Gout, with a section on ocular disease in the gouty

by Llewellyn J. Llewellyn

Discussion of the Foregoing Data

While the researches of the past decade have proved distinctly encouraging, yet we must not blind ourselves to the fact that the foregoing findings, and alike our deductions therefrom, are largely provisional; for we stand in grave danger of over-emphasising the significance of the results forthcoming from the investigation of isolated samples of blood from different individuals. The recorded estimates of the uric acid content of the blood in strictly normal persons are all too few, the findings in diseased subjects too conflicting, to warrant dogmatic inferences, wide generalisations. In truth, the problem is by no means as simple as may at first sight appear, and this but a slight digression will suffice to make clear.

The Significance of Uricæmia.—It is generally maintained that the blood content of uric acid in gout is above normal. Yet the excretion of uric acid, save during acute attacks, rests within physiological limits. Again, à propos of our claim that the blood is surcharged therewith, we have the awkward fact, as yet inexplicable on chemical or physico-chemical grounds, that the blood-stream can hold in suspension far more uric acid than has ever yet been met with in gout, according to Bechhold and Ziegler no less than 50 mg. of uric acid per 100 c.c. of blood serum before deposition tends to occur. On the other hand, urates are less soluble therein, not exceeding 2·5 mg. per 100 c.c. How remote from the limit of saturation the highest figures observed in gout! What a large margin of solubility is still available!

Again, the uric acid blood content in gout is far less than was formerly thought. Only by a few milligrams does it transcend that found in normal individuals. Can this slight disparity have such profound potentialities as to determine the incidence or not of gout? and this with the saturation point still so remote. The urates, too, being practically non-toxic, how difficult to conceive that the almost trivial excess of the uric acid blood content over the normal is adequate to produce the fulminant and dramatic phenomena of acute gout.

Again, though we speak of uricæmia as a dominant characteristic of gout, we are uncertain whether the alleged increase in the uric acid content of the blood is real or merely apparent. We can, it is true, extract uric acid and urates from the blood-stream, but it does not necessarily follow that it is as such that they circulate in vivo. We need walk circumspectly here for, despite the most modern methods of blood analysis, we are still ignorant as to the exact form in which uric acid exists in the blood-stream; whether the purins of the food appear in the blood-stream as sodium monourate, or in organic fusion. Accordingly, in the interests of progress, it were well to bear in mind the pitfalls that beset uric acid estimation, the insufficiently eclectic capacity of even the most modern tests, and to consideration of these more chastening aspects we now proceed.

Sources of Fallacy in Uric Acid Estimation.—With Folin’s findings as his basis, Walker Hall estimates that, excluding the lymphatics and lymph spaces, the entire blood-stream contains normally 70 mg. of uric acid, i.e., 2 mg. of uric acid per 100 grams of blood, 3,500 c.c. (total quantity of blood).

Thence he argues that, inasmuch as about 1 litre of blood traverses the kidney per minute, the total content thereof of uric acid would gain access to the renal organs in three and a half minutes. Now the average total output of the kidneys is 500 mg. per twenty-four hours. Accordingly, assuming that the blood arriving at the kidneys contains as a constant the above 70 mg. uric acid, the total daily output would pass through these organs in twenty-five minutes.

Now, given immediate extraction of all the uric acid by the renal cells, then the blood in the renal veins will become free of uric acid. If so, the estimates of the uric acid content of the blood will reflect exactly the measure of the endogenous or exogenous nuclein metabolism. But, “if the renal vein blood is not purin-free, then the estimations will fail to yield a true picture of the activities of nuclein exchange.”

Again, as to the precise import of isolated estimates of the uric acid blood content, we must recollect that the excretion of purins is not distributed evenly over the twenty-four hours, varying as it does under the influence of food, exercise, sleep, and other factors. A propos of this, Pratt’s observations clearly show that both in gouty and non-gouty subjects fluctuations in the uric acid blood content also occur, and this independently of diet. To what, then, may these variations be referred? Obviously a question of great moment, especially when we recall the eccentric behaviour of the blood uric acid in relation to the incidence of acute gouty attacks. For, until the inward meaning of these vagaries is revealed, the value of recorded estimates must necessarily be discounted considerably.

We must recall, too, that a certain moiety of the purins derived from nuclein metabolism lags in the lymph spaces and lymphatics, and this, as Walker Hall reminds us, must reduce the quantity present in the blood-stream at any one time. Also, as the same authority reflects, the lymph stream being probably richer in sodium ions than the blood, the entry of the nucleins therein may be retarded and so lead to a still further reduction of the blood content.

There is yet another possibility, he reminds us, viz., “that the purin content of the blood varies in the peripheral pulmonary hepatic and osseous streams, and that, while in some parts the purins are being carried to the kidneys for excretion, in others they are being transported from one organ to another for further metabolism.”

For, as before pointed out, the enzymes responsible for the ultimate disruption of the nucleosides are scattered in different organs, and Walker Hall suggests that “a transport of half metabolised nucleotides from one organ to another may form a part of the normal processes of nuclein metabolism.” This may well lead us on to consider the limitations that beset even the most modern tests in use for uric acid determination.

Disabilities of Modern Tests.—With all its outstanding advantages, even the Folin method of uric acid estimation has its drawbacks. As Curtman and Lehrman have pointed out, different workers have, even on identical blood samples, arrived at results which vary widely. Nor, disconcerting though it be, do the limitations of this mode of hæmo-analysis cease here.

Thus we know from Gudzent and Apolant that the soluble but unstable biurate is constantly being transmuted into an insoluble stable type, in other words, metamorphosis from one isomer into another. But, unhappily, the tests to hand fail of differentiation of the several tautomeric forms of uric acid. Also, as isomers of uric acid actually exist, then quâ Walker Hall, why not isomers of purins and pyrimidins also? But here again our tests are insufficiently eclectic. They give us no clue as to the affinities or blends of purins or pyrimidins for or with other substances.

Again, as our criteria fall short of identifying the exact form of the “purin combinations” it follows, therefore, that they tell us nothing as to whether “the increase is due to a more active transport of purins from one organ to another for further metabolism or simply to a transport to the kidneys for elimination.”

In other words, hampered by the above disabilities in our tests, it is beyond our power to determine whether “the increases denote a supernormal nuclein metabolism or an unusual type of nuclein cleavage.” Should it ultimately transpire that the increase in the purin blood content is a real one, viz., made up of “an excess of normally formed and normally bound purins,” a great step forward will have been achieved. For, to account for the same it will, as Walker Hall observed, be necessary to postulate a supernormal nuclear activity of generalised or localised distribution.

Need for Further Investigations.—While none can doubt that, by means of chemical investigation of the blood, the clinical problem of gout will be elucidated to a much greater extent than has been possible by means of urine analysis, still much remains to be done before recent findings can be applied to the solution of the etiology of gout.

The results of blood analyses up to now have afforded us no clue as to the intimate nature of the warp in nuclein metabolism. At the most, the researches in this sphere do but make it increasingly clear that uricæmia is not the cause but the result of gout.

Albeit, this conclusion does not justify us in putting out of court all thought of uric acid in connection with gout. Any tendency thereto will be immediately checked when we recall that uratic deposits, i.e., tophi constitute the solitary unequivocal token of gout, and to this aspect of the question the ensuing chapter will be devoted.

Meanwhile, systematic investigations of the purin content of the blood, not only in gouty but in normal subjects, would surely dissipate much of the obscurity that envelops this complex question. It were well, too, that blood and urine analyses go hand in hand in our investigations. How illumining these have been in connection with atophan, the increased urinary output of uric acid having been found to be correlated with a simultaneous sinking in the level of the uric acid of the blood.

Again, the excretion of urinary purin ebbs and flows with the intake of food and the degree of muscular activity, while sleep also exerts an influence, not to mention constitutional disturbances, e.g., fever infections, etc.

Can it be doubted that the blood content of uric acid varies with these same vicissitudes? Walker Hall tells us that the data to hand, “as to the rapidity of the appearance of purins in the blood-stream after food, infections, fever, etc.,” though few in number, yet suggest that “the excretion by the kidney is tidal in character, and that the blood uric acid has similar characteristics.” In light of these possibilities, we may well pause before attempting to appraise exactly the significance of isolated blood examinations.

What, too, as the above authority observes, of the influence on the gouty uricæmia of infancy, puberty, the menopause, and for that matter the pre-senile and senile periods of life with their associated vascular lesions? The researches of Uffenheimer prove that even in young children the disorders of purin metabolism distinctive of gout are to be met with, i.e., “infantile gout.”

We stand also in urgent need of knowledge as to the uric acid blood content in the early as opposed to the late stages of gout; in need, too, of further examinations of the blood to this end, not only during the passage of acute attacks, but even more under those conditions which are presumed to determine their incidence.

But, despite these gaps in knowledge, these disabilities of technique, there is no need for despair. “It is a slow progress along the zigzag which leads to the centre of the ‘gouty maze,’ but the researches of the last decade have opened up many new and possible pathways thereto.”

CHAPTER 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.