Factors in the Precipitation of Urates - Pathogenesis Of Gout

In gout the overloading of the blood serum and the tissue fluid with uric acid, which has been the subject of so many discussions, is not, however, a necessary condition for the precipitation of the crystalline deposit of acid sodium urate. And also, the fact that this crystalline precipitation does not take place in all tissues, but only in certain definite locations, shows that the purely chemical process caused by a superabundance of uric acid in the plasma cannot be the decisive factor. The consideration must be added, to which attention has already been called, that a similar increase is possible in the blood of those who are not gouty. It is desirable on this account to discuss the question - without taking into consideration the place of the precipitation - of what peculiar forces may act to cause the precipitation of urates from a solution which contains large amounts of uric acid, but is not saturated. This shows the direction for an investigation of the relation between alkalescence and acidity of the blood. Researches on these lines have been conducted by Klemperer (by the determination of the C0₂ content of the blood), by ourselves (Zeitschr. f. klinsch. Med., Bd. 30), and by Magnus-Levy according to the titration procedure of Loewy. In the meantime we have made two further investigations on patients during attacks of gout; but none of the results obtained by the above-mentioned investigators has brought to light any reduction in the alkalescence of the blood. Luff has also had the same experience in the use of Wright's method. Since we have shown by numerous single determinations with what extraordinary tenacity the human organism holds gout 37 to a blood alkalescence within a certain limited range (300-350 mg. NaOH to 100 cc. blood) the influence of the alkalis introduced into the body does not seem of the highest importance in the solution and hence excretion of uric acid. However, it may be mentioned that E. Pfeiffer has succeeded, by the introduction of alkali during a gouty attack, in diminishing the amount of the uric acid deposited from solution; and that, on the other hand, the addition of an acid reacting compound to a solution containing uric acid, or its salts, does not under all circumstances cause the precipitation of uric acid. However, uric acid can be retained in solution, as has been shown by Minsowski and contemporaneously by Goto, a pupil of Kossel, by means of a chemically pure nucleic acid, namely, thymic acid. These à priori conflicting reactions can be explained by the fact that uric acid has been wrongly classified as an acid while the other members of the xanthin group are regarded as bases. Uric acid is, however, only a more complete oxidation product of purin, since trioyxpurin is differentiated only gradually from xanthin (=dioxypurin) and from hypoxanthin (=oxypurin) in its relation to acids and alkalis. Since in the dietetic treatment of gout we shall be obliged to return again to these facts, it is perhaps well to show here in a schematic manner the relations of the various bodies to each other as they have been elucidated by the studies of E. Fischer, Kossel and others.

I. Nucleoproteid -> Albumen - Nuclein -> Albumen - Nucleic acid -> Nuclein bases - Phosphoric acids.

II. Nuclein bases - Xanthin bodies = Alloxuric bodies = Purin derivatives.

Purin C ₅ H ₄ N ₄ Xanthin C₅H₄N₄0₂ Guanin C₅ H₅ N₅ O Uric acid C₅ H₄ N₄ 0₃ Theobromin = Dimethylxanthin C₇H₈N₄0₂ Caffein = Trimethylxanthin C₈H₁₀N₄O₂

The nuclein is broken up by the action of the ferments, nuclease, disamidase, xanthin-oxydase and uricolytic ferment.

With the exception of the reaction of the solvent, the relative amount of the individual salts held in solution is of next importance in the question of the precipitation of the uric acid, that is to say, these compounds of uric acid which are more difficult of solution. Researches on urine have been undertaken along these lines and it has been found that the relationship of monosodium phosphate to disodium phosphate has a very important bearing on the question of the solution of uric acid, and on the conditions of the solution of its salts in the urine (Ritter, J. Strauss, and others). We must also assume for the blood and other fluids that the proportionate amounts of the individual salts are not responsible for the question of the solution, or of the precipitation of the uric acid. As it 5s expressed in common phraseology, when various salts are present in a solution, those which are more easily soluble form compounds; those less easily soluble, if their amount is not so great as to saturate the solution, can be precipitated. To this point Senator was one of the earliest to call attention. His, in his investigations in the domain of physical chemistry, has shown its significance in the question under discussion, and, more recently, Freudweiler has taken it into consideration. We hold it to be extraordinarily important in this connection and believe an especial review of the collected results to be demanded in order to explain the existence of a crystalline separation. If it is considered that in those places where the blood supply is meager (cartilages, tendon sheaths, etc.), diffusion must result much more slowly than in those parts which are very vascular, it will be seen without further explanation that the intermixture of the substances dissolved in the blood and the fluids with the local metabolism products and the uric acid, must be retarded also. This is not less true of the consequent molecular exchange. The experience that the deposition of uric acid when experimentally brought about by the damming back of the kidney secretion according to Zalesky and Chrzons zewsky takes place first in the lymphatics and is greatest there, thereby makes the hypothesis especially acceptable that aside from the vessels, the cartilages or fascia are the most favorable places for such a salt concentration or chemical interchange. In these mentioned locations a precipitation of uric acid can result more easily than the formation of one of its compounds, when the blood serum is overladen but not saturated.* Kionka also observed this preference of uric acid for the cartilages in his experiments in feeding hens; and, furthermore, Almagia has established the fact that the cartilage possesses a special affinity for uric acid even under normal conditions.

* At present we are unable to solve the question whether it is uric acid or its compounds which are actually present in the blood of gouty subjects; nor has it been settled for healthy individuals, in spite of the interesting researches which were made on urine by E. Pfeiffer with Heintz's method.

The importance attributed to the products of local processes in the precipitation of uric acid is not detracted from by the results of more recent animal experiments made by van Loghem, Silbergleit and others, who found that in animals the introduction of alkali favors the formation of urate deposits, while the introduction of acids inhibits it. This can only be explained by the assumption of local metabolic disturbances or changes. This shows that the precipitation of uric acid from a blood serum in which it is contained in excess, demands a local cause. Due consideration has been given this point on many sides, by Ebstein especially. The peculiar relation of the supply of the lymphatics causes it to appear easily comprehensible that here (cartilages), as Ebstein mentioned, a local retardation of the circulation would generate a condition of fluids overladen with uric acid. In these special localities there may be certain factors which excite the production of uric acid precipitating substance. Fagge has designated trauma as the cause of acute attacks of gout. Freudweiler thinks it to be a local inflammatory process; Scudamore blames a condition of plethora; Gairdner, a venous congestion.* A clear conception is extremely hard to gain from such varying opinions. All that is certain is that the entire process is exceedingly complex. Personally we attribute the establishment of a gouty attack to the heaping up of certain products of metabolism, which may be designated as factor X, in localities where there is already an abundance of uric acid, which is consequently precipitated. This results in inflammatory processes and in severe cases leads to necrosis. This outcome is especially favored by the fact that the uric acid in the blood predisposes the tissues to the irritation of a precipitate. And the poor circulation through these tissues which experience has shown to be most often subjected to gouty changes leaves them less able to withstand an approaching necrosis. In our opinion the last word on this question has not yet been spoken. At present we do not consider it advisable for us to make any definite statement concerning this complicated question, or to indicate with certainty any particular substance [chondroitin sulphuric acid or its salts (Minkowski), sulphuric acid (Gemmel), glycocoll (Kionka)] as the means of precipitation. The question of what special conditions cause the increase of the uric acid in the blood of gouty patients, does not, at the present time, lend itself to a general reply, and it can only be said that the attack of gout is occasioned by the co-operation of two factors, one known and the other unknown. The known factor is supplied by the increase of uric acid in the blood serum and in the fluids; this increase may be the result of various causes, the most frequent of which is probably renal. The second, or unknown factor, X, causes the production of a substance which will precipitate the increased uric acid at certain places (cartilages, tendon sheaths, connective tissue, etc.). The presence of both factors is necessary for the occurrence of an attack of gout.

* We have lately seen a case of acute gout affecting the right index finger. The patient had already suffered for a month from stasis of the lower extremities which had induced a secondary scleroderma. While in previous years the arthritis had involved the large joints, the gouty symptoms of this patient had remitted for two years until the time of the above mentioned attack in the finger.