It will be recalled that at the close of our chapter on Pathogenesis we referred to the growing scepticism of Garrod’s views as to the pathogeny of gout. Still, if we except Edward Liveing’s pertinent observation that uricæmia was not peculiar to gout, naught, save alternative hypotheses, unsupported by pathological data, was advanced. Consequently, Garrod’s facts never being seriously called in question, his position remained unassailable, until, in the year 1898, his original observations as to the lowered alkalinity of the blood in acute gout, and the increased uric acid content thereof during the same, were definitely contradicted by Magnus Levy.
Working with more modern and more reliable methods of technique, this observer, in a series of seventeen cases of acute gout, found no evidence of any lessening in alkalinity of the blood or of any augmentation of its uric acid content as compared with the inter-paroxysmal period.
Again, as to Garrod’s claim that there was a diminished excretion of uric acid during the attack, this also, while supported by Minkowski, was called in question by Pfeiffer, Levy, and Badt, who found the reverse to be the case, i.e., a notable increase in the excretion of uric acid during the paroxysm.
These results were again in 1900 confirmed by Chalmers Watson. An exhaustive study of a series of cases of acute gouty polyarthritis convinced him that:—
(1) The alkalinity of the blood is not diminished during the attack.
(2) The excretion of uric acid is not lessened during the paroxysm, but the reverse; there is, therefore, no ground for the supposition that there is a temporary diminution in the capacity of the kidneys to excrete uric acid.
(3) The amount of the uric acid in the blood is not greater during the attack than in the intervening period, and if these points be accepted, we must start de novo in search of the cause of the acute paroxysm.
The iconoclastic revelations of the foregoing researches may well form a preface to our discussion of gout from the triple aspect of:—
The earlier investigations as to the behaviour of uric acid in the organism were necessarily restricted to the noting of any variations in the uric acid output in the urine. That the findings and, alike, the deductions proved bewilderingly contradictory is not to be marvelled at when we recall the many factors that govern the amount of uric acid excreted in the urine.
How fallacious, it now transpires, were the assumptions based upon the mere uric acid output in the urine, and how little understood even to-day the many conditions that determine its variations.[17] But, fortunately, we can now to some extent control and review our urinary findings in light of the uric acid content of the blood. But we anticipate, and meanwhile let us confine our discussion to the variations in uric acid excretion that occur in gout, and this as revealed by more modern students of the disease. This will be more conveniently dealt with if we consider first the oscillations in uric acid output in relation to acute attacks of the disorder, and subsequently the same as met with in its more chronic manifestations.
Generally speaking, there appears to be a consensus of opinion on the following points:—
(1) That in the intervals between acute attacks of gout the elimination of uric acid lies within the normal limits, but that
(2) For one or two days prior to an acute attack an appreciable decline in the output of uric acid occurs. This, however, is not so marked as the subsequent
(3) Increased output of uric acid during the acute attack. According to Magnus Levy the increase may reach from 0·3-0·5 gram, daily, and more, and may sometimes last for a week or even two.
(4) Following attack a tardy decline in uric acid output to former level.
To sum up, during an attack of acute gout the uric acid output stands at a relatively low level between the paroxysms. But one or two days before the oncoming attack a diminution in uric acid output ensues. In contrast with the outbreak of the attack, the uric acid excretion increases markedly, this enduring for a week or more, when the output again declines. The augmented output during the paroxysm is more constant than the diminished excretion antecedent thereto. Now, while it may be taken that the foregoing variations in uric acid output, prior, during, and subsequent to, acute attacks, obtain as a general rule, such behaviour is not invariable; for, unfortunately, as Wells reminds us, instances are met with in which “the uric acid excretion shows no variation from that of normal persons.”
It must never be forgotten that the elimination of uric acid displays wide variations, this even when the subject under investigation is on a constant diet. Consequently, as Folin has pointed out, “even in the case of gout, which is distinctly associated with uric acid, it is an extremely difficult matter to prove by means of urine analyses that the uric acid elimination is not entirely normal.” And he adds, “If it had not been for the fact that uric acid, because of its insolubility, is so easily found in the joints, it would unquestionably have been a very long time before any definite relationship between uric acid and gout could have been established.”
None can gainsay the truth of these reflections, for, when placed on a fixed diet, the uric acid output in the victims of chronic gout differs but little from that of normal individuals on a similar regime; save in this respect, that, following the intake of purin-containing substances, the period of augmented uric acid excretion that ensues is prolonged as compared with the normal.
In 1901 Vogt showed that in gout the excretion of exogenous purins was not only delayed but diminished. Giving simultaneously to a gouty subject and a healthy individual a diet rich in purins, he found that, in the former, retention and delayed excretion of purins ensued. Vogt’s findings were confirmed by Reach, Soetbeer, Pollak, Mallory, and others.
Brugsch and Schittenhelm also observed that, following the intake of purin-containing substances, the exogenous uric acid excretion was retarded and reduced; in other words, the percentage of exogenous nitrogen excreted as uric acid nitrogen is less than in normal individuals, although the increased elimination extends over a longer period of time.
On the other hand, Walker Hall finds that, though there is retardation, there is no diminution in the output in gouty subjects. Thus he states: “When an adult takes a meal consisting of half a pound of beef and a quarter of a pound of sweetbread, containing about 0·620 gram purins, the moiety which usually occurs in the urine, say 0·300 gram, is not fully excreted until 6-10 hours have elapsed. When a similar meal is taken by a gouty individual the full 0·300 gram is eliminated, but the rate of output is delayed, some 48-72 hours being necessary.”
The same observer states that, given intravenous injection of acid into a normal man, its elimination is spread over several days, and the total amount injected fails to appear in the urine. But if the injection be administered during a course of atophan, then the uric acid excretion is completed within twenty-four hours, and the whole amount injected can be recovered from the urine. Now if in a gouty subject the same method of procedure be adopted, the sequence of events is precisely similar, and like results have been reported, following the administration of sodium salicylate to vegetarians of five or more years’ standing. To sum up, the above findings would appear to indicate that:—
(1) A gouty subject can excrete exogenous purins as adequately as a normal man, but he takes longer to do so.
(2) If the extra purins be taken during a course of atophan, even this departure from normal is obliterated, i.e., the customary delay in excretion is obviated.[18]
But, unfortunately for the diagnostic valency of this symptom in gout, viz., retarded exogenous purin output, it has not been found to be invariable. Thus Magnus Levy has shown that, in some instances of gout, the elimination of exogenous purin is neither reduced nor protracted. Pratt, too, has confirmed this observer’s findings, while, as we shall see later, this authority, also McClure, Mallory, and others, have placed on record the still more disconcerting fact, viz., that a diminished and retarded output of exogenous purin is not peculiar to gout.
The inference then would appear to be that:—
(1) Reduction and retardation of the excretion of exogenous purin, though common in gout, is not invariable.
(2) The same is not peculiar to gout, but occurs in other disorders.
(3) Its diagnostic valency, as a characteristic feature of gout, is correspondingly depreciated.
As a rule, gouty subjects, on a purin-free diet, excrete less endogenous uric acid than normal persons. Thus, according to Walker Hall, the average daily endogenous urinary uric acid output of a normal adult is about 0·5 gramme, while that of a gouty subject is about 0·45 gramme. Brugsch and Schittenhelm hold that in about 80 per cent. of cases the average endogenous excretion is lower than normal.[19]
According to these same observers, “the maximum fluctuation during attack-free periods was at first believed to be less than in the normal cases; more recent examinations, however, have shown that in the same case of gout there may be periods of high, and periods of low, endogenous uric acid excretion.” These variations, they hold, are not to be accounted for by either mild or severe attacks of gout, for they occur in the attack-free period.
Again Laird, investigating the elimination of endogenous uric acid in a case of chronic gout, noted that the output thereof was sub-normal, and, as Brugsch and Schittenhelm observed, the same presented marked variations. The leucocyte counts he found normal, but the phosphorus output and the acidity were sub-normal. Bloch again, while he agrees that endogenous purin excretion is usually below the average in gouty subjects, found that the output thereof is at its minimum before an acute attack of gout.
The foregoing observations would suggest that the retention or delayed excretion of uric acid applies both to exogenous and endogenous purins. But, when we come to analyse the foregoing findings as to the variations in uric acid output, both in acute and chronic gout, one feels inclined to agree with O. Folin, “that the clinically useful contributions obtained by urine analysis have not been very numerous.” Thus we cannot, on the basis of the variations in uric acid excretion, presume to diagnose gout; in other words, if we take urine analysis alone, it is extremely difficult to prove that the uric acid elimination in gout is really and truly abnormal. Our uncertainty, moreover, is the more pronounced when we realise that in some cases of rheumatoid arthritis, etc., there is a disturbance of purin metabolism which in some of its features is reminiscent of that obtaining in typical gout. But, before proceeding to discuss this interesting resemblance, it will, we think, be convenient here to recall that the obliquities in metabolism found in gout are not wholly restricted to uric acid.
As Levene and Kristeller have shown, side by side with the delayed excretion of ingested purins, there occurs also a tardy elimination of the other nitrogenous products of protein food. Vogt observed that fluctuations in nitrogen retention and nitrogen loss are quite typical of gouty subjects. As to the why and wherefore, however, of this variability, it remains a mystery. Nor do we know the form in which the nitrogen is retained, though Vogt maintains that the uneliminated moiety takes the form of purin bodies. According to Brugsch, it is during the acute attacks of gout that the nitrogen loss reaches its zenith, and he suggests that the nitrogen retention in the inter-paroxysmal periods is in part compensatory. On the other hand, the gain in weight that ensues is not adequate to account for the sum total of the nitrogen retention; while, as before observed, in gout there occurs, not only retarded elimination of exogenous purins, but also of other nitrogenous products of protein food. Yet, according to Heffter, the ratio of purin bases to uric acid is unaltered in the urine of gouty subjects.
Again, all nucleins contain a phosphoric acid group, and Futcher found that the curve of the uric acid output ran in a striking parallel with that of phosphoric acid. But the attempts of subsequent investigators to show that the two end-products of nuclein disintegration—uric acid and phosphoric acid—go hand-in-hand prove contradictory. Hence Wells, in regard to phosphoric elimination, observes that, “it seems probable that it shows no characteristic alterations in gout.” Lastly, we will recall to the reader that in the chapter on protein metabolism it was pointed out that the amino-acids, especially glycocoll, are found in excess in “gouty” urines.
In conclusion, it must, we fear, be admitted that the results of urinary analyses have proved insufficient of themselves to unravel the intricacies of metabolism in gout, and, after a brief digression, we shall proceed to ascertain whether, on the other hand, chemical analysis of the blood by modern methods can in any way shed further light on this obscure problem.
Working at the Research Hospital for the Study of Special Diseases at Cambridge, Strangeways (1910) commented on the striking resemblance that obtained between certain cases of so-called rheumatoid arthritis and gout, as evidenced by X-ray findings and section of the joints. Their similitude in these respects suggested that the nature of the apparent kinship of the two disorders might be elucidated by a study of purin metabolism in instances of rheumatoid arthritis.
To this end Ackroyd studied the purin metabolism in eleven persons, the victims of rheumatoid arthritis. His conclusion was that there was no important variation from the normal. To quote his own words, he states that “it may be (1) completely normal, or (2) while normal as regards endogenous excretion, the period of increased uric acid excretion which follows the administration of hypoxanthine may be prolonged for more than four days. It is more likely that this effect is individual, than that it is characteristic of any particular form of the disease, excepting those cases in which the prolongation is accompanied by active manifestation of the disease.”
W. J. Mallory, critically analysing Ackroyd’s cases, points out that he used only hypoxanthine in his studies; also that, while hypoxanthine has this advantage, that it is of definite and known chemical composition, furnishing a known quantity of basic nitrogen, it labours under this drawback: “It is by simple oxidation converted into uric acid, and probably calls into action only a limited part of the ferment system concerned in the formation of uric acid.” As a consequence, therefore, the amount of information on metabolism that can be gleaned through its usage is more restricted than if nucleinic acid were invoked in its place; for this substance, on the other hand, calls into action all the various enzymes concerned in the disruption of nuclein or nucleic acid.
Alive to these advantages, Mallory, in addition to hypoxanthine, used nucleinic acid in his investigations of purin metabolism in a series of eight “undoubted cases of so-called rheumatoid arthritis.” The value of the inclusion of nucleinic acid is revealed by the fact that some of the cases, when given exogenous purin in the form of hypoxanthine, showed no deviation from the normal. On the other hand, when given nucleinic acid, a prolongation of the period of increased uric acid excretion ensued; this even though the total amount of basic nitrogen in nucleinic acid is less than in hypoxanthine. Thus 4 grams of nucleinic acid have 0·2632 gram of basic nitrogen, while 0·75 gram hypoxanthine has 0·309 gram of basic nitrogen.
Apart from his own series of cases, Mallory analysed those of other observers, and his conclusions are as follows: “Of nineteen cases of rheumatoid arthritis in which the purin metabolism has been studied by three different observers, nine cases, or 47·3 per cent., show a marked variation from the normal in their reaction to purin-containing substances while they are on a purin-free diet.
“In these cases the period of increased uric acid excretion which follows the administration of purin-containing substances is much prolonged. Following the administration of purin-containing substances, a considerable number of cases suffer from attacks of sub-acute arthritis, accompanied in some cases by an increased uric acid excretion.”
It will be seen that in virtue of:—
(1) The prolongation of the period of exogenous uric acid excretion, and
(2) Increased uric acid excretion during attacks of sub-acute arthritis,
certain cases of rheumatoid arthritis manifest a certain resemblance to gout, though, as Mallory remarks, “other features characteristic of that disease are lacking.”
It may be observed that the attacks of sub-acute arthritis that ensued in rheumatoid subjects followed the administration of hypoxanthine, as shown in Ackroyd’s series. That this reaction to exogenous purin is suggestive of a relationship between rheumatoid arthritis and gout derives colour from the fact that it has been repeatedly induced in gouty subjects by the same means. Thus, Brugsch and Mallory (1910), after giving 0·5 gram of hypoxanthine to a gouty patient, noted a typical outbreak of gout. Again, Brugsch and Schittenhelm, in the same year, reported attacks of arthritis following the administration of nucleinic acid to gouty subjects.
Another feature worthy of note is that, in the cases of rheumatoid arthritis investigated by Ackroyd and Mallory, the percentage of exogenous purin nitrogen excreted as uric acid nitrogen largely exceeds that observed in any case of gout available for comparison by these authors.
Mallory’s final conclusions were that “there seemed to be sufficient data to show that, in certain cases of so-called rheumatoid arthritis, the purin metabolism is not normal. Whether these cases are real gout, or only resemble that disease in certain features, must be determined by further studies.”
Quoting from Mallory’s contribution, we note that Pollak investigated the purin metabolism in a series of cases of chronic alcoholism. In five of the examples a marked derangement of purin metabolism was noted and manifested, “partly in retention, and partly in delayed excretion, or a combination of the two.” Having observed these variations in cases of what he considered were non-gouty alcoholics, Pollak felt justified in attaching but limited diagnostic import to the results of the examination of uric acid metabolism in gout, this though he realises the importance of alcoholic excess as a cause of disturbed purin metabolism.
Mallory’s observations, too, on uric acid excretion in gout complicated by lead poisoning are highly interesting. In two cases of this nature he noted that the percentage of uric acid nitrogen excreted was relatively small—in this respect in full accord with previous observations of Brugsch and Schittenhelm on a gouty patient with a history of plumbism, with this reservation, that in the latter observers’ example there were indications of early renal disease, while in Mallory’s two cases such was absent, the urine being normal, and likewise the blood pressure.
Again, Pollak in a case of lead gout noted an extremely low endogenous average, viz., a daily average endogenous excretion of 0·06 gram uric acid in a period of five days. Eschemburg, quoted by Pollak, has recorded an instance of gout with plumbism in which the excretion fell as low as 0·02-0·04 grams. It may be noted that Pollak’s was the victim also of incipient renal disease.
Reverting to Mallory’s conclusions, this observer’s studies of examples of gout with lead poisoning seem to indicate that “these cases differ from normal persons to a greater degree than do other cases of gout.” It may, he thinks, be affirmed that the subjects of gout and plumbism, as a rule, show “some or all of the following characteristics in a much more marked degree than do cases unassociated with lead”:—
(1) Slight fluctuation in the endogenous excretion.
(2) Low endogenous average.
(3) Small percentage of exogenous purin nitrogen excreted as uric acid nitrogen.
To sum up, then, we see that poisons, other than those responsible for gout, may engender obliquities of general metabolism, with disturbances of purin assimilation and output, viz., lead, alcohol, and the causa causans of rheumatoid arthritis. Also, in respect of lead poisoning and alcoholism, further affinities with gout are discernible in that, like the latter disorder, they tend in their later stages to be associated with arterio-sclerosis and renal inadequacy.
Apart from the fact that gouty arthritis may occur in young children, Comby and other observers have noted that children born of gouty parents display a tendency to inflammatory changes in the cutaneous tissues and also in the mucous membranes.
These proclivities are difficult of explanation, but some further observations by Czerny, Paltauf, Escherich, and Pfaunder are also worthy of note. Under the headings of “exudative diathesis” or “neuro-lymphatismus” they have described a symptom complex marked by lymphatism with asthma, occasional vomiting, defective nervous equilibrium, and eosinophilia. These varied phenomena also are common in the descendants of gouty, diabetic, and arthritic subjects.
The clue to the true nature of these phenomena may possibly reside in the fact noted and emphasised by Uffenheimer, viz., that these children exhibit a purin metabolism identical with that met with in gouty patients.
From the foregoing consideration it is clear that further observations are called for in the sphere of purin metabolism, and it is, perhaps, not too much to hope that extended investigations of the uric acid content of the blood may clarify and illumine the conflicting results obtained by urine analysis.
As before stated, we had intended in the next chapter dealing with the question of “Uricæmia in Gout,” but on second thoughts it appears desirable to us to interpolate a chapter devoted to discussion of the primary renal origin of gout; for we take it that, with the phenomena of uric acid excretion in gout fresh in our minds, it will be more easy at this juncture to attempt solution of this very intricate problem. This achieved, we shall resume our thread and pass to the consideration of uricæmia and subsequently uratosis in gout.