Gout, with a section on ocular disease in the gouty

The two salient features of the gouty diathesis are:—

With the former we have dealt, but before passing to discuss the latter, it will, we think, be advisable to review both these morbid tendencies in relation to gout.

Hyper-uricæmia and uratosis, though they both occur in gout, are by no means of identical pathological valency or significance. In hyper-uricæmia the uric acid, either in a free state or combined, circulates in the blood and lymph. In uratosis the uric acid is anchored in solid form in the substance of the tissues. In the former, then, the uric acid, if it be noxious, acts as a chemical poison, in the latter as a mechanical irritant.

But the more striking contrast is that while hyper-uricæmia is not restricted to gout, but occurs in many other disorders; on the other hand, uratosis is absolutely confined to the gouty state, constituting its pathognomonic stigma.

Again, hyper-uricæmia may exist for prolonged periods without producing uratosis. But uratosis cannot, as far as is ascertained, occur without a co-existing hyper-uricæmia. From these disparities it may legitimately be inferred that the factors responsible for the genesis of hyper-uricæmia and of uratosis, are not identical; in other words, that in uratosis some other agency or agencies are at work over and beyond those that beget hyper-uricæmia.

Lastly, inasmuch as uratosis stamps the seal of specificity upon gout, it follows, from this and the above considerations, that there is a more intimate relation between gout and uratosis than between gout and hyper-uricæmia, and that the factors which make for uratosis have a more intimate bearing upon the pathogeny of gout than those which lead to hyper-uricæmia.

Constitution of Tophi

The view that tophi were composed of chalk prevailed for centuries. As we see such was the conception of Virgil, and in our own country John Hunter entertained the same erroneous notion, while amongst the laity this view as to their nature is held widely even to-day as it was in the time of Dryden.

Albeit, the term “chalk-stones” is a misnomer, as tophi, when pure, may be wholly devoid of lime. Modern analyses, too, have failed to demonstrate the presence of calcium carbonate, the essential ingredient being urate of soda.

On the authority of Rendu, we have it that Tennant and Pierson were the first to demonstrate the presence of uric acid in gouty deposits, which discovery was later confirmed by Fourcroy and Wollaston (1797), these latter observers showing that they consisted almost exclusively of urate of soda.

Subsequently to Wollaston’s day, many analyses have been conducted, by Marchand, Lehmann, Wurzer, and Langier, L’Heretier, Ebstein and Sprague. Of the various findings we append those by Marchand, Lehmann and one of later date by Ebstein and Sprague.

Marchand’s Analysis

Lehmann’s Analysis

Ebstein and Sprague’s Analysis

It will be seen that all of them agree more or less closely as to the essential ingredients being uric acid and soda. According to Ebstein and Sprague they consist usually of almost pure biurate of sodium and potassium. But, as a rule, after a time calcium salts are deposited. Dunin, it may be noted, has found deposits resembling gouty tophi, which contained only calcium salts. Kahn, again, claims that tophi do not always consist solely or even largely of urates, but that these may be replaced by calcium salts. It may be added, too, that M. B. Schmidt has recorded, under the designation of “Calcium gout,” a case in which there existed a generalised deposition of calcium, and this in tissues other than those usually involved in “metastatic calcification.” But, to sum up, although there may be admixture of lime salts and organic matter, the salient chemical constituent of tophi is biurate of sodium.

Mode of Formation

Gouty tophi, like all pathological concretions, are laid down in accordance with a definite law. In the first instance, a central nucleus is essential. To this must be added a “binding substance” or structural framework of different nature from the main mass of the concretion.

Garrod, discussing the intimate structure of “chalk-stones,” observes that, “the large amount of phosphate of lime occasionally met with is probably derived not only from the tissue in which the chalk-stones have been developed, but likewise from secondary deposition, the result of ordinary inflammation around the original nucleus (urate of soda) which acts as a foreign body.”

It is, however, quite possible that some substance other than urate of soda constitutes the primary nucleus, for, as we now know, concretions most frequently gather around masses of mucin, clumped bacteria, desquamated cells, precipitated proteins, etc. Thus, the renal uric acid infarcts, supposed to result from disruption of the nucleo-proteins of the fœtal nucleated red corpuscles, take origin around injured epithelial cells, which latter form the nucleus.

As to gouty tophi, too, it has been suggested that they form in response to any toxin, resistance to which may involve death of the tissue cells with consequent disruption of their nucleins and formation of urates. Such was the view held by Woods. Hutchinson, who also thought that the calcareous accretions might be regarded as “protective,” analogous to the formation of shells in the invertebrates, the process here consisting in the deposition of lime salts in cells already saturated with uric acid and urates.

In any case, whatever be the exact nature of the nucleus, the urate of soda collects thereupon, the acicular crystals tending to assume the form of radiating needles. But the successive depositions not being of regular incidence, the surface of the crystals, in the intervals of quiescence, becomes covered by mucin, animal or earthy matter. Hence, the concretions display not only a radiating, but a concentric or laminated structure.

The mucin acts as the “binding substance,” the crystals lying in its meshes, and, moreover, remaining as the framework of the concretion even after the crystals are dissolved out; in other words, the gouty tophus is made up of a blend of crystalloids and colloids, evolved from solutions of the same character.

The importance of recognising the true nature of this binding substance, i.e., mucin, merits a brief digression, in light of Ebstein’s view that local tissue necrosis is a necessary antecedent to uratic deposition. Now, exhaustive studies of the histology of uratic deposits, both those experimentally induced and of spontaneous gouty origin, have been conducted by Freudweiler, His, Krause, and Rosenbach.

All their results, according to Gideon Wells, “indicate that uric acid and urates excite some slight inflammatory reaction, cause a slight local necrosis, and seem to act as a weak tissue poison.” According to Rosenbach, however, this sequence is not invariable, inasmuch as he noted that such deposits may occur without inducing necrosis. More pertinently to our contention, however, is it that Krause’s experience seems to indicate that errors of interpretation were possible. Thus, he suggests that part of the material in the areas of uratic deposits merely constituted the framework of a crystalline deposit, though such were currently regarded as strands of necrotic tissue.

But, to resume, tophi being blends of crystalloids and colloids, we must recollect that the suspension capacity of colloidal solutions for crystalloids is much superior to that of simple solutions, by reason of the fact that at the surface of each colloidal particle there exists a zone in which the crystalloids are much more closely aggregated than elsewhere, thus permitting more crystalloids to be dissolved in the solvent between the colloidal particles. But, be it noted, this same tendency to concentration of the crystalloids at the surface of the colloidal elements leads to the colloids acting as determinants of precipitation when crystalloids are in excess. Accordingly, when the crystalloids pass out of solution, they form crystals or precipitates intimately blended with the colloids. Thus, for example, when uric acid crystallises out of urine it carries with it the colloidal pigments. On the other hand, if the colloids are precipitated, the solvent capacity of the solution being consequently depreciated, the crystalloids are deposited in intimate relation with the colloids.

Again, Schade has pointed out that colloids may precipitate in reversible form or not. If in irreversible (e.g., fibrin) form, the concretion will remain permanent. But if the colloidal precipitate is reversible, it may be redissolved, as happens with the uric acid infarcts of the infant’s kidney. In conclusion, we see, therefore, re crystalloids and colloids in animal juices, that the conditions of their solubility are most complex, and though they do not explain the nature of gout, the variations doubtless stand in intimate relation to the formation of tophi.

Localisation of Uratic Deposits

Uratic deposits evince a decided predilection for cartilages, tendons, muscles, and skin. This localised distribution of the depositions would seem to suggest their dependence on local tissue peculiarities. Now the presence of sodium salts in a solution diminishes the solubility of urates therein. Consequently, in seeking to explain the incidence of tophi, it was suggested that cartilage and tendons, being richer in sodium ions than the blood, this might account for the fact that urates tend to be precipitated in these particular structures.

Again, Almagia, working in Hofmeister’s laboratory, noted that thin sections of cartilage, if left for some hours in a solution of sodium urate, will take up uric acid. Direct inspection readily reveals the presence of white foci and diffuse opacities due to uratic deposits. The marked affinity of normal cartilage for uric acid is again attested by the fact that, given injection thereof in quantity into the peritoneal cavity of rabbits, the uric acid may often be detected by the murexide reaction in joint cartilage, though apparently not in other tissues.

This behaviour would appear to justify the conclusion that the observed accumulation of uric acid in the cartilages in the presence of states of uricæmia, may be explicable on this same basis. In any case, this marked affinity of even normal cartilage for uric acid seems to disprove the necessity of Ebstein’s postulate, viz., that the dissolved uric acid sets up inflammation, and that an antecedent necrosis precedes the deposition of urates. Still, even if we concede the fact that normal cartilage has a marked affinity for uric acid, how is it that in leukæmics, despite their high blood content of uric acid, no uratic deposits ensue? Does not such disparity seem to indicate that in gout some other factor intrudes? in other words, that the excess of sodium ions in particular tissues, while it may favour deposition therein, is inadequate of itself to actually determine the formation of tophi.

The Causation of Tophi

Many and divers are the theories that have been propounded to account for the genesis of tophi. For some their incidence would appear to predicate something abnormal in the conditions of uric acid solution and circulation. Others have pinned their faith to some affinity on the part of the bodily tissues for uric acid—an enhanced retention capacity on their part for this substance. Some again, impressed by the objective changes that mark the clinical evolution of tophi, have been led to regard them as concomitants or sequels of gouty inflammation. But, be the true explanation what it may, we may well preface our discussion of the various theories by the obvious comment, viz., that the origin of tophi must doubtless depend in the ultimate upon constitutional or systemic, as well as local, factors.

Solubilities of Uric Acid

In the older conceptions of the pathology of gout the hypothesis that found most vogue was that the separation of uric acid from the blood into the tissues was due to diminished alkalinity of the blood and tissue juices; but, as before pointed out, it has been established that the alkalinity of the blood is not reduced, and the theory has consequently been abandoned.

But, with the advent of Gudzent’s findings, viz., that uric acid existed in two forms—one soluble and unstable, and the other insoluble and stable, and that the former is constantly changing into the latter—another conception of the origin of tophi arose. It was supposed that, by reason of the disparity in solubility of these tautomeric types of uric acid, the blood in gouty subjects must at times be in a state of super-saturation with uric acid; and, moreover, that equilibrium could only be restored through abstraction of the urates by crystallisation.

Unfortunately for this theory, it has been shown that the blood of gouty subjects is not super-saturated therewith; indeed, over and above the highest increments hitherto met with in gouty blood, a considerable margin of solubility for uric acid is still available. In truth, the problem is by no means so simple; for the conditions governing the solvency of uric acid in the blood are bewilderingly complex, subject as they are to the manifold variations in solubility exhibited by crystalloids in the presence of the many divers colloids.

But, to resume, Minkowski, it will be recalled, noted that from a mixed solution of uric and nucleinic acids the former cannot be precipitated by either acetic acid or alkaline ammonio-silver-magnesia mixture. Accordingly he advanced the view that uric acid “primarily exists in the blood and the tissue juices in combination with nucleinic acid, and that, not only the conversion of the purin bases into uric acid, but also the solubility and transportation, as well as the further changes of the uric acid in the living body, is regulated by this linking with a nucleinic acid rest.”

But, unfortunately for the value of this hypothesis, there is no proof that nucleinic acid is actually present in the blood; for, as Fürth remarks, is this inhibition of the precipitation of uric acid, in the presence of nucleinic acid, “necessarily indicative of a true acid combination with nucleinic acid,” “but such inhibition of precipitation is rather to be referred to the general group of variations of solubility which are manifested by crystalloid substances in the presence of all sorts of colloids.”

Complex phenomena of solubility of this nature must be considered in connection with the circulating uric acid. Nucleinic acid is not the only important substance, but “the general mass of the blood proteins must be particularly thought of.”

Continuing, Fürth reminds us that uric acid is much more soluble in blood serum than in water, and forthwith envisages this disparity in light of the factors that affect solubility of uric acid in the urine. The latter is markedly influenced by the presence of urea and di-sodium phosphate, and the relation of this to mono-sodium phosphate. Nor, he reflects, is there any doubt “of the importance of such inter-relations, too, in the formation of uric acid deposits in the tissues.” But he adds, “Although the importance of these complex conditions of solubility as they prevail among colloid and crystalloid substances in the animal juices may be accepted in relation to the formation of uric acid concretions, there is no real reason for seeking the explanation of gout in this sphere.”

Tophi in Relation To Uricæmia

It might be thought that some relationship might be established between uratic deposits and the degrees of uricæmia, but the data to hand give no countenance to the assumption. Thus, His has recorded the case of a gouty subject with multiple tophi whose blood did not yield an excess of uric acid. Pratt, again, could trace no relation between the amount of uric acid in the blood and the severity or character of the disease. Two of his patients had numerous and widely distributed large deposits of sodium urate beneath the skin, yet the blood content of uric acid in both was less than the average amount found in gout. Thus, on a purin-free diet, one had 2·4, the other 2·2 mg. These findings, he considers, show that the presence of multiple tophi is no indication that a state of hyper-uricæmia exists.

Walker Hall, discussing this same question, holds that there is but little evidence “as to the relation of uricæmia to the formation of tophi.” He asks the question whether the deposition is the outcome of abnormal purin combination in the blood and lymph stream? which latter at present, he states, are regarded as passive carriers of the urates. For, he says, the small purin increase in gouty blood cannot surely make all the difference, seeing the large volume of solubility still available. The physico-chemical hypothesis, he claims, is inadequate to explain the relationship between uricæmia and the tophi, and hazards the suggestion that after all it may be that “the uricæmia plays little or no part in the depositions, and that these are due to the defective removal of substances resultant from local nuclear activities.” He asks, moreover, whether such substances differ in type from those of normal nuclein metabolism and so fail to be suspended in the surrounding lymph in such a way as to ensure their entrance into the blood-stream? Like others, he notes that atophan brings about a removal of some of the deposited urates. But such diminution of the tophi may, of course, he says, be due to increased flow of serum to the inflamed part; though, on the other hand, the more massive deposits “are surrounded by layers of young granulation tissue and phagocytes and peritophal fibrous tissue, and these in turn offer some hindrance to the permeation of serum or drugs.”

In reviewing the foregoing views as to the formation of tophi, it is obvious we stand in urgent need of more knowledge. Neither the chemical nor the physical theory or a combination of the twain seems adequate. This for the salient reason that, as far as the existing evidence permits us to draw conclusions, it would seem probable that not only local but constitutional or systemic conditions play an important rôle in tophi formation.

But as far as our discussion has advanced, we may, we think, be justified in the following deductions:—

It will be seen from these conclusions that the proximate cause responsible for the genesis of tophi is yet to seek, and in pursuance of our quest we turn to another aspect of this complex subject.

Tissue Affinities for Uric Acid

Injecting uric acid intravenously into gouty subjects, Umber noted that at times the whole was retained, but on some occasions was excreted in fractional portions. On the other hand, a normal individual under similar circumstances eliminates it completely. In explanation thereof, he proffered the opinion that this failure on the part of gouty persons to excrete exogenous uric acid was due to a special affinity of their tissues for uric acid.

As to intravenous injection of uric acid, however, modern investigation has established that, both in normal as well as gouty subjects, its excretion is spread over several days, and the whole is not recoverable from the urine. Now this incomplete excretion or retention of uric acid was attributed to defective elimination by the renal cells; but, as shown in a previous chapter, this conception fails of demonstration. Nor, for that matter is there any proof either that the retention is due to fixation of the uric acid in the blood serum. Accordingly, to our minds, it is permissible then to canvass the further possibility adumbrated by Umber, viz., that an increased affinity of the tissues for uric acid may haply account for the diminished purin excretion, the excess of uric acid in the blood, lymph, and tissues, and that these same may lead to uratic deposition.

This last hypothesis derives colour from the findings of Schmoll, Magnus Levy, Vogt, Reach and Bloch, who noted that, after giving thymus to gouty persons, they found far less uric acid in the urine than in the case of normal subjects. Also, that the ingestion of thymus by the victims of chronic gout repeatedly resulted in acute outbursts of the disease. Moreover, as we saw when discussing the sources of uric acid, there are cogent reasons for avoiding a too restricted conception which would make the leucocytes, the muscles, or the digestive glands alone responsible for the endogenous production of uric acid; in other words, that a more catholic attitude on our part is indicated, one which would envisage it as the outcome of continuous and general cellular wear and tear. That an increased cellular destruction, as induced experimentally, e.g., by exposure to Röntgen rays, is capable of raising the blood content of uric acid in a gouty subject, and of precipitating a gouty paroxysm, may be inferred from the researches of P. Linsen.

Retention Capacity of Tissues for Uric Acid

It may be recalled that Wiechowski and others observed that in man, of parenterally introduced uric acid, 80-90 per cent. reappears in the urine. Accordingly, Schittenhelm and Wiener argued that, if uric acid is indestructible in the human body, then, given retarded elimination, the tissues should contain considerable quantities thereof. Subsequently, in 1914, they sought to investigate human tissues as to their content of uric acid. Their studies were conducted on three examples, a case of anuria, one of pernicious anæmia, and one of gout.

The case of anuria occurred in a male, aged sixty-two, in sequence to thrombosis of both renal veins following operation. Two-hundred gram samples of the following tissues, lung, heart, spleen and liver, were examined for uric acid with wholly negative results. The residue of the organ was worked up together, but only 0·01 gram of uric acid was isolated.

In the case of pernicious anæmia no uric acid was demonstrable. The gouty subject had for twenty-five years suffered from typical attacks and exhibited many auricular tophi. The following organs, in their entirety, were analysed, the liver (1,550 gram), no uric acid; spleen (290 gm.), 10 mg. uric acid (3·5 mg. per 100 gm.); kidney (270 gm.), no uric acid; lung (930 gm.), 15 mg. uric acid (1·6 mg. per 100 gm.); muscle (440 gram), no uric acid; and intestine (420 gram), no uric acid.

It will be seen that uric acid was either absent or present in minimal amounts, and these results Schittenhelm and Wiener interpreted as confirming their long advocated contention as to the destructibility of uric acid in the human organism.

Morris S. Fine, from the results of similar investigations, considered the failure of these observers to isolate uric acid in these cases of anuria and gout as most remarkable. He considers “their results may in part be ascribed to the use of hot sodium hydroxide previous to the precipitation of the proteins in the extraction of the tissues, as the instability of uric acid in alkaline solutions is a well-known property.”

In this criticism Fine would appear to be fully justified, in view of the marked contrast between the findings of Schittenhelm and Wiener, and his own data is recorded in the tables on p. 159.

While it is unfortunate that Fine’s theory contained no instances of gout, his findings are a definite proof that, to quote his own words, uric acid can be demonstrated in considerable concentrations in human tissues. Incidentally, also, his tissue analyses are flatly contradictory to Schittenhelm and Weiner’s persistent contention, viz., that the human organism can decompose uric acid.

Gideon Wells states that in normal individuals the tissues contain but little uric acid, and this not in quantities sufficient to permit readily of its isolation in a pure state. Albeit, Wells found considerable amounts of uric acid in the tissues of a young woman who, in sequence to poisoning with HgCl₂, died after complete suppression of urine for nine days.

Table I.—Concentration of Uric Acid in Human Tissues and Fluids per 100 Grams of Material

Table II.—Concentration of Uric Acid in Miscellaneous Human Tissues per 100 Grams of Material

Again, as before alluded to, Bass and Herzberg found that intravenous injection of uric acid caused less uricæmia in the gouty, despite diminished renal excretion. Hence, they concluded that in gout the retention capacity of the tissues for uric acid is augmented.

Fürth, an ardent advocate of Umber’s hypothesis, emphasises the fact that Wiechowski was never able to detect any evidence of uricolysis in the human body. Continuing, he observes, if we reject all idea of uric acid retention in the tissues, “It would be a particularly difficult thing to understand why gouty patients do not simply expel by a compensatory hyper-excretion the uric acid which is accumulated from a supposed failure of uricolysis; precisely as in leukæmia the patient compensates simply by an exaggerated excretion of the excessive uric acid which is mobilised in the body from the excessive purin decomposition.” His conclusion, therefore, is that, “In the gouty individual there must exist some cause which makes a compensatory uric acid excretion impossible; and that is plainly a retention affinity of the tissues, because of which the uric acid is actually held in the tissues.”

In light of Fine’s revelations the retention capacity of the bodily tissue for uric acid may, we take it, be considered as fairly well established. But, in view of the precipitation or anchoring of urates in the tissues in gout it is most desirable that further investigations be made to discover whether in gouty subjects the tissue retention capacity for uric acid is enhanced.

“The impression,” says Fürth, “grows on one that this hitherto little considered factor, of an increased affinity of the tissues for uric acid in the gouty subject is very much closer to the real kernel of the gout problem than, for example, the question of the fixation of uric acid in the blood about which there has been so much contention, and with which of necessity we are compelled, at least, to some little extent to concern ourselves.” The results of modern researches tend to support this more catholic conception. We would recall that Lewis and his co-workers, seeking the source of the increased endogenous purin excretion that follows ingestion of purin-free food, were forced to reject the view that it was solely derived from katabolism of the nuclear substance of the digestive glands, and to refer it instead to “wear and tear” of the body cells as a whole. Precisely the same change in attitude, we may remind our readers, has overtaken us in regard to the site of urea formation, viz., that not only the liver cells, but those of the muscles also participate in its production.

While admitting that dogmatism is out of place, still to our mind this theory of tissue retention makes strong appeal. In light of it the nebulous “gouty diathesis” seems on its way to become incarnate in some inborn peculiarity of tissue-function, a falling short of full physiological activity, or, as M. Rendu termed it, a “primordial vice of nutrition.”

In other words, in gout there is no rift nor lack of finish in the orderly sequence of enzymatic reactions that eventuate in uric acid. Uric acid is formed and, as far as we know, after a normal fashion. But, here comes the flaw, viz., the uric acid, when formed, fails of transport and elimination. It is precipitated and anchored in the tissues, from whose grip it fails to detach itself. In short, it is not the formation of uric acid, or its failure of further metamorphosis, but the retention of uric acid, and more pertinently, its fixation in the tissues that constitutes the salient feature of gout.

Now, all modern research tends to indicate that uric acid is not an intermediary, but a terminal product of metabolism, and, moreover, that there are no uricolytic ferments within the body whereby its destruction can be accomplished.

If we grant that—

then it follows that man, ipso facto, is potentially liable to uric acid retention and deposition, the same objectivated as tophi. In this innate potentiality of and to uratosis resides the “gouty” diathesis.

If the postulates (1) and (2) be established, then, though it sound rank heresy, it follows that gout is not, chemically speaking, an “error of metabolism.” Not, at any rate, in the ordinary acceptation, viz., not a failure in the transmutation of uric acid into urea and intermediate products. If uric acid be an end-product, then no further cleavage into urea, etc., occurs, and in this connection the failure to discover uricolytic enzymes is significant.

We have before proffered the suggestion that not only local, but constitutional, or systemic influences also play a part in the origin of tophi. Provisionally, therefore, we would infer that—

In other words, we have in these two elements haply the constitutional and local factors that we postulate as essential to the formation of tophi. Albeit, they represent but latent tissue potentialities, inadequate of themselves to determine the eruption of tophi.

Moreover, be it recalled that the causa causans of gout must be responsible not only for the incidence of tophi, but also for the more dramatic features of gout, its arthritic outbreaks, etc. To dissociate the cause or causes of the uratic deposits from that of the joint inflammations would indeed appear impermissible.

But, taking this view, it is clear that, apart from the constitutional and local factors above postulated, tophi and, alike, the arthritic phenomena of gout, demand for their production the intrusion of some further element, some tertium quid, vital and biological. To this end, therefore, we purpose reviewing tophi in their clinical aspects, as herein possibly we may find some further clue to their exact mode of genesis.

Clinical Evolution of Tophi

As to the clinical characters that mark the genesis and maturation of tophi not a little conflict of opinion seems to obtain. Do tophi arise painlessly or not? Do the uratic depositions occasion any local inflammatory reaction? Or, are they merely concomitants or sequels thereof?

With what wearisome iteration has the same question been propounded in regard of gouty arthritis. Are the attacks of pain and inflammation due to deposits, or do the deposits take place at the site of inflammation?

But, restricting our enquiries to tophi, we may remind the reader that Aretæus, writing in the second century, A.D., made the following observations: “Callosities also form in the joints; at first they resemble abscesses, but afterwards they get more condensed, and the humour being condensed is difficult to dissolve; at last they are converted into hard white tophi (Πῶροι στερροὶ λευκοὶ), and over the whole there are small tumours like vari and larger, but the humour is thick white and like hailstones” (Περὶ Αρθριτιδος). To our mind, it would be difficult to emulate, much less to surpass, the succinct and, as we believe, accurate picture here drawn of the various stages that mark the life history of tophi. It will be noted that Aretæus says that in their initial stages they “resemble abscesses,” and, turning to the writings of the elder Garrod and others, we find abundant evidence that it is so.

Discussing the more frequent incidence of tophi in the hands than in the feet, Garrod describes the physical characters presented by tophi in the making as seen in one of his examples of gout. “On the dorsal surface of the second phalangeal joints of three fingers, small rounded protuberances were observed, the skin over them being red; these bulgings appeared soft, as if containing a thick fluid, but not the slightest indication of white matter could be seen through the skin; they might have been either gouty concretions in their early stage of formation or some other form of swelling; from a simple inspection I could form no opinion as to their true nature, but their history convinced me that they arose from a deposit of urate of soda. Upon puncturing one of the little swellings, full light was thrown upon the case, as a thick white fluid immediately exuded, a drop of which placed, under the microscope, with the use of polarised light, gave the appearance represented in Fig. 1; the crystals were proved by analysis to consist of urate of soda.”

We see, therefore, that Aretæus and Garrod were at one in their observation that tophi in their initial stages are betokened by small red swellings; in other words, as Aretæus says, they “resemble abscesses.” Garrod also held that uratic deposits probably form during an attack of gout, but occasionally they appear shortly afterwards. Thus, in one of his cases no auricular tophi were found when the subject left hospital, but within ten days, on re-examination, a deposit was detected. “Perhaps,” he reflects, “some fluid was effused during the fit, but being at first transparent, could not easily be distinguished.”

That Garrod held the swellings to be inflammatory in nature is clear from his writings. Thus, he says, “When tissues little liable to take on inflammatory action become infiltrated (with urate of soda), but slight vascular disturbance is produced. This is especially the case with the fibro-cartilage of the ear, and although we now and then meet with patients aware of the formation of these little nodules, who experience in fact a gouty fit in the ear, yet in the majority of cases attention has never been directed to the part, so slight has been the inflammation caused by the effusion.”

Again, James Moore, whose graphic description of tophi formation is quoted by Garrod, also held that “this process is usually preceded and accompanied by inflammation.” Hilton Fagge, too, says, “it appears probable that the deposition of lithate of soda causes inflammation in other tissues besides the joints. It does, as we have seen, in the ear and occasionally in the skin.” But, he also states, “in the pinna of the ear, in fact, gouty concretions commonly form without any indications of previous inflammatory action. In some instances the patient experiences sensations of heat and pricking, and the part is tender, but more often he is quite unconscious of the fact that such concretions in the pinna are present.”

Duckworth also noted that uratic deposits are not always painless during their formation, and he noted that not only may auricular tophi be painful at this stage, but that, following the subsidence of acute gout in a joint, painful swellings may develop in its vicinity, which subsequently proved to have been tophi in process of formation.

For myself, I am of opinion that each and every process of tophus formation is preceded by local inflammatory reaction of varying grades of severity. In a matter of this sort, positive is more valuable than negative evidence. We see that all the authorities quoted admit that tophi are associated with inflammation and some measure of pain, though they add the reservation that in many instances, if not the majority, these phenomena have apparently been absent. Apparently, we say advisedly, for conceding that the pain attending the formation of auricular tophi is but slight, how all too easy for the subject to have wholly forgotten it when he comes later under notice. By this time the tophi, from being latent, have become overt. The initial soft red swellings, their nature probably misinterpreted at their initiation, are now transmuted into pearly concretions of hard or semi-solid consistence. Small wonder, then, that attempts to elicit the history of slight pain and pricking or tenderness often prove barren; for, be it noted, tophi take months to mature, as Garrod long since pointed out.

Moreover, we would emphasise the fact that tophi, more often than is thought, occasionally precede by some years the outbreak of arthritic attacks. Both Duckworth and Garrod are quite definite on this, and we can confirm them.

In such instances, then, even granted that our attention be drawn to them in their initial stages, how easy to misinterpret their true nature! Thus, we have known tophi in their early stages of formation confused with chilblains. In this connection we might remind the reader that, according to Duckworth, amongst the peculiarities of tissue in those goutily disposed is feebleness of the peripheral capillary circulation, “a condition leading to disorders of chilblain-type, the vessels filling slowly after being emptied.”

We repeat that the cause or causes of tophi and, alike, of the arthritic phenomena of gout are, and must be, one and indivisible, for the process of tophus formation is but an attack in miniature of gout. Although he may never have had an arthritic outbreak, the individual who exhibits a tophus undeniably has gout. More certainly so than if he had had an inflammatory outbreak in his great toe; for this, at any rate, may be of non-gouty origin, but the tophus, never!

Reflecting on the foregoing considerations, we would submit—