Columbia Wini\}tviitp in tfje Citp of ^eto gorfe COLLEGE OF PHYSICIANS AND SURGEONS Jf rom tJje Hihtatp of Br. CJjn'jftian 13. I^erter IDonateb b|> iHrs;. J^enrp B. ©akin 1920 COLUMBIA UNIVERSITY EDWARD G. JANEWAY MEMORIAL LIBRARY GOUT ITS PATHOLOGY AND TREATMENT Founded on the Goulstonian Lectures on " The Chemistry and Patholog-y of Gout," delivered by the author before the Royal College of Physicians of London in 1897 ; with the addition of some recent investigations concerning the Treatment of Gout, and a detailed account of the Treatment of the various forms of Gout. BY ARTHUR P. LUFF M.D.IvOND., B.SC, F.R.C.P. PHYSICIAN IN CHARGE OF OUT-PATIENTS, AND LECTURER ON FORENSIC MEDICINE AT ST. MARY'S HOSPITAL NEW YORK WM. WOOD & CO. MDCCCXCIX PREFACE. 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 IIP includes a series of investic^ations 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 IV. 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. CONTENTS. PART I. THE PATHOLOGY OF GOUT, CHAPTER I. PAGE Uric acid and its compounds — Discussion of the various theories as to the causation of gout — View that excess of some compound or compoiinds of uric acid constitutes tlie primary cause of gout — View that ulloxur bases con- stitute the poison of gout — View that morbid changes in the structure of tissues constitute the primary cause of gout — View that nervous disturbance constitutes the primary cause of gout 1 CHAPTER II. Cause of the presence of ui'ic 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 foraiation and liver disease — Foi-ma- tion of uric acid from nuclein — Different modes of formation of uric acid in health and in blood disorders . 64 vi Gout. CHAPTER VI. PAGE Composition of the amorphous urate deposit of urine — Causes of uratic deposition — Formation of the gouty deposit — Time occupied in the conversion of sodium quadriurate into biurate — Seats of uratic deposition in gout . . 83 CHAPTER TIL Causes affecting the deposition of sodium biurate— Reasons 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 VARIOUS FORMS OF GOUT AXD THEIR CLINICAL FEATURES — DIAGNOSIS AND PROGNOSIS. CHAPTER VIII. .Etiology 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. In-egular gout affecting the alimentary tract — Irregular gout affecting the air-passages and lungs — Irregular gout affecting the heart and vessels — Iiregular 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 — Retrocedent or metastatic gout — Diagnosis and prognosis of gout . . IIG 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 CH.\PTER XI. PAGE Experimental investigatiou 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 CHAPTER XIL 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 quadriiu'ate into sodium biurate — The vegetables most beneficial to gouty subjects loO CHAPTER XIII. Reasons for believing the treatment of gout by alkalies to be erroneous— Expeiimental investigation of the value of the treatment of gout by the various alkalies, by piperazine and by lysidine — Reasons for believing the ti'eatment of gout by salicylates to be erroneous — Experimental in- vestigation of the value of the treatment of gout by salicylates — General conclusions . . . . .176 PART IV. THE TREATMENT OF GOUT AND OF GOUTY CONDITIONS. CHAPTER 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 colchicum — Treatment of subacute and chronic gout— Means of checking the excessive formation of ui'ic acid — Means of promoting the elimination of \mc acid — Local treatment of gouty joints 199 CHAPTER 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 iu 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, or waters comparatively free from sodium salts — Simple alkaline Avaters— Alkaline sulphated waters— Alkaline muriated waters — Common salt or muriated waters — Sulphur waters— Hot and cold mineral watei-s — Classification of mineral waters according to their therapeutic value in the treatment of the various forms of gout .... 226 Index 243 fart 1. THE PATHOLOGY OF GOUT. CflAPTER I. Uric acid and lis cotiipounds — Discussion 0/ the va7-ions theories as to the causation of gout — Yiev:) that ex- cess of some comjwund or compounds of itric acid constitutes the primary cause of gout — View that aUoxur bases constitute the poisori of gout — Vieio that morbid changes in the structure of tissues constitute the primary cause of gou' — Vieio that nervous disturbance constitutes the i^rimary cause of gout. Gout is the manifestation of a number of morbid tendencies, some of which n:iay be inherited and some acquired, and which result in the different diseases associated with the arthritic diathesis. If the joints are aftected, articular or regular gout results : if other oroans 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 H3(C5H2N403). This acid forms the following three classes of salts : — (1) The neutral urates, in which a metal takes the place of all the displace- able hydrogen, such as Na2C-H2N403, the neutral sodium urate. (2) The biurates, in which a metal takes the place of half the displaceable hydrogen, such as NaHCjHoN^Oo, the sodium biurate. The biurates, althoug h acid salts in constitution, are not acid to test paper. (3) The quadriurates, in which a metal takes the p]iiCfi-_QlLxaifizfbiixtliaiL^^ - placeable hydrogen of two molecules of. uric acid ^ such as NaHC^HoN^Os, HoC^HoN^Oa, the sodium ^ qunrlriurate 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 free state under any conditions whatsoever. Tbfi ^odimn qnn|lrinra.tft is t.bn solnblo. nru ?_np.iH^ p.( ^m pound which is originally contained in th^ ^ blood of gouty subjects, and this substance, as jusj 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 quadriuratc is. Formation of Sodium Bi urate. 3 however, an unstable body, and after a certain time it unites with some of the sodium carbojiato 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 /NaHCgHoN.Og, H2C5H2N403\ + NaoCOg = ^ Sodium Quadi-iurate ^ Sodium Carbouate 4 NaHC^HoN^O., + COo + H,0 Sodium Biurate v The sodium quadriurate is, therefore, to be 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 milligramme 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 pathologicall}^ altered humours. Cullen, 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 hold 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 primar}- The Causation of Gout. 5 cause ; and (3) nervous disturbance regarded as the primar}^ cause. The following is a brief review of the various opinions held as to the primary causation of gout, adopting the classification just given : — L — Excess of uric acid 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 Koberts 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 when 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 inflamTiiation. Sir William Roberts is of opinion that uric acid probably does not possess any inherent poisonous quaUty, 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- tor}^ changes by its mechanical irritation. POSSIBLE CAUSE OF IRREGULAR GOUT. Sir William 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 iibrous 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 locahties 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 affections of different viscera peculiar to irregular gout, it may be of interest to mention here the following facts : — C'rystals 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- iirate, 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, Avhich 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 Avhile 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 tiuids 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. Ffeitfer 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 b}- 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 POISOX. 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 ao^ent is that in cases ot" leucocythsemia and severe auEemia 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. ALLOXUR BASES REGARDED AS THE POISOX OF GOUT. Kolischf considers that some antecedents or allies of uric acid are responsible for the toxic * Croonian L3ctures : " Uric Acid Gravel and Gout," 1892. t Wiener klinische JFochenschrift, 1895, p. 787. lo The Pathology of Gout. effect Avhich he believes constitutes the priinarj^ 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 degeneratio n, he infers that these bases^ are concerned in the production of the kidney affiRntifjp which prpped^^ thft develo_p ment of 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 h^^ the observa- tions of Schmoll,t His,| 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 PRIAIARY CAUSE OF GOUT. This group may be divided into two sections ♦ Charite Annalen, 1895, xx., p. 215. t Zeitsehrifc fur klinische Medicin, 1896, xxix., p. 510. J Jierliner /clinische IFochenschrift, 1896, xxxiii., p. 70. ^ Verhandlungen des Cong. f. innere Med., 1896, xiv., p. 33. II Wiener klinische Wochenschrift, 1896, ix., p. 723. EnsTF./N's Views. ii accordingly as the morbid changes are produced by the presence of a sokible urate or not. 1. Necrotic changes in the affected tissues regarded as. the primary cause 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 precedes 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 Gicht," 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 Ebstein's Experiments. 13 he effected by preventing the ehmination of their urinar}^ uratic secretion in two ways — (a) by liga- turing the two ureters, and so damming back upon the circulation the urates which would otherwise have passed away; and (jj) 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 thoFe 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 Avith gout in man. Ebstein found uratic deposits in th^ IIvpt ar^d nui^cu l ar tiss u es oi ' 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 lu'ates, 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 sohition 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: " Uiic Acid Gravel and Gout," 1892, p. 118. Ebstein's Experiments. i5 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. Yery 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 by the urate in solution acting as a chemical irritant. 1 6 The Pathology of Gout. CRITICISM OF EBSTEIN's EXPERIMENTS WITH URATES. The objection to this method of experimenta- tion is that, in the tirst place, the sohition of uric acid in sodium phosphate does not contain the neutral sodium urate, which is the body on which Ebstein relies lor 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 fh^ x\(^\^iv9^ Rnf|ii]Tn nr ate. upon whj iJi he depends foe- the Dtfti'ting ~-Qf-thje--gQuty 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 X I compound, and is decomposed in the presence of carbonates, so that it is impossible for it to exist in I 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 leucocytheemia severe antemia, and other diseases, to which reference will be made later, we know that a considerable c iS The Pathology of Gout. qii a - ntit^ 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 crystalhne 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 Cornil 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 may 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 intlanunation 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 Lectures: ''Uric Acid Gravel and (Jout," 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 acid 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 iorm 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. Bowlby, also considers that uratic deposits only occur in tissues which * -'A Treatise on Gout," 1889, p. 53. 20 The Pathology of Govt. 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 vole 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 c)f 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 cartilasfes 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, hypericmia, collateral oedema, and de- squamation of the skin of the afl[ec ted joint. The degeneration and necrosis ot 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 regards the uratic deposits as an epiphenomenon. and not as the cause of the gouty paroxysm. * Bid. Mtd. Joiirn., 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 tAvo 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 Dyce Duckworth, therefore, regards gout as * " A Treatise on Gout," 1889. 22 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 toxaemia is depen- dent on the inherited gouty neurosis. In second- ary or acquired gout the toxaemia arises from the digestive and excretorj^ 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 aftecting 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 b}^ 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. * *' Oa Megrim and Sick Headache," 1873, pp. 404-5. Nervous System and Gout. 23 l)r. 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. Kalfe 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 * " Croonian Lectures/' 1886. 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 Tnorhi. The details of various experiments that support this view will be given later. 25 CHAPTER 11. Cause of the presence of uric acid in the hlooi of gout — Deficient excretion of uric acid in gouty subjects — - Estimation of uric acid in urine — Detection and estimation of uric acid in hlood. CAUSE OF THE PRESENCE OF URIC ACID IX THE BLOOD OF GOUT. The next question to consider is whether the excess of uric acid present as qnadriurate 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 overcharofinof 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 leucocythaemia 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 kidnej^s, 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 ver}^ excep- tionally met with in childhood and in youth, although the formation of uric acid is greatest in early life, and apparently diminishes Avith the advance of age. VIEW THAT DEFICIENT EXCRETION 01' URIC ACID IS CONNECTED VriTH GOUT. There are many facts to support the view that cfout 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 individuals. Pfeiffer "^ 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 the same age. Dr. John Fawcett f 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 klinische JVochenschrlft, 1892, p. 413. t " Guy's Hospital Eeports," 1895. 28 The Pathology of Gout. 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 grammes, and are calculated per 100 kilogrammes of the body-weight. All the individuals were between forty and fifty years of age. TABLE I. Shoxcing the dally elimination of uric acid in {a) a case of subacute gout ; (ft) a case of chronic gout and plunibism ; (c) a healthy person. Quantities of uric acid given in grammes per 100 Jiilo- grammes of the body-weight. AH the individuals between forty and fifty years of age. Subacute gout. Chronic gout. Healthy subject. 0-260 grm. 0-578 grm. 1105 grm. 0-263 0-617 1-027 )> 0-315 0-665 1-020 >» 0-350 0-715 1-376 5' 0-442 0-443 1-175 )» 0-556 ,, 0-372 1030 ■>1 0-506 0-593 1-252 >> 0-494 0-594 1-203 )> 0-398 »» 0-572 55 1-148 >» (average) (a^'erage) (average) These results probably justify the view that deficient excretion of uric acid occurs in connec- tion with gout. Later the probable role 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 IX URINE. 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 ejnployed for the estimation of uric acid in the urine, including Heintze's process, Haycraft's process, Fokker's process, Salkowski's process, and Ludwig's modification of Salkowski's process. In connection with all these processes there are faults or objections from Avhich the Gowland-Hopkins process is free. This process depends upon the i'act that when urine is saturated Avith 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 bv 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 ths liberation of its uric acid with orreat 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 befj^un, and one millii^ramme 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 made 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 IX 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 for 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 boiline 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 Lclire von K irn,'" p. 94. 22 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 Avater. 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. Klemperer f 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 uric acid 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 reliable results. * " Ueber die klinisohe Bedeutung : Von Harnsaure und Xanthinbasen im Blut," 1891. t Deutsche mediciniache Wochenschr'tft, 1895, xxi., p. 655. 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 i*si the estimation of uric acid in blood with which I am acquainted. PUOCESS FOR THE ESTIMATION OF URIC ACID IN RLOOD, 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 reduce 1 with ease to a fine powder. For 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 ot human blood I used 50 grammes of dried blood. The method employed was to mix 100 grammes ot the powdered blood with a litre of boiling distill^ 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 the uric acid could never be extracted from the blood residue. Various solvents were tr'ed 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 SOURCES 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 formed ? I believe that uric acid is formed in connection with some diseases, notably blood Sources of Uric Acid. 35 diseases accompanied by leiicocytosis, in a different manner to that in which it is produced in heakh, 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. 36 CHAPTER III. Seat or seats of formation of uric acid — Uric acid not a normal constituent of the blood — Pathological con- ditions under which uric acid appears in the blood. 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 formed 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 nitrogenised 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 })ut forward, Sir Alfred ♦ " Transactions of the Koyal Medical and Chirurgical Society," 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 the 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 or^-ans. Kolischf resrards 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 experimental 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 Rojal Society," 1893, pp. 482-484. f Wiener klinlscke Woelxenschrift, 1895, viii., p. 787. 38 The Pathology of Gout. uratic deposits were to be seen after death in most of the organs and tissues, he concluded that the kidneys were the producers as well as the elimi- nators of uric acid. The following experiments also are strongl}^ 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. Wohler and Frerichs found that the administration of potas- sium and sodium urates increased the amount of urea, bu t did not^ augment the quaiitity 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 o f urea, b ut no_ uric acid was dis covered 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 * " Lumleian Lectures," 1883. The Liver and Uric Acid. 39 investigations of Schrijcler 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 lasl- nientioned 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 nmst be present in the blood. As will be shoAvn 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. oP 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, * Lxidii-ig's Festschrift, 1887, p. 89. t Arch. Exp. Fath. ii. FharmaJc., xxi. 40 The Pathology of Gout. 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 derano^ement 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 tbe 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 lu'ic acid does not by itself exert any influence on the origin of gout. VIEWS THAT URIC ACID IS PRODUCED IX VARIOUS TISSUES. Ebstein, who attributes in cases or 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 tibrous 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 cartilaofinous 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. Haio- 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 m 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- cythiemia, severe anoemia, etc., although large quantities of uric acid are formed, yet they are readily eliminated without storage in the system occurrinsf. 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 convej^ed 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 nnirexide 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 Avritings, he has never identified by the murexide test this uric acid reported to be present in the blood and tissues. 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 who are under the poisonous influence of lead. Yon Jaksch f 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 previousl}' * "Lumleian Lectures," 1883. t Deutsche inedicinische Wochenschrift, 1890, xxxiii., p. 7-11. \ Lentsche medic'uusche Wochenschrift, 1895, xxi., p. Goo. 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, * " Lumleian 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 {vijyev communis) for uric acid, but failed to detect any. 4.6 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 a 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 Uric 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 FORMATTOJ^ 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 onl}^ 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 w^ell briefly to consider what these pathological conditions are, and what are the probable sources of the uric acid in such conditions. The investi- 48 The Pathology of Gout. gations of Yon Jaksch, Klemperer, and others have condusively 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 ehminated without causing gout. BLOOD DISORDERS ACCOMPANIED BY THE PRESENCE OF URIC ACID IN THE BLOOD. Yon Jaksch^ found uric acid in the blood of cases of both primary and secondary ana?mia, pernicious anaemia, and splenic tumour. He also found it in the blood in conditions in- ducing dyspnoea, notably in heart disease, pleurisy with effusion, pulmonary catarrh, pneumonia, and emphysema. Klemperer t has recently confirmed the results of Yon Jaksch and others as to the presence of uric acid in the blood of leuco- cythiemia, and many observations have been made of the increased excretion of uric acid that accompanies this disease. Laache % found a daily excretion of 3-7 grammes (nearly six t'mes the average normal amount) in a patient s iffering 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 meiVxcmuche Wochem^chriff, 1890, xxxiii., p. 741 t Deutsche incdicinische Jf'ofhenschr{ft, 1895, xxi., p. 655. J " Klinische Urinanalysc," 1892, p. 31. § Deutsche Archivfiir klinische Mediciv, Pand i., p. 13. II J'jjT^ic/M'* ^m'Jw, Bandcix., p. 390. Sources of Uric Acid. 49 Scherz ^ found a daily excretion of 1*4 gramme (twice the average normal amount). Von Jaksch t concluded that the occurrence of uric 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 Yon 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 ot nuclein, produce uric acid instead of destroying it. RENAL DISEASES ACCOMPANIED BY THE PRESENCE OF URIC ACID IN THE BLOOD. Yon Jaksch J 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. Yon Jaksch's results were confirmed by Klemperer,§ who ex- amined the blood of cases of contracted kidney, and * Tfluger'^s Archii', Band xlvii., p. 13. f "Ueber die klinische Bedeutung. Yon Harnsiiure und Xanthinbasen im Blut," 1890. X Loc. cit. § Loc. cit. 50 The Pathology of Gout. found uric acid always present. OVfYJoncily tliis f ur- ,jiislies a further proof as to th e ^rmin,! oriog n ^uric acid^ when it can be shown that in such cases of ■l-i (ipp.y rj ispnsft (nat associated with gout) in which ^the uric acid excre t ion is diniinished, uric acid . lY^ al-Ac; jj;.Q ap pearance 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 t refers to the early stage at which anoemia 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 cells, yet it is possible that a small amount of the uric acid may result from the sKght leucocytosis accompanying the anaemia of plumbism. FEVERS AND ABSENCE OF URIC 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, v/hen unaccompanied by anaemia. His observations * " A Treatise on Gout," 1876, p. 241. f Goulstonian Lectures on "Lead Poisoning," 1891. Sources of Uric Acid. 51 seem unduubtedly to prove that the presence of uric acid in the blood is not a fuctor 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. FORMATION OF URIC ACID 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 is probably derived from the nuclein of the leucocytes, and as the kidne^^s are in a sound condition it is readily excreted by them. 52 CHAPTER IV. The reiial 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 kidney 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, Eartels, Stadthagen, and Bohland and Scherz, on the excretion of uric acid in cases of leucocythaemia. 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 excretion of uric acid by the kidneys shows that Gout 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. Yogel 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 fa3ces. He found that there was * "The Uric Acid Diathesis," 1894. t Zeitschrift fiir 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. Vogel states that his patients behaved, in this respect, like sufferers from renal disease, although the clinical signs of 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 integrit}^ of those organs. ASSOCIATION OF llENAL DISEASE WITH THE PRE- SENCE OF URIC ACID IN THE BLOOD, AND WITH URATIC DEPOSITS IN THE JOINTS. As previously mentioned, Yon 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 wdio have never been known to suffer 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 who bases his observations on the results of a large number of post-mortem examinations, states that * " Transactions of the International Medical Congress at London, 1881," vol. ii., p. 107. f " St. Bartholomew's Hospital UeporLs, 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 from ostensible gout. Kidney disease. No. of cases. Uratic deposit in joint or joints. Chronic interstitial nei^hritis Chronic parenchymatous ne- phritis 53 11 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 uratic 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 uratic deposition in the joints occurring in subjects in * Zeitschrift fur JcUnische Medicin, 1894, xxvi., p. 293. 56 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 wdiich 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 results of the examinations of the joints of 11 cases of gramdar kidney disease. Uratic deposit in joint or joints. Known to have had gout . . . Never known to have had gout Totals ... 10 31 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 Avere found in one or more of the joints of 31 — that is, in 40 per cent, of the cases, Avhich closely agrees with the 47 per cent, found under similar conditions by l)r. 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 Avhich 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 : — Uratic deposit in joint or joints. Marked granular kidney \ disease ... ... ... j 20 Thus it is seen that among the cases of marked granular disease of the kidneys occurring in persons who w^ere 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 Levison, 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 revealed 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 woukl 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 affected together with that of uric acid does not hold good, if the view is adopted that uric acid is produced in the kidne3^s, 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 affected. Sir Dyce Duckworth believes that changes occur in the kidneys of gouty subjects quite independently of uratic deposits in these Gour 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 sliown 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 6d The Pathology of Gou'i. 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 Avith 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 Renal Origin of Gout. 6\ in which uric acid has been found during Ufe 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 Qrout durino- 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 joints 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 amount 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, Ly 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 behef 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 HabiUty to this functional affection of the kidr.eys 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 of 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 of 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. * Zeituchrift fiir klininche Mcdicin, 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 must be secured or its formation must be limited to the diminished output, so that absorption of it into the general circulation may be avoided. The retention of 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. Origin of uric acid — Formation of uric acid from urea in the 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 OF DIMIXISHED OXIDATION. A COMMONLY received notion as to the origin of uric acid is that 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 metabjlism 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 reptiles 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. 80 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 poorlj^-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 versa, but ap- parently it makes little, if any, difference whether the proteid matter is of animal or of vegetable * Berliner kUnische Woche^ischrifl, 1884. F 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 aniinal than on a vecfetable 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 Avas a considerable rise in the amount of urea excreted, there was very little difterence in the uric acid excretion. After the three days' flesh diet the uric acid excreted in twenty-four hours was 0859 gramme, while after the three days' vegetable diet it was 0-791 grannne. Similar results were obtained by Hirschfeld,! who found that on a diet very poor in nitrogen he excreted daily 0417 gramme of uric acid; on one rich in albumen 0386 gramme ; and on a highly albuminous diet 0*492 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 * Ffliigers Archiv, r>;ind xlv., p. 401. f Virchow's Archiv, Band cxvii., p. 301. Renal Excretion. 6; another class produce urea. Thus, in the urine of the carnivorous Hon and tiger there is a quantity of urea and but very Httle 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 ol urea and but little or no uric acid. Sir AVilliam 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 probabl}^ 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 moditication w^ould require the discarding of the sparino-lv soluble uric acid as a medium for the elimination of nitrogen, and the substitution ot 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 IX THE KIDNEYS. In mammalia, including man,' and in birds uric acid is absent from the blood in health, * Croonian Lectures oa '' Uric Acid Gravel and Gout," 1892. p. 33. 6S The Pathology of Gour. 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 All red 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 lor the formation of urea, and some for the formation of uric acid — and that the ratio between the two may var}- in different classes of animals. One ver}^ 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 ot 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 kidne3^s. Since, according to Sir Alfred Garrod's and my o\vn investigations, urea, and not uric acid, is found in the blood ot birds, and since uric acid, and not urea, is found in the urinary excrement of birds, it * •' Proceedings of the lioval Society," 1893. Formation of Uric Acid. 69 scorns hi<(lily probable that urea is at least one oF the sources ot 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 w uld 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 ot 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 + C2H2(NH2)O.OH = CgHfiNgOg + XH3. Urea Glycocine Hydantoic acid 2. The hydantoic acid becomes dehydrated and forms hydantoin — C3HSN2O3 = CgH.NgOo + H^O. Hydantoic acid Hydantoin 3. From more of the urea biuret is produced — 2 CHjNaO = CJIgNgO^ + NH3. Urea Biuret * " Croonian Lectures," 1886. JO The Pathology of Gout. 4. By combination of hydantoin and biuret uric acid is produced — Hyilantoin Biuret Uric acid The production of uric acid from urea and glycocine may be shown in a single equation as follows — 3 CH.X.O + aH2(NH.,)0.0H = C5H4XP3 + 3 NHg + 2 H.O. Urea Glycocine Uric acid FACTS SUPPORTING THE VIEW THAT URIC ACID IS FORMED FROM UREA AND GLYCOCIXE. There are several reasons for behoving 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 b}^ 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 Avith 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 son^ewhat probable from the fact that in the carnivora, whose urine contains little or no uric acid, the bile contains no glycocholic but only taurocholic acid, and therefore yields no F0R\TATI0N OF UrIC AcID. /f glycocine. The experiments of Halin, 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 the inferior vena cava, and so caused an increased amount of gl^^cocine to be sent ti 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 nitroQ^enous 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 effected 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 "^ Loc. 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 FORMED FROM NUCLEIN. Horbaczewski | has shown that uric acid, as well as xanthin and hypoxanthin, can be prepared from * "A Treatise on Gout," 1889. t " Beitriige zur Kentnisse der Bildung der Harnsiiure und der Xanthinhason." Sitzungsb.richt dor K. Acad. d. Wiss in Wien. C,iii.,1891. 4 Formation of Uric Acid. 'jI spleen pulp. The close relationship of these three bodies to one another is shown by a comparison of their formulae — C5H4N4O3 Uric acid. C5H4NP2 Xanthin. C5H4NP Hypoxanthin. By digesting fresh spleen pulp with hot Avater 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 j-|j-|p1pi|-i^ 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 havinsT thus been shown that uric acid could be prepared from nuclein outside the system, an attempt was next made to ascertain Avhether a similar decomposition could also occur in living- human beings. Horbaczewski found that the excretion of uric acid c?.n 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, wdiich 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- I 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 Avithin the system. I t has been shown b}^ many observers that a ^ temporary or permanent louro cytosis is always ^ ac companied b y_an inc reased excretion of uric ^ np.ifl A relationship between the number of * Zcilschnft fiir Idinische Mcdicin, 1896, xxix., pp. 174-189. Formation of Uric Acid. 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 ^uring digestion, whence they are discharged into the lymph stream, and linally into the blood. Gamprecht f — ^^'ho uses the term " alloxur bodies " in Kossel and Krliger'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 * Arch IV fur Exper. Fathologie und PharniaJcolorjie, Band, xxii., p. 306. •j- Centralblatt far allgemcwe Fathologie iind pathologischea Anatomic, 1896, vol. vii., p. 820. yG 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 leucocythcemia, severe anaemia, etc., where uric acid is present in the blood, it is probably derived from the nuclein of leucocj'tes or other cells. It is, however, in my opinion, wrong to draw the further inference that the source of the uric acjj ftxfvrpitftfl in "health y is" the nuclein derived leucocytes thrp nghou t the bodY . If such were 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 lara^e formation and excretion of uric acid that occurs. In connection with leucocj^thremia, an?emia, etc., the excretion of uric acid in the urine may rise to six times the normal amount, and yet no signs of gout appear. The reason for this non- development of the symptoms of gout in connec- tion Avith these diseases is that ilie kidneys remain in a sound condition, and therefore the uric acid (which in these diseases is "prohcdjly 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 s^out cannot be derived from nuclein. VIEW THAT PART OF THE URIC ACID IS INTRO- DUCED READY-FORMED IX 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 consideis that fiesli 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"0'2 per cent, uric acid = U'TO •2 oz. fish . . „. 003 ,, ,, = 0-26 3 oz. meat . . „ O-Oi „ ,, =: 0-52 \ drachm meat extract „ 0-80 ,, „ .— 0-24 1-72 * Brit. Med. Journ., 189-i, ii., p. 1299. yS The Pathology of Gout. As far as I can ascertain from Dr. Haig's writings, he has never identified b}^ the nuirexide test this uric acid reported to be present in these various articles of diet. These estimations depend solely on the application of Haycraft's process to the articles of diet, and the subsequent calcula- tion of the silver precipitate so obtained in terms of uric acid. Recently Dr. Haig has shown a tendency to shift the responsibility from uric acid to xanthin, and therefore refers to the amounts of uric acid or xanthin which he states are present in various foods. This assumption, that the sub- stance stated to be present in foods, if not mic acid, is xanthin, is however untenable, since xanthin is not estimated by Haycraft's process. That Dr. Haig's view as to the direct introduction of uric acid in articles of diet is an erroneous one is shown by the absence of uric acid from the blood of man and animals in health. RATIO OF URIC ACID ELIMINATION TO THAT OF UREA. Dr. Haig has also advanced the theory that normally there is a constant ratio of 1 to 85 between the uric acid and urea formation, and that if the uric acid excretion falls below this ratio it is due to the retention and storage of uric acid in the liver, .spleen, kidneys, joints, and fibrous tissues, whereas an increase in the pro- portion of uric acid to urea is due to the washing out from its storage places of the deposited uric acid. According to this view, the amount of Uric Acid and Urea. 79 uric acid produced in relation to urea in each individual is a constant factor, the variations in the amounts eliminated being due on the one hand to excessive storage, and on the other to the discharge of the stored-up supply. This theory of the existence of a normal ratio of uric acid to urea, and of every departure from it being due to a pathological cause, is disproved by the follow- ing experiments: — (1) Bleibtreu and Schultze,^ experimenting on themselves, showed that the ratio between uric acid and urea can be con- siderably altered by means of the diet without the general health being influenced. (2) Dr. Herringham and Mr. Groves,! as the result of a series of experiments that they made, entirely fail to corroborate Dr. Haig's observations, and think that either what was true for his system was not true for theirs, or that Dr. Haig's results were, to quote their own words, " inaccurate and de- ceptive owing to his having employed a very uncertain and inaccurate method for the estimation of uric acid." (3) The following results of the determinations which I have made of the total daity eliminations of uric acid and urea in the urine of a healthy adult man, and which consist of observations extending over a period of fifty days, show that the ratio of uric acid to urea varied from 1 : 28 to 1 : 55 (the average being 1 : 42), although throughout the entire period the individual re- mained in good health. * FjVdger's Archiv, Band xlv., p. 401. ■f Journal of F/i//siolor/i/, 1891. TABLE III. Fifty daily eliminations of uric acid and urea of a healthy adult man on a mixed diet. No. of oz. of Uric acid excreted Urea excreted per Ratio of uric acid urine per diem. per diem (gram me). diem (grammes). to urea. C3 0-65i 28-34 1:43 68 0-714 31-62 44 72 0-626 29-82 47 42 0-532 29-39 55 61 0-819 30-19 37 56 663 25-22 38 65 0-616 27-67 45 59 0-612 24-44 40 41 0-826 30-32 11 57 0-705 21-91 31 49 618 31-27 50 • 63 0-751 27-57 37 43 0-722 28-89 40 61 0-569 23-44 41 51 0-652. 29-89 46 6) 0-608 2700 44 56 0-591 27-71 47 50 0-561 27-54 49 6C 0-630 27-91 44 45 07*2 26-56 36 45 0-550 23-60 40 60 0-640 31-34 49 61 0-581 28-34 49 61 0-537 22 35 41 64 0-572 26-49 46 53 0-595 21-24 36 55 0-7G4 24-73 :32 69 0-637 28-58 45 63 0-526 23-13 :44 72 0-583 28-88 .49 45 0-620 24-26 :39 45 0-698 28-01 :40 52 0-680 3004 :44 69 0-705 33-16 :47 40 0-837 25-62 :31 42 0-728 30-54 :42 67 0-605 30-11 :45 44 0-550 29-50 :53 54 0-554 29-88 :54 62 0-582 26-13 :45 55 0-515, 22-15 :43 55 632 27-14 :43 54 0-585 28-34 :48 66 0776 28-05 :36 49 0-536 25-20 :47 67 0-560 23-56 :42 45 0-550 21-63 :39 35 0-660 23-10 :35 55 0-624 23-09 :37 87 0-691 19-76 1.28 Uric Acid and Urea. 8i TABLE IV. Excretion of Exci'etiou of Eatio of uric uric acid. urea. acid to urea. Paily average in gTanimes ... 0-639 26-89 1 :42 Daily average in grains 9-8 41o0 1:42 Average in 24 hours for each lb. of bodv weight (in grains) •07 3-19 It is evident from the above results that no constant ratio exists in a given individual between the excretion of uric acid and urea. Variations in the daily elimination of uric acid in healthy individuals are not due to the sweeping out of uric acid from the different organs and tissues into the blood, for uric acid is never found in the blood of healthy persons. Differences from day to clay in the uric acid excretion probably depend upon the amount of glycocine leaving the liver and passing on to the kidn-eys ; this factor vv^ould be affected by variations in the metabolism of the liver, which may be induced by changes in the quality or quantity of the diet, by the amount of exercise, and by various nervous in- fluences. Dr. Latham ^ has suggested a possible reason why those persons wdio have a tendency to gout and who take little exercise tend to develop the disease. It is that insufficient muscular exercise tends to the formation of glj^cocine. This is seen in the case of horses which wdien put to hard w^ork eliminate benzoic acid in the urine, * " On the Formation of Uric AciJ in Animals," 1884, p. 42. Sz The Pathology of Gout. but if kept in the stable for some time benzoic acid appears in the urine in combination with glycocine as hippuric acid, which is benzoyl- glycocine. DIFFERENT MODES OF FORMATION OF URIC ACID IX HEALTH AND IN BLOOD DISORDERS. From a consideration of the various views as to the origin of uric acid, I think it is evident that there are two distinct and different ways in which uric acid may originate. (1) In health I believe that it is only formed in the kidneys, probably from urea and glycocine, and that it is at once eliminated in the urine. If, fr mi any functional or organic affection of the uric acid-eliminating cells of the kidneys, its proper excretion is inhibited, then it is absorbed into the general circulation and constitutes the store from which the uratic de- posits of gout are formed. (2) In diseases which are accompanied by leucocytosis I believe that uric acid may be formed from the nuclein of leucocytes in the spleen and possibly throughout the system generally, but that such uric acid is readily eliminated by the kidneys, which remain sound as regards their uric acid-secreting struc- tures ; consequently gouty deposits never occur in connection with such diseases. The two different modes of formation of uric acid might be dis- tinguished as the urea formation and tie nuclein formation of uric acid. 83 CHAPTER YI. Composition of the amorjjhous urate deposit of urine — ■ Causes of uratic deposition — Formation of tJie gouty dejjosit — Time occupied in the conversion of sodium quadriurate into hiurate — Seats of uratic deposition in gout. As I take the view tliat the uratic deposits of o'out are derived from uric acid absorbed into the o blood from the kidneys, it will be advisable to consider next the various causes for its crystal- lisation in the form of sodium biurate from the blood, and the reasons wdiy the biurate selects certain tissues as seats for its deposition. It is necessar}^ briefly to consider (a) the form in which uric acid is absorbed into and circulates in the blood : (/>) the form in which it is deposited from the blood or fluids of the body. FORM IX WHICH URIC ACID EXISTS IN THE CIRCULATIOX. Sir AYilliam Roberts ^ has shown that the amorphous urate deposit of human urine is of the same composition as the solid or semi-solid urinary excrement of birds and serpents, the only difference being one of physical form. The deposit from human urine is amorphous, whilst the urinary excrement of birds and serpents consists ot minute crystalline spheres. Sir William Eoberts shows * Crooniiii Lectures on " Uric Acid Gravel and Gout," 1892. 84 The Pathology of Gout. that this clifterence in physical form is a mere accident of molecular aggregation, since, under certain conditions, the amorphous urate deposit can be transformed into crystaUine spheres, whilst the crystalline urinary substance of birds and serpents can be converted into amorphous deposit. Dr. Bence Jones ^ was the first to show that the amorphous urate deposit yielded to water, a soluble moiety consisting of true biurate, and left a sedi- ment consisting of pure uric acid, and from the results of his analj^'ses he inferred that the amorphous urate deposit consisted of, or at least often contained, a molecule of biurate in loose combination with a further molecule of uric acid. Sir William Roberts took up and continued the investigation dropped by Dr. Bence Jones thirty vears before, and has conclusivelv shown that a third order of uric acid salts — the quadriurates — exists, and that the amorphous urate deposit of human urine and the urinar}^ excretion of birds and serpents belong to this order, and consist of a true and definite compound of biurate and uric acid in the proportion of one molecule of each. Sir William Roberts concludes that the quadriurates are the physiological combinations of lU'ic acid. They exist normally in the urine, and constitute the only form in which uric acid exists in normal urine. All the morbid phenomena due to uric acid probably arise from secondary changes in the quadriurates. The amorphous urate or quadriurate dej^osit of urine is generally referred * Journal of the Chemical Society, 1862, vol. xv., p. 201. - Amorphous Urate Deposit. 85 to as consisting of a mixture of the potassium, sodium, ammonium, and calcium urates. As far as I can ascertain, however, no quantitative deter- mination of the bases in the deposit has yet been made. The nearest approach to it is an analysis made b}^ Sir WiUiam Roberts ^ of a sample of amorphous urate deposit prepared by an artificial process with potassium carbonate, which would therefore most probably contain more potassium than the natural deposit. I therefore considered it advisable to determine the actual bases present in the amorphous urate deposit and their relative proportions, COMPOSITION OF THE AMORPHOUS URATE DEPOSIT OF URINE. The deposit was obtained from several gallons of acid urine passed by patients suffering from febrile diseases, and was collected on a filter and allowed to drain. It was decomposed by boiling with distilled water and excess of hydro- chloric acid, the mixture was then allowed to cool, filtered from the deposited uric acid, and the fil- trate, -which, then contained the bases in the form of chlorides, was evaporated to dryness. The residue was taken up with distilled water, filtered from th.e minute amount of uric acid left in solution after precipitation of the bulk of the acid, and evaporated to dryness. Part of the residue was submitted to qualitative analysis, and found to * Croonian Lectures on " Uric Acid Gravel and Gout," 1892, p. 20. 86 The Pathology of Gout. contain ammonium, sodium, and potassium, with vei'}' small traces of calcium and magnesium. The amounts of ammonium, sodium, and potassium Avere then estimated in the usual manner in the other portion, when their relative quantities were found to be as follows : — Parts per 100. Ammonium ... ... ... ... 46 Sodium... ... ... ... ... 40 Potassium ... ... ... ... 14 These amounts, calculated as the respective quadriurates, would approximately give the follow- ing composition for the amorphous uratic deposit that naturally forms in acid febrile urines : — 7 molecules NH4HC5HJN4O3, H^,CgH2X403- Ammonium quadriiu-ate. molecules XaHCgH^X^Og, HoC^HoX^Oo— Sodium quadriurate. 1 molecule KHC^H^N^Oo, H^CgH.jX403 — Potassium quadi-iurate. The uric acid which is formed in the kidneys is probably at once converted into the mixture of these three quadriurates, which in the normal state are then excreted dissolved in the urine. If, hoAvever, any absorption of them takes place into the blood, as probably occurs in the gouty state, the ammonium and potassium quadriurates would be converted by the sodium carbonate of the blood into sodium quadriurate, which would constitute the sole compound of uric acid at first circulating in the blood. It is from this bod}' that the sodium biurate, of which the gout}^ deposits consist, is derived FORMA.TIOX OF THE GOUTY DEPOSIT. Sir William Eoberts investigated the behaviour of free uric acid with blood serum and kindred Artificial Blood Serum, 87 media, Avith tlio objecfc of endeavouring to tln-ow light on the mode in which sodium binrate originates in the body, and on the conditions which control the precipitation of sodium biurate in the gouty system. He experimented with sohitions of uric acid in blood serum and in a standard solvent which was prepared as follows : — CompoHition of Itohcrts's standard f'Olvcnt — • Socliiim chloride ... ... ... O'o gramme. Sodium bicarbonate ... ... ... 0'2 gramme. Distilled water... ... ... ... 100 c.c. This solution represents the blood serum, in so far as its saline ingredients arc concerned. Sir William Roberts found that it reacted with uric acid and the urates in the same manner as blood serum itself, and in the same manner as a solution comprising all the salts of the serum in their proper proportions. He found that blood serum and the standard at the temperature of the human body both dissolved uric acid to the extent of about one part in 500, thus exhibiting about twenty times the solvent power that the same media exer- cise on sodium biurate. The chemical and solvent power is dependent on the sodium carbonate contained in them, and is due to that body con- verting the uric acid into sodium quadriurate. This sodium quadriurate which remains in solution is gradually converted by the excess of sodium carbonate into sodium biurate, and this, on account of its lessor solubility is eventually precipitated in the crystalline form. Sir William Roberts infers from these results that, in the normal state, uric acid is primarily taken up in the systein as quadri- S8 The Pathology of Gout. urate, and that, as such, it circulates in the blood. The detained quadriurate, circulating in a medium rich in sodium carbonate, is gTadually transformed by the latter into sodium biurate, which is less soluble and is probably less easily excreted by the kidneys than the quadriurate. This biurate is prob- abl}^ not precipitated at once, since it vrould most probablj^ pass at first into the hydrated or gela- tinous condition which is a much more soluble modification of sodium biurate than the crystalline form ; but wiih due laj^se of time, and increasing accumulation, it passes into the anhydrous or crystalline condition, and, as this form is almost insoluble, precipitation of it occurs, or is likely to occur. The reason that in leucocyth^mia and other blood diseases no uratic deposits occur is that the uric acid produced in the various organs or tissues is discharged into the blood as a quadriurate, and, as this requires some hours for its maturation before it is possible for it to deposit sodium biurate, there is abundant time for the kidneys to eliminate it, pro- vided these organs are sound. In connection with gout, if the view is correct that defective elimina- tion of uric acid by the kidneys always occurs, the conditions are quite different. In gout uric acid is absorbed from the kidneys into the general cir- culation owing to the partial failure of the uric acid- excreting function of the kidneys. The uric acid is absorbed as the sodium quadriurate, Avhich, dis- solved in the blood, gradually passes through the maturation process and forms sodium biurate. Deposition of Sodium Biurate. 89 ~When the amount of the biurate in the blood is more than that fluid, can retain in solution, then deposits of it occur in those tissues which, either on account of having received previous slight injuries or because of their poor v-ascular supply, specially favour its deposition. TIME OCCUPIED IN THE CONVERSION OF THE QUADRIURATE INTO THE BIURATE. The period of time required for the conver- sion of the sodium quadriurate contained in the blood into the biurate is variable, and is doubtless dependent on several factors, such as the amount of quadriurate present, and the proportions ot various saline constituents of the blood, which may either hasten or inhibit the change. This last-mentioned group of factors is a most import- ant one in connection with the therapeutical treatment of gout. From an experimental in- quiry into the subject that I have made, I find that when the blood serum is saturated with sodium quadriurate and kept at the body tem- perature, deposition of sodium biurate does not commence till the end of t^vo hours, and is not complete till many hours — sometimes days — have elapsed. Probably in no pathological condition is there so much sodium quadriurate present in the blood as to produce saturation. The smaller the proportion of quadriurate present, the longer is the deposition of sodium biurate delayed, and the longer is the time required to complete its precipitation. 90 The Pathology of Gout. seats of u;uvtic deposits in" gout. Uratic deposits are found almost exclusively in structures belons^ino^ to the connective-tissue class — in cartilages, ligaments, tendons, and in the cutane- ous and subcutaneous connective tissue. They are conspicuously absent from the muscular tissue, and from the substance of the liver, spleen, brain, and lungs. Uratic deposits have been very occasionally found in the following places : — In the mitral and aortic cardiac valves, in atheromatous patches in the aorta, in the walls of veins, in the crico-arytenoid Hofaments, in the vocal cords, in the Avails of bronchial tubes, in the mucous follicles of the pharynx, upon the meninges of the brain and spinal cord, upon the spinal nerve sheaths, in the sclerotic coat of the eye, and the fibrous envelope of the retina. It is always in the fibrous tissue which participates in the formation of the nervous envelopes, that the deposit is found. Uratic crystals have also on two occasions been detected in the sputa of gouty patients. Sir William Roberts considers that the visceral neuroses and the thrombosis and embolism mot with in gout are not the result of the dissolved uric acid in the blood, but are duo to precipitation of minute crystals of sodium biurate either in the substance of the organs or in the blood itself. ANATOMICAL SEAT OF THE DEPOSIT IN CARTILAGES. The uratic deposit first occurs in the central por- tion of articular cartilage — a point farthest from the network of nutrient capillaries and a point Urat/c Deposits av Cartilage. 91 whose nutrition is more easily retarded. It. is also probably the point of greatest pressure, hence a long walk, a dance, or similar violent exercise may precipitate an attack of gout. Uratic deposits occur in cartilages, ligaments, synovial membranes and their fringe-like processes. In synovial mem- branes the deposit is not on the surface, but in the subserous tissue. Ebsteui * states that directly under the surface of the cartilage a very shallow tissue layer exists in which crystals are wanting, and in the layer immediately beneath this the crystals are most plentiful. He agrees with Sir Alfred Garrod that only two-thirds of the thickness of the cartilage is usually infiltrated, although, exceptionally — as shown by Cornil and Ranvier — the whole cartilage may be infiltrated. With regard to the exact relation of the uratic deposit to the various elements of articular cartilage, the cartilage cells are held to be the centres of primary deposit by Cornil and Ranvier, Charcot, Rindfleisch, Budd, and Garrod. Cornil and Ranvier consider that nutritive disturbances in the cartilage cells precede the deposition of sodium urate. Rindfleisch and Budd, however, consider that the cartilage cells do not take any active part. Some observers, in- cluding Sir Dyce Duckworth, consider that the deposition occurs quite indiscriminately, not select- ing for its original site any particular element of the cartilage. Others, as Bramson, Rokitansky, and Auguste Foerster, think that urates deposit in the intercellular cartilaginous substance. * "Die Natur und Behandluno- der Gicht," 1882. 92 CHAPTER YIT. Caufies affecthig the deposition of sodium hivrale — Reasons for the special selection oj the great toe and ear as seats of gouty deposits — Cause of the inflam- mation accoiyipa vying the gouty paroxysm. DEPOSITION OF SODIUM BIURATE ENCOURAGED BY CONCENTRATION OF MEDIUM AND PROPORTIONS OF SODIUM SALTS PRESENT. Sir William Roberts found that sodium binrate is very sparingly soluble in blood serum ; at blood heat the amount dissolved is about one part in 10,000 (about one-tenth of its solubility in Avater). This lessened solubility is entirely due to the saline ingredients of the serum, as on depriving the serum of its salts by dialysis, it was then found to exercise the same solvent action on the biurate as simple water. Sir AVilliam Roberts foimd that the sodium salts especially diminish the solvent power of a medium on sodium biurate, and that tliis diminished power is mainly, if not entirely, due to the sodium, and is apparently not much, if at all, influenced by the acids com- bined with it, since solutions of sodium bicarbonate, chloride, sulphate, phosphate, and salicylate, pre- pared so that the percentage of sodium in them was the same, exhibited the same low solvent action. His experiments also show that if a Deposition of Sodium Bi urate 93 medium be rich in urates, but poor in sodium salts, its tendency to precipitation is feeble, and vice versa. Since structures belonsfino- to the con- nective-tissue class are rich in sodium salts and are also liable to uratic deposits, while muscle, brain, liver, and spleen are poor in sodium salts and not liable to uratic deposits, he considers that the pro- portion of sodium salts in a tissue is an important factor in determining the deposition of urates in that tissue. PRECIPITATIOX OF S0DIU3I BIURATE FilOM SYNOVIAL FLUID. Another factor in facilitating the precipitation of urates is to be found in the sj-novial fluid. Sir William Roberts's view is that the uratic pre- cipitation actually takes place from the synovial fluid, and does not originate in the cartilaginous substance. This view is based in part on the microscopic appearance of vertical sections of gouty cartilage, in which the deposit is seen to be greatest on the synovial surface of the cartilage and to be- come gradually sparser and sparser towards the deeper layers, and in part on the fact that synovial fluid has been repeatedly found heavily laden with crj'stals of sodium biurate. He considers (as opposed to Ebstein's view) that the process of deposition in the cartilage is a purely passive and physical one, and that the synovial fluid, charged with its dissolved urate, penetrates hy liquid diti'usion into the superficial layers of the car- tilage, and that, when the criticpJ moment arrives. 94 The Pathology of Gout. precipitation takes place simultaneously in the s}^- novia and in the cartilage. According to this view, the after- consequences are entirely secondary, and are due to inflammation set up by the presence of the foreign body in the tissue. As regards the varying liability of diflferent joints to gouty attacks, Sir William Roberts con- siders that it is, at all events, in part, dependent on a greater concentration of the synovia of some joints, and on a variable proportion of sodium salts and possibly of sodium biurate. The experiments made by Frerichs^ on the comparative composition of the synovia of animals leading idle and active existences somewhat support this view. Frerichs found that the synovia of stall-fed horses and oxen, leading an idle existence, was more watery and contained a larger proportion of sodium salts than the synovia of similar animals doing work or roam- ing in the meadows. Moreover, the joints of the idle animals contained twice as much synovia as the joints of similar animals taking active exercise. DEPOSITION OF SODIUM BIURATE ENCOURAGED BY SLUGGISH MOVEMENT OF MEDIUM. It is highly probable that the very sluggish move- ment of fluids in the cartilag^inous and fibrous tissues favours the deposition of urates from the medium in which they are dissolved. As illustrating the fact that whatever interferes with the movement of the animal fluids favours the production of gouty * K. Wagner's " ILmdw orti-ibuch der FJiysiologie," 1884, Bainl iii., Part i., pp. 463-466. Deposition of Sodium Biurate. 95 symptoms, or of an actual attack of gout, an in- teresting case has been recorded by Charcot,^ who observed, in ahemiplegic woman of forty, that most of the articular cartihiges on the right, paralysed, side were infiltrated with urates, whereas those of the non-paralysed side showed no such deposits. Sir William Roberts considers that the chief reason why, in the post-mortem room, the cartilages figure more prominently than the fibrous structures as the scat of deposition of sodium biurate is to be found in the fact that in the fibrous tissues there is a comparatively free lymph How, which exercises a more effective solvent action on uratic deposits than can be effected by the sluggish lymph How in the cartilao^es. With regard to the reason or reasons that gouty precipitation takes place preferentially in synovia rather than in the seriun of" blood and lymph. Sir W. Roberts considers that the motion- less condition of synovia as compared with the state of rapid movement of blood and lymph would give to synovia a priority in uratic precipitation. In addition it is possible that, as Sir Alfred Garrod suggests, there is some special attraction in the joints for uric acid. DEPOSITION OF SODIUM BIURATE ENCOURAGED BY NERVOUS INFLUENCES. It is possible, given the condition in which there is a fair amount of sodium quadriurate or biurate circulatino- in the blood, the amount not * "]\raladies des Yieillards et les Maladies chroniques, 1874 g6 The Pathology of Gout. being quite up to saturation point, that nervous influences may accelerate deposition of sodiunl biurate. It is well known that whatever pro- duces depression of the nervous system, such as excessive exercise carried to the point of fatigue, rage, fright, worry, excitement or venereal excess, may cause an attack of gout in a gouty subject. It appears to me that a possible explanation of this result is that nervous influence affects the kidneys and depresses their excretory poAver for uric acid, which is consequently absorbed into the general circulation and rapidly raises the quantit}' of urate in the blood to the point of over saturation. Prob- ably the well-known effect of an exposure to cold inducing a paroxj'sm of acute gout is due to a similar cause. DEPOSITIOX OF SODIUM BIURATE ENCOUllAGED BY ABNORMAL CONSTITUENTS OF THE BLOOD. As previously stated, in cases of chronic lead- poisoning there is a deficient excretion of uric acid in the urine and an accuuudation of it in the blood. As to the natural way in which the lead favours or hastens tiie deposition of sodium biurate and so produces gout, there are different opinions. Sir William Koberts ^ considers that it is difficult to believe that lead-poisoning produces the same con- stitutional diathesis as that which exists in true gout, and prefers to think that, while gout and plumbism differ in all other respects, they have one * "Transactions of the Medical Society," vol. xiv., d. 88. Gout and Plumb ism. 97 tx3nd€ncy or vice in common, namely, the tendency to uratosis — that is, to the deposition of sodium biurate. He considers it is more accurate, instead of speaking of ordinary gout and satiiniine gout, to speak of gouty uratosis and saturnine uratosis. It appears to me that gout and plumbism have more in common than this tendency to uratosis — that is, to the deposition of sodium biurate — in that they both have the same tendency to cause the presence of an excess of urates in the blood. The association of lead-poisoning with gout has been repeatedly observed, but Oliver * states that in the north of England this intimate relationship between gout and lead-poisoning is not seen. He is not satisfied that the reason why gout is so little kno^vn in the north as a symptom of lead -poisoning, while it is so common in the south, is entirely due to the difference in the drinking habits of the people — whisky being the general alcoholic drink in the north and malt liquor in the south. At the same time he confesses his inability to ofier any further explanation. I am of opinion that the influence of lead in producing gout depends solely on the extent to which the kidney parenchyma is damaged. With much damage done to the kidney cells, w^hose function it is to excrete uric acid, absorption of quadriurate into the blood occurs ; the subsequent development of an attack of gout entirely depends on the amount of absorbed quadriurate, which in its turn depends on the amount of kidney mischief * Goulstonian Lectures on "Lead Poisoning," 189L H 98 The Pathology of Gout. deposition of sodium biurate encouraged by injury to joints or by interference with their nutrition. A slight injury to a joint, which in a healthy person would speedil}^ pass off, in a gouty person renders the part susceptible to the deposition of sodium biurate if sodium qnadrinrate be cir- culating in the blood. This susceptibility is prob- ably in some way connected with an impairment of the nutrition of the affected tissues. Fagge, indeed, regarded a paroxysmal attack of gout in the light of an accident occurring in the course of an essen- tially chronic change in the joint affected. As regards the relation between gout and rheumatism. Sir Alfred Garrod has remarked that if gout supervene in individuals who have suffered from rheumatism, it is generally the articulations which were the seat of rheumatism that are Urst attacked by gout. So that joints Avhich have been the seat of acute rheumatism are especially predisposed, in gouty subjects, to be- come the seat of uratic deposits. Dr. Latham "^ thinks it is probable that the uric acid cir- culating in the blood might exert a toxic effect on certain portions of the spinal cord which control the nutrition of the joints, and so cause nutritive changes or inflammation in the joints connected with that portion of the cord. As a result of the inflammation or nutritive changes in the joints, sodium biurate deposits in them or in the tissues around the affected joints. * " Croonian Lectures," 1886. Views of U ratio Deposition, 99 Ebstein^ considers that deposition of sodium biurate is dependent on and is produced by previous necrosis of the affected tissues, and that the uratic deposit never occurs in a normal tissue. His view is that the neutral sodium urate circulating in the blood acts as an irritant and produces necrosis of the car- tilages or other tissues, in which the sodium biurate is subsequently deposited ; as a result of this necrosis he considers that an acid is developed which converts the neutral urate into acid urate, which compound is then deposited in the necrosed areas. This theory is obviously an erroneous one, since the neutral sodium urate cannot exist in the circulation {see p. 17). Klempererf does not consider that uric acid is responsible for the necrotic changes in tissues, nor that the phenomena of gout can be due to mere crystallisation of sodium biurate from the blood, because in leucocythsemia, where an excess of urate is present in the blood, neither local necrosis nor uratic deposits occur. He believes that some unknown substances, in gout, lead to inflammatory and necrotic processes in various tissues ; these necrotic areas then attract the uric acid from the blood, the chemical affinity of the necrotic parts for uric acid being so great that the blood cannot re-dissolve it. Yon Noorden thinks the unknown substance, which starts the inflam- matory and necrotic processes is a ferment, and that the uric acid crystallises out in the necrotic tissues. * *' Die Natur und Behandlung der Gicht," 1882. f Deutsche medici/nisehe W&chenschrift, 1895, vol. xxi., p. ^bb>^ ioo The Pathology of Gout, DEPOSITION OF SODIUM BIURATE NOT AFFECTED BY DIMINISHED ALKALINITY OF THE BLOOD. A^arious writers have put forward the opinion that uratic deposition is dependent upon a diminution of the alkaUnity of the blood. Mordhorst"^ considers that the tissues affected by gout are less alkaline than the blood, and that, if the alkalinity of the latter becomes lowered, then deposition may take place. Dr. Haig considers that diminished alka- linity of blood causes deposition of uric acid in the liver, spleen, fibrous tissue, and joints, and that increased alkalinity of the blood causes its re-solution. The view that diminished alkalinity of the blood causes uratic deposition, and that increased alkalinity of the blood causes re-solution of the uratic deposits, is in my opinion erroneous and untenable for the following reasons : — (1) The Adew is apparently based on the deposit being uric acid, whereas it is sodium biurate, the solution of which, as Sir William Roberts has shown, is not increased by increased alkalinity of the blood ; (2) the occurrence of a gouty attack is not neces- sarily accompanied by any diminution in the alkahnity of the blood {see pp. 129, 130) : and (3)from a series of experiments that I have conducted, and which will be subsequently described, it appears that a diminution of the alkalinity of a medium does not affect the deposition of sodium biurate from that medium. * " Vorhandlungen des Congress fur Innere Medicin/' 1896, 1). 405. Gouty Deposits in Great Toe. ioi reasons for the special selection of the great toe and ear as seats of gouty deposits. There are several reasons to account for the special causation of uratic deposits in the great toe. (1) There is the liability of the metatarso-phalangeal joint to injury from having to support the weight of the body, and from being subjected to sudden shocks. (2) The remoteness of the joint from the heart, and the force of the circulation being consequently at its minimum at that part. (3) The poor vascularity of the tissues of the joint. The liability of the joint to injury is shown by Garrod's examinations of the great-toe joints of twenty subjects known not to have had gout. In fourteen he found ulceration of the cartilages of one or both joints. Of these twenty subjects three were under thirty years of age and showed no ulceration of the cartilages ; the remaining seventeen were over thirty years of age, and of these fourteen, or 82 per cent., showed ulceration of the cartilages. All the subjects over fifty years of age showed ulceration. In the helix of the ear the slusfS'ish circulation and the coldness of the organ are quite sufficient to account for the frequency with which uratic deposits are found in that part. CAUSE OF THE INFLAMMATION WHICH ACCOMPANIES THE GOUTY PAROXYSM. The gouty paroxysm is due to precipitation of sodium biurate, which always takes place in the 102 The Pathology of Gout. crj'stalline form, the crystals being distributed through the impHcated tissue in the form of delicate needles, aggregated into tufts, bundles, and stars. When deposition occurs in cartilage the crystalline deposit acts as an irritant and causes inflammation leading to proliferation and necrosis of cartilage cells, which may be followed by erosion of cartilage and of uratic deposits, and consequent displacement of the latter into the cavity of the joint. Along the borders of the cartilage, where the deposits are com- paratively small and the tissues are relatively rich in capillary vessels, the inflammatory processes may produce a more luxuriant growth of the cartilage cells, resulting in the formation of occhondroses at the margins of the articulation. Although I consider that the inflammatory part of the gouty attack is secondary to the deposition of sodium biurate crystals, yet it must be granted that such deposition should occur fairly copiously and suddenly in order to start the inflammatory process. Undoubtedly the biurate may deposit slowly and quietly in joints without the develop- ment of any acute attack, or for some time antecedent to the development of an acute attack. The observations of IMoxon and Fagge support the conclusion that the discovery after death of uratic deposits in a joint is not always to be regarded as a certain proof that the joint has passed through an inflammatory gouty attack. Sir Alfred Garrod's views, which are shared bj^ Sir William Roberts and supported by abundant General Coxclusions. 103 evidence, are in favour of the deduction that the deposition of the crystalline biurate is not merely an accompaniment, but is the direct cause of the joint troubles of gout. It is therefore of practical importance to know what are the various factors or conditions which may influence the conversion of sodium quadriurate into biurate, which ma}' alter the solubility of sodium biurate in the blood, lymph, and synovia, and which may affect the precipitation of the sodium biurate. These points will be dealt with in Part III. GENERAL COXCLUSIONS AS TO THE PATHOLOGY OF GOUT. The main points and conclusions arrived at in the preceding account of the pathology of gout are as follows : — 1. Uric acid is not normally present in the blood of man and other mammals, nor in the blood of birds. 2. Uric acid is normally produced only in the kidneys. 3. Uric acid is normally foraied from urea, probably by conjugation of that substance with glycocine in the kidneys. 4. Uric acid is present in the blood in gout as the soluble sodium quadriurate. In its soluble form it is not a toxic agent. It deposits from the blood as sodium biurate, which acts passively and physically as a foreign body ia the tissues or organs in which it is deposited. 5. The presence of uric acid in the blood in I04 The Pathology of Gout. gout is dae to its deticient excretion by the kidnej^s, and to the subsequent absorption of the non- excreted portion into the blood from those organs. 6. Gout is probably always preceded by some affection of the kidneys, functional or organic, which interferes ^vith the pro2>er excretion of uric acid. The probable seat of the kidney aft'ection giving rise to gout is in the epithelium of the convoluted tubes. 7. In certain blood diseases and disorders accompanied by leucocytosis uric acid is formed within the system from nuclein. In such circum- stances it passes at once into the blood and is rapidly eliminated by the kidneys. 105 lart II. iETIOLOGY OF GOUT — THE VARIOUS FORMS OF GOUT AND THEIR CLIN- ICAL FEATURES — DIAGNOSIS AND PROGNOSIS. CHAPTER VIIL jEtiology of gout — Predisposing causes of gout — Exciting causes of gmit — Acute gout — Chronic gout — Satur- nine or lead gout — Irregular or aharticular gout. MUlOUyOY OF GOUT. Ag"e. — Gout is mainly a disease of middle and late life, but it may occur earlier if there is a marked hereditary tendency. Sex. — Gout is much more common among males. This tendency is no doubt mainly due to the fact that the habits of men, with regard to diet and alcoholic drinks, are more conducive to the development of the disease than the more tem- perate habits of life of the majority of women. Hereditary predisposition. — This is the most important factor in the development of gout. The females of gouty families frequently escape the apparent development of gout in themselves, but transmit the disease, or the liability to it, to their children. It is doubtful, however, whether true atavism occurs in connection with gout ; that is. io6 The Etiology of Gout. whether gout entirely misses a generation. It is more probable that it appears in some form, irregular or otherwise, in the generation that it is supposed to have passed over. Habits of life.^The abuse of alcohohc drinks, especially those of the fermented class, such as wines and beers, and the excessive consumption of nitrogenous, rich, and indigestible food, are powerful factors in the development of gout. Indolent habits and inadequate physical exercise also strongly predispose to gout. Lead-poisoning. — Chronic lead-poisoning pre- disposes to gout, most probably by causing a chronic affection of the kidneys, which interferes with the proper elimination of uric acid by those organs. Uric-acid gravel in the kidneys. — Those who suffer much in early life from uric-acid gravel are also prone in later life to develop gout. The reason for this liability probably is that the deposits of uric acid, which no doubt in such circumstances occur in the kidneys, produce that pathological condition of those organs which, by interfering with the proper elimination of uric acid by the kidneys, constitutes the starting-point of gout. Immediate exciting cause. — An attack of acute gout is frequently induced by unusual indulgence in food or drink, or by some powerful emotion — such as a fit of anger, worry, or anxiety, or by exposure to cold, or by the receipt of some injury. For the production of gout, whether of the regular Acute Gout. icy (articular) or irregular (abarticular) type, the deposition of sodium biurate in the organ or tissue affected is, in my opinion, essential. The mere presence of uric acid in the blood in the lorm of the sodium quadriurate is insufficient for the produc- tion of any form of gout, in the absence of deposi- tion of the biurate from the fluids of the bod3\ That such is the case is illustrated by those blood disorders, such as leucocyth^emia and severe amiemia, in Avhich the blood is laden with uric acid, and yet no symptoms of cither regular or irregular gout arise. The absence ot such symptoms is due to the fact that the uric acid, which is present in the blood as sodium quadriurate, is completely and lapidly eliminated by the kidneys before there is time for the formation and deposi- tion of the biurate. THE VARIOUS FORMS OF GOUT AND THEIR CLINICAL FEATURES. ACUTE GOUT. A slow deposition of sodium biurate within the joints, accompanied by twinges of pain, may oc- casionally precede the acute attack, but, as a rule, no warning ushers in the first attack of gout, and the individual usually feels in good health just prior to the attack. Subsequent attacks, however, may be preceded by symptoms of dyspepsia, constipation, mental depression, or loss of appetite. The seizure of acute gout most frequently occurs in the early hours of the morning, but may io8 The Various Forms of Gout. come on at any hour of the day or night. Usually between the hours of one and four in the mornincr the patient is awakened by severe pain, generally in the great toe, sometimes in the ankle, instep, heel, or knee. Slight shivering attacks and a little elevation of temperature may follow. The pain increases in intensity, so that the slightest jarr'ng of the affected part may cause extreme torture. After some hours partial abatement of the pain occurs, and is accompanied by gentle perspiration. In the morning the toe is swollen, the skin is tense, shiny, and extremely tender, and the veins are distended. On the second night the severity of the pain may recur, and such recurrences may, in the absence of suitable treat- ment, occur for many days. The pain in the joint is excruciating, and is quite out of proportion to the external signs of inflammation. When the attack is subsiding the swelling and redness of the affected part lessen, the skin itches and pits on jDressure, and desquamation follows. Sir Willoughby Wade ^ has pointed out that in an acute attack of gout in the great toe a line of tenderness extends from the base of the great toe across the foot to the outer side. This line is the site of a nerve-trunk, Avhich is distributed to the periphery of the gi-eat toe. The cause of the tenderness is probably due to a deposition of sodium biurate in the nerve sheath, or in the nerve itself The oedema around the joint is characteristic, and is of great assistance in dio- * lii-it. Mad. Joiirn., 1897, i., p. 509. Acute Gour. 109 tinf^uishing the affection from rheumatism. Gouty inflammation of a joint is not followed by supjjura- tion. The temperature most commonly ranges from 99° to 102° F., and the attack is generally accompanied by thirst, anorexia, and constipation, whilst the urine is scanty, high-coloured, and usually deposits amorphous urates on cooling. Temporary albuminuria has been frequently observed during the early stages of an attack of acute gout, and occasionally, slight albuminuria lasts throughout the attack, owing to the affection of the kidneys which constitutes the primary cause of the gout. An attack of acute gout lasts on an average from eight to fourteen da3^s in persons of strong constitution, but with advancinof ao-e the duration of the attack becomes prolonged. A first attack of gout may not be followed by another, provided attention be paid to diet and to the general mode of life. On the other hand, frequent recurrences may occur. At first the attack of gout is most liable to occur towards the end of winter or begin- ning of spring, but after repeated annual attacks at the period mentioned, autumnal attacks may be added, or even, in exceptional cases, summer attacks. Although the majority of first attacks of gout occur in the great- toe joint, yet the disease may start in other joints, of which those most commonly so affected, placing them in their order of liability to such attacks, are the ankles, the knees, the small hand-joints, the elbows, and, rarely, the shoulders and hips. The selection of 1 10 The Various Forms of Gout. any particular joint for a primary attack is no doubt dependent on slight inflammatory or trophic changes in the particular joint from some recent injury or strain. Cases of typical acute gout are now much less frequent than they were in the days when the disease was so graphically described by Sydenham. This is mainly due to the greater temperance in eating and drinking which prevails in the present age, and in part, no doubt, to the spread of athleticism, and to the development of healthy outdoor exercises. Still in many cases the faults of the ancestors have transmitted to their descend- ants a tendency to the minor forms of gout, which frequently require treatment at the hands of the physician. CHRONIC GOUT. "With the earlier attacks of gout it is not usual ior more than one or two joints to be affected, but after repeated seizures a number of joints may become involved. As the recur- rence of gout becomes more frequent the attacks also become more prolonged, and last for weeks or even months unless efficacious treatment is re- sorted to. In chronic gout the deposits of sodium biurate linger in the joints, leading to deformities and crippling of the parts. Slight recurrences readily occur, and various forms of irregular gout may then become added to the gouty condition. In the subjects of chronic gout tophi are apt to form in various localities ; these deposits are most frequently seen in the male sex, and con- Chronic Gout. i i i stitute the so-called tophaceous gout. These tophi consist mainly of deposits of sodium biurate under the skin, and are principally found in the auricles of the ears, in the vicinity of joints, and in bursne over joints. If excessive accumulation of the biurate occurs, these tophi assume a great size, and may then cause the integument to give way, when a discharge of a thick creamy fluid containing an abundance of crystals of sodium biurate takes place. The swelling in the vicinity of a joint may give rise to fluctuation, but such swelling should never be opened. Tophi may communicate with a joint, or may be situated beneath the skin and remote from a joint. Considerable enlargement and deformity of jomts may occur in connection with chronic gout to which the deposits of sodium biurate only con- tribute in small part. In such cases the enlarge- ment is due to thickening of the synovial membrane, and to overgi'owth of the cartilages and of the ends of the bones. This form constitutes the so-called cl ironic deforming gout. Permanent deformity of the affected joints may result, and partial dis- locations and ankyloses may also occur. On the other hand, the uratic deposits may undergo complete solution, and the joint be left in an apparently normal condition. THE KIDNEYS IN CHRONIC GOUT. When chronic gout is accompanied by much deposition of biurate it is a sure indication that the kidneys are incapable of excreting the whole of the 112 The Various Forms of Gout, uric acid formed in them, and that consequently daily absorption of the non-excreted portion is oc- curring into the general circulation. In such cases a most careful and systematic examination of the urine should be made. The urine of chronic gout is somewhat increased in quantity, and is of lower specific gravity and somewhat paler than normal. The amount of uric acid eliminated is diminished. A trace of albumen is frequently present, and permanent albuminuria is a fairly common occur- rence in confirmed gout. If the renal condition is allowed to become very aggravated, then cardiac failure follows, with pulmonary congestion, oedema of the lungs, bronchitis, congestive enlargement of the liver, gastric catarrh, dropsy, and symptoms of urtemia. In such cases pneumonia is apt to supervene and to be attended by a fatal issue. THE HEART AND GOUTY KIDNEY. Changes in the heart and circulation, conse- quent on gouty affections of the kidneys, are indicated by hypertrophy of the left ventricle, a strong cardiac impulse, displacement of the apex beat to the left, loudness and occasional redupli- cation of the first sound, and accentuation of the aortic second sound. The pulse is of high tension, and the arteries are hard, tortuous, and sometimes atheromatous. Under such conditions a cerebral haemorrhage may occur. If compensa- tion fails then dilatation of the heart occurs, the area of dulness is greatly increased, the action of the heart becomes rapid, and the usual signs of Saturxixe or Lead Gout. 113 backworking of the blood from the left side of the heart follow. True angina pectoris, associated with widespread arterial degeneration and softening of the walls of the heart, occasionally occurs in gouty subjects, the gouty condition no doubt being a powerful factor in the production of the degenerative changes leading up to the anginal attacks. Pseudo-angina pectoris unassociated with any general arterial degeneration also may occur in the gouty, and is accompanied by severe pam in the region of the heart, passing down the left arm, a feeling of suffocation, flatulency, and gastric disturbance. SATURNINE OR LEAD GOUT. As previously described (see p. 59), chronic lead-poisoning gives rise to both chronic kidney disease and gout. The cause of the liability of those suffering from chronic plumbism to be attacked by gout has already been considered {see pp. 60, 96, 97). Briefly stated, it most probably is due to the action of lead salts on the kidney epithelium causing a diminution in the excretion of uric acid, so that consequently an absorption ^f the non-excreted portion takes place from the kidneys into the general circulation. This view is supported by the well-known fact that the medicinal administration of lead salts notably diminishes the excretion of uric acid by the kidneys. A prolonged period of lead intoxication — on the average about twenty-one years — is required to produce true saturnine gout. I 114 1^^^ Various Forms of Gout. The patient suffering from saturnine gout, unlike the majority of sufferers from inherited gout, is pale, thin, and auiemic. The gouty attacks are frequently repeated and affect many joints, whilst signs of interstitial nephritis make their appearance. If the lead-poisoning has been of short duration the lesions may yield to treatment, but after a prolonged absorption of lead into the system the kidney condition is generally incurable. IRREGULAR OR ABARTICULAR GOUT. Gout appearing in any situation other than a joint is regarded as irregular or abarticular. Differ- ent forms of irregular gout may accompany arthritic gout, or may take its place, or may alternate with it. Although attacks of irregular gout may occur in persons subject to articular gout, yet they more frequently occur in those who have never suffered from gout in the joints, but who are predisposed to gout either by inheritance or by their mode of life. Undoubtedly the terms "irregular gout" and " suppressed gout " have frequently been applied to pathological conditions in no Avay con- nected with gout, and it is therefore important that a diagnosis of irregular gout should be based on good and sufficient grounds. The most important points to pay attention to in the diagnosis of irregular gout are the question of heredity, the habits of the patient, the nature of the attack, a careful examination of the urine and, if possible, of the blood or blood serum, and, lastly, the successful reaction to therapeutic remedies. Irregular Gout. i i 5 Cramps and aching pains in various muscles and tingling sensations in the hands and feet are frequently associated with irregular gout. I believe that all forms of irregular gout are due to the precipitation in the crystalline form of sodium biurate in the organ or tissue aiYected. Sir William Roberts also considers it quite possible that attacks of irregular gout are due to the irritation produced by deposits of sodium biurate in the affected viscera. Deposits of sodium biurate have been found after death in the valves of the heart, in the walls of arteries and veins, in the vocal cords, in the mucous follicles of the pharynx, in the walls of the bronchial tubes, in the meninges of the brain and spinal cord, and in several other localities. Although deposits of sodium biurate have not been found in the walls of the alimentary tract, yet it is quite possible that such deposits might occur, and either have been overlooked at a post-mortem examination, since they would be most difficult to detect, or have undergone solution before death. ii6 CHAPTER IX. Irregular gout affecting the alimentary tract — Irregular gout affecting the air-2?assages and lungs — Irregular gout affecting the heart and vessels — Irregular gout affecting the neroous system — Irregular gout affecting the genito-urinary system — Irregular gout affecting tlie skin — Gouty glycosuria and diabetes — Gouty hepatic congestion — Gouty affections of the eye and ear — Retrocedent or metastatic gout — Diagnosis and prognosis of gout. The various forms of irregular gout may be con- veniently classified into the following groups: — (1) Irregular gout affecting the alimentary tract; (2) irregular gout affecting the air-passages and lungs; (3) irregular gout affecting the heart and vessels; (4) irregular gout affecting the nervous system; (5) irregular gout affecting the genito- urinary system; (6) irregular gout affecting the skin ; (7) complications and sequelae of gout. IRREGULAR GOUT AFFECTING THE ALIMENTARY TRACT Gouty pharyngitis is by no means an uncommon condition. The mucous membrane of the pharynx is congested and swollen. The uvula assumes a dusky-red colour and is cedematous. Gouty tonsillitis may also occur. Gouty oesophagismus occasionally occurs, and may be severe. Irregular Gout, iij Goufy dyspepsia is a very common form of irregular gout. It is usually accompanied by excessive gastric acidity, flatulence, and heartburn. Gastric pain, dilatation of the stomach, and pyrosis are occasionally associated with this form of d^^spepsia, which is frequently of a prolonged and obstinate nature. Chronic gastro-intesfinal catarrh is an occa- sional form of irregular gout. It is generally accompanied by vomiting, colic, and constipation ; occasionall}'- diarrhoea occurs. IRREGULAR GOUT AFFECTING THE AIR-PASSAGES AXD LUXGS. Gouty laryngitis. — Deposits of sodium biurate have been found in the vocal cords, the ar3^tenoids, and the crico-ar3'tenoid ligaments and joints. Congestion and swelling of the mucous membrane occur, and the congestion may extend to the vocal cords. The principal symptoms are hoarseness, irritable cough, and scanty expectoration, which is occasionally streaked with blood. Gouty tracheitis. — This affection is accompanied by ver}^ irritable cough and scanty expectoration. Acvie gouty bronchitis frequently precedes an arthritic attack, and often subsides when the joints become affected. The symptoms of acute gouty bronchitis may be very severe, and the heart's action often becomes irregular and feeble. The expectoration may be blood-stained, and the dyspnoea is frequently severe. Chronic gouty bronchitis. — This affection is ii8 The Various Forms of Gout. accompanied by an irritable cough and scanty expectoration. It is especially liable to alternate with arthritic attacks. Goiiiy asthma. — Attacks may alternate with arthritic attacks, or gouty asthma may occur in early life and, later, articular gout may develop, or gouty asthma may be the only form of gout inherited irom a parent who was the subject of articular gout. Gouty puZmonari/ congestion. — This is usually at the base of the lungs, but occasionally may be apical. It is accompanied by hsemoptysis, and is a condition that may be mistaken for phthisis. IRREGULAR GOUT AFFECTING THE HEART AND VESSELS. Cardiac irritability. — Paroxysmal attacks ot cardiac irritability are very apt to occur in gouty subjects. The attacks are nervous in origin, and are evidenced by irregularity, tachycardia, or oc- casionally bradycardia, and by dyspnoea if organic disease of the heart exist. Anginal and pseudo- anginal attacks. — These attacks may occur either in connection with chronic gout, or as an occasional manifestation of irregular gout. For a description of the associated symptoms see pp. 113, 215, 216. Gouty iMehitis. — This affection is a fairly common complication of chronic gout, but it may also be a phase of irregular gout. It may occur either in the veins of a portion of a limb which is the seat of gouty inflammation, or in veins quite Irregular Gout. 119 apart from the presence of gouty inflammation in the vicinity. The veins of the lower extremities are most commonly affected, especially the veins of the calf This affection is not uncommonly of prolonged duration, and is very apt to recur. In consequence of the thrombosis that ensues great care must be exercised to prevent detachment of the clot, and the consequent risk of pulmonary embolism. The oedema of the limb consequent on the thrombosis generally persists for some time. IRREGULAR GOUT AFFECTING THE NERVOUS SYSTEM. Migraine and neuralgia. — Attacks of migraine and of neuralgia not unfrequently occur in persoES of gouty habit, and are in certain cases dependent on the gouty condition. The commonest form of gouty neuralgia is sciatica, the next commonest is facial neuralgia. Neuritis. — Peripheral neuritis of gouty origin occasionally occurs. Gouty neuritis or perineuritis may occur ; the symptoms are numbness, tingling, loss of power in the affected part, muscular wasting occasionally, and sometimes very severe pain. The sciatic nerve and the brachial plexus and its branches are most liable to this form of perineuritis or neuritis. The affection is probably started by a deposit of sodium biurate in the nerve-sheath setting up a perineuritis, with subsequent effusion of lymph within the sher.th, and consequent com- pression of the nerve fibres. When this occurs 120 The Various Forms of Gout. in the sciatic nerve it is the cause of the severe and prolonged sciatica that some gouty subjects suffer from. Inf),so7)inia is an occasional accompaniment or manifestation of irregular gout. This condition may be due to the ingestion of improper food, giving rise to abnormal gastric fermentation, or to hepatic derangement. In such cases it is fre- quently accompanied by heartburn and palpitation. Mental depression is frequently associated with gouty attacks affecting the liver, and, as a rule, is almost immediately relieved by a dose of blue pill at night, followed by a purge of Epsom salts in the morning. Attacks of vertigo and epilepsy are occasionally associated with the gouty state. Gouty inflamma- tion of the meninges of the spinal cord occasional!}' occurs, associated Avith pain and tenderness over the affected area, and with pain and hyperiesthesia in the lower extremities. Three cases of transient paraplegia supposed to have been due to gouty congestion of the spinal cord have been described. IRllEGULAR GOUT AFFECTIXG THE GEXITO-URIX.\RY SYSTEM. Gouty kidney. — As previously stated (see pp. 60 — 63), I hold the view that a functional affection of the kidneys, interfering with the proper elimina- tion of uric acid, is the primary factor in the pro- duction of gout. This functional affection may subside if the exciting cause of it be removed, or it may pass on to a structural lesion, which is then Irregular Gout. 121 of the contracted granular type. The symptoms associated with the gouty kidney so produced are those usually met with in cases of contracted granular kidney. There is increased frequency of micturition, and more than the normal quantity of urine is passed. The urine may or may not con- tain a small quantity of albumen. The arterial tension is increased, and this constitutes a point of great importance to be noticed, since cerebral haemorrhage, hypertrophy and dilatation of the heart, and cons^estion of the luno-s are liable to supervene on this condition. JJ'vic acid gravel and calculi. — These deposits frequently occur in early life among those with a gouty inheritance, and are not uncommonly fol- lowed later in life by true gouty attacks. The pres- ence of uratic deposits in the kidney may produce a referred pain down the back and sometimes the front of the thigh. This pain may be sufficiently severe to interfere with walking, and is apt to be confounded with sciatica or rheumatism. The pain is a referred one and is dependent on the irritation produced within the kidneys, which irritation is caused by uratic deposits, or by the passage of fine uric-acid gravel, or occasionally by the passage of an excessive amount of uric acid, as sometimes occurs in cases of gouty diabetes. A careful ex- amination of the urine and palpation of the kidneys wdll reveal the source of such referred pains. Irritahility of the bladder is associated wdth the passage of scanty urine of high specific gravity, which 3^ields a copious deposit of amorjDhous 122 The Various Forms of Gout. urates on cooling. Gouty cystitis, urethritis, orchitis, ovaritis, and metritis have been described, but it is doubtful whether they are true gouty affections. IRREGULAR GOUT AFFECTING THE SKIN. Gouty subjects are peculiarly liable to certain affections of the skin, and amongst those who have inherited a gouty tendency the skin affections may constitute the only manifestation of gout. It is doubtful whether these skin affections are ever due to the direct irritant effect of either sodium quad- riurate or biurate contained in the sweat. They are more probably nervous in their origin. The following are the skin affections liable to be associated with the gouty state. Eczema. — This disease of the skin more fre- quently occurs in association with gout than any other. It frequently precedes arthritic gout, and may even occasionally be the sole manifestation of gout. It may assume either the acute or chronic form, and generally occurs symmetrically on both sides of the body. It is most prone to occur in spring, and is very apt to recur. Gouty eczema occurs most frequently in the following situations : the external ear and around it, the face and fore- head, the back of the neck, the flexures of the joints, the scrotum and prepuce, the backs of the hands and feet, the interdigital surfaces, and more rarely on the arms, legs, and trunk. Herpes is not unfrequently met with in associ- ation with gout. Irregular Gout. 123 Pruritus and pr-w-Wf/o occasionally occur in gouty subjects, especially in connection with gouty glycosuria. Pruritus is generally localised, and especially affects the arms and the vulva; occa- sionally it is general. Urticaria sometimes occurs as a result of the gouty state. Psoriasis, acne, boils, and carbuncles have been stated to be occasionally associated with gout. The nails of gouty subjects tend to become thin and brittle, and usually present a longitudinal striation, producing the condition known as " the reedy nail." OTHER IRREGULAR GOUT AFFECTIONS. Glycosuria and diabetes. — The development of glycosuria or diabetes in persons of gouty ancestry is undoubted. The glycosuria is in all probability frequently hepatic in its origin. Glycosuria is generally associated with some form of irregular gout, and but seldom with the ordinary articular gout, but very occasionally it alternates with true gouty attacks, and then, while the glycosuria lasts the patient is quite free from articular gout, audi vice versa. The glycosuria may at first be very slight, but if not checked by proper dietetic treatment it may lapse into true diabetes. With regard to the prognosis in gouty diabetes, much depends on the manner in which the affection responds to dietetic treatment. If the sugar in the urine quickly dis- appear, and if several months elapse before its re- appearance, then the prognosis is fairly good, and life may continue for many years. 124 The Various Forms of Gout. Hepatic congestion. — A condition of congestion of the liver, or possibly of subacute parenchymatous hepatitis, popularly known as " gout in the liver," is occasionally met with in gouty subjects, or in those who have inherited a gouty tendency. Gouty affections of the eye.— A. gouty inflamma- tion of any of the structures of the eye may occur. Conjunctivitis and iritis are the two commonest 83^6 affections caused by the gouty condition. Deafness. — Occasionally a gouty neuritis affect- ing the terminations of the auditory nerve causes deafness. RETROCEDENT OR METASTATIC GOUT. This form of gout occurs when a sudden sub- sidence of the inflammation in a gouty joint is succeeded by the development of the disease in one or more of the internal viscera, such as the stomach, intestines, heart, or liver. Persons subject to retrocedent gout are generally in a debilitated condition, and of feeble constitution. The attacks frequently follow an exposure to cold while suffering from an articular attack, and especially after in- discretion in diet. Attacks of retrocedent gout have also not uncommonly followed the extremely baneful practice of suddenly plunging a gouty foot into cold water. If the attacks rapidly shift their position the affection is termed flying gout. It is quite possible that attacks of retrocedent gout are caused by a deposition of the crystalline sodium biurate in the affected viscus, and that this crystal- line biurate acts as a mechanical irritant, and so Retrocedent Gout. 125 produces inflammation of the organ. On the other hand, these attacks may simply be of nervous reflex origin, due to vaso-motor disturbance producing a condition of hyper^emia or congestion of the affected viscus. The following are the principal forms of retrocedent gout, with the symptoms indicative of the sudden transference of the attack to the affected viscus. Retrocedent gout of the stoTnach. — The symp- toms are severe pain in the stomach, accompanied usually by vomiting and a feeling of general oppression, depression, and faintness. Palpitation may occur. Retrocedent gout of the intestines. — The usual symptoms are severe abdominal pain, vomiting, tympanites, and constipation. Retrocedent gout of the heart. — The symptoms are severe paljDitation, pain in the region of the heart, a sensation of constriction of the chest, dyspnoea, a small feeble pulse, and great anxiety. Syncopal attacks may occur. Retrocedent gout of the brain. — Apoplexy is the most frequent symptom. Congestion of the brain or meninges may occur, and may be followed by headache, stupor, convulsions, delirium, and occa- sionally by maniacal attacks. Transient attacks of aphasia, amnesia, and hemiplegia sometimes occur, and are probably due to congestion of the brain. Gouty orchitis and parotitis of meta- static origin have occasionally been know^n to occur. 126 The Diagnosis of Gout. diagnosis and progxosis. The diagnosis of an attack of acute gout as a rule presents no difficulty (see pp. 107,108). In its sub- acute and chronic forms gout must be distinguished from rheumatism, rheumatoid arthritis, and from synovitis of traumatic, pyaemic, or gonorrhoea! origin. The appearance of the joint (see p. 108), the discovery of tophi, and the family history are the main pomts on which to rely. Distinction of gout from rheumatism. — The sweating in acute rheumatism is much more copious than in acute gout. Rheumatism especially attacks the larger joints, whereas gout attacks the smaller joints most frequently, wdth the exception of the knees. The oedema around the gouty joint and the pitting on pressure are characteristic and of great assistance in distinguishing the affection from rheumatism. In gout desquamation of the cuticle of the affected joint occurs later, but not in cases of rheumatism. In connection with attacks of gout in the larger joints, such as the great toe and knee joints, inflammation of the con- tiguous lymphatic vessels occasionally occurs, and the glands in the neighbourhood of the affected part are usually enlarged and tender on pressure. As previously mentioned, the discovery of tophi and the family history are of immense service in distinguishing gout from rheumatism. Distinction of gout from rheumatoid arthritis. — The severity of the pain generally serves to dis- tinguish gout, there being no very acute pain in Prognosis of Gout. 127 the affected joints of rheumatoid arthritis. More- over, in connection with rheumatoid arthritis there is a history of the different joints being affected at different times, but without the invasion of a new joint being accompanied by amehoration of those previously affected, and the history of the disease shows a continuity in the affection of the joints, instead of a periodicity as in gout. Chronic gout of the hands may be distinguished from rheumatoid arthritis by the greater symmetry that is generally displayed in the finger joints of the two hands in . connection with the last-mentioned disease. Prognosis. — If no complications arise, if the attacks are not too frequent, and if no serious amount of albuminuria occurs, the disease is not likely materially to shorten life, especially if the patient is amenable to proper treatment and discipline. Moreover, although gout has generally been regarded as a more or less incurable disease, the view as to its renal origin renders the possibility of cure much more reasonable. 128 \^m III. THE AUTHOR'S INVESTIGATIONS OF CER- TAIN 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 hiurate. THE ALKALINITY OF THE BLOOD IX HEALTH AND IN GOUT. It is well known that an attack of gout may be accelerated by ingestion of food or beverages harmful either as regards their quality or quantity. Such substances may exert a direct or indirect chemical action which facilitates the precipitation of sodium biurate — this is the chemical view — or they may possibly exert a physical action only in hastening such precipitation — this is the mechanical view. A view which has previously been referred to, and which is commonly held as to the influence of diet and certain beverages in accelerating an attack of gout, is that such sub- stances reduce the alkalinity of the blood and so hasten the precipitation of sodium biurate. It is remarkable what a number of writers incline to the view that diminution of the alkalinity of the blood Alkalixity of the Blood. 129 cai.ises tlie deposition from it of sodium biuratc, and that a subsequent rise in alkalinity causes solution of the previously formed deposits. It is assumed that a nitroQfenous animal diet diminishes the alkalinity of the blood and so causes deposition of sodium biurate. It is also assumed that a similar result is caused by the acids contained in wines and beers ; and that the pains in the joints, that frequently occur in gouty subjects soon after taking certain wines or beers, are due to deposition of biurate following on the reduction of the alka- linity of the blood by the acid so introduced. Now, in the first place, is there any substantial proof that the alkalinity of the blood is much re- duced in connection with gout ? Careful experi- ments, conducted by Klemperer,"^ show that the alkalinity of the blood of gout is but very little, if at all, diminished, and that corresponding varia- tions in the alkalinity may frequently be met with in healthy individuals. In the following table (Table Y.) are shown the results of the determina- tions that I made of the alkalinity of the blood f of a patient suffering from subacute gout ; the estimations were made mostly on alternate days, throuo^hout the duration of the attack. The nor- nial alkalinity of healthy blood is shown for com- parison at the foot of the table. This normal, * Deutsche medicinische Wochenschrift, 1895, xxi., p. 6o5. f The process employed for determining the alkalinity of the blood was the one recently devised and dtscribed by Dr. A. E. Wright [The Lancet^ Sept. ISlh, 1897). This process is an ex- tremely ingenious and reliable one, and possesses the great advantage of not requiring more than two or three drops of blood in order to make an accurate determination of the alkalinity. J I30 A UTHOR s Investiga tions. alkalinity is the average of the determinations that I made of the alkalinity of the blood of twenty-five healthy male adults. TABLE V. Sltowlng the results of the determination of the alkalinity of the blood of an adult man during an attack of subacute gout. Dates of determinations, and relations to treatment. Alkalinity represented as percentage of an- liydrous sodium car- bonate jn'esent in the blood. Feb. 4th (commencement of attack, and be- fore treatment was begun) 0-167 6th\ 0-167 8th 0167 j> r^th ' (Treated with colchicum only) 0-156 0167 j> loth 0-158 17thj 0-158 19th \ 0167 )> 22nd (Treated with citrate of potas- 0-180 24 th sium and iodide of potassium 0-173 •5 26th 28th only) 0161 0179 .Mar .2nd 167 Average alkalinity throughout the attack ... 166 Alkalinity of normal blood ... {Average of the determinations of the alkali)iitg of the blood of tiventy-Jire healthy male adults.) 0-10< The alkalinity of healthy blood varied from 0161 to 0185, the average being 0167, and it is seen in the table that the alkalinity of the gouty blood varied from 0156 to 0180, the average being 01 60, which is practically the same as the normal alkalinity. These results show that in this case of subacute gout the variations in the Alkalixity of the Blood. 131 alkalinity of the blood were not greater than those met with in healthy individuals. There is certainly no good ground for the belief that an " acid dyscrasia " underlies the gouty condition. Recent researches show that a diminution of the alkalinity of the blood is a common pathological condition in diseases that are in no way associated with uratic precipitation, such as acute rheumatism, leukaemia diabetes, carcinoma and pyrexia. In the second place, I have been unable to meet with any experi- mental proof that a diminution in the alkalinity ot blood, containing uric acid in solution, either facilitates the deposition of sodium biurate from it, or diminishes its solvent power for sodium biurate or for uric acid. I therefore considered it advis- able experimentally to investigate these different points, and for that purpose the following series of experiments were undertaken. EXPERIMENTS SHOWING TO WHAT EXTENT THE RATE OF FORMATION AND PRECIPITATION OF SODIUM BIURATE IS EFFECTED BY DIMINISHING, BY THE ADDITION OF ACIDS, THE ALKALINITY OF BLOOD SERUM CHARGED AVITH URIC ACID. Seven bottles, each containing 40 c.c. of blood serum, were raised to 100° F., and then charged with uric acid to the extent of 1 in 1,000. As soon as the uric acid was dissolved, varyino- quantities of hydrochloric acid were added to the contents of three of the bottles, and of tartaric acid to another three, so as partially to reduce the n2 A uTHOR 's In ves tig a tions. alkalinity of the.serum ; the contents of the seventh bottle Avere left unaltered. The bottles were kept in a warm chamber at 100° F., and the commence- ment of the precipitation of sodium biurate crystals was then looked for by examining some of the contents of the bottles under the microscope every few minutes, so as to note the time when the formation of biurate crystals commenced. The quantities of hydrochloric acid added to the con- tents of three of the bottles were such as to neutralise respectively three-fourths, one-half, and one-fourth of the alkalinity of the serum remaining after solution of the uric acid. To the other three bottles corresponding quantities of tartaric acid were added to produce similar results. The follow- ing tables (Table VI. and Table VII.) show the results of these experiments. TABLE VI. The results of experiments made with Hood scrum charged uith uric acid, to show the effect which the diminution of the alkalinity of the serum, by the addition of hydrochloric acid, has on the pre- cipitation of sodium biurate. Si)lutioii. Blood Eerum containing I in 1,000 uric acid. The same one-fourth neutral- ised by hydrochloric acid. The 8ame one-half neutralised by hydrochloric acid. Tlie same three-fourths neuti-al- ised by hydrochloric acid. Coinineufcnieiit of jireciiatation. Crystals of sodium biurate first appeiired in 6 — 7 hours. Do. Do. Some crystals of uric acid ap- peared in minutes. Crystals of todium biurate first ap- peared in 12 hoxu'S. Experiments with Sodium Bi urate, 133 It will be seen from the results of these experi- ments that the effect of diminishino^ the alkalinity of blood serum as far as one-half has no influence whatever in hastening the conversion of the sodium quadriurate into biurate, or, in other words, does not influence the deposition of sodium biurate from the serum. When the alkalinity is reduced by three-fourths, by the addition of hydrochloric acid, some crystals of uric acid were almost immediately precipitated, but when this precipitation of uric acid had ceased, then the deposition of sodium biurate did not begin till twelve hours had elapsed. The reason that the deposition of sodium biurate was delayed a longer time than in the cases of the serum, the alkalinity of which was reduced respec- tively by one-fourth and one-half, was that the removal of some of the uric acid rendered the solution of sodium quadriurate weaker, and, as has been pointed out by Sir William Roberts, the amount of uric acid in solution exercises a very important influence on the rate of maturation of the quadriurate, and the advent of precipitation of the biurate. This early shower of uric acid crystals that occurred when sufficient hydrochloric acid was added to the blood serum to neutralise three-fourths of its alkahnity has no bearing whatever on the chemistry of the gouty attack, since the gouty deposit always consists of sodium biurate, and never of uric acid. The following table shows the results of the experiments obtained with blood serum, the alkalinity of which was partially reduced by means of tartaric acid 134 Author's Investigations. TABLE Yir. The results of experiments made ivith blood serum, charged tvith uric acid, to show the effect which the diminution of the alkalinity of the serum, by the addition of tartaric acid, has on the precipita- tion of sodium biurate. Solution. Commencement of precipitation. Blood serum containing- 1 in 1,000 uric acid. Crystals of sodium biurate first appeared in 6 — 7 hours. The same, one-fourth neutral- ised by tartaric acid. Do. The same, one-half neutralised hy tartaric acid. Do. The same three-fourths neu- tralised by tartaric acid. Do. From these experiments it is evident that even the reduction of the alkahnitj of blood serum by three-fourths has no influence in hastening the precipitation of sodium biurate from blood serum impregnated with uric acid. The view, therefore, that a diminution of the alkalinit}^ of the blood promotes an attack of gout by favouring the depo- sition of sodium biurate is, in my opinion, untenable. In order to s^ive an idea of the amount of acid that would be required to reduce the alkalinity of the blood of an adult human being by three-fourths, I made the following estimation and calculation. I found that the acidity of some 1847 port, reckoned as tartaric acid, was equal to six grains of acid to the wineglassful. In order to neutralise three- fourths of the alkalinity of the blood serum of a man of average weight, it would be necessary that all the acid contained in two bottles of such port Experiments with Uric Acid. 135 should be introduced at one moment into the circulation. EXPERIMENTS TO SHOW THE SOLVENCY OF URIC ACID IN BLOOD SERUM, THE ALKALINITY OF WHICH HAS BEEN REDUCED BY THE ADDITION OF AN ACID. The effect of hydrochloric and tartaric acids re- sjDectively Avas investigated. As will be seen from the results, there is a remarkable difference in the solvent power of partially neutralised blood serum for uric acid, accordingly as its alkalinity is reduced by the addition of hydrochloric or tartaric acid. The experiments were carried out in the following manner : — Four bottles containing 25 c c. each of blood serum were taken; three of them were treated respectively with different quantities of hydrochloric acid, so as to reduce the alkalinity of the serum in one case by one-fourth, in the second case by one-half, and in the third case by three- fourths ; the contents of the remaining bottle were left untouched. The bottles were placed in the warm chamber till their contents were at 100^ F., and then an excess (60 — 70 milligrammes) of uric acid was added to each. They were kept in the warm chamber for two hours, during which time they were frequently agitated ; the contents of the bottles were then filtered from undissolved uric acid, and the dissolved uric acid in each filtrate was estimated. The following table shows the results. 136 A uthor's Ixvestiga tions. TABLE VI 11. SJiouing the solnhUittj of uric acid at 100° F. in tmaltered blood serum and in blood serum the- alkalinity of which is proportion- attly reduced by the addition of hijdroohloric acid. Scilvtnit. Unaltered serum >Serum one-fourth neutralised by hydro- chloric acid .. . Serum one-half neutralised hy hydro- chloric acid ... Serum three-fourths neutralised hy hydro- chloric acid... Uric afiil dissolved. 2-03 per 1,000 148 „ 1-00 „ 45 Similar pxperiments were carried out using tartaric acid in the place of hydrochloric acid. The follow- ing table shows the results. TABLE IX. Showing the solubility of uric acid at 100° F. in unaltered blood sei-ntn and in blood strwn the alkalinity of which is proportion- ately reduced by the addition of tartaric acid. SolY.nt. Unaltered serum Serum one-fourth neutralised by tartaric acid ... ... Uric acid dissolved. 2-03 per 1,000. 201 Serum one-half neutralised by tartaric acid 201 202 Seium three-fourths neutralised by tartaric acid It is seen from the results of these experiments that if the alkalinity of blood serum is reduced by the addition of hydrochloric acid, the solvency of the serum for uric acid is correspondingly altered. Experiments with Uric Acid. 137 This is what would be expected, since the conver- sion of some of the sodium bicarbonate of the serum into sodium chloride renders that portion of the sodium unattainable by the uric acid, and prevents the solution of a corresponding amount of the latter as sodium quadriurate. Such a result, however, does not follow the reduction of the alkalinity of the serum by the addition of an organic acid, such as tartaric acid. It will be seen that serum, the alkalinity of which is reduced respectively by one-fourth, one-half, and three- fourths, practically does not vary at all as regards its solvency for uric acid. The explanation, no doubt, is that the uric acid is able to displace the tartaric acid from its combination with sodium, and utilise the sodium of the tartrate as readily as the sodium of the bicarbonate to form the soluble sodium quadriurate. Since the acidity of wines is due to organic acids (mainly tartaric, mahc, and succinic acids), it would seem very doubtful, judg- ing from the results of these experiments, whether, even if any alteration in the allialinity of the blood were produced by the drinking of acid wines, the solubility of uric acid in such blood could be affected m the shghtest degree. EXPERIMENTS TO SHOW THE SOLVENCY OF SODIUM BILTRATE IN BLOOD SERUM, THE ALKALINITY OF ^VHICH HAS BEEN REDUCED BY THE ADDI- TION OF AN ACID. The effect of hydrochloric and tartaric acids respectively was investigated. The experiments 138 A UTHOR '5 In ves tig a tions. were carried out in a similar manner to those just described, except that an excess of sodium biurate was substituted for the uric acid, and the disrestion with the sodium biurate was carried on at 100"^ F. for five hours. The following tables show the results : — TABLE X. Shouing the .solabillti/ of sodium biurate at 100° i^. in unaltered blood serum, and in blood serum the alkalinity of which is proportion- aiehj reduced b;/ the addition of hydrochloric acid. Solvent. Unaltered serum Serum one-fourth neutralised by hydro- chloric acid ... Serum one-half neutralised by hydrochloric acid Serum three-fourths neutralised by hydro- chloric acid ... Sodium biurate dissolved. 0-05 per 1,000 0-05 „ 0-07 0-10 These results show that sodium biurate is slightly more soluble in serum which has been partially neutralised by the addition of hydro- chloric acid than it is in unaltered serum. TABLE XI. Showing the solubility of sodium biiirate at 100' F. in unaltered blood serti-n, and in blood serum the alkalinity of tchich is pro- portionately reduced by the addition of tartaric acid. Solvent. Sodium biurate dissolved. Unaltered serum 005 per 1,000 Serum one-fourth neutralised by tartaric acid 0-08 „ Serum one-half neutralised by tartaric acid 0-08 Serum three-fourths neutralised by tar- taric acid 0-12 Experiments with Sodium Bi urate. 139 These results also show that sodium biurate is more soluble in serum the alkalinity of which has been reduced by the addition of tartaric acid than it is in unaltered serum. I think that the view that uric acid is deposited in the liver, spleen, joints, and fibrous tissues owing to diminished alkalinity of the blood should be abandoned. It is based on an error — viz., that the deposit is uric acid, whereas it is sodium biurate. The results of the experiments that have just been described indicate that diminution of the alkalinity of the medium does not promote the deposition of sodium biurate. The other view, that increased alkalinity of the blood dissolves and sweeps out the accuinu- lations of uric acid from the various organs and tissues, should also, in my opinion, be abandoned. It is based on the same error — viz., that the deposit is uric acid, whereas it is sodium biurate. That this body is not more soluble in highly alkaline fluids has been proved by the experiments of Sir AVilliam Roberts,^ and is confirmed by the experiments that have just been described. Another erroneous idea in my opinion is that uric acid may be precipitated from the blood in the form of insoluble urates by certain metallic salts ; these insoluble urates are supposed to be deposited in various tissues or organs, and yet in some mysterious manner to be subsequently redissolved when the alkalinity of the blood rises. There is absolutely no experimental proof to support such a statement. * Crconian Lectures on " Uric- Acid Gravel and Gout," 1892. 140 CHAPTER XL Experimental investigation of the influence exerted by the mineral constituents of meat, tnilk, and vege- tables respectively on the sohtbility of sodium biurate — The influence of alcoholic beverages on the gouty process. INFLUENCE OF CERTAIN ARTICLES OF DIET ON THE PRECIPITATION OF SODIUM BIURATE. It is well known that the excessive consumption of rich nitrogenous food, combined with excesses in wine and malt liquors, both induce and excite gout. The comparative immunity of females and young people from gout is mainly explained by the absence of such determining causes of the gouty attack, combined Avith, in the case of young people, the absence of predisposing cause, and also the fact that the secreting functions are in full activity. The subjects of gout are generally persons who live well and consume a large amount of animal food. Dr. Budd, speaking from a long and ex- tensive professional connection with a large rural district, states that ho never knew an instance of gout occurring among agricultural labourers. The generally accepted view that a highly nitrogenous animal diet necessarily produces an excessive amount of uric acid is disproved by Animal and Vegetable Diets. 141 the experiments of Bleibtreu and of Hirschfeld previously referred to. Those experiments show that there is an increased elimination of urea to compensate for an excessive intake of nitro- genous food, and that the amount of uric acid remains practically undiminished. Judging by the results of the experiments which have been previously described, it is highly improbable that any diminution in the alkalinity of the blood, which might be produced by the consumption of an excessive amount of animal food, could in any way affect its solvent powers for uric acid, or accelerate the precipitation of sodium biurate. My own view is that, as regards the production of uric acid from proteid matter, it is of little importance whether the proteid is of animal or vegetable origin. The same harm may result from an excessive consumption of either form of proteid. But although animal and vegetable proteids may react alike with regard to the pro- duction of uric acid, it is quite possible that the different saline constituents of animal and vege- table foods might very materially affect the solu- bility of sodium biurate and therefore influence its precipitation. As I have been unable to find any record of experimental work bearing on this matter, I thought it advisable to ascertain if the saline substances contained in different articles of diet appreciably affected the solvency of sodium biurate at the temperature of the human body, as obviously the subject might have both a pathological and therapeutical bearing. The 142 Author's Investigations. following experiments were therefore carried out. EXPERIMENTS SHOWING THE INFLUENCE OF THE MINERAL CONSTITUENTS OF MEAT, MILK, AND VEGETABLES RESPECTIVELY ON THE SOLUBILITY OF SODIUM BIURATE AT 100' F. A series of experiments were undertaken, operating upon the ash respectively of lean beef, milk, and mixed vegetables (potatoes, spinach, and French beans). The experiments were carried out in the following manner: — The contents of a number of bottles, each containins: 100 c.c. of distilled water, were mixed with known quantities of the different ashes and placed in the warm chamber until their contents were at a temperature of 100' F., when an excess of sodium biurate was added to each. The bottles were kept at 100° F. for five hours, during which period they were frequently agitated. At the end of that time the contents of the bottles Avere filtered and refiltered through double filters until perfectly clear filtrates were obtained. The amount of uric acid in each of the filtrates was then estimated by adding an excess of strong sulphuric acid, and titrating with the standard potassium permanganate solution ; the quantity of uric acid found was subsequently calculated into terms of sodium biurate. The results thus obtained are shown m the following tables. The solubility of sodium biurate in distilled water is placed at the head of each table for comparison. Experiments with Sodium Bi urate. 143 TABLE XII. Showing the injlaencc of the mijieral constUuc/its of meat {lean beef) oil the solabllUi/ of sodium hluratc at 100°/''. Mulveiit. yodium tlissD bi unite Ived. Water MO per 1,000 Water containing- : — l-O par oont. of moat ash 0-93 0-5 0-2 55 5) 55 55 0-76 0-56 O-l 55 55 o:v2 O-Oo 5 ' 55 • • * • • • • • * 0-15 0-02 55 55 0-11 0-01 55 55 0-85 From the above table it is seen that the mineral constituents of meat, in all proportions between 10 and 001 per cent, diminish the solvency of sodium biurate. The effect is most marked Avhen the proportions are between 01 and 0'02 per cent., which are proportions that may certainly be present in the blood after eatino^ a few ounces of meat. It is therefore quite possible that the Avell-known influence of excessive meat-eating on the hastening or maturing of an attack of gout may, in part at least, be due to the action of the mineral con- stituents of the meat. TABLE XIII. Showing the influenee of the mineral constitacnts of milk on the soliihility of sodium biurate at 100° F. Solvent. Sodium 1 dissol .)iurate i'ed. Water . •• Water containing : — 1-10 per 1,000 rO per cent . of millv ash 0-62 55 O-o 5' 0-58 55 0'2 55 •• • 0-49 >> 0-1 55 0-44 5> 0-05 55 0-72 55 0-02 55 0-90 55 0-01 55 • • • ••• 0-94 55 144 A UTHOR 'S I A VES TIG A TIONS. 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 01 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 Ol 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 soluhiiity of sodium biurate at 100° F. Sodium biurate Solvent. (iissu Ive.l. Water... 110 per 1,000 Watei' containinj.^ : — ro per cent. of vegetable ash 2- 1.5 0-0 »> 1-70 0-2 >, l-3o 01 ,, 1-1.5 005 ,, 110 002 ,, ... ... 1-10 001 ,, 1-10 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, w^ould 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 DRINKS 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 consumed 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^ K T46 A UTHOR '5 In ves tig a tions. succinic, malic, acetic, formic, propionic, butyric and oenanthic. 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 3 and 7 per cent. I found the acidity of some 1847 port, reckoned as tartaric acid, to be 0*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 (b) 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 beers arranged in order of acidity and go^it-inducing power («) Acidity (beginning with the (b) Gout-inducing power (1 leginning most acid). with the must powerful). Moselle Tort Bliine wines Sherry Burgundy C)ther stronger wines Madeira Champagne Claret Stout and porter Champagne Strong ales Port Claret Sherry Hock IM alt liquors Moselle Weaker kinds of ; lies Claret, hock, moselle and the weaker kinds of ales have comparatively little gout-inducing power. Alcoholic Beverages and Gout. 147 gout-inducing properties of certain wines and lieers not due to acids or sugar. Sir Alfred Garrod considers that acidity of 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 efiect 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. 1 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 oenanthic ether and other ethereal salts of wines exerting any etlect 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 solubiUty or hastening the precipitation of sodium biurate. As to the modus ojyerandi of certain wines, such as port, etc., in hastening an PV/NBS 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 clue to the eftect they exercise on the metabolism of the liver,.. and. . the- consequ^nt_i»— . creased amount of gljcocine that passes on to the-' Jddneys. 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 , absorpti on of the surplus uric acid wojili_laka„ place into, the ofeu£i'al 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 i;o CHAPTER XIL Experimental investigation of the relative effects exerted hy the mineral constituents of various vegetables on the solubility of sodium biur ate— Experimental investigation of the influence exerted by 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 the preUmuiar}^ 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 bearinor on the treatment of f^out.* EXPERTMENTAL mQUIRY TO ASCERTAIN THE SOLVENT EFFECTS EXERTED BY THE MINERAL CONSTITUENTS OF VARIOUS VEGETABLES ON SODIUM BI URATE. 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 influence of the mineral constituents of spinach on the solubility of sodium biurate at 100° F, Solvent Sodium biurate dissolved. Water MO per 1.000 Water containing : — rO per cent, of spinach ash ... 3-36 )> 0-5 „ „ 2-76 )> 0-2 „ „ 2-12 >> 0-1 „ „ 1-90 j> 0-05 „ „ 1-52 )> 0-02 „ „ 1-21 »> o-oi „ „ lis >> * The results of these experiments were first communicated to the Koyal Medical and Chirurgical Society of London in a paper read on June 14th, 1898. 152 A UTHOR '5 In ves tig a tions. TABLE XVII. Allowing the influence of the mineral constituents of Brussels sprouts 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 Brussels sprouts ash 3-06 ,0-5 „ „ 2-21 „ 0-2 „ „ 1-68 „ 01 1-62 . „ 005 1-52 „ 0-02 1-30 „ 0-01 1-23 TABLE XVIII. Showing the influence of the mineral constituents of potato on the solubility of sodium biurate at 100° F. Sodium 1 biurate Solvent. dissol ved. Water ... 110 per 1,000 Water containing : — 1-0 per cent .of potato ash ... 2-49 05 2-17 0-2 „ 1-92 01 „ 1-47 005 1-36 0-02 1-12 0-01 MO TABLE XIX. Showing the influence of the mineral constituents of asparagus on the solubility of sodium biurate at 100° F. Sodium biurate Solvent. dissul ved. Water MO per 1,000 Water containing : — 10 per cent, of asparagus ash 2-77 0-5 „ „ 2-09 0-2 „ „ 1-58 0-1 „ „ 1-45 0-05 „ „ 1-33 002 „ „ 112 01 „ „ MO Experiments with Vegetable Ashes. 153 TABLE XX. Shoiving the wflucnce of the mineral constitttents of Savoy cabbage on the aolubilih/ of sodium hinyatc at 100° F. yodiuiii 'iuratL- Sulvent. dissol ved. Water MO pci 1,000 Water containing : — 1 '0 per cent, of Savoy cabbage ash ... 2-32 0-5 „ „ 1-92 0-2 „ „ 1-77 0-1 „ „ 1-57 0-05 „ „ 1-34 0"2 „ „ 1-13 0-01 „ „ MO TABLE XXI. Showing the influence of the mineral constituents of French beans on the solubility of sodium biurate at 100° F. Solvent. Sodium l)inrate dissolved. Water Water containing- : — 10 per cent, of French beans ash 0-5 0-2 01 005 002 001 MO per 1,000 2-48 1-87 1-68 1-56 1-28 1-16 110 TABLE XXII. Showing the influence of the mineral constituents of lettuce on the solubility of sodium biurate at 100° F. Sodium biurate Solvent. dissolved. Water MO per 1,000 Water containing : — rO per cent, of lettuce ash ... 2-72 0-5 ,, ,, 1-92 0-2 1-57 0-1 1-53 0-05 „ „ 1-21 0-02 „ „ MO 001 ,, ,, 1-09 154 A UTHOR 's Inves tig a tions. TABLE XXIII. Showinj the injlaenee of the mineral constituents of beetroot on the solabilitij of sodiicm biurate at 100° F. Sodimii biurate Solvent. dissolved. Water Water containing ; — MOpe f 1,000 1-0 per cent, of beetroot ash .. 2-46 >j 0-5 „ ,, 1-82 ?) 0-2 „ „ 1-60 >> 0-1 ,, ,, 1-45 >> 0-05 „ ,, ... ... 1-34 5) 0-02 ,, ,, 1 15 5» 001 ,, „ MO )J TABLE XXIV. Showing the injlaoice of the mineral constituents of winter cabbage on the solubility of sodium biurate at 100° F. Solvent. Sodium biurate dissolved. Water .. AVater containing ; — MO poi ' 1,000 rO per cent of cabbage ash 2-30 0-5 ., 214 0-2 ,, 1-63 01 ,, 1-31 0-05 » 1-23 C-02 i> MO 0-01 ., ... ... ... MO TABLE XXV. Shoicing the influence of the mineral constituents of celery on the solubility of sodium biurate at 100° F. Solvent. Sodium disso] biurate ved. Water ... 11 per 1,000 Water containing : — rO per cent. of celery ash ... 2-20 0-5 1-84 0-2 1-53 01 1-44 0-05 „ 1-30 002 „ 1 10 0-01 „ lOG Experiments with Vegetable Ashes. 155 TABLE XXVI. Showing the influence of the mineral constituents of turnip tops on the solubility of sodium biurate at 100° F. Sodium )i urate Solvent. dissol ved. Water 1-10 pel 1,000 Water containing : — 1 per ceni . oft unip tops ash 216 0-5 3> 1-82 0-2 }J 1-58 0-1 J» 1-42 O-Oo »J 1-20 0-02 > J l-Vi 0-01 1-11 TABLE XXVIL Showing the influence of the mineral constituents of turnips on the solubility of sodium biurate at 100^ F. Sodium biurate Solvent. di ssolved. Water MO per 1,000 Water containing : — 1-0 per cent, of turnip ash ... 2-Oi 0-5 „ „ 1-78 0-2 „ „ 1-50 0-1 „ „ 1-42 0-05 „ „ 1-32 0-02 „ „ 1-U 0-01 „ „ MO TABLE XXYin. Shoiving the influence of the mineral constituents of carrot on the solubility of sodium biurate at 100° F. Solvent. Sodium biurate dissolved. Water Water containing : — 1-10 per 1,000 10 per cent, of carrot ash ... 1-63 05 1-53 0-2 1-47 0-1 1-4.5 0-05 1-33 02 1-13 0-01 Ml •> 156 A UTHOR 's In ves tig a tions. TABLE XXIX. Show'inj the hiflncncc of the mineral comtituenta of cauVijlower on the solubility of sodium biurate at 100" F. Solvent. Water Water containing : I'O per cent, of cauliflower ash. o-i 0-05 002 001 So'linm clissol ilurate i-ed. MO pel 1,000 l-o2 1-50 5» 1-42 5» 1-3-t 5? 1-28 1-09 5» 1-09 TABLE XXX. Showing the injfuence of the mineral constituents of seakale on the solubility of sodium biurate at 100" F. Solvent. Water Water containing 1 per cent, of seakale ash 0-5 ,, „ 0-2 01 O-Oo 0-02 001 Sodium li urate dissol ved. 110 per 1,000 1-49 >> 1-47 >» 1-3.5 5» 1-23 ■» 110 9» 110 >» MO TABLE XXXI. Shotcing the influence of the mineral constituents of green peas on the solubility of sodium biurate at 100" F. Solvent. Water... Water containing : 10 per cent, of gieen peas ash Co „ „ 0-2 0-1 005 002 o-oi Sodium biurate dis.so Ived. MO per 1,000 0-99 101 104 110 110 110 MO Experiments with Vegetable Ashes. 157 From the 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 sohtary 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 vesretable on the sodium biurate was not proportional to the alka- linity of the ash was very easily determmed. 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 solubilit}' 158 A UTHOR 's In ves tig a tions. exerted by the mineral constituents of vegetables on sodium biurate, and the alkalinity of thos3 con- stituents. TABLE XXXir. Shoiving that the solvent effect on sodium biurate of the mineral constituents of vegetables is not dependent on the alkalinity of those constituents. Vegetables arranged in order of solvent effect of tlieir Vegetables arranged in order of the alkalinity mineral constituents on of their ashes, and showing percentages of sodium biurate. Com- alkalinity reckoned as sodium carbonate. mencing with tliose exert- | Commencing with the most alkaline. ing the greatest effect. Spinach Spinach ... 26-00 Brussels sprouts Celery ... 20-80 Potato Turnip ... 20-80 Asparagus Potato 17-55 Savoy cabbage Beetroot ... 15-60 French beans Cauliflower 13-20 Lettuce Carrot ... 1300 Beetroot Brussels sprouts 12-35 Cabbage ' 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, Avhile its alkalinity is low ; on the other hand, the solvent efi'ect 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 reofards 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 alkalinity 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 ]3otassium 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 A UTHOR 's In ves tig a tions. vegetables on sodium biurate, and the proportions of potassium salts present. TABLE XXXIII. Showing that the solvent ejf'ect 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 ; iroportions of solvent effect 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 tliose exert- Commencing with those richest in pota.ssiuni ing the greatest etfect. salts. Spinach Potato .. 56-03 Brussels sprouts Turnip ... .. 5405 Potato Carrot ... .. 53-36 Asparagus Lettuce ... .. 48-01 Savoy cabbage J^renehbeans .. 46-50 Freuch 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 ... .. 3314 Tui-nip 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 ves^etables 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 solv- 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 ix Vf.getadles. i6i solubility of the biurate effected by the inineral constituents of vegetables is not due to the sodium salts. The following table contains a comparison of the solvent powers exerted by the inineral con- stituents of vegetables on sorlium biurate, and the proportions of sodium salts present. TABLE XXXIV. Showlnj that the solvent effact on sodium binrate of the minercl constituents of vegetables is not dependent oil the amoioits resent and showing the percent iges of sudium salts present in the ashes, reckoned as sodium oxide. Com- mencing with those richest in sodium salts. Spinuch Serikale ... ... 33-84 Brussels sprouts Spinach ... ... 31-42 Potato Beetioot... ... 31-17 Asparagus French beans ... ... 30-50 .S.tvoy cabbage Celery ... ... 19-33 French beaus Asparagus ... 16-79 Lettuce Carrot .. 1417 Beetioot Savoy cabbage . , ... 13-86 Cabbctge Brussels sprouts ... 12-60 Celei y Lettuce ... 11-80 Turnip tops Cauliflower ... in-87 Turnip Turnip ... ... 6-37 Carrot Gieen peas 5-20 Cauliflower Turnip toi)S 4-19 ISeakale Cabbage ... 2-:;9 Green peas i'otato ... 21S It is evident from this table that the solvent effect of the mineral constituents of vegetables on sodium biurate bears no relationsbip, either of a direct or an inverse ratio, to the proportions of sodium salts present. For instance, it can be seen that the solvent effect on the biurate of the ash of potato is high, while the proportion of sodium salts is low : on the other hand, the solvent effect on the 1 62 A UTHOR 's Inves tig a tions. biurate of the ash of seakale is low, while the pro- portion of sodium salts is high. In like manner it can be demonstrated that the increased solubility of the biurate effected by the mineral constituents of vegetables is not due to the calcium salts. The following table contains a comparison of the solvent powers exerted by the mineral constituents of vegetables on sodium bi- urate, and the proportions of calcium salts present. TABLE XXXV. Showing that the solvent effect on sodium biurate of the mineral constituents of vegetables is not dependent on the amoimts of calciuin sal's present. Vegetables arranged in order of solvent etfect of tlieir mineral constituents on sodium biurate. Com- mencing witli those exert- ing the greatest effect. Vegetables arranged in orderof the proportions of calcium salts present, and showing the percentages of calcium salts present in the ashes, reckoned as calcium oxiile. Com- mencing with those richest in calcium salts. Spinach Turnip tops ... 37-15 Brussels sprouts Seakale ... ... 27 -56 Totato Cauliflower ... 23 33 Asparagus French beans ... ... 17-48 Savoy cabbag-e Cabbage ... 17-14 French beans Lettuce ... ... 15-02 Lettuce Savoy cabbage ... ... 14-83 Beetroot Turnip ... ... 13-38 Cabbage Celery ... ... 13-03 Celery Spinach ... ... 10-64 Turnip tops Carrot ... ... 6-88 Turnip Brussels sprouts ... 616 Carrot Potato ... 5-46 Cauliflower Asparagus ... 505 Seakale Green peas ... 4-98 Green peas Beetroot... ... 2-58 It is also evident from this table that the solvent effect of the mineral constituents of vege- tables on sodium biurate bears no relationship, either of a direct or an inverse ratio, to the propor- tions of calcium salts present. For instance, it can Phosphates in Vegetables, 163 be seen that the solvent effect on the biurate of the ash of potato is high, while the proportion of calcium salts is low ; on the other hand, the solvent effect on the biurate of the ash of seakale is low, while the proportion of calcium salts is high. Similarly it can be shown that the increased solvent effect on the biurate exerted by the mineral constituents of vegetables is not due to either the magnesium or iron salts present. It can also be demonstrated that the increased solubility of the biurate is not due to the phos- phates present in the vegetables. The following table contains a comparison of the solvent powers exerted by the mineral constituents of vegetables on sodium biurate, and the proportions of phos- phates present. TABLE XXXYI. Showing that the solvent efftct on sodium biurate of the mineral constituents of vegetables is not dependent on the amounts of phosphates present. Vegetables arranged in order of solvent effect of their mineral constituents on sodium biurate. Com- mencing witli those exert- ing the greatest eftect. Spinach Brussels sprouts Potato Asparagus Savoy cabbage French beans Lettuce Beetroot Cabbage Celery Turnip tops Turnip Carrot Cauliflower Seakale Green peas Vegetables arranged in order of the proportions of phosphates present, and showing the percentages of phosphates present in the ashes, reckoned as phosphoric anhydride. Commencing witli those ricliest in' phos- phates. Green peas 35-62 Cauliflower 22-14 Asparagus 21-93 Potato 15-99 CaiTot ... 15-02 Celery ... 14-39 Brussels sprouts 14-20 Savoy cabbage ... 13-19 French beans . . . 12-21 Cabbage... 11-99 Ijettuce ... 9-62 Turnip ... 9-26 Spinach ... 8-56 Beetroot... ... 8-25 Seakale ... 800 Turnip tops 6-15 164 Author 's Ix i 'es tig a t/ons. It is also evident from this tabie that the solv- ent 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 phosphates present. For instance, it can be seen that the solvent effect on the biurate of the ash of spinach is high, Avhile the proportion of phosphates is low : on the other hand, the solvent effect on the biurate of the ash of green peas is low, Avhile the proportion of phosphates is high. It can also be demonstrated that the increased solubility of the biurate is not due to the sulphates present in the vegetables. The following table con- tains a comparison of the solvent powers exerted by the mineral constituents of vegetables on sodium biurate, and the proportions of sulphates present. TABLE XXXVII. >ihowinfj that the solvent effect on so ii -m hlurateofthe m'lneraJ constitueydfs of vegetables is not dependent ou the amounts of sulphates present. Vegetables arranged in onler j of solvent effect of their j mineral constituents on ; sodium biurate. Com mencing with those exert ing the greatest effect. Vegetables arranged in order of the proportions of sulphates present, and showing the per- centages of sulphates pi-csent in the ashes, reckoned as sulphuric anhydride. Com- mencing with those richest in suljihates. Si)inach Brussels sprouts Potato Asparagus Savoy cabbage French beans Lettuce Beetroot Cabbage Celery Turnip tops Turni]) Carrot Cauliflower Seakale Green peas Seakale ... ... 19-78 Turnip U)\)< ... 15-27 Cauliflower ... 141(3 Savoy cabbitge ... ... 12-8.) Turnip ... Brussels sprouts Cabbage French beans ... ... 12-47 ... 8-31 ... 7-28 ... 6-82 Potato ... 5-60 Asparagus Carrot ... 5-40 ... 5-20 Spinach ... ... 4-44 Green peas 4-36 Lettuce ... 3-92 Beetroot... ... 2-4 1 Celerv 1-10 Chlorides in Vp.gktadlbs. 165 It is also evident from this table that the solv- ent 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 sulphates present. For instance, it can be seen that the solvent etfect on the biurate of the ash of spinach is high, while the proportion of sulphates is low ; on the other hand, the solvent effect on the biurate of the ash of seakale is low, while the proportion of sulphates is high. Finally, as disposing of all the mineral con- stituents of any importance in vegetables, it can bo demonstrated that the increased solubility of the biurate is not due to the chlorides present in the vegetables, as seen in the following table. TABLE XXXVIII. Shoiving that the solvent (ffcct on scdium biurate of the mineral constituents of vegetables is not dependent on the amounts of chlorides present. Vegetables arranged in order of solvent ettect of their Vegetables arranged in order of tlie proportion mineral constituents on of chlorides present, and showing tlie per- sodinni biurate. Com- centages of chlorides present in the ashes, mencing with those exert- ing the greatest effect. reckoued as chlorine. Commencing with those richest in chlorides. Spinach Celery ... 2214 ]3russels sprouts Beetroot... 18-13 Potato Seakale ... 15-46 Asparagus Cabbage ... 9-09 Savoy cabbag-e Lettuce ... 8-80 French beans Spinach ... 7-78 Lettuce Savoy cabbage . . . 7-53 Jicetroot Turnip tops 7-33 Cabbage Asparagus 6-62 Celery Turnij) ... 6-06 Turnip toi)S Cauliflower 4-83 Turnip Carrot ... 3-70 Carrot Brussels sprouts 3-00 Cauliflower Potato 2-50 Seakale French beans . . . 2-50 Green peas Green peas 2-10 1 66 Author's Investigations. It is also evident from this table that the solv- ent effect of the mineral constituents of vegetables on sodium biurate bears no relationship, either of a direct or an inverse ratio, to the projDortions of chlorides present. For instance, it can be seen that the solvent effect on the biurate of the ash of Brussels sprouts is high, while the proportion of chlorides is low ; on the other hand, the solvent effect on the biurate of the ash of seakale is low, while the proportion of chlorides is high. These results collectively show that the solvent effect exerted on sodium biurate by the mineral constituents of vegetables is not due to any one constituent. EXPERIMENTAL PROOF THAT AN ARTIFICIALLY PRE- PARED ASH DOES NOT REACT TO SODIUM BIURATE IN THE SAME MANNER AS A NATURAL VEGETABLE ASH. I next endeavoured to ascertain whether an artificially prepared ash of the same composition as the natural ash of one of the vegetables would exercise a similar effect in increasing the solubility of the sodium biurate to that possessed by the natural ash. For this purpose I selected the spinach ash, which has the greatest solvent effect on the biurate. An artificial ash was prepared, which was made with the same proportions of potassium, sodium, calcium, sulphates, phosphates and chlor- ides as those present in the natural spinach ash, and also of precisely the same degree of alkalinity. Experiments were carried out with this artificial Artificial and Natural Ash. 167 ash and the biurate in a similar manner to that employed in working with the natural vegetable ashes. The following table shows the results of these experiments: — TABLE XXXIX. Showing the influence of the artificial spinach ash on the solubility of sodium biurate at 100° F. Solvent. Sodium dissol biurate ved. Water 1-10 per 1,000 Water containing : — 1-0 per cent, of artificial spinach ash. 0-20 0-5 0-34 0-2 0-62 0-1 0-86 0-05 0-96 0-02 1-04 0-01 1-06 These results are very remarkable, as they in- dicate that the artificial ash exercises in all pro- portions a deterrent effect on the solubility of the biurate. This deterrent effect is well seen by con- trasting the results with those of the natural ash, which show the marked solvent effect exerted by the latter on the biurate. TABLE XL. Shoicing the different influences exerted by the artificial and natural spinach ashes on the solve)ic>j of the biurate at 100° F. Solvent. Sodi uni biurate dissolved iu 1,000 parts. Water MO Artificial spinach asli. Natural spinach ash. Water containing : — I'D per cent, of ash 20 3-36 O-o 0-34 276 0-2 0-62 2-12 0-1 0-86 1-90 05 „ 0-96 1-52 0-02 „ 1-04 1-21 001 „ 1-06 1-18 1 68 A UTHOR 5 L\ I '£S TIG A TIONS. The only explanation that I can oifer of these remarkable results is that in the natural ash there is some combination of the mineral constituents Avhieh cannot be artificial!}^ imitated, and that upon this natural combination of the salts is dependent the increased solvent effect exerted on the biurate by the mineral constituents of most vegetables. If this view be correct, then modern science is but > confirming the correctness of the practice of those ancients who employed vegetable ashes in the treatment of gout. It is well to make here a brief reference to the experiments described on p. 143, which show that the mineral constituents of meat exercise a marked deterrent effect on the solubility of sodium biurate ; and that this effect is most marked by proportions of the mineral constituents which may certainly be present in the blood after eating a few ounces of meat. The following table shows in contrast the effects exercised respectively by the mineral con- stituents of lean beef and spinach on the solubility of the biurate. TABLE XLI. Showing the respective effects exercised by the minernl constituents of beef and spinach on the solnbdity of sodium biurate at 100° F. Solvent. odium biurate dissolved in 1,000 parts. Water r cont^iininc^ : — 1] 10 Beef ash. Spinach asli. Wat€ 10 per cent. of ash 0-93 3-36 o 0-76 2-76 2 »> ... 0-56 2-12 1 32 1-90 0(.5 1 5 1 -02 02 0-11 1-21 001 ,. 0-85 118 Vegetable Ashes and Quadriurate. 169 expellimental inquiry to ascertain the effect exerted by the mineral constituents of various veoetables on the conversion of sodium quadriurate into sodium biurate. It is well known from the researches of Dr. Bence Jones and of Sir William Roberts that sodium quadriurate, which is the form in Avhich uric acid first appears in the blood in gout, is an unstable body, and is gradually converted by com- bination with the sodium carbonate of the blood into sodium biurate, which latter body, on account of its comparative insolubility, deposits in the tissues and thus constitutes the gouty uratic deposit. This gradual conversion of the quadri- urate into biurate is known as the matviration iwocess. It is obviously of therapeutical importance to know whether the mineral constituents of any of the vegetables, in addition to exerting an increased solvent effect on the biurate, possess the power of delaying this maturation process; or, in other words, of inhibiting the conversion of the quadri- urate into the biurate. In order to ascertain this, I conducted a series of experiments. In all these experiments I employed Sir William Roberts's standard solution, as being a more convenient medium to work with than blood serum. This standard solution contains Ob per cent, of sodium chloride and 0*2 per cent, of sodium bicarbon- ate dissolved in distilled water. Sir William Roberts found that this solution is a fairly exact 170 Author's Investigations. representation of blood serum, in so far as its saline ingredients are concerned, and that it reacted with uric acid and the urates in the same manner as blood serum itself, and in the same manner as a solution comprising all the salines of the serum in their due proportions. The experiments were conducted in the follow- ing way. Pure sodium quadriurate was prepared by shaking for one minute ten grammes of uric acid with a litre of a boiling hot 5 per cent, solution of sodium acetate. This was filtered hot, and the filtrate was then rapidly cooled on ice. The quad- riurate, which falls down, was at once collected on a filter, washed with absolute alcohol, and dried at 100° F. Ten milligrammes of pure sodium quadriurate were well rubbed with ten drops of the standard solution, and the mixture placed in a small corked bottle in the warm chamber and kept at 100° F. Every half-hour a small quantity of the mixture was examined under a high power of the microscope, and the time at which crystals of sodium biurate first appeared was noted. This represented the time occupied by the maturation process when the standard solution was saturated with sodium quadriurate. Similar experiments were conducted with the same amount of sodium quadriurate in the same quantity of standard solu- tion containing respectively 01 per cent, of the mineral constituents of each of the vegetables in ordinary use. The results are shown in the follow- ing table. Vegetable Ashes and Quadriurate. 171 TABLE XLII. Showing the effects exerted by the mineral constituents of vegetables on the conversion of sodium qtiadrinrate into sodium biurate. Cry.stals of sodium biuiate Solvent. first appeared in — Standard sol ntion 2 hours Standard solution containing : — 0-1 per cent. of potato ash 2 cauliflower ash... 2 lettuce „ ... 2 carrot ,, ... 2 asparagus ,, ... 2i beetroot ,, ... 3 green peas „ ... 3| celery ,, ... 3^ Brussels sprouts ash . . . 4 cabbage , , 4 ' turnip tops ,, 4 turnip ,, 4 SaA^oy cabbage , . 4 seakale ,, 4 French beans ,, H spinach „ 5 These results show that the mineral constituents of some of the vegetables — notably spinach, Brussels sprouts, French beans, cabbage, turnip tops, and turnips — very considerably delay the conversion of sodium quadriurate into sodium biurate. The in- ference is that if such mineral constituents were present in suitable proportions in the blood of gouty subjects, and if, at the same time, proper measures were adopted for promoting excretion of the quadriurate by the kidneys, the elimination of that body might be secured without the occurrence of any precipitation of the biurate in the tissues. Moreover, it must be borne in mind that these experiments were conducted under very stringent conditions, in that they were all carried out with a 172 A UTHOR 's In ves tig a tions. saturated solution of tlie quadriurate, and it is extremely unlikely that the fluids of the body are ever, in gouty subjects, saturated with so soluble a compound as the sodium quadriurate ; therefore, it is but fair to infer that, with smaller proportions of the quadriurate in solution, the inhibitory efifects of the mineral constituents of vegetables woidd extend over much longer periods than actually occurred in the carrying out of these experiments. RESULTS OF THE EXPERIMENTAL INQUIRY. The net residts of all the experiments de- scribed indicate that the mineral constituents of most vegetables increase the solubility of sodium biurate, and also, in several cases, delay for con- siderable periods the conversion of the sodium quadriurate into the biurate. On the other hand, the mineral constituents of meat diminish the solubility of sodium biurate, and, as I have shown elscAvhere,^ exercise but little effect in delaying the conversion of the quadriurate into the biurate. I wish it to be clearly understood that I do not attribute the different effects of animal and vege- table diets on gouty subjects to the saline con- stituents alone. I think, however, that the results of these experiments clearly show that it is to the different mineral constituents of animal and vege- table foods, and to the different physical effects they exercise on the quadriurate and biurate, that we must look for a partial and perhaps a main explanation of the known facts that an excessive ♦ The Laiirt, April 17th, 18'.»7, p. 1074. Results of Exp/cr/mexts. 173 diet of the one tends to produce gout and of the other tends to retard it. • A reference to some of the tables previous!}' o-iven will show that certain veo'etables stand out prominently with regard to the effect exercised by their mineral constituents both in retarding the conversion of the sodium quadriurate into the biurate, and in increasing the solubility of the latter. These vegetables are spinach, Brussels sprouts, French beans, winter cabbage, Savoy cabbage, turnip-tops, turnips, and celery. These are the vegetables which I consider are likely to prove most beneficial to gouty subjects. Of these, in so far as the effects produced by their mineral constituents are concerned, spinach occupies the first place, both as regards inhibiting the decom- position of the quadriurate and increasing the solubility of the biurate. Spinach has the further advantage of being extremely rich in mineral con- stituents, since it contains 16'27 percent, of mineral matter as compared w^ith 8-50, which is the average percentage of the mineral constituents of all the vegetables experimented with. It may be urged that a drawback to the employment of spinach is that it cannot be obtained fresh throuo-hout the year. Very excellent spinach is, however, now obtainable in the desiccated and compressed state, and when cooked naakes a dish which is practically indistinguishable from the fresh vegetable. Owing to the undoubted action which I have shown the mineral constituents of several ves'e- CT tables possess in delaying the conversion of sodium 1/4 A UTHOR 's Inves tig a tions. quadriurate into biurate, and in increasing the solubility of the latter, it is possible that a table salt composed of vegetable ashes might prove advantageous to the gouty. Sir W. Koberts has sho^vn that small quantities of sodium chloride introduced into blood serum containing quadri- urate in solution always appreciably hastened the formation and precipitation of the biurate. In addition, sodium chloride very considerably dimin- ishes the solubility of sodium biurate, while the mineral constituents of vegetables increase it. This is well shown in Table XLIIL, representing the comparative effects of Ol per cent, solutions, respect- ively, of sodium chloride and of the mineral constitu- ents of vegetables on the solubility of sodium biurate. TABLE XLIII. Shoiving the comparative effects of 0\ per cent, solutions respectively of sodium chloride and of the mineral constituents of various vegetables on the solubility of sodium biurate. Solvent. Sodium disso' biurate ved. Water 1-10 per 1,000 Water containin<5 :- — 01 per cent . of sodium chloride 0-4o )) spinach ash . . . 1-90 )i Brussels sprouts ash 1-62 >» Savoy cabbage )5 1-57 )) French beans ,, 1-56 >» lettuce ?5 1-53 >» potato ,, 1-47 >» beetroot J) 1-45 »» carrot „ 1-45 j> asparagus ,, 1-45 » celery- ■)■> 1-44 >> turnip >> 1-42 >» turnip tops J) 1-42 )) cauliflower )? ... 1-34 >» cabbage ,, 1-31 »> senkale ,) 1-23 >) »' green peas n 110 V 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 01 per cent, of the mineral constituents of vegetables into the fluids of the body. 176 CHAPTER XIII. Reasons for believing the treatment of gout hij alkalies to he erroneous — Experimental investiyation of the value of the treatmetit of gout hg the various alkalies, bg j^ip^raziiie, and bg lysidine — Reasons for believing the treatment of gout bg salicylates to be erroneous — Experimental investigation of the value of the treatment of gout by salicylates — General conclusions. For a considerable period of tiaie two methods of treatment Avhicli 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 salicjdates. 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 physical behaviour of these substances is entirely different from that of uric acid. As I have for some time believed that both these methods ol treatment are wrong in principle and action I thought it expedient to submit the matter to experimental investigation. Experiments with Alkalies. 177 lleasoxs for uelieving the treatment of gout by alkalies 'jy) re erroneous. The plea for 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 William 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 1/8 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 COXD'JCTING THE EXPERIMENTS WFTH SODIUM QUADRIURATE. These experiments were undertaken in order to ascertain w^hether 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 COXDUCTIXG THE EXPERIMENTS WITH SODIUM QUADRIURATE. Ten milligrammes of sodium quadriurate were well rubbed with ten drops of a 01 per cent, solu- tion of the druo- 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 'ui^ffnencc exerted on the decoivposition of sodium quadrl- iirate by artificial blood serum alone, and by artificial blood serum coutaininj O'l per cent, of various drugs in solution. Sodimn bi urate cr.vs- iSdlveiit. tals appeared after the lapse of — Artificial blood serum ... ... 2 hours J> 55 containing 01 per cent, of potassium bicarbonate >» 5> 5) containing O'l per cent, of potassium citrate 55 55 J» containing 01 percent, of lithium carbonate ... M !5 n containing 0*1 per cent, of lithium citrate ij J5 iy containing O'l per cent, of sodium bicarbonate . . . >> J5 ?' containing 0- 1 per cent, of sodium phosphate .. M ?5 ?> containing 0"1 per cent, of pipcrazine 5) ,, containing O'l percent, of lysidine 11 These results show that none of the drugs men- tioned in the table exercise the slightest effect in delaying the conversion of the quadriurate into the l)iurate, 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 saUs 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 solubility of * In order to have 0-1 jDer 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. ExPERfMEXTS WITH A LK A LIES. l8[ the bi urate deposited in the joints and tissues, Sir William Roberts'^ has shown that sodium bi- carbonate and sodium phosphate diminish the sohibiHty 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 recur with full severity when the urine has been for a lono^ 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 i\.lfred 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 foitnd that the cartilage immersed in the lithium solution was restored to its natural condition ; that in the potassium solution was much acted upon, wdiile that in the sodium solution appeared to be un- altered. These results are somewhat in opposition to those of Sir AVilliam 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 Lecture?, 1892. 1 82 Author'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 sokibiHty 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 Ijsidine. Much greater proportions of the drugs were em- ployed than could possibly be introduced into the blood by medicinal administratioix The results are shown in the following tables :- — TABLE XLY. Showing the soluhUity at 100° F. of sodium biurate in artifcial blood serum alone, and in artifcial blood serum containing different proportions of potassium bicarbonate. Solvent. Sodium biurate I ULssolved. Artificial Mood serum ■ 0-11 per 1,000 Artificial blood serum containing 001 per | cent, of potassium bicarbonate ... ... 010 ,, Artificial blood serum containing 010 per cent, of potassium bicaiboiiito ... ... 010 ,, Artificial blood serum containing 0"20 per cent, of potassium bicarbonate ... ... 0*11 „ These results show that potassium bicarbonate Experiments with Alkalies. 183 would not in tlie slightest degree increase the solvent j)ower of the blood for gouty deposits. TABLE XLYI. Shoicing the soJiihility at 100° F. of sodluin biurate in artificial blood serum alone, and in artificial blood serum containing different proportions of potassium citrate. Solvent. Artificial blood serum Artificial blood serum containing- O'Ol per cent, of potassium citrate .. Artificial blood serum containing O'lO per cent, of potassium citrate.. Artificial blood serum containing 0"20 per cent, of potassium citrate... Sodium biurate dissolved. 0-11 per 1,0C0 0-10 „ 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 XLYII. Showing the solubility at 100° F. of sodium liura^e in artificial blood serum alone, and in artificial blood serum containing different proportions of lithium carbonate. Solvent. Artificial blood sei'um Artificial blood serum containing 0-005 per cent, of lithium carbonate Ai'tificial blood serum containing O'Ol per cent, of lithium carbonate Artificial blood serum' containing O'lO per cent, of lithium carbonate Sodium l)i urate dissolved. 0-11 per 1,000 0-11 0-11 0-15 These results show that lithium carbonate would not in the slio-htest deo'ree increase the solvent power of the blood for gouty deposits, even when present in far larger proportions than could be 1 84 A UTHOR 'S Ix I ^ES TIG A TIOXS. 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 XLVIII. Showing the solubility at 100^ F. of sodium biurate in artificial blood serum alone, and in artificial blood scrum 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 l)er cent, of lithium citrate ... Oil „ 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 serum containing different proportions of sodium bicarbonate. Solvent. Artificial blood serum Artificial blood serum containing O'Cl per cent, of sodium bicarbonate Artificial blood serum containing 010 per cent of sodium bicarbonate Artificial blood serum containing ()-20 per cent, of sodium T)icarbonato Sodium biurate di.s.solved. Oil per 1,000 0-10 003 OOS Experiments with Piperazixe. i8i These results show that sodium bicarbonate would sKghtly decrease the solvent power of the blood for gouty deposits. TABLE L. iShoiCing the solubility at 100' F. of sodium hinratc in artificial blood sennn alone, and in artificial blood serum containing different proportions of sodium phosphate. .S-lveut. Artificial blood serum Artificial blood serum containing O'Ol per cent, of sodium phosphate x\rtiticial blood serum containing 0-10 per cent, of sodium phosphate Artificial blood serum containing 0-20 per cent, of sodium phosphate Sodimii biiirate dissolved. O-Il per 1,000 0-11 0-11 Oil 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 biurate in artificial blood serum alone, and in artificial blood serum containing different proportions of piperazine . Solvent. Artificial blood serum Artificial blood serum containing 0-01 pe cent, of piperazine... Artificial blood serum containing O'lO per cent, of piperazine... Artificial blood serum containing 0"20 per cent, of i^iperazine... Sodium biurate dissolved. 0-11 per 1,000 0-09 „ . o-u 0-13 These results show that piperazine would not i86 Author's Investigations. in the 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. Showing the solnhiUty at 100° F. of sodium binrate in artificial blood serum alone, and in artificial blood serum contai)iing different proportions of hjsidine. Solvent. Artificial blood serum Artificial hlood serum containing O'Ol per cent, of lysidine Artificial blood serum containing 10 per cent, of lysidine ... Artificial blood serum containing 0-20 per cent, of lysidine ... S / ^ v / v^ y B / X / ■* * , '" " "' '^ 1 I \ \ ^ \ \ "" i / — \ \ \ At fUt, '^aii ^ p^ Ur tne \ / ^^^ ^^^ ^^* ^^^ 1 1 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 the 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 1.9th to 28th, the urine remained alkaline, there was no corresponding rise in the alkalinitj^ oi 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- linity of the blood and the acidity of the urine. REA.SOXS FOR BELIEVIXG 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 before, during, and after treatment with sodium salicylate. The diet was of the same nature throughout the experiment. N 194 A uthor's In I 'es tig a tions. TABLE LIV. Showing the daily excretion on successive days of uric acid by a healthy man before, during, and after treatment tvith sodium salicylate. Daily excretinii of uric acid in gianunes. ( 0-547 Before taking salicylate J 0-589 ( 0-731 Average 0-622 , 0-852 Fifteen grains of sodium salicylate taken \ 0942 three times a day.. ... i 0-826 I 0-784 Average ... 0851 Salicylate left off Average f 0-340 0-581 0-543 0-677 ^ 0-686 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 sliofhtest increased solvent effect on the biurate. Salicylates and Gout. 195 TABLE LV. Showing the soluhility at 100^ F. of sodium biurate in artijicial blood serum alone, and in artijicial blood serum containiny diffi rent proportions of sodium salirylate. Solvent ' Sodium biurate dissolved. Artificial blood serum 0-11 per 1,000 Artificial blood serum containing O'OOS per cent, of sodium salicylate... ... ... 0-11 „ Artificial blood serum containing 006 per cent, of sodium salicylate... ... ... i 0-11 ,, Artificial blood serum containing Q-Ol per i cent, of sodium salicylate... ... ... j 0-11 „ Artificial blood serum containing O'lO jjer ! cent, of sodium salicylate... ... ... O'll These results show that sodium saHcylate avouIcI not in the sUghtest degree increase the solvent power of the blood for gouty deposits, even when present in far larger pro23ortions 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 01 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 containing sodium salicylate m far larger proportions than could be introduced into the blood by medicinal * Guy's Hospital Eeports, 1895. ig6 Author's Investigations. administration has no effect whatever in delaying the conversion of sodium quadriurate into the biurate, as is shown in the following table : — TABLE LVI. ShoiCDig the xufiuence exerted on the decompontion of sodinm qual- riurate by artijicial blood (■erum, and by artijiclal blood scrum containing 0"1 per cent, of sodium salicylate in solution. Solvent. Sodium biurate cryslals api>eared after the lapse of — Artifioial blood serum Artificial blood serura containing 0"1 per cent, of sodium salicylate ... 2 hours 2 hours It therefore appears from the results of the experiments given in Tables LY. and LYI. that sodium salicylate 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 power 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 Avith 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 eliminatino: 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 afiected by a diminished alkalinity of the blood produced by the addition of organic acids. 3. The deposition of sodium bi urate 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- i 198 Author's Investigations. ished by the presence of the mineral constituents of meat. 8. The mineral constituents of certain 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 alkahes, 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. xso 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 inhich the treatment of gout is based — Examination of the urine — IVeatment oj acute gout — Diet in acute gout — The action of colchicum — T'reatment of subacute and chronic gout — Means of checking the excessive formation of uric acid — Means of p7'omoiing 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 place 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 frequentl}^ 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 Treatmrxt of Gout. I of the subacute or chronic condition and the pre- ( vention of the recuiTence of an attack, which may \ be effected by the promotion of the elimination of I uric acid, by checking any excessive formation of I uric acid that occurs in some subjects, and by care- / ful attention to diet and general hygiene : and (3) I the treatment of the affected joint or joints, with 1 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 amount 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. 20I It is desirable before commencing treatment, and from time to time during treatment, to know the amount of uric acid that is being daily ehmin- ated in proportion to the body- weight of the patient. This determination of the amount of uric acid ehminated 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 Gowland- 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. Siniilarly the determination of the percentage of urea in a sample of the urine is no g^iide to the amount of nitrogenous elimination that is taking place from the kidneys. To ascertain that factor the total output of urea for the twenty-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 : — Sodaa carb. Linim, belladoniife Tinct. opii Aq. ad - 5J- 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- chicum 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 colchicum 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 P URGA TI VES. 203 of acting^ as a diuretic and of diminishinf' the acidity of the urine, may, if desired, be given as an effervescing 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 diminishing 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 h3^oscyamus and a grain and a half of the compound extract of colocynth will, in many eases, 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 anodj^ne. 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 aftected 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 Action of Colchicum. 205 of salutaris water, or of some mineral water free from sodium salts (for list of such waters, nee, p. 280), should be encouraged. The milk diet should bo continued until 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 liberal 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 believe that its beneficial effect is mainly due to its d i minishing th e uric acidpro;^ ductiq n^ 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. efficacy 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 LYIL) shows the diuiinished 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 Colchicum. 207 TABLE LVII. Shotcing the decreased elimination of uric acid in a case of sub-acute gout during the administration of colchicum. Urir acid in graiinnes. Daily elimination at the commencement of the attack 0-438 Average of the daily eliminat'ons for fourteen days "while under treatment with colchicum. (Vin. colchici iiixxx were given as the fh'st dose, and then -»!_ xv three times a day through- | out the fourteen days of treatment.) ... ... ' 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 gouty 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 bkie pill and euonymin, followed by a purge of Epsom salts, will be iound 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, mix vomica or strychnine may be given with potassium citrate. Iron preparations are not as a rule well tolerated by the gouty, but if ancemia is present the citrate of iron and ammonium or the carbonate of iron Avill be found the best to administer. Means of promoting the elhnination of uric acid. — The elimination of uric acid may be eftected 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 ma}^ 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 cartilaofes and fibrous structures, and a chranic inflammatory thickening of the fibrous o 2IO The Treatment of Gout. tissues. For the 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 combined 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 {see 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 of Jo/xts. 2 1 1 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 TllEATMEXT 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 strono- solution of common salt will be found serviceable. The application of the so-called solvents of uric acid externally to affect 3d joints is useless, as they are not solvents of sodium biurate. Careful massage and gentle exercise of the stiftened 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 stiflhess 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 suffering 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 withovit the gouty joints having to bear the weight of the body. CHAPTER XV. Treatment of retrocedent or itietastatic gout — Treatment of tlie various forms of irregular gout — Treatramd of gouty glycosuria and diabetes — Preventive treat- ment of gout — Diet in gout — Alcohol in gout. THE TREATMENT OF RETROCEDENT OR METASTATIC GOUT. Immediate treatment. — If tlie 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 leet in a hot mustard-and-water bath, containing a full tablespoonful of flour of mustard to a gallon of water. Treatment 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. Treatment of the ca/rdiac form. — Heart tonics, such as digitalis, convaUaria, 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 prtecordial region. For the treatment of 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. Treahneiit 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 VARIOUS 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. GoiUy 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 (jovdy 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 convallaria and strychnine will be suitable. If anginal attacks occur, 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 m 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 2i6 The Treatment of Gout. of atheroma of the vessels. For the immediate rehef of the actual attacks nitrogl3'cerine 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 nitroglj^cerine 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 nitroglj'cerine, 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 ibllowed 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 jy] debit is. — 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 axd 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 irregular 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 course 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 subacet. ... ... 5i] Tinct. opii ... ... ... 5iv Aq. rosaj ad ... ... ... ^viij 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 paraffin 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 alkalinity 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 teiwper. — 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 glycosuria. The best test of the suitability of the diet is the fact that the weight of the patient is not diminish- ing, Avhile, at the same time, the excretion of sugar is becoming less. The patient should, therefore, be weighed once a w^eek, and the whole of the urine for twenty-four hours should be collected once a w^eek, 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 tAvo 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 dikite 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 o^ettinQf 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 effected by (1) 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 Tkeatmest. 221 have for their aim the carry mg 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 pill containing two grains of blue pill and two gi'ains 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 utihty 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 The Treatment 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 the gouty is erroneous, since the production of uric acid depends on the ingestion 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 effect 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 may 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 Diet in Gout. 223 disagree and agree with him. If, 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 Avays, 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 msal. 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 calf's 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 should 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. Anj^ of the other ordinary vegetables may be taken, but those that I consider most likely to prove 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 liability 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. Nigld. — 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 Gout. 225 moderate quantities of alcohol should certainly be 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 w^ine is taken by the gouty, those which are least open to objection are light but sound clarets and hocks. Old wines w^ith 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 power- 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 XYI. Tlie uses of mineral waters in tlie treatment of gout — The mineral waters best suited for the removal of gouty deposits — Classification of the mineral waters used. ill the treatment of gout — The simple waters — Simple alkaline water's — Alkaline sulphated waters — Alka- line muriated waters — Commori salt or muriated waters — Sulphur waters — Hot and cold mineral waters — Classification of mineral ivaters 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 treatment 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 Uses 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 natural 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 ordinar}^ 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 b}^ the patient to treatment, the careful dieting that is frequently observed, the change of surroundincrs, 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, Contrexeville, 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 Avaters containing sodium salts can be put for the treatment of many gouty affections of the viscera and other structures, but I wish 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 IV. i teas. 229 sodium salts. On the other hand, m cases of shiggish action of the hver, 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 Avith 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 irom sodium salts, whilst, on the other hand, the advocates of another mineral water Avill 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. CLASSIFICATIOX 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 connnon salt or muriated waters. G. 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. Shorring the proportioyif of sodium talts, represented as grains of sod'cnn per [laJlon, in the principal simple waters. Mineral water. Grains of sodium per gallon. Teplitz Strathpoffcr . . . 0'20 0-15 Contrexcvillo 0-79 Aix-les-Bains 1-34 Buxton 1-47 Pf acf ors 1 61 Gastein 5-89 Wildb.'id ... 7-63 Bath 9-42 Vittel 12-39 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. Contrexeville (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 becrinninor 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 sweUing 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 b}' 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 Ma}" 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 Batli is mild, and it is therefore a good Avinter resort. Vittel (France). The waters are cold. Altitude 1,100 feet. The season is from May to September. SIMl'LE 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 Yichy, Vals, Xeuenahr, 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 Yichy waters, but those springs containmg 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 10-i° 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 Avith the Yichy 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 SULPHATED 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 (OS"" to 162° R). Altitude 1,1 GO 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- Alkalixe Sulpha ted Waters. 235 merit of gouty glycosuria. The Avatcrs 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 Avaters are useful for the same class of cases as mentioned in connection with the Carlsbad waters. The season is from the middle of June to the middle of September. Brides-les-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 w^ith gout. 2^6 The Treatmext of Gout. Leamington (England, Warwickshire). The waters are cold. Baths are provided. The waters are useful in the treatment of torpid conditions of the hver and of the gastro-intestinal tract asso- ciated with gout, and also in the treatment of gouty glycosuria, ALKALINE MUPJATED WATERS. These waters contain sodium bicarbonate and sodium chloride. They are useful in the treatment of gouty dyspepsia and of gouty catarrhal affections ot" the respiratory organs. The principal waters of this class are those of Ems, Royat, 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 fi'om 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. MURIA TED I Va TERS. 23/ La Bourboule (France). The water is hot (130^ F.). Altitude 2,780 feet. Baths are provided. The waters arc arsenical as well as alkaline inuriated, and may be useful in certain cases of chronic gouty skin disorders. The season is from the beginning of Jime 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. Hornburg (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 d3^spepsia 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 150^ 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 (Basraria). 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^ F.). Altitude about 650 feet. Baths, douches, and electric baths arc 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 iound at Llandrindod. The muriated waters are useful in the treatment of 5 ULPHUR Wa TE A'S. 239 gouty gastro-intestinal catarrh and congestion of the liver, 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 usefid in the treatment of stiff- ness and thickening of the joints in cases of chronic articular gout, 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, Kadnorshire), 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), Allevard (France), Saint-Honore (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 : — TAIiLE LIX. Classification of the various mineral ivaters used in the treatment of gout into hot and cold waters. Hot. Cold. Aix-les-Bains Cheltenham Aix-la-Chapelle Baden Contrexeville Harrogate Baden-Baden Homburg Bith Brides-les-Bains Kiss in gen Leamington Buxton Llandrindod Carlsbad IMarienbad Kins Salzbrimn (iastein La l>oxnboule Strathpelier Tarasp-Schuls Nauheim Yals Xeucnahr Kagatz-Pfaefers Yichv (some spi-ings) Vittel Koyat Teplitz ' Vichy (some spiings) Wiesbaden Wildli.ul Uses of Mineral Waters. 241 THERAPEUTIC USES OF THE VARIOUS MINERAL WATERS FOR THE DIFFERENT FORMS OF OOUT. 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. Classijicatioii of the various mineral waters according to their therapeutic value in the trea>nent of the various forms of gout. Object of taking the water. The waters best suited for the purpose. Absorption of gouty Aix-les-Bains, Bath, Buxtou, Contrexeville, deposits from the Gastein, Pfaefers, Strathpeffer, Teplitz, joints and tissues. Vittel, Wildbad. Treatment of gouty Brides-les-Bains, Carlsbad, Ems, Homburg, dyspepsia. Kissingeu, Xeuenahr, Koyat, Yals, Vichy, Wiesbaden. Treatment of gouty congestion and torpor of the liver, and of gastro-in- testinal catarrh and torpor. Treatment of gouty affections of the re- spiratory organs. Baden-Baden, Boiu-bonne, Carlsbad. Chel- tenham, Contrexeville, Harrogate, Hom- burg, Kissingen, Leamington, Llan- drindod, Marienbad, Xeuenahr, Tarasp- Schuls, Vals, Vichy, Vittel, Wiesbaden. Ems, Royat. Treatment of gouty glycosuria and diabetes. Treatment of gouty skin affections. Carlsbad, Contrexeville, Kissingen, Lea- mington, Llandriudod, Marienbad Xeuenahr, Yals, Vichy, Vittel. Sulphur waters and baths [see pp. 239, 240j. Q t. <) Lc/yv*>Tv_-A.^-'V-«v INDEX. Abarticular £,'oiit, 114-124 Acidity and gout, 190-193 Acne, Gouty, 123 Acute gout, 107-110 , Clinical features of, 107-110 , Diet in, 204, 205 , Symptoms of, IDS, 109 , Treatment of, 201-205 etiology of gout, 105-107 Age and gout, 105 Aix-la-Chapelle waters, 240 Aix-les-Bains waters, 231, 240, 241 Albuminuria, Treatment of, 210, 211 Alcohol and gout, 145-149, 224, 225 Alkalies and gouty deposits, 180-190 , Treatment of gout by, 17G-192 Alkaline niuriated waters, 236, 237 sulpliated waters, 234-230 waters, 233, 234 Alkalinitv of blood of gout, 129-131, 189 Allevard waters, 240 Alloxur bases and gout, 9, 10 Amido bodies and uric aci'l, (58, 69 Amorphous quadriurates, 7 urate deposit, 84-86 Ana'mia, Uric acid in blood of, 48 Angina ]iectoris, Treatment of, 215, 216 Anginal attacks. Treatment of, 214 Animal diet and uric acid, 65, 66 Asparagus ash, Effect of, 152 Assinannshausen waters, 236 Asthma, Gouty, US , Treatment of, 236 Aussee baths, 239 Baden-Baden waters, 238, 241 Baden waters, 240 Bagneres-de-Luchon waters, 240 Bath waters, 232, 241 Baths, Thermal, 211 Beers, Aeidity of, 146 Beers and gout, 145-149 , Gout-inducing power of, 140, 148, 140 Beetroot ash, Effect of, 154 Birds, Urinary excrement of, S3, 84 Biurate, Causes of deposition of, 92- 100 , Gelatinous form of, 88 , yolubility in serum of, 92 Biurates, Composition of, 2 Bladder, Irritability of, 121 Blood, Detection of uric acid in, 31-34 disorders and uric acid, 48 , Estimation (if uiic acid in, 31-34 , Introduction of uric acid into, 25, 82 of birds, Examination of, 44, 45 of gout, Alkalinity of, 129-131, 139 of mammals, Examination of, 44 of man. Examination of, 43, 44 of reptiles. Examination of, 45 , Uric acid compnund in, 2 , Uric acid not normal constituent of, 43-47 Boils and gout, 123 Bourbonne-les-Bains, 239 Bridesdes-Bains waters, 235, 241 Brine baths, 239 Bronchitis, Gouty, 117, 118 , Treatment of, 236 Brussels sprouts ash. Effect of, 152 Buxton waters, 232, 241 c Cabbage ash. Effect of, 154 Calculi, Treatment of renal, 218 , Uric acid, 121 Carbuncles, Gouty, 123 Cardiac irritability, IIS Carlsbad waters, 234, 235, 241 Carrot ash, Effect of, 155 Cartilage, Uratic deposition in, 90, 91 Cauliflower ash, Effect of, 156 Causation of gout, 5-24 Celery ash, Effect of, 154 Cheltenham waters, 235, 241 Chronic deforming gout. 111 Chronic gout, 110-113 '; Treatment of, 20S-212 , Urine of, 112 Colchicum, Action of, 205-208 and uric acid excretion, 206, 207 in gnut, 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 Contrexeville waters, 231, 241 Cycling and gout, 212 244 Gout. D Deafness, Gouty, 124 Detection of uric acid in blood, 31-34 Diabetes, Gouty, 123 , Mineral waters for, 241 , Treatment of, 219, 220 Diagnosis of gdut, 126, 127 Diet and uric acid exeretiou, 65-li7 formation, 65, 66 in acute gout, 204, 205 in gout, 204, 205, 222-225 Distinction of gout from rheumatism, 126 rlieumatoid arthritis, 126, 127 Droitwich batlis, 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, 10, 17 Eczema, Goutv, 122 , Treatment of, 218, 239 Ems waters, 23(1, 241 Epilepsy and gout, 120 Estimation of uric aciil in blood, 31-34 urine, 29-31 Exciting causes of gout, 106 Exercise and gout, 212 Fibroid tissue degeneration and gont, 19 Flesh diet and uric acid, 65, 66 Flying gout, 124 French beans ash, Effect of, 153 G Gastein waters, 232, 241 Gastrointestinal catarrh. Gouty, 117 , Mineral waters for, 241 , 'I'reatment of, 233, 234, 237, 239, 241 torpor. Mineral waters for, 241 Glyoocine and nric acid fonuation, 68-71 Glycosuria, Gouty, 123 , Mineral waters for, 241 , Treatinent of, 219, 220, 233, 234 Gout, Abarlicular, 114-124 , Acule, 107-110 , ylCtiology of, 105-107 , Alkalinity of blood of, 129-131, 139 and alcohol, 14.'5-149 and deficient excretion of uric acid, 26-28 and kidney affections, 52-03 anil nervous system, 21-23 and nitrogenous diet, 140, 141 Gout and iheumatism, Distinction of, 126 and rhetunatoid 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, 110-133 , Chronic deforming, 111 , Clinical features of, 107-125 , Conclusions as to jiathology of, 103, 104 , Definition of, 1 , Diagnosis of, 126, 127 , Diet in, 204, 205, 222-225 , Diet in acute. 204, 205 , Disfinction 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 , • — -, Causation of, 6, 7 , Metastatic, 124, 125 , Pathology of, 1-104 , Predisposing causes of, 105-107 , Preventive treatment of, 220, 221 , Primary cause of 53 , Prognosis of, 127 , Renal oiigin of, 60-63 , Retrocedent, 124, 125 , Suppressed, 114 , Symj'toms of acute, 108, 109 — . chronic, 110-113 , Tophaceous, 111 , Toxic agents causing, 59, 60 , Treatment of, 199-241 , acute, 201-205 , 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 catarrl), 117 glycosuria, 123 — , Treatment of, 219, 220, 233, 234 heart, Treatment ff, 215 hepatic congestion, 124 herpes, 122 insomnia, 120 joints. Treatment of, 201, 202, 209-212, 2.30-233 kidney, 120, 121 , Signs of. 2'-0 and heart 112,113 Index. 245 Gouty laryngitis, 117 migraine, 119 neuralgia, 119 neui-itis, 119, 120 , Treatment of, 217 oesopliagismus, 110 orcliitis, 125 parotitis, 125 paroxysm, Cause of, 101-103 , Treatment of, 201, 202 pharyngitis, 1U'> phlebitis, 118, 119 , Treatment of, 21(5, 217 prurigo, 123 pruritus, 123 psoriasis, 123 pulmonary congestion, IIS sciatica, 119 '-, Treatment of, 217 tracheitis, 117 urticaria, 123 vertigo. Treatment of, 214 Go^vland-Hopkins' jirocess, 30, 31 Granular disease of kidneys and gout, 55-57 Gravel, Uric aciil, 121 Great toe and gout, 101 Green-peas ash, Effect of, 150 Guaiacum in gout, 20S, 221 Guruigel waters, 210 H Harrogate waters, 239, 240, 241 Heart and gouty kidney, 112, 113 irregular gout, IIS , Treatment of gouty, 215 Hepatic congestion, Goutv, 124 , Treatment of, 233, 234, 237. 239 derangements and gout, 71, 72 Hereditary factor of gout, •32 Heredity and gout, 105, 10(3 Herpes, Gouty, 122 Heustrich waters, 240 Homburg waters, 237, 241 Hot-air baths, 212 mineral waters, 240 Humoral theoiy of gout, 4 Hypoxanthin, 73 Inherited gout. Cause of, 62 Insomnia and gout, 120 , Treatment of, 204 Irregular gout, 114-124 , Causation of, 6, 7 , Treatment of, 214, 220 Irritability of bladder, 121 Irritable t^emper, Treatment of, 219 Joints, Causes of uratic deposition in, 98-101 Joints, Gouty, 98-101 , Treatment of gouty, 201, 202, 209-212, 230-233 K 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 bj-, 53 in chronic gout, 111, 112 Kissingen waters, 238, 241 Kreuznach baths, 239 La Bourboule waters, 237 LarATigitis, Goutv, 117 Lead gout, 113, 114 Lead poisoning and gout, 59, 60, 9Q>, 97 uric acid, 50 Leamington waters, 236, 241 Lettuce ash. Effect of, 153 Leucocvthfemia, Uric acid in blood ' of, 4S Leucocytosis and uric acid, 74-77 Lithium carbonate, Experiments with, 179-181, 183, 187-189 citrate, Experiments with, 179, ISO, 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 a ad uric acid formation, 71, 72 , Gout in the, 124 Llandriiidod waters, 238, 240, 241 Llangam march Wells, 239 Lysidine, Effect of, 180, 186 , Experiments with, 179, ISO, 186 M Marienbad watex's, 235, 241 Massage and gout, 211 Mental depression and gout, 120 Metastatic gout, 124, 125 , Treatment of, 213, 214 Migraine, Gouty, 119 Mineral waters, Alkaline muriated, 236, 237 . Alkaline sulphated, 234, 236 , Classification of, 229, 230, 240, 241 , Cold. 240 24^ Gout. Mineral waters for gastro-intestinal catarrh, 241 torpor, 241 gouty deposits, 241 diabetes, 241 - dyspe))sia, 241 glycosuria, 241 skin affections, 241 liver affections, 241 resiiiratory affec;tions, 241 , Hot, 240 , Muriated, 237-239 , Objects of using, 226-220 , Simple, 230-233 , Simple alkaline, 233, 234 , Sulphur, 239, 240 , Tlierapeutic uses of, 220- 229 , Uses of, 226-229, 241 Murexide test, 3 Muriated 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, 05, 96 system and gout, 21-23 Neuenahr waters, 233, 241 Neuralgia, Gouty, 110 Neuritis, Gontv, 119, 120 , Treatment of, 217 Nitrogeuised diet and uric acid. Go Nitrogenous diets and gout, 140, 141 Nuclein formation of uric acid, 72-77 (Esophagismus, Gouty, 116 Orchitis, Gouty, 125 Parotitis, Gouty, 125 Paroxysm, Cause of gouty, 101-103 Pathologv of gout, 1-104 Pfaefers waters, 232, 241 Pharyngitis, Gouty, 116 Plilebifis, Gouty, 118, 119 , Treatment of, 21t), 217 Piperazine, Effect of, 180, 1S5, 186 , Experiments with, 179, 180, 185, 186 Plumbism and gout, 50, 60, m, 97 and uric acileen and uric acid formation, 40 Strathpeffer waters, 231, 240, 241 Subacute gout, Treatment of, 208, 209 Sugar aiid gout, 14S Sulpliur mineral waters, 239, 240 springs. Cold, 24 J , Hot, 240 Suppressed gout, 114 Synthesis of uric acid, 09, 70 Tarasp-Sclmls waters, 285, 241 Teplitz waters, 231, 241 Test for uric acid, 3 Thymus and uric acid excretion, 74 Toe, Gouty dejiosits in great, 101 Tophaceous gout. 111 Tophi, 110, 111 Toxic agents causing gout, 59, 00 Tracheins, Gouty, 117 Treatment of acute gout, 201-205 angina pectoris, 215, 210 clironic gout, 208-212 constipation, 203, 204, 233-239 diabetes, 219, 220, 233 dyspepsia, 233, 234, 230, 237 gastro - intestinal catarrh, 233, 234, 237, 239, 241 glycosuria, 219, 220, 233, 234 gout, 199-241 gout. Preventive, 220, 221 gouty asthma, 230 bronchitis, 236 heart, 214 ioints, 201, 202, 209-212, 230-233 neuritis, 217 phlebitis, 210, 217 sciatica. 217 vertigo, 214 hepatic congestion, 233, 234, 237, 239 irregular gout, 214-220 irritable temjier, 219 metastatic gout, 213, 214 portal congestion, 234 pseudo-angina pectoris, 216 renal calculi, 218 retrucedent gout, 213, 214 skin disorders, 218, 239 subacute gout, 20S, 209 Turnij) ash. Effect of, 155 tops ash, Effect of, 155 Urates, Neutral, 2, 17 Uratic deposit. Formation of, 86-89 Uratic deposits and renal disease, 54- 57 . Seats of, 90 Urea a normal constituent of blood, 44, 45 and uric acid ratio, 78-81 , Formation of uric acid from, 08-72 Uriage waters, 240 Uric acid absent from blood in health, 43-47 and blood disorders, 48 lead poisoning, 50 nitrogenised diet, 65 nucleiu, 72-77 proteids, 05, 60 urea ratio, 78-81 calculi, 121 , Cause of abnormal forma- tion of, 09 , Composition of, 2 compound in bluod, 2 , Daily outpi.t of, 201 — , Deficient excretion of, 20-28 ■ — -, Discovery of, 4 elimination in health, SO, 81 excretion and diet, 05-07 by kidneys, 53 in gout, 'il, 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 anfemia, 48 in urine, 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-jtroduction of, 20 , Promotion of elimination of, 209 , Renal formation of, 37, 38 , Salts of, 2 , Sources of, 34, 35 , Synthesis of, 09, 70 , Test for, 3 , Variations in elimination of, 81 Urine, Amorphous urate deposit of, 84-80 , 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, 05, 00 Vegetables and gout, 144, 150-175 248 Govt Vegetables, Calcium salts in, ] 62 , Chlorides in, 165 for the gouty, 173 , Phosphates in, 103 , Potassium salts in, 160 , Sodium salts in, 161 , Sulphates in, 104 Vertigo and gout, 120 , Treatment of gouty, 214 Vichv -n-aters, 233, 241 Vitte'l waters, 233, 241 W Waters, Alkaline, 233, 234 muriat-ed, 230, 237 sulphated, 234-236 , Classification of, 229, 230, 240, 241 Waters, Cold mineral, 240 , Hot mineral, 240 , Muriated, 237-239 , Simple, 230-233 , Sulphur, 239, 240 , Uses of mineral, 220-229, 241 Weilbach uaters, 240 Wiesbaden waters, 237, 238, 241 Wildbad waters, 232, 241 Wines, Acidity of, 140 and gout, 140-149 , Gout-inducing powers of, 146, 148, 149 suitable in gout, 225 Woodhall Spa waters, 239 Xanthin, 73 Printed Hy Cassell & Companv, Limited, La BtLLE Sai'Vaob, London, E.G.