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.