Chemical Pathology

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Uric acid is a by-product of purine metabolism in humans and certain apes who lack uricase, the enzyme that breaks down uric acid (Figure 1).

PRPP + Glutamine *

+ Glycine, Formate *

Inosinic Acid

Guanilic acid ^ Adenylic acid

* Inosine t

Guanine i R Adenosine Adenine

^ Hypoxanthine

Xanthine *

Uric acid

Figure 1 Simplified pathway of uric acid metabolism. PRPP, 5-phosphoribosyl-Apyrophosphate. (Modified from Seegmiller JE, Rosenbloom FM and Kelly WN (1967) Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Science 155:1682-1684.)

When uric acid production is normal, and its clearance by the kidneys is normal, this metabolic quirk has no ill effects. However, this minor metabolic inconvenience becomes of pathological importance because uric acid is so poorly soluble in aqueous solutions that it can crystallize and cause the various conditions recognized as gout. Uric acid can be ingested directly in the diet (especially in organ meats such as liver, kidney, and sweetbreads), or it can be produced in the body by two pathways involved in purine metabolism (Figure 1). The de novo synthesis of uric acid proceeds directly from ribose-5-phosphate, whereas the salvage pathway consists of production of the uric acid precursors inosine from adenosine and xanthine from guanine. The medication allopurinol, which blocks the conversion of xanthine to uric acid by xanthine oxidase, is effective because xanthine is far more soluble in aqueous solutions than is uric acid.

The precise mechanism by which uric acid leads to gouty arthritis remains somewhat unclear. However, uric acid is known to be proinflammatory in that it can initiate an immune response with recruitment of white blood cells after uric acid crystals are phagocytosed by polymorphonuclear leukocytes or macrophages. These white blood cells also release tumor necrosis factor and inter-leukin-1, recruiting more white cells, which release lysosomal enzymes that lead to cartilage destruction and joint erosions with repeated attacks. In addition, ingestion of uric acid leads to death of the phagocytosing cells, leading to release of the uric acid and additional proteolytic enzymes, thus reinforcing the inflammatory condition. However, the crystals become progressively less phlogistic after several cycles of ingestion and release, and the inflammation relents over a period of 10-14 days. The natural history of untreated gout progresses through four stages from (i) asymptomatic hyperuricemia to (ii) acute gouty arthritis, (iii) intercritical gout, and (iv) chronic tophaceous gout. In addition, renal manifestations of gout develop in up to 50% of patients, depending on the amount of uric acid they excrete.

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