Gout, with a section on ocular disease in the gouty

by Llewellyn J. Llewellyn

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.”