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.”