XII. URATOSIS IN RELATION TO GOUT

The two salient features of the gouty diathesis are:—

(a) The tendency to excess of uric acid in the blood, i.e., hyper-uricæmia, and

(b) The tendency to uratic deposition, i.e., uratosis.

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

“Et tophus scaber, et nigris exesa chelydris Creta.”

Virgil, Georg., ii., 214.

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.

“Knots upon his gouty joints appear, And chalk is in his crippled fingers found.”

Dryden, Pers.

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

Urate of soda 34·20 Urate of lime 2·12 Carbonate of ammonia 7·86 Chloride of sodium 14·12 Animal matter 32·53 Water 6·80 Loss 2·37 ------ 100·00 ======

LEHMANN’S ANALYSIS

Urate of soda 52·12 Urate of lime 1·25 Chloride of sodium 9·84 Phosphate of lime 4·32 Cellular tissue 28·49 Water, loss, etc. 3·98 ------ 100·00 ======

EBSTEIN AND SPRAGUE’S ANALYSIS

Uric acid 59·70 Tissue, organic matter 27·88 Sodium oxide 9·30 Potassium oxide 2·95 Calcium oxide 0·17 MgO, Fe, P₂O₅, S Traces.

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:—

(1) That tophi are blends of crystalloids and colloids and subject to the complex conditions of solubility attaching to such combinations.

(2) That the relatively high sodium content of certain tissues, e.g., cartilage, favours the incidence of uratic deposits therein.

(3) That tissue necrosis is not necessarily an antecedent to uratic deposits.

(4) That no relationship can be established between the incidence or multiplicity of tophi and uricæmia.

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

------------------+-------+-------+-------+---------+---------+ Case. | E. E. | T. D. | S. H. | M. F. | C. M. | |Uremia.|Uremia.|Uremia.|Diabetes.|Diabetes.| ------------------+-------+-------+-------+---------+---------+ | mg. | mg. | mg. | mg. | mg. | Blood | 15·4 | 14·3 | 17·0 | 0·7 | 0·7 | Pleural fluid | 16·7 | 15·9 | | | | Ascitic fluid | 18·0 | | | | | Pericardial fluid | | 14·3 | 18·0 | | | Subcutaneous fluid| 18·0 | | | | | Spinal fluid | 2·8 | 2·0 | 4·7 | | | Skeletal muscle | 8·0 | 3·9 | 5·8 | 0·7 | 2·6 | Heart muscle | 10·0 | 7·3 | 8·8 | | 1·2 | Liver | 18·0 | 15·6 | 11·5 | | 5·0 | Spleen | 12·6 | 14·3 | 9·1 | | 1·2 | Skin | | 13·0 | | | | ------------------+-------+-------+-------+---------+---------+

------------------+-----------+---------- Case. | S. T. | H. J. |Amputation.|Pneumonia. ------------------+-----------+---------- | mg. | mg. Blood | 0·7 | Pleural fluid | | Ascitic fluid | | Pericardial fluid | | Subcutaneous fluid| | Spinal fluid | | Skeletal muscle | 2·0 | Heart muscle | | Liver | | 4·0 Spleen | | Trace Skin | | ------------------+-----------+----------

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—

(1) Uric acid is not an intermediate but an end-product of metabolism; and

(2) That the human body is devoid of uric acid-destroying enzymes,

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—

(1) The tissues of gouty subjects display an abnormal affinity for uric acid, i.e., an increased retention capacity for the same;

(2) That certain chemico-physical factors, previously alluded to (content of sodium ions, etc.), favour the incidence of uratic deposits in particular tissues.

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—

(1) That tophi are always preceded by local inflammatory reaction of varying grades of severity, and that the uratic deposits are sequels thereto;

(2) That in their early stages their presence is betokened by soft red swellings associated often with sensations of pricking and tenderness;

(3) That their transmutation into white pearly concretions is a process that takes months to mature;

(4) That tophi and arthritic outbreaks have a common causal origin.

The question that now thrusts itself upon us is,—What, then, is the cause of the inflammatory phenomena which determines the eruption of tophi, and alike of the arthritic outbreaks?

THE CAUSE OF THE INFLAMMATORY PHENOMENA

Garrod’s discovery that uric acid was present in the blood in gout not unnaturally led to the assumption that herein lay the origin of its symptomatology, and what else than confirmatory could be the deposition of uratic deposits here and there in the body. The corollary seemed obvious that, given the presence of a certain proportion of uric acid in the blood, then gout must result. But, unfortunately, it was not so; for, lo! and behold, an excess of uric acid in the blood is in no sense pathognomonic of gout.

Thus, the blood in leukæmia contains a high percentage of uric acid, in some cases exceeding that found in gout, and enduring, moreover, for a longer period. Yet no symptoms distinctive of gout appear, nothing that can be referred to uric acid. But it was contended the reason why gout does not ensue is because simultaneously with increased formation there is increased elimination of uric acid. But, unfortunately, despite augmented excretion, the percentage of uric acid in the blood is still maintained at a high level, and still no gout occurs.

Moreover, it is met with also in nephritis, simple and pernicious anæmia, intestinal inflammation, certain fevers, notably in malaria between attacks, and in typhus after the febrile stage, pneumonia, plumbism, etc. Indeed, the ubiquitousness with which uric acid is found in the blood, and this in conditions wholly distinct from gout, would of itself seem sufficient to dissipate any lingering doubts as to its being anything more than a symptom of gout and not its proximate cause.

Obviously, with these revelations the uric acid theory was within measurable distance of being uprooted. Deposed from its high estate as a causal agent, and accredited with only a symptomatic value, the question arose whether indeed this bogey, “uric acid,” was even capable of fulfilling a minor rôle, of originating any symptoms, much less gout, in its entirety. In other words, is uric acid toxic or non-toxic?

NON-TOXICITY OF URIC ACID

The adherents of the uric acid theory did not hesitate to attribute to its toxic action, not only the severe phenomena of acute attacks, but even all the functional disorders of so-called irregular or visceral gout. By the more ardent advocates, such as Haig, we were treated to a word picture of how solid crystals of uric acid erupted out of the blood-stream, and anchoring themselves in nerve sheathes, the renal substance and the mucous membrane, gave birth to chronic neuralgias, nephritis, rhinitis, and so forth. But, alas, there is very serious doubt as to whether uric acid or the urates are capable of acting even as mechanical, much less as true toxic irritants.

Perhaps the most cogent evidence of the slight toxic effects of uric acid or urates is that derived from a study of the uric acid infarcts so frequently noted in infants dying within the first two weeks of birth. According to Gideon Wells, “little or no change occurs in the renal tubule as a result of these depositions, except such as can be attributed to their mechanical effect.” This same observer, discussing this question of the toxicity of uric acid, observes, “It may be safely stated that at the present time there exists no good evidence which makes it probable that uric acid is responsible for any pathological conditions whatever, except uric acid calculi, uric acid infarcts in the kidneys, and certain manifestations of gout.” His further conclusion is that uric acid possesses but a very slight degree of toxicity, and that an actual intoxication of the organism with this substance probably never occurs.

Again, we have the fact that in instances of malnutrition in children excess of uric acid may occasionally be found in the blood. Yet no symptoms comparable to gout occur, even though uric acid calculi form. Also, as has been pointed out, showers of uric acid may be present in their urine, and yet no symptoms arise, save those referable to mechanical irritation of the renal or vesical tissues.

Turning to experimental researches, the evidence is cumulative as to the non-toxicity of uric acid. Rabbits and dogs seem quite irresponsive, either to its ingestion in large quantities in their food, or to repeated intravenous injections of 1 or 2 grammes thereof, save only that the urine showed a large increase in uric acid.

Again, Ransom, of New York, found that no systemic disturbance ensued in two cases of chronic nephritis, following the taking by the mouth of 3 grammes of uric acid per diem for three days in succession. All that resulted was a notable increase in the uric acid output. In one case, he went further, and on the fourth day administered 6 grammes, but nothing happened.

Walker Hall, with commendable devotion, took large doses of uric acid with resultant headache and malaise, which endured for some hours. But as Luff shrewdly observes, “almost any substance, however (common salt for example), will produce toxic effects if taken in very excessive quantities.” Despite his brief indisposition, Walker Hall maintains that uric acid is rather a symptom of, than the precise materies morbi in gout.

Nor, apparently, even in gouty subjects can aggravation of the condition be induced by intravenous injection of uric acid. Bass and Herzberg did so until the blood content of uric acid reached the high level of 10 mg., and yet no joint attack supervened. Neither, for that matter, has it been possible to establish any relationship between degrees of uricæmia and the incidence or severity of gouty paroxysms.

Again, taking a typical instance of acute gout in the big toe, how difficult to conceive that the same owes its origin to uric acid circulating in the blood especially when we realise that the blood content of uric acid in gout exceeds but by a few milligrammes that in normal blood. Moreover, if it does so, then why does it fail to ensue in leukæmia and in other states associated with uricæmia. Also, we like to think that the penchant of acute gout for the toe is that the circulation is inefficient at this peripheral site. But how often is the circulation all too vigorous in gout, and for that matter frequently feeble in leukæmia and in ill-nourished children. But, notwithstanding that in the two latter conditions, uricæmia exists yet, despite favouring circulatory conditions, they develop no gout.

Garrod contended that the violent pain, intense inflammation, and profound constitutional disturbance of acute gout were due to mechanical irritation occasioned by the sudden deposition of biurate crystals in the delicate interior of the implicated joint. Also, that the absence of constitutional disturbance in the inter-paroxysmal periods was because the deposition of urates, being gradual, the tissues acquired tolerance, and yet, forsooth, this same substance is held responsible for the fulminant outbreak that ensues anon.

But it is, as Ringrose Gore shrewdly observed, “against the usual laws of nature that, if an irritant foreign body remains in any organ the symptoms should quickly subside, while the irritant actually increases, for after each attack, and during the intervals between the attacks, the deposits of such biurate enlarge.” In conclusion, is it not infinitely more probable, as Gore states, that the inflammatory reaction precedes the deposition of urates and that these latter, in short, are the consequence and not the cause of the gouty arthritis?

Reverting to tophi, their experimental production, it is claimed, has been achieved by His.[24] Administering alcohol to dogs and simultaneously injecting them locally with sodium mono-urate, he produced deposits which seemed identical with tophi produced spontaneously in gout. But, unfortunately, up to the present, it has been found impossible to induce their formation by flooding the circulation with urates. The utmost, indeed, that His and other workers in this sphere feel able to postulate is that uric acid is a “weak tissue poison.”[25] Scarcely the words in which to describe the poison responsible for gout! for, as we have before stated, the agent that is responsible for tophi must also be capable of inducing the arthritic phenomena and other features of the disorder.

The sum of our reflections is that the toxicity of uric acid has been grossly over-estimated, and that, like its relative urea, it is practically non-irritating and inert; in other words, it cannot any longer be regarded as the essential cause of the acute or chronic forms of gout, whether of articular or ab-articular site. Moreover, far from its presence in excess in the blood being pathognomonic of gout, it must, as Walker Hall contends, be held merely “as symptomatic of conditions which help or prevent its solubility and excretion and does not itself cause lesions which accompany uricacidæmia.”

ARE THE PRECURSORS OF URIC ACID TOXIC?

Naturally the upholders of the uric acid theory were loth to find their fetish uric acid was allotted a meaningless rôle. That it should be deemed inert was to dislodge the very corner-stone of the imposing superstructure they had been at such pains to raise. Uric acid not responsible for the genesis of gout! But, haply, maybe their position was still unassailable; for what of the purin bases, the forerunners of uric acid? Might not the blame lie with these?

Straightway xanthin, hypoxanthin, adenin, etc., were credited with pernicious potencies.[26] Nor did they lack apparent support from the experimental side. Thus, Mandel affirmed that purin bases, apart from infection, might originate pyrexia. Others, again, noted that in dogs and rabbits fed on adenin, degenerative changes in the kidneys ensued, with deposits resembling uric acid and urates in their substance. The fact, too, that guanin-gout was occasionally met with in swine, also lent colour to their views.

Moreover, that ingestion of these congeners of uric acid led in animals to renal lesions, seemed to support the contention of many, that renal disorder might be the primary cause of gout. But, unfortunately, Kolisch and Weintrand’s assertion that the alloxur bases were found in increased quantities in the urine of gouty patients was contradicted by Schmoll, His, Laquer, and others.

Still more cogent, apparently, the announcement in 1910, by Brugsch and Mallory, that they had seen a typical attack of gout ensue in a gouty patient in sequence to a dose of 0·5 gram of hypoxanthin. Nor did this reaction of gouty persons fail of confirmation, as in the same year, Brugsch and Schittenhelm, in gouty patients, noted attacks of arthritis, after the administration of nucleinic acid.

Nevertheless, we must beware of laying too much stress on isolated experiments of this nature, so hypersensitive are some of the victims to any strange or unaccustomed ingesta. Were all the myriad other determinants of gouty attacks eliminated, over-drinking, trauma, mental disturbances, etc.? for be it recollected, all the victims of these experiments with hypoxanthin and nucleinic acid were gouty subjects, i.e., potentially liable to attacks at any moment.

Even admitting the ingestion of, e.g., hypoxanthin was followed by a gouty outbreak, it must be insisted that mere sequence does not establish causation. Clinically, on the whole, there is little or nothing to support the contention that the purin bases have much to do with the pathogeny of gout. “The proof of the pudding is in the eating,” and contrary to the view, at one time so prevalent, that purin foodstuffs were most deleterious, it has been found that, for the average gouty person, a purin-free dietary is not only not essential, but prejudicial. Those, therefore, who may be inclined to see in the above sequence proof of a causal connection, would do well to recall Bacon’s dictum that “there is in the human mind a peculiar tendency to dwell on affirmative and to overlook negative instances.”

In conclusion, we must affirm our belief that neither uric acid nor its precursors is responsible for the fever, local inflammation, and general constitutional disturbance in gout, for uric acid and the urates are themselves practically non-toxic. Albeit, though holding this view, I do not for one moment suggest that uric acid has nothing whatever to do with gout. The fact that tophi, its pathognomonic stigmata, are compounded of biurate of soda, would per se stamp such an attitude as untenable. On the other hand, uric acid must be viewed in its proper perspective as a concomitant or sequel of gout, the essential cause of which must be sought elsewhere.

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XIII. THE RISE OF THE INFECTIVE THEORY

With the abandonment of the uric acid theory of the causation of gout we see a reversion, curiously enough, to the hypothesis held by the ancient physicians as to its pathogeny. Like Cælius Aurelianus and Paulus Ægineta, we now incline to refer the origin of the disorder to some derangement of the gastro-intestinal tract. This conception indeed endured up to the latter half of the eighteenth century, and was definitely maintained by Van Swieten in his commentary on the aphorisms of his great preceptor, Boerhaave. For him the fons et origo mali in gout was disturbance of the functions of the alimentary tract.

“Indigestio viscorum pro origine proxima hujus morbi habitur.”

The English Hippocrates, too, Sydenham, in his classic treatise observes: “The more closely I have thought upon gout, the more I have referred it to indigestion, or to the impaired concoction of matters both in the parts and juices of the body.”

Not only in regard of the initial site are we reverting to the views of old-time physicians, but the tenor of our reflections upon the nature of the disorder exhibits a like trend. Thus the older physiologists, doubtless impressed by its fulminant onset and clinical features, ranked gout amongst the fevers, describing it indeed as a “tertian fever terminating in fourteen days.”

Indeed, the great Boerhaave avowed his belief that gout was contagious—a forecast, we may take it, of the modern theory of infection. Subsequently his pupil, Van Swieten, went a step further, maintaining that sometimes wives, while nursing husbands afflicted with gout, contracted the malady!

Passing now to relatively modern times, it will be noted that in 1864 Laycock classed acute gout with rheumatic fever as an “excretory fever,” while Parkes even prior to this, in 1860, wrote: “I define gout after Garrod as a febrile infection with inflammation about the joints leading to a deposition of urate of soda.”

But it must be freely acknowledged that, subsequent to Garrod’s discovery of uric acid in the blood in gout, the spell exercised by the uric acid theory was such that it dominated medical thought almost to the exclusion of all other possibilities. All energies were forthwith centred upon endless laborious researches into possible modes of uric acid formation, but which, alas, did little to purge men’s minds of their obsession that uric acid was the proximate cause of gout.

Still it would be unfair to infer that the disabilities attaching to the uric acid hypothesis were wholly unrealised. Indeed, it may be fairly said of Duckworth’s reflections on the pathogeny of gout that they definitely foreshadowed the infective theory. His views postulated what may be termed a toxic tropho-neurosis, wherewith to explain the paroxysmal nature, the periodicity and protean symptomatology of the disorder.

But in the early part of 1900 we may, I think, discern in some words of Chalmers Watson a change coming over our thoughts as to the pathology of gout, this as the result of some studies of a series of examples of acute gouty polyarthritis. The results of his researches were such that he challenged the accuracy of Garrod’s original observations as to the lowered alkalinity of the blood during acute attacks, also his claim that the uric acid content of the blood was increased and the uric acid excretion diminished during the paroxysm. If these points be accepted, he says we must start de novo in search of the cause of the acute paroxysm.

He noted also the interesting fact that during acute attacks of gout a very marked leucocytosis was present. Another outstanding feature was the presence in large numbers of peculiar myelocyte-like cells, half as many in number as the ordinary finely granular oxyphil leucocytes. Reflecting on these findings, he observes: “It would, I think, be well if much less attention were centred on the excretion of uric acid alone as the all-important factor in the disease, whether in its acute or chronic form. The results obtained by the line of investigation here followed suggest the advisability of more attention being devoted to the histo-chemical characters of the blood, the ratios of uric acid to other important products of metabolism, and, if opportunity be afforded, an examination of the bone marrow.”

To other interesting features of these researches of Watson’s we shall allude later, but, concerned here more with tracing the evolution of the infective theory of gout, we would hasten to add that in September of the same year Ringrose Gore, discussing the inadequacy of the uric acid theory, boldly avowed and ably propounded his belief in the infective origin of the disorder.

Thus he writes: “I consider a toxin to be the cause of this disease. If so, such toxin must be formed in the intestine. As the symptoms of gout are constant, it must be a definite toxin, the product of a definite bacillus acting upon the intestinal secretion. As gout is capable of being caused in any subject, it must be one of the bacilli normally found in the intestinal canal.”

Nor did Gore lack supporters in his suggestion that the alimentary tract was the primary source of the changes in the metabolism of gout. For in the same year Minkowski, Le Gendre, and in this country Watson, hazarded the view that intestinal derangements, through the medium of their resultant toxins, initiate disturbances in the liver, and these in turn determine those obliquities of metabolism typical of gout.

At the same time their contentions derive colour from the researches of Grübe, who, despite traditional views, maintained that in gout the hydrochloric acid of the gastric juice, far from being increased, was in most cases diminished or wholly lacking, while, on the other hand, lactic acid was present in some instances.

In 1903 Woods-Hutchinson ably contended that “gout and lithæmia are mere symptom names for a miscellaneous group of chronic toxæmic processes of widely varied origin, characterised by the production of uric acid and the urates.” He held that the uric acid in gout as well as the associated phosphoric acid are merely a criterion of the measure to which the nucleins of the body cells (chiefly probably of leucocytes) have undergone destruction in consequence of their invasion by a toxin or toxins of organic or inorganic nature. He furthermore contended that the rôle of the liver in gout was purely negative, consisting in its inability “to absorb or transform into harmless excretory substances the excess of toxins brought to it by the portal vein.”

In 1904 Falkenstein furnished collateral evidence that the starting point of gout lay in a diseased condition of the gastric glands, those responsible for the secretion of hydrochloric acid. The supply of hydrochloric acid being deficient in the gouty, their digestive capacity is distinctly lowered. Abnormal fermentation ensues with insufficient oxidation, and “the substances containing quantities of nuclein are partly prevented from being further split up, and partly favour the synthetic formation of uric acid.” He would thus refer the excessive formation of this latter directly to the diseased glands. He further observes that, despite the deficiency of hydrochloric acid, the gastric juice is often hyperacid, this being due to the presence therein of organic acids, such as butyric, lactic, and acetic acids.

In the same year Chalmers Watson, as the outcome of investigations into gout as it occurs in the fowl, held that:—

(a) There is ample evidence to prove that the uric acid in the blood is not the primary factor in gout, and

(b) Uric acid can be deposited in cartilages and other tissues, even in considerable amount, without the association of any inflammatory phenomena.

He concludes that the last-mentioned point clearly proves that:—

He then proceeds to inquire as to the nature of the toxic principles in the blood, and the factors that influence their passage thence into the tissues. In connection with these queries he emphasises the necessity of envisaging the all-important part played by the alimentary canal, holding that herein doubtless resides the clue to the solution of the problem.

Post-mortem examination of the fowl revealed marked catarrh of ileum, duodenum and large intestine, while the pancreatic duct was filled with catarrhal products. The congested spleen, apart from proliferation of its endothelial elements, exhibited a marked increase in the number of granular leucocytes in the capillaries and sinuses as compared with the features of the control sections, which, as Chalmers Watson observes, is the characteristic reaction of this organ to invasion by bacteria or their products. The kidneys on examination revealed here and there uratic deposits surrounded by inflammatory tissue. The relationship of these to the inter-lobular arteries was such as to suggest an infection by the blood stream.

The collecting tubules in the deeper part of the cortex and medulla were markedly dilated and choked with granular leucocytes. Sections of the organs were examined bacteriologically by Muir, the necrosed areas revealing the presence of “rod-like bodies of the size of large bacilli massed together in dense clusters; the appearance suggested that these rods were either degenerated cell products of an unusual character, degenerated bacteria, or crystalline in nature.” Examination of the same by polariscope by Marshall disposed of the possibility that they were crystalline. Finally it was thought that the appearances generally favoured the view that the rods in question were bacteria which had lost their reaction to bacterial stains owing to bacteriolytic or other changes.

As to the inference that the defunct fowl fell a victim to acute gout, Watson based it on the existence of the uratic deposits in the tissues, the changes in the synovia, the widespread thromboses, and the renal necroses. As to the other lesions, the chief interest centres in those located in the intestine, pancreas and kidney. The state of the pancreatic duct raises the question as to whether it points to any connection between these changes and the common occurrence of glycosuria in gouty subjects. The alteration in the leucocytes merits notice in that similar changes were found by Watson in the blood in acute gouty polyarthritis, the same, moreover, being subsequently confirmed by Bain.

Chalmers Watson’s final conclusion was that “the clinical features of gout—regular or irregular, acute or chronic—are more adequately explained by the light of our present knowledge of infections, relapses, and immunity than by any other theory. The distinctive feature of this infection in gout is that the toxin or toxins have a special property of disturbing nitrogenous metabolism in a manner favourable to the deposit of uric acid in certain tissues.”

SUGGESTION OF A SPECIFIC INFECTION

It will have been noted that, despite the growing number of adherents to the infective theory, no attempt had been made to saddle any particular organism with the responsibility of initiating gout. But in 1905 Trautner, holding mucous colitis to be one of the initial manifestations of gout, affirmed his belief that the bacillus coli communis was the responsible microbic agent.

He claimed that this particular organism, during its passage through the system, gives rise to a reducing agent which is subsequently transmuted into xanthin and uric acid. This is, of course, but a variant of Gore’s original view that the toxin of gout is a product of certain bacteria normally present in the intestine, but which under certain conditions take on a pathogenic action.

The microbic theory fast gained ground. Thus Luff, who in the first edition of his work advocated the renal origin of gout, subsequently renounced the same in favour of its infective origin. To sum up, the opinion generally was that it was more than probable that gastro-intestinal derangements, with their altered secretions, exert an influence on the intestinal flora with resultant formation of toxins, and that these same, acting chiefly on the liver, put in motion those obliquities of metabolism which eventuate in gout.

Sikes, however, in 1907, discussing the rôle of gastro-intestinal disorders, expressed a doubt as to whether the same are primarily or secondarily related “to the actual chemical processes at the base of the disease.”

He thinks it at least as probable that the gastro-intestinal disorders are due to an alteration in the intestinal secretions from an internal cause as that they are due to bacteria in the formation of toxins, or, he suggests, to some alteration in the epithelial cells, so that they take up chemical compounds of different nature from the ordinary. To him it does not seem at all probable that gout will ever be found affiliable to any specific micro-organism, inclining rather to the belief that a solution of the riddle will only be found in a closer and more extended study of that most difficult subject, the actual chemistry of the cell protoplasm.

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XIV. GOUT AS AN INFECTION

“The old order changeth, giving place to new,” and the uric acid theory having failed us, it is essential that we cast round for some other solution of the problem, carrying with us, however, this guiding principle, that uric acid, having lost its etiological status, be viewed in its right perspective as not the cause, but the consequence, of gout.

Happily, with the advent of bacteriology our views, or rather our hazards, as to the nature of joint diseases underwent profound modification. But, strange to say, though quick to apprehend the significance of infection, its causal relation to other joint disorders, we still seem unaccountably loth to discard our time-worn conception of “gouty” arthritis as of purely metabolic origin. This, to my mind, is the more remarkable in that the onset, clinical phenomena, and course of acute gout, and no less the life history of the disorder as a whole, are emphatically indicative of the intrusion of an infective element in its genesis.

In developing this hypothesis I purpose devoting the present chapter to consideration of the frequency with which local foci of infection are met with in gout, the frequency, too, with which exacerbations of the disorder are presaged by acute glandular affections of undeniably infective source. The latter part of the text will concern itself with the rival claims of auto-toxæmia and infection or sub-infection. In the subsequent chapter we shall analyse critically the component elements of the acute paroxysm of gout, their compatibility or not with an infective origin. The affinities between gouty arthritis and the specific infective arthritides will then be noted, and, finally, an endeavour made to link up the specific stigmata of gout—its uratic deposits—with the postulated infective element.

LOCAL FOCI OF INFECTION

The extreme frequency with which infective foci are met with in the victims of gout is by no means adequately realised. Moreover, we are only now beginning to appreciate the grave significance of such “nests” of infection and how devious are the ways in which they work their malign influence. For our forefathers gout began, and, forsooth, often ended, in the “stomach,” or it was the “liver” that was impeached. But the portal to the alimentary canal was for them only a cavity, the contained structures of which, albeit, to their mind often betrayed evidences of a “gouty diathesis.” They distinguished “gouty” teeth, “gouty” tonsillitis, “gouty” pharyngitis, even “gouty” parotitis; but all these they classed as tokens or sequelæ of gout—not possible causes or excitants thereof.

Nevertheless, their observations on “gouty” teeth are of deep interest, though their significance was misinterpreted.

Thus, Duckworth, for example, wrote: “The tendency to shed sound teeth has been noted with some frequency in middle or later life in goutily disposed persons, and they are more than others liable to occasional and fugitive attacks of pain in several sound teeth at a time, with a sensation as if these were starting from their sockets, being tender to bite upon.” In truth, a succinct picture of pyorrhœa alveolaris, of unprejudiced source, hence the more valuable.

Garrod again tells us that he saw an initial attack of gout supervene after extraction of a tooth, a sequence attributed by him to loss of blood. How interesting this, in light of the fact that exacerbations of joint disease have frequently been seen to follow the removal of septic teeth. The same authority also noted the incidence of a primary attack of gout following epistaxis, and the same after copious hæmatemesis, and Todd several times observed such articular outbreaks after venesection.

Lastly, says Garrod, “cases illustrative of the effects of the suppression of an habitual hæmorrhoidal discharge are by no means uncommon, and ... numerous instances arising from boils and carbuncles have come under my notice.” By Garrod and his contemporaries all these various determinants of gouty paroxysms, i.e., loss of blood, etc., were believed to exert their influence viâ the nervous system, with consequent disturbed equilibrium of nutritive processes throughout the body. But while it may be admitted that depression of the vis resistantiæ plays a part, it does so, I believe, by favouring the occurrence of infection.

Let us turn now to modern findings, and we shall see that they do but confirm those of the older clinicians. Lambert in 125 cases of gout found the teeth unsound in 82 per cent. of males and 1 per cent. of females, while in 9 per cent. of the former and 17 per cent. of the latter there was associated chronic dyspepsia. Two years after (1909) Wynn, Wirgman and Turner noted the invariable correlation of gout with local foci of infection. In the majority, pyorrhœa alveolaris was present. Tonsillar sepsis, too, was not uncommon, and much more rarely nasal disorders. Again, out of fifty-two examples of so-called “gouty” throat Edward McCracken found pyorrhœa alveolaris to be present in thirty-nine, and Fenner also tells us that this affection is common in the subjects of gout.

In truth, the victims of gouty arthritis are no more immune from dental lesions than those of other types of joint disease. Thus, Mr. Macdonald, dental surgeon to the Royal Mineral Water Hospital, Bath, informs me that this form of oral sepsis is extremely common in gouty individuals, and in my experience it is but rarely that evidences of its presence are not forthcoming in these subjects. The desirability of early recognition of such foci—in light of their highly probable etiological significance—can scarcely be overestimated. For their consequences, both local and remote, are of paramount importance.

Thus, G. I. Stewart’s recent observations have conclusively demonstrated that “bad teeth” are causally related to tonsillar affections. How illumining this, in view of McCracken’s experiences in “gouty throats.” As we saw, pyorrhœa alveolaris was present in more than half the examples. But, more pertinently to the point at issue, he comments on the frequency with which the victims of gout develop acute tonsillitis, of lacunar or parenchymatous type, also that such attacks frequently precede outbreaks of arthritic gout. Duckworth again noted the same liability of the gouty to unsound teeth and tonsillitis, and that the latter was often followed by articular outbreaks. Luff also observed that “gouty” tonsillitis was occasionally a precursor of articular gout, always subsiding on the appearance of the latter complication.

Again, acute and chronic pharyngitis are proverbially common in “gouty” subjects. Moreover, in both types the subsidence of the throat affection has frequently been signalised by an articular outbreak of classic site. Parotitis, too, has been repeatedly met with in gout, and, according to Luff, “rapidly subsides on the appearance of regular gout in one or more joints.”

In truth, whether we peruse recent or older works on gout, we cannot fail to remark the unanimity of opinion as to the frequency of incidence of these glandular affections—these states of oral sepsis—in the subjects of gout. Equally noteworthy is their insistence on the constancy with which such local affections have proved harbingers of oncoming articular outbreaks. Lastly, the mere fact that our forefathers dignified these local disorders with special appellations, “gouty” tonsillitis, pharyngitis, etc., is cogent proof that they regarded them as among the integral features of gout.

Now, as to the true significance of these acute glandular affections, held by clinicians of repute to be of “gouty” origin. What of “gouty” tonsillitis, pharyngitis, etc.? Still more, what of our deductions regarding the relationship of these same when met with in association with other joint disorders? Do we not hold them each and all as evidences of infection—“acute rheumatism,” “gonorrhœal arthritis,” etc.?—and we may well ask, Why not in gout?

Says Duckworth, “Angina tonsillaris—very painful but not suppurating—may in the gouty suddenly yield to an acute articular attack.” Is it not here more than likely that the tonsil was the initial site or portal of infection, and the arthritis secondary thereto? Is not this same interpretation in all probability true also of all forms of “gouty” throats when followed by arthritic outbreaks?

The marvel, then, is that not only have we held, but apparently many still hold, that the tonsillitis, pharyngitis, even the gingivitis—like the subsequent articular lesions—are one and all attributable to the underlying gout. We certainly would not do so in the case of any arthritis other than “gouty,” and to my mind the time is ripe for a change of attitude. The “gouty” throats, like the “gouty” teeth, should be regarded not as symptomatic of gout, but etiologically related thereto. We should cease to talk of “gouty” throats, teeth, etc., should renounce the prefix, for there is nothing specific of gout either in the tonsillar, pharyngeal, or dental lesions. We should instead view these various local disorders in their true perspective as foci of infection, causally related to the subsequent and secondary “gouty” arthritis.

Gastro-Intestinal Disorders.—It is a matter of common experience that acute attacks of gout are often preceded by or associated with flatulence, heartburn, acidity, loss of appetite, confined bowels, scanty, high-coloured urine, and a feeling of lassitude. In short, nothing is more certain than that exacerbations or relapses very commonly follow symptoms referable to gastro-intestinal and hepatic disorders.

How well established is it that these subjects after unusual, though not necessarily excessive, indulgence at the table, almost inevitably, and sometimes almost immediately, suffer twinges in the big toe, if not frank outbreaks of gout. Such reaction seems to indicate clearly that the functional disturbances in the alimentary tract stand in some causal relation to the subsequent arthritic phenomena. The assumption gains colour, too, from the very certainty with which freedom from such gouty manifestations is attained by abstinence from, or more moderate indulgence in, articles of diet predisposing to such ebullitions.

So much by way of prelude as to the probability—attested by clinical observation and the results of treatment—that the intestinal canal is often the source of the responsible microbe or toxin. Let us now pass to consider what factors other than an oral sepsis may favour the incidence of functional disorders of the alimentary tract.

Variations in Free HCL.—Some years ago Grübe and Falkenstein found that in gout the hydrochloric acid of the gastric juice, far from being increased, was in most cases diminished or wholly wanting.

Now, as we know, the gastric juice when of normal acidity is quite capable of dealing with moderate quantities of pathogenic bacteria. But in the presence of oral sepsis it is probable that a greater number are swallowed than can be satisfactorily coped with.

Given therefore excess of pathogenic organisms and relative insufficiency of free HCL, conditions favourable to the growth of bacteria ensue, while incidentally the chance of such reaching the intestine is materially enhanced.

When, however, the defensive barrier is wholly withdrawn, viz. when there is an absence of free HCL, then of course the necessary inhibition of microbic growth fails of achievement. Moreover, also owing to diminished acidity, ill-digested protein substances gain access to the intestine, and their subsequent putrefaction is favoured.

In opposition to the foregoing, many hold that an excess of free HCL in gout is not uncommon, and unquestionably some are thus troubled. The pernicious effects of the hyperchlorhydria are accentuated by the fact that intestinal indigestion ensues secondarily, owing to the acid chyme completely antagonising pancreatic secretion and thus impairing digestive capacity.

Intestinal rather than gastric indigestion is, I think, more typical of the gouty subject. It will be recalled that the food nucleins are unaffected by the gastric juice, and though the protein moiety is split off from the nucleinic acid by the pancreatic ferments, yet neither the poly- nor the mono-nucleotides are thereby acted upon. It is in truth the succus entericus with its nucleotidase that plays the most important digestive rôle as regards nucleins, breaking them up into nucleosides which are, to a large extent, absorbed as such.

To resume, this condition of intestinal indigestion may arise from a variety of causes: excess or deficiency of gastric juice, defective motility, and diminished secretion of intestinal juices, and in all cases improper food may determine such intestinal derangement.

The clinical features presented are very variable. It is often difficult, if not impossible, on the basis purely of the subjective symptoms, to decide in any given instance how far the symptoms are referable to intestinal stasis, or to a chronic infection, with a resultant catarrhal state of the mucosa, or to both causes combined in varying proportions.

But, be the explanation what it may, in our experience the most common antecedent or concomitant of gout is intestinal dyspepsia. Its secondary consequences are far reaching, especially if the small bowel be involved, catarrh of which may lead to reduction in the secretion of bile and pancreatic juice.

How commonly in these cases do we meet with symptoms indicative of sluggishness of the hepatic functions, such as turbidity of the urine, a pale or abnormally dark colour of the alvine evacuations. Also, whatever be its true etiology, they exhibit not so uncommonly sugar in the urine, the so-called “gouty” glycosuria.

Now, as a mere glance will show, diminution and impairment of the biliary and pancreatic secretions have far-reaching consequences. Foodstuffs undergo abnormal changes, are less easily absorbed, and simultaneously chemical products are formed which irritate the intestinal mucosa. Nor do the baneful effects cease here, for, owing to the unusual nature and reaction of the intestinal content, the bacterial flora in the bowel undergo modifications.

Thus, organisms normally present only in small numbers in the small intestine find the altered medium more suitable for their growth and multiplication; while others, whose usual habitat is the large bowel, migrate upwards, and infect the ileum and duodenum, and ultimately the biliary and pancreatic passages.

In the presence of such deficiency in the intestinal juices, proteins are imperfectly digested, and putrefaction under microbic action favoured. At the same time the digestion of carbohydrates is impaired, organic acids are formed, and gases in larger amounts liberated. Ultimately, owing to absorption of these irritating products, a condition of chronic toxæmia results.

SUMMARY

It now devolves upon us to decide whether the phenomena of gout are best explicable as the outcome of auto-intoxication, or of infection or sub-infection. The uric acid theory was in truth one of auto-toxæmia, the varied manifestations of gout being attributed to mechanical or toxic irritation by uric acid, the end-product of purin metabolism. But, as we hope to have shown conclusively, uric acid is not toxic, and per se is apparently as innocuous as those other and intermediary products of metabolism which give rise to cystinuria and alkaptonuria.

The question then arises, Is gout haply due to a retention of other metabolites? That outbreaks of gout follow fast on the heels of dietetic irregularities is proverbially true. But there is no certain evidence that the symptoms generally ascribed to auto-toxæmia are referable to substances derived from the foodstuffs under the action of the digestive juices. Toxic as are peptones and primary proteoses when they gain direct access to the tissues, the symptoms produced in no way resemble those affiliated to alimentary toxæmia, much less those of gout. Rather, according to Adami, do they approximate to those typical of anaphylactic shock.

Normally, too, the mucous membrane proves an efficient barrier, these poisonous bodies during their passage through it being transmuted into harmless substances. Nor can we refer the symptoms of gout to a toxæmia secondary to intestinal stasis or other causes. In other words, it cannot be attributed to assumed toxic action on the part of the intermediary and terminal products of protein disintegration. For seemingly these chemical outcasts of the economy become progressively less toxic on their downward path to effete matter.

The diamines, too, produced by bacterial action on foodstuffs, are so minimal as to be negligible, while the toxicity of cholin and neurin is unestablished; and as for indol and skatol, they are with difficulty absorbed from the healthy colon. Experimental researches on carbohydrate and fatty disintegration have likewise proved sterile, while there is no evidence that the anaerobes present in the digestive tract produce ecto-toxins, or undergo lysis with release and absorption of their endo-toxins.

In short, it is but too clear from the foregoing brief résumé of recent experimental findings that, if uric acid cannot be held responsible for the causation of gout, there is no evidence likewise that the disorder owes its genesis to any other of the as yet isolated chemical products of gastro-intestinal digestive activities. Having dealt with this aspect of the question, we shall now pass on to consider whether the phenomena of gout can be more adequately explained on a basis of infection or sub-infection.

Infection or Sub-infection.—Our knowledge as to the exact manner in which local foci of infection work their malign effects almost daily undergoes expansion. It will be recalled that Stewart has shown that “bad teeth” are often etiologically responsible for tonsillar inflammation. It further is well established that streptococci are of common incidence in the tonsils, and Rosenow and Brown from experimental observation have established that these hemolysing organisms, migrating viâ the blood stream, exhibit a marked predilection for forming a fresh nidus in the gall bladder. Here they may initiate a cholecystitis, and secondly gallstones, and in sequence thereto the symptoms associated with gall-bladder-dyspepsia. The same formidable list of sequels may follow infection of the gall bladder from the teeth, stomach, or intestines, notably from the vermiform appendix.

In like fashion the origin of appendicitis may be traced back to septic foci in the mouth, tonsils, naso-pharynx, or to the gastro-intestinal tract. Here again there ensue the symptoms of so-called appendix-dyspepsia. As in the case of the gall-bladder variety, the primary lesion in the appendix may be latent, and the exact diagnosis may be a matter of great difficulty, often indeed only to be achieved retrospectively, viz., when abatement of the symptoms follows ablation of the appendix.

We see, therefore, how far-reaching are the consequences of local foci of infection in the mouth or elsewhere. Now, the gouty subject enjoys no immunity from the remote sequels of local sepsis. But as a rule, unfortunately, whatever be the nature of his dyspeptic symptoms, they are, like his dental anomalies, his tonsillar inflammations, forthwith dismissed as symptomatic of gout, not etiologically related thereto.

Now, I have seen pyorrhœa and chronic appendix-dyspepsia running side by side in the same subject with recurring classical attacks of gout in the big toe. The faulty teeth were extracted, and later the chronically inflamed appendix removed; and though he had an attack of gout shortly after the operation, there has as yet been no recurrence thereof.

Again, by the older writers “gout in the liver” was most firmly believed in—as one authority puts it, “a subacute catarrh of the intrahepatic biliary system which may lead to a subacute parenchymatous hepatitis”! But more pertinent to my point is the insistence of older authors upon the frequent association of gout and gall-stones. Senac, of Vichy, claimed indeed that out of 166 cases of biliary lithiasis 95 had gout or an hereditary predisposition thereto. Judging by modern experience, this is probably a gross over-estimate. In contrast, our own countryman Murchison dwelt upon the frequency of jaundice in gout independently of biliary colic. And, as we shall see later, Brinton held that many of the dramatic phenomena accredited to “retrocedent gout” were unrecognised examples of biliary colic.

But, controversy aside, the point I would lay stress on is, that we should refrain from labelling offhand “dyspeptic” symptoms in a “gouty” subject as gouty, this when we are so constantly confronted with local foci of infection in the mouth, or elsewhere, which afford us an explanation of the gastro-intestinal symptoms at once more obvious and more rational. This also the more especially in that—as far as subjective symptoms go—those deemed typical of so-called “gouty” dyspepsia are indistinguishable from those met with in appendix- or gall-bladder-dyspepsia. Indeed, I might go further and point out that the variations in free HCL in the gastric juice—as observed in gout—conform to those met with in the above disorders. Thus, in “gouty” dyspepsia, the free HCL may be normal, in excess, or wholly absent, as in gall-bladder or appendix-dyspepsia. I would therefore plead that in any “dyspepsia” arising in a genuinely gouty subject we endeavour to elucidate the exact nature of the underlying lesion, but to this we shall return again when discussing diagnosis.

Again, the fact that gall-bladder or appendix lesions may be the outcome of septic foci in the mouth enables us the more easily to explain the not infrequent co-existence of gout and glycosuria. For an infected gall-bladder may by extension determine a chronic pancreatitis.

Lastly, what of the relationship of local foci of infection to “gouty” synovitis and arthritis? Is one focal infection more than another particularly related to arthritides? Whatever be the true inference, if we take arthritides as a whole, nothing seems so efficient a cause of their production as oral sepsis. Accordingly, some are inclined to think that organisms, e.g., streptococcus viridans, at the roots of the teeth or others in the tonsillar crypts, pass, viâ the blood-stream, direct to the joints. Others, again, hold that, given oral sepsis, infection of the stomach and lower levels of the alimentary tract and its accessory cavities ensues. And in sequence thereto infection of the joints may take place from local foci throughout gastro-intestinal tracts.

Those who favour the view that direct infection viâ the blood from foci of oral sepsis is the more probable modus operandi are wont to produce the following points in support of their view. Arthritis, they say, is relatively rare in enteric fever. In yet another disorder, dysentery, which gives every chance of absorption from the intestine, arthritis when it occurs is seldom very acute, while in appendicitis it is distinctly uncommon.

On the other hand, we must recall that even in normal animals the alimentary and respiratory tracts, and alike the liver and kidneys, constantly afford cultures of pathogenic and non-pathogenic bacteria. Such was established by Adami and his co-workers, who moreover found that such organisms, through the agency of leucocytes, continually pass into the system, where subsequently in the healthy animal they as constantly undergo destruction.

If, however, inflammatory processes are at work, their migration into the tissues is favoured. For under such conditions leucocytes aggregate at the reactive focus, and concurrently, their migration being more active, larger numbers of bacteria achieve entry into the system. The subsequent course of events is determined by the number and virulence of the organisms that effect a lodgment in the tissues, where under favourable conditions they originate other foci of infection or sub-infection.

By sub-infection is understood the fact that microbes carried into the system undergo slight, if any, numerical increase, and do not set up foci of suppuration. Here we may note that “gouty” inflammation, however intense, never ends in pus formation. But, to resume, the bacteria, instead of multiplying, undergo lysis, and, their endo-toxins being released, the more highly specialised tissue cells in the vicinity are destroyed. Coincidently the lower grade connective tissue elements are by the self-same poisons stimulated to proliferate, and an area of chronic interstitial fibrosis is formed.

Incidentally this is interesting, inasmuch as the visceral organs in gout evince a tendency to fibrosis. But, as Gideon Wells observes, “the actual increase of uric acid in the blood and tissues in gout is so slight that we are not warranted in saying that the usual tendency to sclerosis in all the organs in gout is due to the action of uric acid rather than to some other unknown agent or agents.” In view of these revelations, is it not infinitely more likely that the chronic interstitial fibroses in gout are the outcome of such sub-infection?

The assumption gathers weight in light of the experimental proof adduced by Adami that not only tubercle bacilli, but streptococci and other organisms, taken orally, can gain an entrance into the system. Upon this basis we get a clear conception of the possible relationship of gout to local foci of infection. Thus, whether it be a condition of oral sepsis—pyorrhœa alveolaris, tonsillar sepsis, sinus disease, intestinal disorders, constipation, and so forth—we see that it is highly probable that organisms at any one of such infective foci may gain access to the blood-stream with subsequent installation of local lesions in joints or other structures.

Now, as pointed out, inflammatory states or functional derangements of the alimentary tract, whether focal or diffuse, favour the ingress into the tissues of organisms. Is it not reasonable, therefore, we ask, to suppose that the functional derangements which so commonly precede or accompany gout may modify the character of the intestinal flora, and promote their migration inwards in greater numbers? The inevitable swiftness with which relapses or exacerbations of this disorder follow even venial dietetic indiscretions distinctly favours this assumption, one, moreover, substantiated by the amelioration or immunity which follows abstention from the offending foodstuffs. The often prolonged course, too, of gout, and its marked liability to periodic recurrence, would be explicable as the outcome of a continued or intermittent series of sub-infections.

My conclusions then are that:—

(1) The majority of cases of gout are marked by the presence of local foci of infection, pyorrhœa alveolaris, tonsillar, pharyngeal or nasal sepsis, etc., or by gastro-intestinal derangements, constipation, etc.

(2) The said local foci should be regarded not as symptomatic of, but etiologically related to, gouty arthritis, and that the same is strongly indicated by the fact that

(3) Acute glandular affections of undeniably infective source—tonsillitis, pharyngitis, etc.—frequently and immediately precede acute paroxysms of articular gout, and, lastly,

(4) The gastro-intestinal defects, secretory or motor, which chequer the course of gout, enhance the pathological activities of the intestinal flora, and incidentally the liability to infection, at various sites of the alimentary tract.

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XV. GOUT AS AN INFECTION (continued)

ANALYSIS OF THE ACUTE PAROXYSM

If we reflect on the general features and local characters of an initial outbreak of gout they are precisely such as would, did they occur anywhere but at the classic site, the big toe, suggest an infection. The abrupt onset, the local signs, the crisis, and no less the subsequent swift restoration to health, how strikingly reminiscent of an exanthematous fever! Moreover, does not this outward clinical resemblance seem to predicate an inward pathological similarity? And now to scrutinise more narrowly the component elements that make up the content of a paroxysm of gout.

Its fulminant onset, with shivering, if not a definite rigor, in a person in sound and sometimes exuberant health, irresistibly reminds one of the sudden onfall of an infective disorder. Doubtless, as Duckworth says, “the conditions leading up to the attack have been some time previously in operation.” But, as he rightly contends, “some determining factor must now be invoked to explain how, as it were, the train is fired.” Quite so, and what more likely to call into the open these latent morbid potentialities than an infection?

The constitutional disturbance is often profound, certainly out of all proportion to the severity and extent of the local phenomena. Especially prominent are the nervous concomitants—the excruciating pain, the irascibility, etc. Viewing these in light of the paroxysmal nature and periodicity of gout, Duckworth postulated a kinship between the disorder and the paroxysmal neuroses. But, given an infective element, what more plausible than to attribute the nervous phenomena of gout to the simultaneous action of its toxins on the higher centres?

The temperature curve, again, is obviously compatible with this conception. It begins abruptly, its course punctuated by daily remissions. No specific peculiarities apparently differentiate it from other arthritides of established or assumed infective origin, but its relatively low grade pyrexia recalls that typical of gonococcal arthritis. Its most striking feature, however, is the disproportion between the level of the pyrexia and the intensity of the general and local phenomena. Moreover, the temperature is not only low, but relatively ephemeral in duration, while the inflammatory reaction in its violence emulates that of the most sthenic forms of arthritis.

Albeit both the febrile disturbance and the local reaction display infinite grades of severity. Thus, acute gouty polyarthritis may be afebrile and the asthenic varieties of the affection marked by little inflammatory reaction. All these vagaries, however, are quite compatible with infection—the reflex, as it were, of varying degrees of toxæmia.

Says Duckworth, “The pyrexia proper to acute gout is paroxysmal with remission, and the pain of gout is likewise paroxysmal. One is reminded of the influence of marsh poison upon the nervous centres. This paroxysmal no less than periodic element in gout stamps a nervous character upon the malady and binds it in alliance with other well-recognised neuroses.”

How interesting these reflections by this distinguished physician in light of latter-day revelations! For, in so far as these features in gout are reminiscent of malaria, they disclose an affinity, not for a malady of nervous, but one of established infective, origin.

Simultaneously with the onset of pyrexia the pulse quickens. The blood shows that increase in fibrin characteristic of inflammation, a fact noted by Gulland, Cabot, Buchanan and others. But more significant is the presence of leucocytosis. It may be of high grade. In a case of acute gouty polyarthritis recently under my care the leucocyte count reached 27,000. Even in a subacute example of the classic monarticular type the leucocyte count attained 25,920. It was of leucoid type and attended by moderate anæmia due to deficiency of red corpuscles.

Nor is leucocytosis restricted to the periods of exacerbation, but it may be met with in the inter-paroxysmal stages. In my experience, even in cases of definitely chronic type it may reach 14,000. The higher grades of leucocytosis are obviously very suggestive of an infection, and that lesser degrees should be encountered in examples of definitely chronic type seems to point to gout being of the nature of a chronic or serial infection.

I would here add also that the converse of leucocytosis, viz., leucopenia, is sometimes met with in chronic cases. Dr. Munro and I have met with two instances of such in chronic gout in the intervals between paroxysms. This decrease in the number of leucocytes (leucopenia) is, of course, deeply interesting and, needless to say, quite compatible with infections, e.g., enteric, malaria, tuberculosis. In fact, it suggests that gout may be the outcome of divers infections, and not due to any specific organism.

Enlargement of the lymphatic glands was, by older authors, believed not to occur in gout. But obviously the lack of macroscopic evidence does not exclude the possibility of microscopic changes in these structures. The likelihood of such, moreover, is enhanced by the occasional occurrence of lymphangitis in connection with the inflammatory articular lesions. Buzzard, indeed, long since claimed that there was “clinical evidence of subacute gouty inflammation of lymph spaces in certain regions due to uratic deposit and influence.”

As a matter of fact, enlargement of the lymphatic glands does occur. Thus, my colleague James Lindsay cites an instance thereof. The subject, a painter, fifty-three years of age, had gout of some three years’ standing. During an acute paroxysm thereof “there was a mass of glands in the right groin, synchronous with an acute inflammation affecting the right knee and periarticular tissues. On the subsidence of the gouty inflammation the glands became smaller, but never entirely disappeared during the four weeks he was subsequently under observation.”

Splenic enlargement, states Duckworth, has been met with in many cases of gout, and occasionally infarcts. But such splenic enlargement is, he thinks, not specifically related to gout, but is due to associated conditions. Personally, I have not as yet met with splenic enlargement in gout.

This aside, is it not palpably significant of infection that Paget, Garrod, and others, repeatedly noted the incidence of acute phlebitis in a limb the seat of acute articular gout? Did we observe such a complication in any arthritis other than gouty, should we not inevitably regard it as indicative of the spread of an infection from the joint to the related veins?

Reverting to the local articular phenomena, they are not only compatible with, but emphatically suggestive of, an infective source. The typical signs of inflammatory reaction are swiftly installed in acute classical gout, and this with an intensity unrivalled save by the most sthenic types of acute arthritis. Witness how insistent were our forefathers, e.g., Scudamore, on the differentiation of acute gout, not so much from acute rheumatism as from erysipelas or phlegmon. Garrod, indeed, held that “if a medical man, by chance entirely ignorant of the nature of gout, were to see a toe affected by this disease in its full intensity, swollen, hot, red, and tender, he would probably think that the affection must of necessity terminate in suppuration, yet I believe this never happens as the result of simple gouty inflammation.” This leads us to note a salient feature of gouty inflammation, viz., it never results in pus formation. Now, allowing for the increased powers of discrimination that happily to-day are ours, is it not, I ask, significant that the disorders deemed most likely of confusion with acute gout belong to the frankly infective category?

That Garrod’s caveat was not uncalled for I feel sure, having myself known an acute gouty arthritis incised in the hope of evacuating pus. Sometimes the error in judgment is reversed and pyæmic or septic conditions in or near the great toe joint confounded with gout. Thus, Sir James Paget tells of an instance in which a pyæmic abscess forming near the great toe and consequent upon ligaturing of piles was thus confused. I recall, too, another example in which the supposed gouty arthritis of a great toe was of pyæmic nature, the outcome of a suppurating otitis media. Garrod, it may be recollected, ranked pyæmia as one of the disorders to which gouty subjects were especially liable.

Gouty inflammation resembles most other forms of the same morbid change, but some, however, contend that the association of œdema therewith is pathognomonic. Indeed, by some of the older authors this concomitant feature of gouty inflammation ranked as a criterion differentiating it from “true rheumatic inflammation.” Œdema, of course, is not distinctive of gouty as opposed to other forms of inflammation. But its occurrence therein is, we would submit, but another token of its affinity with the infective arthritides. We need but recall the constancy with which local œdema is met with in, e.g., gonococcal arthritis. More typical of gout, however, is the desquamation of the cuticule that follows the subsidence of the acute arthritis. Here we are reminded of the similar peeling of the skin that occurs in another infective disorder associated with arthritis, i.e., scarlatina.

Acute gout is definitely paroxysmal. The attack, at any rate when primary, is relatively ephemeral, lasts but a few days, and after it has passed, as Cullen says, “leaves the person in very perfect health, enjoying greater ease and alacrity in the functions of both body and mind than that for a long time before experienced.”

In short, acute gout would appear to be a self-delimited disease, its fleeting duration predicating that if an organism be responsible, the same is short-lived. Even in chronic gout, though it never quite loses its grip of those it has made its prey, yet nevertheless there are intervals of respite between the attacks, however long the latter may be. In other words, the disease never loses its paroxysmal character, which to my mind is very suggestive of a serial infection.

The periodicity of gout was, as we have seen, well known to the ancients. Its recurrence in early spring and late autumn has even been celebrated in verse:—

“On whose sacred internodial Altars I Each Spring and Fall at least will sacrifice Morbifick, painful loads of Matter tartarous, With recrements of nervous juice impregnate.”

“The Honour of the Gout,” by Philander Misaurus.

Scudamore referred its prevalence at these particular seasons to their attendant vicissitudes of heat and cold (the strongest of all the exciting causes of gout). Trousseau states that “gout with successive paroxysms shows itself early or late in the year, at the beginning of spring or late autumn, the wherefore I know not.”

This tendency on the part of acute gout to seasonal rhythm is ultimately lost. For, once the disorder is established, no period of the year confers absolute immunity. Whatever be the explanation of the vernal and autumnal incidence of gout in its early stages, this peculiarity is at any rate not incompatible with its infective origin. In this connection it may be recalled that it was once described as “a tertian fever terminating in fourteen days.”

Again, further evidence may be obtained from the action of colchicum, our sheet-anchor in the treatment of gout. Thus, Dixon and Malden have shown that colchicine has no action on the metabolism of purins or on the kidney. On the other hand, it causes a primary diminution followed by a marked increase in the number of leucocytes, which suggests the possibility that it exerts its beneficial effects by combating infection.

Lastly, turning our attention to the anatomical changes as disclosed after death during an acute articular paroxysm, these present appearances quite compatible with their infective origin. Dr. Munro, in one of my examples of acute gouty polyarthritis, aspirated the knee joint. The results of cytological examination were precisely such as are deemed characteristic of arthritides of infective source.

The results of our analysis of the component elements of an acute paroxysm of gout are, for the following reasons, strongly indicative of the intrusion of an infective element:—

(1) The onset, temperature curve, the character of the local phenomena, and course of the disorder.

(2) The presence of leucocytosis with secondary anæmia, and exceptionally of leucopenia.

(3) Enlargement of the lymphatic glands, and possibly of the spleen.

(4) Occasional complication of the acute articular disorder by lymphangitis and phlebitis.

(5) The paroxysmal nature and periodicity of the disorder.

(6) The compatibility of the morbid anatomical changes and the cytological content of aspirated joint fluid with their genesis by infection.

THE EVOLUTION AND LIFE HISTORY OF GOUT

If the onset, phenomena, and course of acute gout are reminiscent of infection, so, also, does a review of the life history of the disease, as a whole, carry with it the same inference.

For the course of gout, like other arthritides of chronic type, is not one of steady, uninterrupted progress, but one marked rather by periodic or intermittent advances, as if seemingly due to a series of successive infections or sub-infections. One is reminded of gonococcal arthritis in its more severe forms, the acute exacerbations which chequer its course being generally referred to intermittent absorption of fresh doses of the toxin from some smouldering infection in the prostatic urethra.

Now, if the general course or evolution of gouty arthritis is notably similar to that of the specific infective arthritides, so, also, do the clinical features approximate. Thus its onset, more often than not, is abrupt and attended by pyrexia of irregular or septic type, with an occasional leucocytosis.

Again, that not all cases of gout are of acute fulminant type may be admitted. We know that it may assume the guise of a fleeting arthralgia or “flying gout,” a transient synovitis, as well as an acute arthritis of mono-, oligo-, or poly-articular extent. This same polymorphism in respect of the joint lesions in gout is a replica of that met with in the specific infective arthritides. The milder varieties betokened by arthralgia or synovitis tend commonly to disappear, as it were, spontaneously in precisely the same manner as the arthralgias or synovites that follow the exanthemata, and we presume that, comparably with these latter, the source of infection dries up and restitutio ad integrum of more or less completeness follows.

But with repeated attacks, as in the specific infective arthritides, progressive infiltration and thickening of ligaments, capsule, and related tendinous and aponeurotic structures ensue. As far as these anatomical changes are concerned, gouty arthritis and the specific arthritides are at one, but with this outstanding difference, the associated uratic deposition. Save in respect of this last, the analogy is complete, and herein resides the specificity of gouty arthritis.

Chalmers Watson, from his observations of “gouty deposits” in human subjects in their relation to tendons, cartilage, and bone, came to the conclusion that the tout ensemble of the pathological lesions was very reminiscent of that typical of the more chronic types of infective disorders. Thus necrotic areas in gouty tendons stood in such clear relationship to the vascular supply as to suggest some infection viâ the blood-stream. Again, areas of erosion in the cartilage were found to be due, not to uric acid, but to the disintegrating action of small round cells of the nature of granulation tissue.

As to uratic deposits located in the bones, it was noted that their vicinity was characterised by marked vascularity, the existence of giant cells, and an accumulation of the small round cells so commonly correlated with the action of bacterial toxins.

In reviewing the foregoing clinical and pathological data and, alike, the inferences as to their significance, it cannot, we think, be gainsaid that, collectively, they are more readily explicable as being due to an infection than to any other morbid source.

ANALOGIES BETWEEN GOUT AND THE SPECIFIC INFECTIVE ARTHRITIDES

A striking parallel can be drawn between the varied manifestations of gout and those met with in specific infections. But, to begin with, we must recall that our attitude towards infective disorders, e.g., acute rheumatism, gonorrhœa, etc., is altered in that we regard them now, not as local, but general, systemic infections.

Thus, following the revelations of bacteriologists, we now, for example, recognise that in gonococcal infection not only may there be articular involvement, but that muscular and nervous lesions may be associated therewith. This same, also, in acute articular rheumatism. True, its causal organism is still sub judice, but data accumulate as to the frequency with which the muscles are involved, and, to a less extent, the sheaths of nerves.

Take dysentery, again; it, too, as Sydenham pointed out, may be complicated, not only by arthritis, but by myalgias, while more recent experience emphasises the frequency with which neuralgias are associated therewith. In syphilis, also, the association of articular, muscular, and nerve lesions is well attested; and by French physicians it is insisted that, in tubercle, myalgias and neuralgias, as well as joint disorders, are infinitely more common than is generally realised.

To sum up, this triad of arthritic, muscular, and nerve lesions, either serially or simultaneously, is the most common complication of specific infections. Now, is not this same congeries of articular, muscular, and nerve disorders precisely the clinical content of gout?

Thus its articular manifestations constitute the most striking feature of the disease. As to the muscular troubles, there is a consensus of opinion as to their relative frequency. Inflammatory foci with associated uratic deposit have been found in muscles and tendons. We may here recall that the purin bases of the body exist, not only in the bound form (nucleic acid), but also free, especially in muscular tissue, also that from such free purin bases uric acid can be as readily formed as from those liberated by disruption of nucleic acid.

Clinically, one meets with all forms of fibrositis in actual association with acute articular gout. Such may affect either the neck, shoulder, loin, or sciatic nerve. In their work on “Fibrositis,” Bassett Jones and Llewellyn have shown that the disorder develops with significant frequency in the victims of gout. This but confirms the conviction held by Gowers, Garrod, Hilton Fagge, and others, viz., that the muscular and nervous types of fibrositis are frequently and obviously related to gout.

How noteworthy the well-established proclivity of gout to involve bursæ, tendon sheaths, and fasciæ, especially the plantar! Is not this exactly paralleled in certain infections? Note the predilection of post-scarlatinal rheumatism for bursæ and tendon sheaths; that of the gonococcus for these structures as well as fasciæ, not to mention the frequency with which bursal enlargements are traceable to syphilitic, tuberculous, and other infections.

We see, therefore, that in virtue of its tendency, not only to arthritic, but also to muscular and nerve disorders, gout falls into line with the specific infections. Its predilection for bursal and fascial structures is but another evidence of affinity with this group of disorders. In view of these similitudes, one may well ask, Are not these gouty manifestations, all of them, susceptible of a like explanation, viz., that they are the outcome of an infection?

For, in reviewing the foregoing analogies, it cannot, we think, be denied that in the aggregate they are emphatically suggestive of an infective origin.

CORRELATION OF THE METABOLIC PHENOMENA OF GOUT WITH THE POSTULATED INFECTIVE ELEMENT

In essaying this difficult task, we must recall to the mind of the reader our findings or deductions from the data disclosed in preceding chapters.

The outstanding conclusions that we felt justified in formulating were that:—

(a) Uric acid is not the cause but the consequence of gout.

(b) Inflammatory reaction is, we believe, an invariable precursor in all gouty processes.

In other words, we suggest that, although abnormalities of metabolism form an integral part of gout, they are of themselves inadequate to achieve its efflorescence. Thus, when we came to consider the elemental manifestations of gout, i.e., uratic deposits or tophi, we saw that neither the purely physical nor the purely chemical theory of their origin would suffice, nor, for that matter, could any solution of this complex problem be gleaned from even a blend of the twain. In short, such hypotheses are too mechanical. The intrusion of some other factor, “some vital something biological,” seems essential for the elucidation of uratosis, i.e., uratic deposition. For this, not uricæmia, is the specific characteristic phenomenon of gout. If we cannot explain uratosis on physical or chemical grounds, then how much less, in view of the non-toxicity of uric acid, can we, on this basis, account for the inflammatory phenomena of the disorder?

Inflammatory reaction is, we hold, an invariable antecedent in all gouty processes, whether of articular or ab-articular site. Granted that inflammatory reaction is a necessary prelude, the specificity of gout is attested by the fact that this same is followed by the deposition of urates. But while the sequential uratic deposition invests all forms of “gouty” inflammation with a specific character, unshared by any other disease, it follows that the cause of the said inflammation must, if possible, be ascertained.

For Walker Hall “the contention that gout lowers the general tissue resistance, and so opens the way to bacterial infections, is so obvious that it need hardly be formulated.” In light of this, we need have the less diffidence in hazarding our opinion that the morbific agent responsible for “gouty” inflammation is an infection or sub-infection. Now, in all forms of arthritis other than gouty, the intrusion of a germ is held to be self-explanatory and final; in short, all the local morbid changes and constitutional disturbances are held satisfactorily accounted for by the organism or its toxins.

The problem of gout, however, is not so simple. Its arthritis is peculiar in that it is always accompanied or followed by uratic deposition, which, be it noted, is not an ordinary sequel of inflammation. It is, in short, the outcome of inflammation supervening in an individual of gouty diathesis. What do we know of this latter?

The researches of the bio-chemists reveal that uric acid is the end-product of nuclein metabolism—the summation of a long chain of enzymatic reactions. Some indeed have thought to find an adequate explanation of gout in enzymatic abnormalities. Thus, Adami and McCrae suggest that gout is the outcome of insufficient oxidation, whereby the precursors of uric acid and similar bodies are not fully oxidised, and, by their accumulation and toxicity, set up morbid changes, and the uric acid formed is, in its turn, imperfectly oxidised and accumulates. This diminished oxidation is due to a constitutional deficiency of oxydases, inherited or acquired.

This opens up the old problem as to whether uric acid is an intermediary or a terminal product of metabolism. But, from evidence cited in preceding chapters, it appears probable, if not certain, that uric acid is an end-product. Moreover, as Gideon Wells observes, “the failure of recent studies on the enzymatic transformation of purins to locate anywhere in the human body an enzyme-destroying uric acid makes hazardous the attempt to explain gouty metabolism as a result of enzymatic abnormalities.”

Indeed, in view of this, as hitherto ascertained, absence of uricolytic enzymes, there can, as Wells says, “be little doubt that the fundamental reason for the existence of uric acid gout in man lies in the inability of the human organism to destroy uric acid. Consequently, inasmuch as man, unlike other mammals, cannot destroy uric acid rapidly by oxidation, he is always a potential victim of uric acid retention and deposition.”

Now we have, we hope, shown that there is no evidence that the uric acid retention in gout is due to functional inability on the part of the kidney to excrete uric acid. This being so, we have, as Von Noorden rightly says, no right to do violence to the facts by assuming that, in a case lacking any other evidence of nephritis, a condition of “latent nephritis” is the cause of the uric acid retention and deposition.

Similarly, there is at present no evidence forthcoming that the retention of uric acid is due to abnormal purin combinations in the blood. Nay, according to Wells, on the best evidence obtainable, uric acid exists in a free state in the blood, and not combined, as has been urged by many workers in this sphere.

But if the cause of uric acid retention lies neither in the kidneys nor in the blood, there must exist something abnormal in the gouty individual which renders impossible what may be termed a compensatory uric acid excretion. Now, as disclosed in the previous chapter, experimental research, in diseases other than gout, has shown that the bodily tissues have an appreciable capacity for retention of uric acid (Fine). This, moreover, gains probability from the fact that Wiechowski, in his prolonged studies as to the possibility of uric acid decomposition in the human body, was never able to detect any evidence of uricolysis. Furthermore, on the clinical side, the fact that intravenous injection of uric acid does not produce a corresponding degree of uricæmia seems, as Bass and Herzberg suggest, to indicate that in gout the retention capacity of the tissues for uric acid is augmented. Lastly, in the precipitation and anchoring of urates in the tissues in gout, we have objective proof, i.e., tophi, that the uric acid is actually held in the tissues.

Does not this seem to indicate that there are peculiarities of tissue in the gouty? What, then, the subtle change that determines the retention and deposition of urates in the tissues in gout?

May we not, with Walker Hall, hazard the reflection that there may be differences between the nucleotides of normal and gouty tissues? For, doubtless, if there be peculiarities of tissue in the gouty, these will be reflected in abnormalities of tissue function and metamorphosis.

Gowlland Hopkins, discussing the metabolism of purins, holds that in gout there is some disturbance or defect in the fermentative functions of the tissues. Of a verity the range of intranuclear activities offers scope enough when we recollect that the cells of all tissues contain not only nucleinase, but also nucleotidase and nucleosidase. Even so, the resultant nucleins, the nucleotides, and nucleosides, have still further changes of deaminisation and oxidation to undergo, these carried out in the liver and elsewhere!

We may talk of defects in the enzymatic functions of the tissues, but, viewing gout clinically, and more particularly the hypersensitiveness of its victims to the most varied stimuli, dietetic and other, one inclines rather to predicate in their instance an inherent instability of nuclein metabolism. For in the gouty, as Walker Hall observes, “a slight injury or indiscretion of diet, an overloaded intestine, or increased toxicity of the intestinal flora, may be followed by a disturbance of the general nuclein metabolism, and a local reaction in certain tissues.”

With this pronouncement all clinicians will be in accord, and herein, too, we may, I think, discern how the latent tissue idiosyncrasies of the gouty are evoked, i.e., by infection; in other words, that, under the influence of these morbific agents, the innate morbid potentialities of the gouty become overt and manifest.

The exact modus operandi whereby the assumed organisms or their toxins determine the efflorescence of gout is uncertain. We know that, following the intake even of non-purin-containing foodstuffs, an increase in uric acid excretion ensues, and that the same is the outcome of the stimulation of general nuclein metabolism. Is it not conceivable that the responsible toxin acts in like fashion, and haply by disturbing the orderly sequence of those exquisitely delicate enzymatic reactions which culminate in the formation of uric acid, and with which potentialities every living cell in the organism is dowered? Further than this we, pending future researches by the bio-chemists, may not go, for “the positive material is much too insufficient, and much too ambiguous.”

In conclusion, I would postulate that in gouty subjects:—

(1) There is an inherent abnormality or instability of nuclein metabolism, and conjoined therewith an enhanced tissue affinity or augmented retention capacity for uric acid.

(2) These latent tissue peculiarities, through the agency of infections or sub-infections, become manifest as gout.

(3) The said organism or organisms excite inflammatory reaction with sequential uratic deposition, either of articular or ab-articular site.

(4) The predilection of such uratic deposition for certain particular tissues is determined by their greater content of sodium ions as compared with the blood.

(5) The local and general phenomena of gout, its paroxysmal nature and tendency to periodicity, are most readily explicable on the basis of a chronic infection supervening in a subject the victim of those innate peculiarities of tissue with their correlated obliquities of function which connote what we term the “gouty diathesis.”

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XVI. CLINICAL ACCOUNT

ACUTE LOCALISED GOUT

If we would clarify somewhat the obscurity that enshrouds the genesis of disease, our watchword must here, as in other spheres, be “Despise not the day of small things.” We know not the proximate cause of gout, it is true, nor the exact modus operandi of those agents, infective or other, which bring to fruition the latent morbid potentialities of its victims. But, even if so handicapped, we should be quick to descry those portents of the coming storm, those minor backslidings from physiological righteousness, that doubtless foreshadow the outbreak of the disorder.

For it cannot be doubted that the evil potentialities which make for gout are for long in operation before their definite installation in its chosen seat, the joints, ensues. As Trousseau puts it, “The diathesis is in action before there is time for the local affection to show itself in a precise form.” In short, given imminence of an attack, the whole system is charged with gout, or, as Sydenham laconically expressed it, “Totum corpus est podagra.”

PRODROMAL SYMPTOMS

While we recognise that local inflammatory reaction in the joints is more particularly characteristic of gout, it is no less necessary that we take cognisance of the general precursory symptoms that often, if not always, usher in its onfall. Gout begins in a disorder of function.

Uncomfortable sensations may obtain days and weeks before the incidence of the fit. To old time sufferers they are sufficiently alarming. But their significance, as heralds of an initial attack, by victim and too often by physician also, is usually only appreciated when the threatened fit becomes an actuality. Speaking of premonitory phenomena in gout, Sydenham remarked, “Its only forerunner is indigestion and crudity of the stomach, of which the patient labours some weeks before,” and doubtless this is in the main true.

As Trousseau long since observed, the patient’s appetite often becomes capricious. He likes his meat strongly spiced, and craves for acids. But his satisfaction is short-lived. For eating is followed by drowsiness, feelings of oppression and fulness, with unpleasant eructations, or more rarely definite retching. The bowels are generally costive, but in exceptional instances diarrhœa has been noted. The state of the urine is variable. Generally scanty and high-coloured, it may in some be copious and pale.

Uneasiness in the right hypochondrium and even slight swelling of the liver was noted by Trousseau and also by Scudamore. Such congestion of the portal system and hepatic enlargement may be only fugacious, but often the same is permanent, a penalty of the same cause—free living—which leads to the production of gout. For in many instances but too true is it that “for years together,” as Sydenham said, “a man has drunk and feasted, has omitted his usual exercise, has grown slow and sluggish, has been over-studious or anxious, in short, has gone wrong in some important point of life.”

But more palpable to his friends than to himself are the concomitant changes in his disposition and character. From being good-natured and easy-going he becomes morose and irritable. The irascibility of the gouty is proverbial, and the explosive mental outbursts to Duckworth appeared at times to be “a metamorphic substitution for a more overt and regular attack,” or, as Sydenham expressed it, “Non rectius podagræ quam iracundiæ paroxysmus omnis dici potest.”

Sometimes his mental vagaries are exchanged for or accompanied by neuralgia, painful cramps in the limbs, etc. In truth, the premonitory phenomena of gout are protean, inasmuch as, given any prior weakness or functional derangement of any viscus, the symptoms of oncoming gout are masked by aggravation of the same, it may be by cardiac irregularities, vesical irritability, or in an old bronchial subject by increase of cough, etc.

But it may be objected, there is nothing specific about these various functional disturbances. They are not more common in the gouty than in others. Moreover, the habits of life productive of gout favour the development of gastric and hepatic derangements. The mental irritability, the gastric disturbances, etc., may be quite as well accounted for by overeating and overdrinking as by gout.

Now, if there be nothing specific of gout in these so-called prodromata—“heartburn, acidity, flatulence, etc.”—then what is their true significance? For, obviously recognition of their true import is most essential. Now to my mind the said “dyspeptic” symptoms should be regarded not as symptomatic of gout, but as etiologically related thereto.

For, though the etiology of gout is still much debated, the same obscurity will certainly not be clarified, if we merely content ourselves with dubbing such “dyspeptic” symptoms as “gouty.” On the other hand, if we, at this early stage, endeavour to elucidate the true origin of the “dyspeptic” symptoms, who will deny that this is the more rational and scientific mode of procedure? The timely elimination of septic foci in the mouth, tonsils, and naso-pharynx conjoined with modification or restriction of food intake and recognition betimes of the signs of intestinal infection and constipation would perhaps stave off or avert the threatened articular outbreak.

It has been suggested that there is some statistical evidence that “acute rheumatism” has declined in frequency since the introduction of tonsillectomy. In the same way, I cannot help thinking that the growing infrequency and attenuation of gout is in part due to increasing appreciation by the laity and the profession of the vital importance of oral hygiene and timely and radical treatment of local foci of infection. The fact that in children, victims of so-called infantile gout, the purin metabolism may show those same derangements held typical of the subjects of gout, is surely an indication that the disorder begins betimes, and that we too must not tarry if we would prevent these evil potentialities coming later to fruition.

Now, if there be nothing specific of gout in the “dyspeptic” derangements held prodromal thereof, the reader may well ask the pregnant question, Are there any symptoms or signs that will enable one to identify the victim of these minor discomforts as being “actually” or “potentially” a “gouty” subject? In attempting to answer this reasonable query one would emphasise the fact that tophi in the ears or at other sites sometimes antedate articular outbreaks.

Now given that an individual exhibits auricular tophi, one or many, can anyone deny that he is “gouty,” nay more, that he has gout, this even though he never has had, or may never have, an articular outbreak? In truth, the eruption of a tophus in the ear is as essentially a “fit of gout” as if it had occurred at the classic site, the big toe.

How vivid the light then thrown upon the import, the etiological significance, of otherwise inexplicable functional derangements! How grim the potentialities of, e.g., “dyspeptic” symptoms as revealed by detection in the subject of a tophus! Whether viewed from the diagnostic or prognostic aspect, its importance cannot be overestimated. For let us not forget that the tophus is the one incontrovertible token of the “gouty diathesis.” This morbid localisation is the sole outward expression of the inward and dominant pathological trend.

The great Charcot did not despise its aid. He narrates the case of a man thirty-five years of age, a sufferer for some months from “acid dyspepsia,” in whom he predicted a fit of gout from noting an uratic concretion in one ear. Is not the moral obvious that in an individual complaining of gastric or hepatic disturbances, etc., we should, at any rate, examine the ears for tophi?

For, far more often than is currently realised, their eruption antedates the articular outbreaks.[27] Moreover, they may not be solitary, but numerous, the cutaneous gravel of older authors. In truth, these cases of tophi, uncomplicated by articular lesions, seem to merit some distinguishing term, representing as they do a purely ab-articular form of gout.[28] They constitute what might be termed primitive elemental gout, of which the subsequent articular outbreaks are but an extension, a further manifestation of the “gouty diathesis.” For it is just this same tendency to uratosis or deposition of sodium biurate, and this alone, that to our mind constitutes gout, this “primordial vice of nutrition,” not the congeries of distempers that with the passing ages have clustered around the primitive gout, well-nigh submerging its identity.

Premonitory Symptoms of Tophus Formation.—While tophi may antedate articular attacks, we do not always meet with them as mature concretions easily recognisable as such. We must have regard therefore to the symptoms and signs indicative of their impending eruption. Consequently in a patient complaining of the various functional disturbances that so frequently anticipate gout we should never dismiss as trivial any complaints of pricking or tenderness in the ears.

Sometimes the pain in the ears is acute, the tenderness such as forbids their pressure on a pillow. Graves, of Dublin, not only noted that the pain in some instances was agonising, lasting a few hours, but he himself suffered also from such attacks of auricular pain, which only disappeared when gout supervened in his fingers. I have myself frequently known the pain and soreness referred to chilblains, though later their tophaceous nature was disclosed.

Given such auricular pain and tenderness, we should examine the pinna for small red swellings.[29] These, when definitely localised, should be punctured and the thick white fluid which exudes examined microscopically for urate of soda crystals. In some instances the creamy-like exudate does not yield a crystalline deposit, and Dr. Munro and I are inclined to believe that there is a pre-uratic stage in the evolution of tophi. We have observed this absence of crystalline deposits in apparently unmistakable tophi, as evidenced by the usual pearly white concretions in the rim of the ear. I recollect that the late Sir William Osler, when visiting our laboratory, was deeply interested in this possibility, as suggested by Dr. Munro, of a pre-uratic stage. Needless to say, all local sources of fallacy—Woolner’s tip, fibroid nodules, sebaceous cysts—were excluded, while, in the lack of crystalline proof, the evidence in favour of the associated arthritis being gouty rested on its being at the classical site, the great toe. Moreover, as an alternative explanation we have the possibility of reabsorption. We may recall Duckworth’s well-known example where a man had two attacks of gout in the right great toe joint, yet autopsy revealed no speck of uratic deposit. We know, too, that, following an acute attack, tophi may diminish in size or even disappear, while coincidently fresh tophi form at other sites.

Premonitory Articular Pains.—Again, when, in association with indigestion or other premonitory symptoms, twinges in the toe recur from time to time, especially after consuming wines or certain articles of food, these same are very suggestive of impending gout. Garrod is very definite on this point: “I have no doubt that many persons experience extremely slight attacks of gout before the development of the affection in an acute form, and several of my patients have assured me that for years before their first severe attack in the great toe they have felt slight periodic twinges. I am of opinion that when such twinges occur deposition has already taken place.”

In conclusion, we would urge that, given gastric or hepatic disturbances, etc., in a subject predisposed by heredity or habits to gout, we should note the presence or absence of the following:—

(1) Pain, pricking, or tenderness in the ears, with or without small red swellings.

(2) Similar sensations at site of finger joints, with dorsal swellings over which the skin may be red or unchanged.

(3) The existence or not of pearly white concretions, i.e. mature tophi (as tested microscopically), at the above sites or elsewhere.

Further signs that may be sought for in cases of doubtful nature, i.e. unevidenced by tophi, would be:—

(4) The presence of uricæmia.

(5) A lowered or sub-normal output of uric acid in the urine.

(6) Diminution or retardation of the output of exogenous purin.

To take up the thread of our narrative regarding the prodromal symptoms which at any moment may give place to an articular outbreak. The determinants or exciting causes having been already dealt with in the section on etiology, we shall here only note those symptoms or signs that portend the imminence of the paroxysm. These are very variable. But it is suggestive if without any change in the habits the “dyspeptic” symptoms abate somewhat or disappear.

Indeed, it is well recognised that, whatever the nature of the prodromal phenomena, they all tend to cease just before the oncoming attack. Occasionally a pre-existing depression gives way to a feeling of exuberant health or well-being. We recall the instance of a celebrated physician whose lectures always just prior to an attack took on an added brilliance.

Reverting to more definite harbingers, it has been noted that the urine becomes scanty, and its content of uric acid much diminished, some three or four days before the paroxysm, though such is not invariable. Easier of note and widely recognised is the fact that in those exhibiting tophi pricking pains or tenderness are experienced at their site. Scudamore, Garrod, and Duckworth are all agreed on this point. Another sign noted by Sydenham was that the veins of the part about to be affected become engorged—a feature confirmed by Trousseau and others.[30]

THE ACUTE PAROXYSM

A brief interlude, lasting a few hours or a day, frequently intervenes between cessation of the prodromal discomforts and the onset of the attack. This delusive sense of well-being deceives none but the uninitiated, for to the old time sufferer it is but the truce before the threatened assault.[31]

Still the subject feels better and more placid than his wont, seeks his bed, and sinks to sleep (“sanus lecto somnoque committur”). But suddenly, more commonly an hour or two after midnight, he awakes to a pain in the foot, usually in the ball of the great toe, though more rarely in the heel, instep, or ankle. Simultaneously he becomes chilly, shivers, or has a rigor. But as the pain, at first bearable, grows in intensity, these feelings lapse, giving way to feverish restlessness. Posture after posture is renounced, but, toss as he will, he strives in vain to find a place of ease for the tortured limb. Even the pressure of the bedclothes is intolerable. But towards morning (“sub galli cantu”) the pain remits as suddenly as it began. Anon the sufferer breaks into a gentle sweat, falls asleep, and wakes to find the painful part red, swollen, tense, and shiny, surrounded with œdema and turgid veins.

The same series of events recurs, though often in mitigated form, for some days and nights. During the day his pain is lulled, but towards evening it gathers in intensity to cease or diminish towards morning. The cycle continues from eight to ten days; then pain ceases, redness fades, œdema subsides, and the inflamed cuticle peels, with itching. The temperature meanwhile has sunk to normal, the local tenderness and stiffness gradually pass off, and health is restored. “Gout is the cure of the gout,” said Mead long since, and certainly recovery from the first attack of gout is usually speedy and complete. A renewed sense of bien-être ensues, free from the discomforts that led up to the outbreak. Indeed, in exceptionally rare instances the disease seemingly exhausts itself in a single paroxysm, or decades may pass before another visitation. Sir William Roberts tells of a Yorkshire squire who sustained a classical attack in his twenty-seventh year, the next in his eighty-ninth year. Frequently a second attack may not occur for one, two, or even three years. But the tendency to recurrence usually becomes more and more pronounced as the years roll on, and eventually the gouty man resigns himself to the doleful expectation of an attack once or twice a year, during spring or fall, with some approach to periodic regularity.

Initial attacks of gout are usually monarticular, but consideration of the polyarticular variety will best be postponed until we come to consider acute gouty polyarthritis. Also we think it will be more convenient for us to defer discussion of retrocedent gout to the chapter dealing with the irregular or anomalous types of the disorder. Meanwhile we will now proceed to detailed description of the individual phenomena that make up the clinical content of acute gout.

DETAILED CONSIDERATION OF PHENOMENA

Onset.—From Sydenham’s classical account it might be inferred that the onfall of gout is always fulminant. But this is far from being the case. For I find myself in agreement with Hilton Fagge that in many, if not the majority of instances, even the initial outbreak of the disorder is installed in a far less dramatic manner. Certainly in not a few cases its manner of approach is insidious, not to say stealthy. At onset then the nature of the case is therefore frequently misinterpreted both by victim and physician. The free liver, fearing that Nemesis has overtaken him, is fertile in suggestion. He has overwalked, his boot pinched him, or it is a sprain. Local appearances may be non-committal. There may be no swelling nor redness, and no access of pain at night. Still there is discomfort when he walks. The so-called sprain lingers, and one morning the great toe, instep, or ankle, is swollen, tender, flushed, and the victim’s fears and the physician’s suspicions are converted into certainty: it is gout!

Still in this matter of the onset I must not overlook the findings of my colleague James Lindsay. In 569 cases, the onset was sudden in 458, and in the remaining 111 examples gradual. It was noted that only 14·5 per cent. of the male cases were of gradual onset. But no less than 47·1 per cent. of the female cases developed after this fashion.

Again to resume, it is by no means invariably the case that the onset is nocturnal. For, as Duckworth has pointed out, many attacks begin during the day, and this is perhaps more often the case after the disorder is fully established.

Locality.—Gout in its classical form is monarticular in distribution. In 375 out of 512 initial seizures, Sir Charles Scudamore found that the metatarso-phalangeal joint of the great toe of one or other foot was the joint affected. Garrod, too, noted that, excluding the great toe, in not more than 5 per cent. were other joints implicated. As to the frequency of incidence in joints other than the big toe, opinions differ. For Scudamore it is the ankle, for Garrod the instep, and afterwards the outer side of the foot and the knee. In contrast, Hilton Fagge holds that next to the great toe gout vents its initial fury with greatest frequency upon the metacarpo-phalangeal joint of the index finger, adding, “certainly not the thumb.” Most authorities however agree that gout in its early stages rarely attacks the joints of the upper limb, and even in its most inveterate form the shoulder and hip joints are immune. Personally, I have never seen a case of gout in the shoulder or hip; such cases are usually examples of osteo-arthritis.

Exceptionally, even in first seizures, more than one joint may be affected. Thus it may migrate from one big toe to its fellow, or travelling further afield, may invade ankle, knee, wrist, or elbow, or small joints of hand. W. Gairdner held that in gout the joints of the left were more commonly attacked than those of the right limb. But James Lindsay’s figures would appear to indicate precisely the reverse, viz. a predilection for the right side of the body.

Pain.—If we may accept the lurid imagery of its victims, even the tortures of the Inquisition failed to transcend in agony the—

“... pangs arthritic that infest the toe of libertine excess.”

Cowper.

Sydenham said that at its onset the pain was as that of a dislocation (ossium dislocatio). At its zenith it was as if the flesh was being gnawed, squeezed in a bootscrew, or scalded by molten lead or boiling water. Sensory perversions are superadded, and, as Ambrose Paré said, “some patients say they burn, while others complain of icy coldness.”

Its peculiarly exasperating nature is well illustrated by Hosack, an old time Professor of Medicine of New York, who thus delivered himself: “Some compare it with the gnawing of a dog, the pressure of a vice, or the pain of the actual cautery; this probably is not far from the truth, judging from the anecdote I have heard of a man subject to gout. This man falling asleep barefooted before a large fire, the fire fell, and a large coal found its way to his foot; half awake and half asleep, he cried out: ‘There’s that d——d gout again!’ He at length awoke, when he found a large coal frying his great toe. The sensation of the two evils was probably the same.”

The pain is aggravated in that frequent “startings” of the limb prevent the victim keeping the foot at rest. The slamming of a door, or the incautious shaking of the bed, so quickens its throbbing intensity as provokes a literal frenzy of rage. But fortunately it is not always so. For though the pain of gout is unquestionably severe, at times excruciating, yet it presents infinite grades of severity. Also one must recollect that but too many of its victims are already in a high state of irritability before the outbreak. Moreover, their powers of self-control are too often sapped by unbridled self-indulgence, and they have but slight reserves of patience and fortitude to draw upon.[32]

Apart from the personal factor, in subacute cases the pain is notably less severe than in the acute sthenic form. The pain of gout, as a rule, is more intense than that of acute rheumatism, and, I fancy, than that of all other varieties of acute arthritis.[33] Sir Thomas Watson in his fascinating lectures tells of a witty Frenchman who, comparing acute gout and acute rheumatism in respect of pain intensity, remarked: “Screw up the vice as tightly as possible, you have rheumatism; give it another turn, and that is gout.”

Lastly, in respect of the duration of the pain, it is not always true that it wholly intermits at the approach of dawn. It does so frequently, it is true, but in some instances pain, more or less severe, continues during the day as well as the night. Occasionally, on a crescendo scale, it continues increasing almost up to the crisis. Generally speaking, too, the shorter the duration of the paroxysm the more intense the pain, and the more prolonged the less the degree of suffering.

Following the crisis, the pain gradually becomes less and less, giving place to a feeling of numbness of the toe, which in older subjects may endure for some days.

General Phenomena.—Symptoms, other than those referable to the affected part, vary widely in different cases. In this respect the acute sthenic forms contrast with the acute asthenic types. In the former the pulse quickens; the temperature rises, but rarely exceeds 101°-102°, though Garrod saw it reach 104°. The tongue is furred, the breath foul, with anorexia and thirst. Though the appetite is frequently impaired or lost, yet in some instances it is retained. Dyspeptic symptoms, hiccough, eructations, etc., are sometimes prominent, but often wholly lacking. The bowels are constipated, as a rule, the stools pale, or dark and extremely offensive. The urine is generally scanty, high-coloured, with a lateritious sediment on cooling. It may contain a trace of albumen. Severe cramps affecting muscles of the leg, thigh, and upper parts of the body, are more or less prominent symptoms in a considerable number of instances.

The pyrexia appears to be symptomatic, more or less in proportion to the acuteness of the local phenomena. Comparably the highest temperatures are usually met with in sthenic forms in relatively young or robust middle-aged subjects. Duckworth noted the interesting point that “a preliminary rise is commonly noted for one, two, three or four days before a joint is actively involved.” With the articular outbreak the febrile movement becomes more active. The temperature runs up to 100° or over, but with the morning abatement sinks to normal or nearly so. The following evening it rises again frequently to a higher level, 102° with a morning remission, and so it continues for a variable number of days, it may be only two or eight to ten. It then subsides, and frequently for a few days remains sub-normal. Lastly, the acute asthenic forms, that occur often in women (Garrod), may be wholly afebrile.

Changes in the Blood.—Apart from its increased content of uric acid, further morbid changes take place in the blood in gout.

Neusser in 1894 described what he termed “perinuclear basophilic granules” over and about the nuclei of the leucocytes in the blood of gouty patients. He held that the dark granules constituted the mother substance from which uric acid was derived, and that their presence in the blood was distinctive of the “gouty diathesis.” Subsequent researches, however, by Futcher and others appear to have shown the absence of any interrelationship between the amount of these granules and uric acid elimination, though Neusser claimed that cases showing them excreted uric acid in excess.

More significant, however, is it that the blood in acute gout may show a high grade leucocytosis with secondary anæmia.

In a case under my care of acute gout at classic site, though by no means of unusual severity, the following was the content of the blood picture:—

BLOOD COUNT.

Red corpuscles, per c. mm. 3,692,000 = 73·8 per cent. Hæmoglobin 80 ” Colour index 1·08 ” Leucocytes, per c. mm. 25,920

DIFFERENTIAL COUNT.

Lymphocytes 8·0 per cent. = 2,074 per c. mm. Large mononuclears 3·5 ” = 907 ” Polymorphonuclears 87·0 ” = 22,550 ” Eosinophiles 0·5 ” = 130 ” Mast cells 1·0 ” = 260 ” ----- 100·0

The salient feature of the blood picture is the high grade leucocytosis of leucoid type with moderate anæmia—appearances quite compatible with, and suggestive of, an infective arthritis. To these interesting blood changes we shall again refer when dealing with the acute polyarticular variety, the above case being of monarticular type, i.e., the big toe.

Uric Acid Excretion.—If when on a purin-free diet a gouty subject develops a paroxysm, the curve of uric acid excretion in the urine is so characteristic as to be almost pathognomonic of the disorder. As His pointed out, immediately before the onset of the paroxysm the endogenous uric acid sinks to a lower level (termed by Umber the anacritical stage of depression). With the onset of the attack the uric acid content of the urine quickly increases, to reach its zenith on the second or third day. F. Pfeiffer, who first noted this point, termed it an uric acid wave. Subsequently, with the gradual subsidence of the paroxysm, it again drops into what Umber termed the post-critical stage of depression. While this curve of endogenous purin excretion may be modified by oft recurring exacerbations, still Umber holds that nevertheless it is of decided value in differential diagnosis.

Local Phenomena.—The site and character of the pain having been dealt with, we now pass on to consider the objective changes in the affected part. The local engorgement of veins that precedes the articular outbreak becomes more pronounced, extending from the vicinity of the painful joint as far as the leg. The overlying skin of the joint quickly becomes red and tumid. It is not a bright, but a dark red, the superjacent skin taking on a shining smoothness that has been compared to the peel of an onion. Indeed, in its more violent form it resembles but too closely the ordinary appearance of an abscess, over which the skin is becoming thin. The redness is not strictly confined to the surface of the joint, but spreads a little beyond, and where it ceases œdema is perceptible.

The redness in its intensity attains its zenith in from twenty-four to forty-eight hours, and then in hue becomes more violaceous. On the other hand, the œdema may go on increasing for some days. At first, owing to tension, the presence of œdema may not readily be elicited. But with the subsidence of inflammation the swollen parts readily pit on pressure. It is scarcely possible to detect intra-articular effusion unless it be the ankle joint that is involved.

According to Duckworth, in the more sthenic forms there may be local ecchymoses. With the crisis the redness, œdema, and venous turgescence die down. The previously distended skin becomes wrinkled, and with complete subsidence of inflammation desquamation ensues. This process is generally attended with troublesome itching. It is most noticeable about the feet and hands, but more rare at other sites. Scudamore said that in seventy-eight out of 234 cases no peeling occurred, but, as Garrod observed, it may readily be overlooked unless especially sought for.

The exquisite sensitiveness of the parts, as before noted, gives way to numbness. The diminished sensibility, coupled with stiffness of the joint, renders walking difficult for some days, and, indeed, a month or more may elapse before the joint, even in favourable cases, recovers its customary mobility.

In acute asthenic forms great contrasts appear. Pain and tenderness in the toe may be moderate, but there may be little local heat or redness and no pyrexia. But œdema is generally in evidence, and the usual desquamation of skin follows.

Tophus Formation.—To the local changes that mark their eruption at ab-articular sites we have already alluded. Here we would only reiterate that their formation follows the local joint inflammation. Consequently if a few days after the attack local pain or tenderness, with or without swelling in the vicinity of the joint, should be complained of, it should not be dismissed as of no account, but the affected parts should be scrutinised carefully and, where possible, at short intervals. This in the interests of diagnosis of a joint affection which may at the time have been of doubtful nature, more especially if the primary attack occur elsewhere than at the classical site. Some observations of Trousseau are well worth quotation: “Physicians who have watched the progress of the evolution of tophus believe that it is formed during the paroxysm of gout. They are mistaken: the deposit appears during the interval between attacks, or at least when the attacks have not been of long duration, and when they do not recur in such rapid succession as to run into one another, in which cases their secretion has commenced during the preceding and continued during the succeeding attack.”

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XVII. CLINICAL ACCOUNT (continued)

ACUTE GENERALISED GOUT

While gout may throughout its life history confine its ravages to the foot, if not solely to the toe joints, it may, even in the initial attack, involve many articulations. Such cases usually, if not always, occur in persons of marked gouty heredity. In its simplest forms the orthodox monarticular seizure is simply exchanged for a sequential implication of each big toe joint. If so, as Trousseau pointed out, the joint that is the last to be involved is least affected, and the soonest to get well again, while the accompanying œdema is of shorter duration. But in more severe cases not only the big toe, but the tarsal joints, the knee and the hand, may be invaded in the first attack. Occasionally, too, the disorder displays concomitantly its tendency to involve other structures, tendons and aponeuroses, e.g., the tendo Achillis, plantar fascia. Such widespread initial involvement is usually preceded by prodromal phenomena of unusual severity and prolonged duration. These initial attacks of polyarticular distribution are extremely rare.

Far more commonly acute gouty polyarthritis supervenes after several attacks of classic location have been suffered. The gouty inflammation in these cases invades the joints after a serial fashion. But each joint as it becomes involved goes through the same painful cycle. Thus, for five or six days the pain goes on increasing, then abates, and finally the wished-for crisis comes. So it happens that the gout may be raging simultaneously in several articulations, though in each at different stages of evolution. Consequently the symptoms do not pursue an even tenor, but are made up rather of a series of little attacks—series et catena paroxysmulorum, to invoke Sydenham’s expression.

Frequently periods of apparent recovery take place. The temperature remains normal for some days, and welcome convalescence seems established, when, to the victim’s despair, the temperature again rises, and the same weary cycle, though perhaps shorter, is yet to be endured. Running this chequered career, the disorder may last for six weeks or two or three months.

In such attacks not only the feet, knees, hands, and elbows, may be promiscuously involved, but often also the ligaments, bursæ, tendon sheaths, and aponeuroses. The suddenness with which the disorder shifts its seat from one joint to another, or from joints to bursæ or muscles, often leads to its confusion with acute rheumatism. In other words, that fixity distinctive of gout in its monarticular forms is here exchanged for mobility, that specific quality of acute rheumatism.

Naturally, the implication of so many varied structures casts its impress on the clinical picture, inasmuch as the physical characters vary with the different textures involved, their capacity for inflammatory distension, etc. On the dorsum of the hand and foot redness and œdema will be prominent, and Scudamore noted that the flush might be widely diffused, simulating erysipelas, with here and there small ecchymoses.

When structures more deeply placed, i.e., tendon sheaths at ankle, knee, and wrist, are singled out for attack, swelling is less marked and redness of the skin more patchy in distribution. The bursæ at the elbow or back of the knee may swell with extraordinary rapidity. The parts become exquisitely tender and painful, while the overlying skin takes on an angry blush. They may subside, but more often continue permanently enlarged, defiant of reduction.

Involvement of the olecranon bursa is very typical of gout. Pratt, of Boston (1916), tells of a case in which the subject had during twenty-seven years suffered from recurring attacks of acute gouty polyarthritis. The eight or ten physicians who had treated him had all regarded the disease as rheumatic fever. Pratt himself observes: “I did not feel sure of the diagnosis until I saw the swelling on his elbow, which presented the typical picture of a chronic gouty olecranon bursitis.”[34] Occasionally the bursæ when filled with uratic deposit undergo suppuration following injuries. The bursa in connection with the great toe frequently becomes acutely inflamed, and Scudamore in a gouty hand saw an old ganglion take on the same inflammatory reaction.

The tendon sheaths when involved lead to great disablement, as even the most tentative attempts at movement give rise to sudden and agonising cramp. The tendo Achillis is a favourite site, or the tendons of the wrist, or the ligament of the patella. The same is true of the aponeuroses, the predilection being for the lumbar or gluteal fascia, in which instance it may extend to the sheath of the sciatic nerve. These extensions of gout to tendon and nerve sheaths frequently outlast the articular lesions, and may become the dominant element in the clinical picture.

Naturally, when not only joints, but bursæ and other structures, are involved and implicate both upper and lower limbs, the victim presents a pitiful spectacle, one of almost complete helplessness. Œdema and general venous turgescence may be very pronounced in one or more members, giving a subjective sensation of almost overwhelming weight in the limb.

Reverting to the constitutional symptoms, the outstanding feature is that, notwithstanding the widespread involvement of joints with manifest local inflammatory reaction, the pyrexia is of moderate grade, and so frequently, indeed, is it afebrile that this peculiarity is of diagnostic significance.

Changes in the Blood.—The findings are extremely interesting in view of the high grades of leucocytosis to be met with both in pyrexial and apyrexial examples.

In a case of acute gouty polyarthritis under my care the blood picture was a very striking one. The patient had suffered from gout for some eleven years, with recurrent acute exacerbations. There was widespread involvement of the joints both in upper and lower limbs. On the dorsum of the mid-phalangeal joints small semi-solid swellings were present, the exact nature of which was somewhat puzzling. But inasmuch as the pinna in both ears was studded with tophi, this seemed to provide a clue. The auricular tophi were verified microscopically. The extra-articular phalangeal swellings were then aspirated with a hypodermic syringe. A turbid straw-coloured fluid issued, which microscopically was found to contain biurate crystals. His temperature rose nightly from 101° up to 102° F., with morning remissions. The left knee and wrist were the seat of effusion, and some of the small finger joints were inflamed.

BLOOD COUNT.

Red corpuscles, per c. mm. 4,432,000 = 88·6 per cent. Hæmoglobin 60 ” Colour index ·68 ” Leucocytes, per c. mm. 27,200

DIFFERENTIAL COUNT.

Lymphocytes 9 = 2,450 Large mononuclears 13 = 3,540 Polymorphonuclears 78 = 21,220 Eosinophiles 0 = 0 Mast cells 0 = 0 ----- 100·0

The left knee joint was aspirated by Dr. Munro. A clear fluid of straw yellow tint was withdrawn, which yielded some fibrin on standing. The cytological examination gave the following results:—

TOTAL COUNT.

44,800 per c. mm. (nearly all leucocytes).

DIFFERENTIAL COUNT.

Polymorphonuclears 92 Lymphocytes 7 Large mononuclears 1 Eosinophiles 0 Basophiles 0 --- 100

Attempts at culture on broth and agar proved sterile. In addition three separate blood cultures, taken at intervals of a few days, on agar slopes and broth, all gave negative results.

In another instance of polyarticular distribution the subject was seen during the inter-paroxysmal period. He displayed auricular tophi, the crystalline content of which was verified microscopically.

BLOOD COUNT.

Red corpuscles, per c. mm. 5,732,000 = 194·6 per cent. Hæmoglobin 65 ” Colour index ·57 ” Leucocytes, per c. mm. 13,200

DIFFERENTIAL COUNT.

Lymphocytes 34 = 4,490 Large mononuclears 3 = 400 Polymorphonuclears 61·5 = 8,120 Eosinophiles ·1 = 130 Mast cells ·5 = 66

Chalmers Watson some years previously investigated the blood in cases of acute gouty polyarthritis both during an exacerbation and in the inter-paroxysmal period. His findings were as follows:—

During the attack the films showed very marked leucocytosis. Also there was present a large number of peculiar myelocyte-like cells, these more than half as numerous as the ordinary finely granular oxyphil leucocytes.

“Each of these cells contained a large oval or horse-shaped nucleus, poor in chromatin. The nucleus occupied about half of the total area of the cell. It did not stain uniformly, and it was usually situated to one side, coming right up to the cell outline, and occupying from a third to a half of the total circumference. In many of these cells the nucleus was almost round, with but one slight indentation; in others the indentation was pronounced. The whole cell stained a pale blue, presented a degenerated appearance, and contrasted markedly with the ordinary leucocyte seen in the same film, with its brilliant blue nucleus and bright red eosinophil granules. The special cells under description were also remarkable for their size, measuring about 15 m. in diameter, a few being smaller, about 10 m. Some of them contained vacuoles in the cytoplasm. The general appearance of these cells suggested exhaustion in so far as the cytoplasm did not contain the typical fine oxyphil granules characteristic of the myelocyte. From the character of the nucleus and cytoplasm, they were undoubtedly distinct from lymphocytes. The large lymphocytes were scarce; small lymphocytes were numerous. True eosinophil cells were also scarce. The main bulk of the leucocytes consisted of the ordinary finely granular oxyphil leucocytes and the peculiar myelocyte cells described.

“Blood plates.—Some of the blood-plates were large (4 m. in diameter), and often formed very irregular torn-looking masses. The red cells were apparently normal.”

Shortly after Chalmers Watson, Bain published his results of blood examination in acute gouty polyarthritis. He also noted the presence of a distinct leucocytosis. A differential count disclosed a marked increase of the eosinophil cells, and he adds: “There was present a moderate number of the peculiar myelocyte-like cells originally described by Chalmers Watson.”

Dr. Munro, though he carefully examined the gouty blood films to this end, was unable to identify the myelocyte-like cells noted by these observers.

Recently, through the kindness of my colleague Dr. Waterhouse, Dr. Munro and I had again an opportunity of examining the blood in a case of this kind during the inter-paroxysmal period. The subject, a male, had had repeated attacks at the classic site, with subsequent extension to other joints. Multiple tophi were present in both ears, and the crystals of uric acid were demonstrated microscopically.

BLOOD COUNT.

Red corpuscles 7,364,000 = 147 per cent. Hæmoglobin 74 ” Coloured index 0·5 ” Leucocytes 21,400

DIFFERENTIAL COUNT.

Lymphocytes 28·5 per cent. = 6,099 per c. mm. Large mononuclears 2·5 ” = 535 ” Polymorphonuclears 64 ” = 13,696 ” Eosinophiles 3·5 ” = 749 ” Basophiles 1·5 ” = 321 ”

The blood picture, it will be seen, is one of erythræmia—a marked leucocytosis, a normal differential percentage count, pronounced secondary anæmia.

Da Costa also notes, in a case of gout, erythræmia (7,125,000) with a leucocyte count of 14,000. Ewing, too, records an instance of chronic gout with huge tophi, seen in an acute exacerbation, in which the blood gave a leucocyte count of 21,000 with 70 per cent. hæmoglobin. In another severe instance of subacute type the same observer again met with leucocytosis (15,000).

In regard to these interesting blood findings, it is to be cordially hoped that as the somewhat rare opportunities occur they will be taken full advantage of.

As to the other general clinical features the nervous system, as might be expected, is often greatly perturbed, and the mental distress and anxiety in some instances appear to cause even more irritation than the bodily pain. Febrile movement when present accords with that observed in monarticular sites, save only in the tendency to relapses. Sweating is not a common feature, as in acute rheumatism. Neither does acute endocarditis occur in gout. On the other hand, as this acute polyarticular form may recur throughout years, it may in its later stages be complicated by nephritis.

Furthermore, in its differentiation from acute rheumatism the more advanced age of the sufferer, always over thirty-five and more often nearer fifty or over, will be of help. The presence of an hereditary taint, the nature of the occupation and personal habits, and more pertinently the history of a classical attack in the great toe, may give a clue.

But in this, as in all other varieties of gouty arthritis, the one and only unequivocal objective proof of the nature of the disorder is the presence of tophi. Lamentable indeed is the frequency with which this fact is forgotten, to our confounding and the patient’s detriment. As Hilton Fagge, discussing the diagnosis of gout, long since observed: “All those parts which are apt to be the seat of tophi should be examined. If a single deposit of urate of soda can be found it settles the question.”

In conclusion, before passing to consideration of chronic articular gout, it will be convenient here to discuss certain concomitant phenomena of the acute types. We refer to the muscular and nerve forms of fibrositis, which, we hasten to add, are of common occurrence also in the chronic types of articular gout.

COLLATERAL PHENOMENA OF GOUT

The liability of acute articular gout to be complicated by muscular and nerve disorders has already been briefly alluded to. Also it was pointed out that in respect of this tendency gout displayed an analogy with the specific infections, viz., in that these latter too are prone not only to arthritic, but to muscular and nerve, lesions also.

Our forefathers, greatly exercised by this apparent overlapping of “gout” and “rheumatism,” in their efforts at discrimination drew fanciful contrasts between the subjective sensations produced by gout and rheumatism, but all to no end, for said Heberden, “It must be owned that there are cases in which the criteria of both are so blended together that it is not easy to determine whether the pain be gout or rheumatism.”

Gradually, however, a change in attitude made itself felt. It became no longer customary to regard such examples as blends of gout and “rheumatism,” but to hold the muscular and nerve disorders as also attributable to the underlying gout. Thus, so impressed was Garrod with the frequency of the incidence of lumbago and sciatica in gouty subjects that he was doubtful as to whether they ought to have been classed by him as among the “diseases to which gouty persons are particularly liable.” He thought “they might perhaps have been properly classed among the forms of irregular gout.”

Duckworth, again, felt sure “that much so-called ‘muscular’ rheumatism is really gouty,” and forthwith ranked its manifestations among the irregular forms of gout. Hilton Fagge was likewise convinced that the muscular types of fibrositis are frequently and obviously related to gout; while Sir William Gowers, discussing this same muscular fibrositis, is even more explicit: “It is currently associated with gout, and the truth of the belief is soon impressed upon the practitioner. But it is gout with a difference: it may occur in those who are gouty in the common sense of the word, but some of the most severe cases I have seen, especially the brachial form, have been in those who have inherited a tendency to gout, but have not merited its development.”

Turning to the nerve manifestations, Charcot long since pointed out that gout and sciatica might co-exist, while Gowers is insistent that “underlying most cases of sciatica is either the state of definite gout, or that ‘rheumatic diathesis’ in which the fibrous tissues suffer, especially those that are connected with the muscles, a form closely connected with common gout by co-existence or descent.”

As to my own opinion, I have, in collaboration with Bassett Jones, discussed in detail this relationship of gout to fibrositis in our monograph on the latter disorder, and I shall largely transcribe our remarks therein on this vexed point.

Of all the conditions reputed to be etiologically related to fibrositis, in none of them is the connection more obvious or more easily traceable than between this affection and gout. Whether or no the hyperplasia of the connective tissues be directly due to the gouty toxin must perforce for the present remain uncertain. But there is no doubt as to the relatively frequent incidence of fibrositis in “gouty” subjects. It is as true to-day as when Scudamore wrote it that occasionally “a patient when he has gout in the regular situations suffers, in consequence of some partial exposure to cold, a rheumatism in other parts, as in the muscles of the neck, or in the shoulder joints; and a seizure of lumbago at the time of the invasion of the gout is also not uncommon.”

Apart from the simultaneous incidence of gout and fibrositis in the same subject, it is equally certain that the victims of a “gouty” heritage are unusually prone to develop fibrositis.

Thus, in a series of 1,000 cases hereditary or acquired gout was present in no less than 281—viz., a percentage incidence of 28·1. While this taint was more in evidence in fibrositis of the joints, it obtained appreciably in regard to all muscular types of the affection, more especially lumbago, its influence also being very obvious in the case of sciatica and other types of nerve sheath involvement.

In light of this, we must admit being somewhat nonplussed by those who confidently affirm that “gout” plays little or no part in the production of “fibrositis.” Speaking from an extensive experience, we confidently believe the reverse is the case, and that the gouty element is but too frequently overlooked in examples of this affection.

Approaching another aspect of this vexed question of the relationship of gout, what of the ambiguous attitude of those who, while denying it any share in the causation of lumbago and other types of muscular fibrositis, yet at the same time attribute to gout an important etiological rôle in the allied conditions sciatica and brachialgia?

Thus, they maintain that the fleeting attacks of lumbar fibrositis or lumbago which ensue after dietetic indiscretions have no relation to gout, but are simply indicative of some digestive disability on the part of the individual for certain articles of diet. Hardly to our mind a satisfactory mode of differentiation; much less can it be held to put out of court the influence of gout. For are not the gouty precisely the very persons who display this inability to cope satisfactorily with unusual or excessive meals? Hence the frequency with which in their instance attacks of lumbar fibrositis, often transient, almost invariably ensue when any unwonted excess of purin-containing food has to be disposed of, and especially when at the same time katabolic changes have been stimulated in the body by the ingestion of alcohol, not necessarily excessive in amount.

That the lumbar regions should have been singled out is the more remarkable, for, if there be one form of fibrositis more than another prone to be associated with gout, it is precisely lumbago.

Our difficulty, moreover, in appreciating the cogency of this plea for excluding the influence of gout in muscular fibrositis is the more accentuated in that those who advocate it claim that this very gout is the salient etiological factor in sciatica and brachialgia.

This position is untenable, and for the following reasons: the pathological lesion in both instances is the same—viz., fibrositis; in lumbago and deltoid rheumatism it implicates the sheaths and interstitial tissues of the muscles, in sciatica and brachialgia the similar investments of the nerves.

Strictly speaking, therefore, any differentiation that we can effect between muscular and neuralgic types of fibrositis is perforce merely topographical. To draw etiological distinctions is well-nigh impossible, for the very continuity of the fibrous tissues favours the passage of one type into the other. Hence clinically we find that the bulk of our cases of sciatica are preceded by lumbago, and similarly many cases of brachial neuralgia or neuritis develop by extension out of a pre-existing deltoid fibrositis.

In light of such transitions of muscular into neuralgic types of fibrositis, it seems inconsistent to postulate a gouty origin for the latter and at the same time to deny it any share in the production of the former. For ourselves, we fully recognise gout as the most potent predisposing factor in sciatica and brachialgia, and ergo in the closely associated and often antecedent muscular types of fibrositis.

While insisting on the importance of gout as a predisposing factor in fibrositis, we feel called upon to emphasise the fact that we are not sheltering ourselves under that nebulous term “latent” gout, for our contention is based on the ground that in the vast majority of the cases for which we claim a gouty origin unequivocal proofs of gout, such as tophi, etc., were present.

INCIDENCE OF GOUTY STIGMATA IN VARIOUS TYPES OF FIBROSITIS

Out of 343 instances of fibrositis of the joints such stigmata of gout were present in 118 males and nine females. Of muscular types, taking as our example lumbago, we find that out of twenty-seven examples no less than ten displayed definite evidences of a gouty taint. Similarly, out of thirty-eight cases of lumbago complicated by other manifestations of fibrositis eleven males and one female were of gouty habit. Also in twenty-three cases of lumbago associated with arthritic fibrositis six males, but no females, displayed the same proclivity. Lastly, out of thirty-eight cases of lumbago complicated by right or left sciatica ten were of the same diathesis.

Passing in turn to consider this same factor in relation to sciatica, we note that out of 142 examples twenty-four men and three women were gouty. Occasionally, too, apart from glycosuria, it appears to be responsible for bilateral sciatic pains, for in three examples of this nature gout was present.

James Taylor is also very definite on this point, that, glycosuria aside, affections of individual peripheral nerves occur frequently in the gouty. There is little doubt, he says, that sciatica is “frequently present in the gouty and is sometimes directly due to that state.” While admitting that in many, if not most, cases of sciatica there are associated arthritic changes in the hip joint, he yet affirms his belief that “there are some in which the neuritis is a primary condition.”

With this statement my own experience accords, but with a reservation, viz., that the sciatic neuritis is apparently secondary to a lumbar or gluteal fibrositis, with sequential involvement of the sciatic nerve sheath and extension to the nerve trunk.

Taylor holds also that anterior crural and brachial neuritis may be directly due to gout. As to brachial neuritis, he says: “I have known it occur apart from any recognisable arthritic change in a patient who was the subject of gout.”

Having regard to the flippant manner in which the term “neuritis” is but too frequently bandied about, it is refreshing to note that in all Dr. Taylor’s cases “the existence of the neuritis” was shown “by the tenderness of the nerve trunks, the spontaneous, often severe, pain, and atrophic changes both in the skin and the muscles—the glossy skin and atrophied muscles.”

As for the involvement of other nerves, trigeminal neuralgia is held to be the most common; but, for myself, I have never felt justified in claiming any such example as gouty. Nor am I satisfied that persons of gouty habit are more prone than others to attacks of migraine.

Lastly, I cannot confirm out of my own experience Duckworth’s statement that “herpetic attacks in all varieties of ‘gout’ are common.” Nor have I seen shingles co-exist with acute gout, neither have I come across any examples of so-called gouty spinal meningitis!

In conclusion, I would submit that:—

(1) Acute articular gout is not infrequently complicated by fibrositis.

(2) The same infection that determines the articular outbreak is responsible for the concomitant muscular and nerve phenomena.

(3) Persons of gouty heritage are especially liable to fibrositis, notably lumbago and sciatica.

(4) Gout predisposes to fibrositis in that the inherent pathological attributes of gouty tissues favour the incidence of infection.

In regard of this last postulate, it is well known that gouty persons who contract gonorrhœa are more prone than the non-gouty to develop gonorrhœal rheumatism, in other words, to sustain a widespread infection involving the fibrous tissues, not only of the joints, but of the muscles and even of the nerve sheaths. With this concrete example to hand, is it not reasonable to suppose that such a constitutional taint will favour the incidence also of other infections or sub-infections, and that this may explain the relative frequency of fibrositis, not only in the actually gouty, but in those of gouty heritage, this the more cogently having regard to the fact that so much exact evidence is forthcoming in favour of local infection as the cause of all types of fibrositis?

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XII. URATOSIS IN RELATION TO GOUT…

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