causes of deposition of, 92- 100 , Gelatinous. form of, 88 , Solubility in serum of, 92 Biurates, Composition of, 2 Bladder, Irritability of, 121 Blood, Detection of uric acid in, 31-31 disorders and uric acid, 48 , Estimation of uric acid in, 31-34 , Introduction of uric acid into, 25, 82 of birds. Examination of, 44, 45 of gout. Alkalinity of, 129-181, 139 of mammals, Exiimination of, 44 of maUj Examination of, 43, 44 of reptiles. Examination of, 45 , Uric acid compound in, 2 , Uric acid not normal constituent of, 43-47 Boils and gout, 123 Bourbonne-les-Bains, 239 Brides-les-Bains waters, 235, 241 Brine baths, 239 Bronchitis, Gouty, 117, 118 , Treatment of, 236 Brussels sprouts ash. Effect of, 152 Buxton waters, 232, 241 Cabbage ash. Effect of, 164 Calculi, Treatment of renal, 218 , Uric acid, 121 Carbuncles, Gouty, 123 Cardiac irritability, 118 Carlsbad waters, 234, 235, 241 Carrot ash. Effect of, 155 Cartilage, Uratic deposition in, 90, 91 Cauliffower ash. Effect of, 158 Causation of gout, 5-24 Celery ash. Effect of, 154 Clieltenham waters, 235, 241 Chronic deforming gout. 111 Chronic gout, 110-113 , Treatment of, 208-212 . , Urine of, 112 Colchicum, Action of, 205-208 and uric acid excretion, 206, 207 in gout, 202, 203 Cold mineral waters, 240 Common salt and gout, 174 Conclusions as to pathology of gout, 103, 104 Connective tissues and uric acid formation, 40, 41 Constipation, Treatment of, 203, 204 233-239 OontrexSville waters, 231, 241 Cycling and gout, 212 244 Gout. Deafness, Gouty, 124 Detection of uric acid in blood, 31-34 Diabetes, Gouty, 123 , Mineral waters for, 241 , Treatment of, 219, 220 Diagnosis of gout, 126, 127 Diet and uric acid excretion, 65-67 formation, 66, 66 in acute gout, 204, 205 in gout, 204, 205, 222-225 Distinction of gout from rheumatism, 126 rheumatoid arthritis, 126, 127 Droitwich baths, 239 Dyspepsia, Gouty, 117 , Mineral waters for, 241 , Treatment of, 233, 234, 236, 237 E Ear, Gouty deposits in, 101 Ebstein's views and experiments, 11-18 , Criticism of, 14, 16, 17 Eczema, Gouty, 122 , Treatment of, 218, 239 Ems waters, 236, 241 Epilepsy and gout, 120 Estimation of uric acid in blood, 31-34 urine, 29-31 Exciting causes of gout, 106 Exercise and gout, 212 Fibroid tissue degeneration and gout, 19 Flesh diet and uric acid, 65, 66 Flying gout, 124 French Deans ash, Effect of, 163 Gnstein waters, 232, 241 Gastro-intestinal catarrh, Gouty, 117 , Mineral waters for, 241 , Treatment of, 233, 234, 237, 239, 241 torpor, Mineral waters for, 241 Glycocine and uric acid formation, 68-71 Glycosuria, Gouty, 123 , Mineral waiiers for, 241 , Treatment of, 219, 220, 233, 234 Goat, Abarticular, 114-124 , Acute, 107-110 , ^Etiology of, 105-107 , Alkalinity of blood of, 129-131, 139 and alcohol, 145-149 and deficient excretion of uric acid, 26-28 and kidney atfections, 62-63 and nervous system, 21-28 and nitrogenous diet, 140, 141 Gout and' rheumatism. Distinction of, 126 and rheumatoid arthritis. Dis- tinction of, 126, 127 and uratic deposition, 5, 6 — and vegetables, 144, 150-175 , Author's view of cause of, 24 , Causation of, 5-24 , Cause of heredity of, 62 , Chronic, 110-183 , Chronic deforming. 111 , Clinical features of, 107-125 , Conclusions as to pathology of, 103, 104 , Definition of, 1 , Diagnosis of, 126, 127 , Diet in, 204, 206, 222-226 , Diet in acute, 204, 205 — — , Distinction of rheumatism from, 126 , rheumatoid arthritis from, 126, 127 , Exciting causes of, 106 , Forms of, 107-125 • , Humoral theory of, 4 in the liver, 124 , Irregular, 114-124 , , Causatiqn of, 6, 7 , Metastatic, 124, 126 , Pathology of, 1-104 , Predisposing causes of, 105-107 , Preveutive treatment of, 220, 221 , Primary cause of 53 , Prognosis of, 127 , Benat origin of, 60-63 , Betrocedent, 124, 125 , Suppressed, 114 , Symptoms of acute, 108, 109 ■ , chronic, 110-113 , Topliaceous, 111 , Toxic agents causing, 69, 60 , Treatment of, 199-241 , acute, 201-206 , chronic, 208-212 , subacute, 208, 209 , Various forms of, 107-125 Gouty acne, 123 asthma, 118 bronchitis, 117, 118 cardiac irritability, 118 deafness, 124 deposits. Formation of, 86-89 , Mineral waters ,for, 241 , Treatment of, 230-233, 241 diabetes, 123 , Treatment of, 219, 220, 233 dyspepsia, 117 eczema, 122 gastro-intestinal catarrh, 117 glycosuria, 123 , Treatment of, 219, 220, 233, 234 heai't, Treatment of, 215 hepatic congestion, 124 — - herpes, 122 insomnia, 120 joints, Treatment of, 201,' 202, 209-212, 230-233 kidney, 120, 121 , Signs of, 200 and heart, 112, 113 Index. 245 Gouty laryngitis, 117 migraine, 319 neuralgia, 119 neuritis, 119, 120 : , Treatment of, 217 cesophagismus, 116 orchitis, 125 parotitis, 125 paroxysm, Cause of, 101-103 , Treatment of, 201, 202 pharyngitis, 116 phlebitis, 118, 119 , Treatment of, 216, 217 prurigo, 123 pruritus, 123 psoriasis, 123 pulmonary congestion, 118 sciatica, 119 , Treatment of, 217 tracheitis, 117 • urticaria, 123 ■ vertigo, Treatment of, 214 Gowland-Hopkins'process, 30, 31 Granular disease of kidneys and gout, 65-67 Gravel, Uric acid, 121 Great toe and gout, 101 Green-peas ash, Effect of, 156 Guaiacum in gout, 208, 221 Gurnigel waters, 240 H H:irrogate waters, 239, 240, 241 Heart and gouty kidney, 112, 113 irregular gout, 118 , Treatment of gouty, 215 Hepatic congestion. Gouty, 124 , Treatment of, 233, 284, 237, 239 derangements and gout, 71, 72 Hereditary factor of gout, 62 Heredity and gout, 105, 106 Herpes, Gouty, 122 Heustrich waters, 240 Homburg waters, 237, 241 Hot-air baths, 212 mineral waters, 240 Unmoral theory of gout, 4 Hypoxanthin, 73 Inherited gout. Cause of, 62 Insomnia and gout, 120 , Treatment of, 204 liTCgular gout, 114r-124 , Causation of, 6, 7 , Treatment of, 214, 220 Irritability of bladder, 121 Irritable temper. Treatment of, 219 Joints, Causes of uratic deposition in, 98-101 Joints, Gouty, 98-101 , Treatment of gouty, 201, 202, 209-212, 230-233 Kidney affection causing gout, Nature of, 62 affections and gout, 52-63 disease and uratic deposition, 54-57 , Treatment of, 210, 211 , Gouty, 120, 121 , Signs of gouty, 200 Kidneys and uric acid formation, 37, 38 , Excretion of uric acid by, 63 in chronic gout. 111, 112 Kissingen waters, 238, 241 Kreuznaoh baths, 239 La Bourboule waters, 237 Laryngitis, Gouty, 117 Lead gout, 113, 114 Lead poisoning and gout, 59, 60, 96, 97 uric acid, 50 Leamington waters, 236, 241 Lettuce ash. Effect of, 153 Leucocythaemia, Uric acid in blood of, 48 Leucocytosis and uric acid, 74-77 Lithium carbonate. Experiments with, 179-181, 1S3, 187-1S9 citrate. Experiments with, 179, 180, 184 salts and gouty deposits, 183, 184, 187-189 Liver affections. Mineral waters for, 241 and uric acid formation, 38-40 derangements and gout, 71, 72 disease and uric acid formation, 71,72 , Gout in the, 124 Llandrindod waters, 238, 240, 241 Llangammarch Wells, 239 Lysidine, Effect of, 180, 186 , Experiments with, 179, ISO, 186 M Marienbad waters, 235, 241 Massage and gout, 211 Mental depression and gout, 120 Metastatiogout, 124, 125 , Treatment of, 21S, 214 Migraine, Gouty, 119 ' Mineral waters. Alkaline muriated, 236, 237 , Alkaline sulphated, 234, 236 , Classifleation of, 229, 230, 240, 241 , Cold, 240 246 Gout. Mineral waters for gastro-intestinal catarrh, 241 torpor, 241 goity deposits, 241 diabetes, 24L — dyspepsia, 241 glycosuria, 241 ' skin affections, 241 liver affections, 241 — ; respiratory affections, 241 , Hot, 240 , Mnriated, 237-239 , Objects of using, 226-229 , Simple, 230-233 , Simple alkaline, 233, 234 , Sulphur, 239, 240 ^ Therapeutic uses of, 226- 229 , Uses of, 226-229, 241 Murexide test, 3 Mnriated mineral waters, 237-239 N Nauheim waters, 238 Necrotic changes and gout, 11 Nenndorf waters, 240 Nervous disturbance as cause of gout, 21-23 influences and gout, 95, 96 system and gout, 21-23 Neuenahr waters, 233, 241 Neuralgia, Gouty, 119 Neuritis, Gouty, 119, 120 , Treatment of, 217 Nitrogenised diet and uric acid, 65 Nitrogenous diets and gout, 140, 141 Nuclein formation of uric acid, 73-77 CEsophagismas, Gouty, 116 Orchitis, Gouty, 126 Parotitis, Gouty, 125 Paroxysm, Cause of gouty, 101-103 Pathology of gout, 1-104 Pfaefers waters, 232, 241 Pharyngitis, Gouty, 116 Plilebitis, Gouty, 118, 119 , Treatment of, 216, 217 Piperazine, Effect of, 180, 185, 186 , Experiments with, 179, 180, 185, 186 Plumbism and gout, 59, 60, 96, 97 and uric acid, 50 - Portal congestion. Treatment of, 234 Potassium bicarbonate. Experiments with, 179-182, 187-189 citrate. Experiments with, 179- 183 — salts and gouty deposits, 181-183, 187-189 Potato ash. Effect of, 152 Predisposing causes of gout, 105-107 Preventive treatment of goiit, 220, 221 Prognosis of goutri27 Proteids and uric acid, 65, 66 Prurigo, Gouty, 123 Pruritus, Gouty, 123 Pseudo-angina pectoris, Treatment of, 216 Psoriasis, Gouty, 123 , Treatment of, 218, 239 Pulmonary congestion. Gouty, 118 Purgatives in gout, 208, 204, 233-239 Q Qnadriurate and vegetable ashes, 169- 172 , Decomposition of, 178, 179 Quadriurates, Amorphous, 7 , Composition of, 2 R Ratio of uric acid to urea, 78-81 Beicl>enhall baths, 239;'" Renal affection causing gout, 62 calculi. Treatment of, 218 disease and uratic deposition, 54-57 disease. Treatment of, 210, 211 and uric acid in blood, 49, 54-67 formation of uric acid, 37, 38 origin of gout, 60-63 Respiratory affections and gout, 117, 118- , Mineral waters for, 241 , Treatment of, 236, 211 Retrocedent gout, 124, 125 of brain, 125 of heart, 125 of intestines, 125 of stomach, 125 ; Treatment of, 213, 214 Rlieinfelden baths, 239 Riieumatism and gout. Distinction of, 126 Rheumatoid arthritis and gout. Dis- tinction of, 126, 127 Roberts's standard solvent, 87 Royat waters, 236, 241 Saint-Honord waters, 240 Salicylates contra-indicated in gout, 197 , Treatment of gout by, 193-197 Salzbrnnn waters, 234 Saturnine gout, 113, 114 Savoy cabbage ash. Effect of, 153 Schinznach waters, 240 Sciatica, Gouty, 119- , Treatment of, 217 Seakale ash, Effect of, 156 Serpents, Urinary excrement of, 83, 84 Sex and gout, 105 Simple mineral waters, 230-233 Skin affections and gout, 122, 123 , Mineral waters for, 241 , Index. 247 Skin affections, Treatment of, 218, 239 Sodium bicarbonate, Experiments witli, 179-181, 184 biurate, 2 , €auses of deposition of, 92- 100 , Formation of, 3 , Solubility of, 92 , Neutral urate of, 2, 17 phosphate. Experiments with, 179, 180, 185 qnadriurate, 2 Spas, Mineral water, 931-240 Spinach, Advantages of, 173 Spinach ash. Effect of, 161 Spleen and uric acid formation, 40 Stratlipeffer waters, 231, 240, 241 Subacute gout, Treatment of, 208, 209 Sugar and gout, 148 ' Sulphur mineral waters, 239, 240 springs. Cold, 240 , Hot, 240 Suppressed gout, 114 Synthesis of uric acid, 69, 70 Tarasp-Schuls waters, 235, 241 Teplitz waters, 231, 241 Test for uric acid, 3 Thymus and uric acid excretion, 74 Toe, Gouty deposits in great, 101 Tophaceous gout. 111 Tophi, 110, 111 Toxic agents causing gout, 59, 60 Tracheitis, Gouty, 117 Treatment of acute gout, 201-205 angina pectoris, 215, 216 chronic gout, 208-212 constipation, 203, 204,- 233-239 diabetes, 219, 220, 233 dyspepsia, 233, 234, 236, 237 gastro - intestinal catarrh, 233, 234, 237, 239, 241 glycosuria, 219, 220, 233, 234 gout, 199-241 gout. Preventive, 220, 221 gouty asthma, 236 . bronchitis, 236 heart, 214 joints, 201, 202, 209-212, 230-233 neuritis, 217 phlebitis, 216, 217 sciatica, 217 vertigo, 214 bepatic congestion, 233, 234, 237, 239 . irregular gout, 214-220 irritable temper, 219 metastatic gout, 213, 214 portal congestion, 234 pseudo-angina pectoris, 216 renal calculi, 218 retrocedent gout, 213, 214 skin disorders, 218, 239 subacute gout, 208, 209 Turnip ash. Effect of, 155 tops ash Effect of, 166 Urates, Neutral, 2, 17 Uratic deposit. Formation of, 86-89 Uratic deposits and renal disease, 54- 67 ■ , Seats of, 90 Urea a normal constituent of blood, 44,45 and uric acid ratio, 78-81 , Formation of uric acid from, 68-72 linage waters, 240 Uric acid absent from blood in health, 43-47 and blood disorders, 48 lead poisoning, 50 nitrogenised diet, 65 ■ nuclein, 72-77 • proteids, 66, 66 urea ratio, 78-81 calculi, 121 , Gause of abnormal forma- tion of, 69 , Composition of, 2 compound in blood, 2 , Daily output of, 201 , DeHcient excretion of, 26-28 ■ ■ , Discovery of, 4 elimination in health, 80, 81 excretion and diet, 65-67 by kidneys, 53 ■ ■ in gout, 27, 28 , Formation of, 34, 35, 68-77 formed from urea, 68-72 gravel, 121 in blood. Detection of, 31-34 , Estimation of, 31-34 of ancemia, 48 in uriue,Estimation of, 29-31 , Introduction into blood of, 25,82 not a normal constituent of blood, 43-47 — not a poison, 9 not present in food, 77, 78 ■ , Over-production of, 26 , Promotion of elimination of, 209 , Renal formation of, 37, 38 , Salts of, 2 , Sources of, 34, 35 , Synthesis of, 69, 70 , Test*r, 3 , Variations in elimination of, 81 Urine, Amorphous urate deposit of, 84-86 , Estimation of uric acid in, 29-31 , Examination of, 200, 201 of chronic gout, 112 Urticaria, Gouty, 123 Vals waters, 233, 241 Vegetable ashes. Alkalinity of, 158 diet and uric acid, 65, 66 Vegetables and gout, 144, 150-176 248 Govt Vegetables, Galciam salts in, 1 G2 , Chlorides in, 165' for the gouty, 173 , Phosphates in, 163 , Potassium salts in, 160 , Sodium salts in, 161 , Sulphates in, 164 Vertigo and gout, 120 , Treatment of gouty, 214 Viohy waters, 233, 241 Vittel waters, 233, 241 W Waters, Alkaline, 233, 234 mniiated, 236, 237 sulphated, 234-236 , Classification of, 229, 230, 240, 241 Waters, Cold mineral, 240 — r, Hot mineral, 240 , Muriated, 237-239 , Simple, 230-233 , Sulphur, 239, 240 , Uses of mineral, 226-229, 241 Weilbaoh waters, 240 Wiesbaden waters, 237, 238, 241 Wildbad waters, 232, 241 Wines, Acidity of, 146 and gout, 146-149 Gout-indueing powers of, 146, 148, 149 suitable in gout, 225 Woodhall Spa waters, 239 Xanthin, 73 Pbinted By Cassell & OoMPANy, Limited, La Bclle Sahvaqe, London, B.C. 10.299 MANUALS FOR Students and Practitioners of Medicine Published by CASSELL & COMPANY, . 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