Uric acid metabolism and gout

Abstract

Dr. Gutman: Gout is a disorder of purine metabolism characterized by hyperuricemia and recurrent acute arthritis, often eventually associated with urate deposits in the tissues which may be manifest as tophi or as typical roentgenographic changes. The natural history of the disorder is generally divided into two phases: “acute gout,” the period of single or recurring acute attacks of gouty arthritis with complete freedom of symptoms between attacks; and “chronic gouty arthritis,” when the interval between acute attacks no longer is symptom-free but is characterized by progressive disability due to stiffness and deformities of joints, and the appearance of tophi and typical roentgenographic changes. The course of the disease is variable, however, and many patients with acute gout do not, even upon observation for many years, develop the manifestations of chronic gouty arthritis. An important recent development is the realization that uric acid is derived not only from ingested preformed nucleoprotein or puririe but is synthesized within the body at a vigorous rate from the simplest carbon and nitrogen compounds. It has been established by isotope studies that glycine and ammonia contribute nitrogen to the formation of uric acid and that the carbon atoms are derived from formate, glycine and carbon dioxide. Evidently, ingested carbohydrate, fat and proteins, as well as preformed purines, all must be considered to be precursors of uric acid. It has also been shown that incorporation into nucleic acids is not an obligatory step in the biosynthesis of uric acid. Another important advance in elucidation of the mechanisms of gout is the development of a method for estimating the turnover rate and extent of the miscible pool of uric acid. This is accomplished by measuring the rate of dilution of N 15-labeled uric acid after intravenous injection. The method has already revealed that in the normal subject some 700 to 850 mg. of uric acid is formed daily; it has not yet been established whether or not the rate of production of uric acid is excessive in the gouty patient, an important point. It has been demonstrated further that the miscible pool of uric acid is increased in gout, even when uric acid deposits are not clinically or roentgenographically apparent. The method offers a means of measurement of these deposits although a serious limitation derives from the circumstance that the uric acid incorporated into tophi probably does not mix readily with the injected labeled uric acid, hence is not included in the miscible pool. Finally, additional evidence has been provided that uric acid is not degraded to any significant extent in man. With regard to the role of the kidneys in gout, several important advances have been made. A maximum tubular transport capacity, Tm, has been established for uric acid in normal man, indicating an “active” (enzymatic) tubular transporting mechanism of limited capacity. The tubular capacity for reabsorption of urate is large, however, in excess of any load that would be imposed even in gout. Of further significance are recent data indicating that many patients with gout excrete greater than normal amounts of uric acid so long as kidney damage, as measured by the ordinary laboratory criteria, is not appreciable. It is not yet possible to state definitely whether the hyperuricemia of gout is due to increased production of uric acid, decreased destruction of uric acid or impaired renal excretion of uric acid. The available evidence suggests, however, that increased production of uric acid occurs at least in some instances, in which it appears to be a primary factor. Impaired renal excretion of uric acid is an important secondary factor which in many cases contributes significantly to hyperuricemia, particularly in the later phases of gout. In the management of gout the mainstay of treatment of the acute gouty attack is still colchicine, with ACTH and cortisone as additional effective agents. In patients subject to frequent bouts of acute gout colchicine should be taken regularly as an important prophylactic agent. When there are indications of the development of chronic gouty arthritis uricosuric agents should be employed. Of these Benemid appears to be the most promising yet developed. With regard to dietary restriction in gout, the situation still is unsettled. In patients subject to frequent recurrences of acute gout and in those with chronic gouty arthritis it seems prudent to restrict the purine, protein and alcoholic intake.