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Gout is a historic medical malady with an impressive clinical presentation of acute, intense pain and erythema, often involving the big toe (podagra). This singular clinical finding made gout easy to recognize and diagnose, and defined it as a rheumatologic disease. However, with advanced understanding of biochemistry and renal function, it has become clear that in most cases, gout is actually the rheumatologic manifestation of renal disease, with hyperuricemia most often the result of decreased renal urate excretion.1
Urate is a byproduct of nucleic acid metabolism. The production, degradation, and recycling of nucleic acids is critical for reproduction of cells and for directing the synthesis of proteins. For most animal species, uric acid is metabolized by the enzyme uricase2 to allantoin. However, man does not produce uricase, resulting in an accumulation of uric acid. Figure 1 shows key elements of nucleic acid metabolism. Allopurinol3 and febuxostat4 are xanthine oxidase inhibitors and result in increased concentrations of xanthine, with decreased urate production.
Why do humans not have uricase? The gene for producing uricase is actually found in the human genome, but there are two separate mutations that occurred over time that resulted in the inability to synthesize urate.5 There are a number of theories as to why uric acid might be beneficial to humans. An important theory proposed by Dr. Richard Johnson6, 7 is that in primitive cultures that were in general sodium deficient, uric acid resulted in changes in vascular tone in the renal microvasculature, resulting in an increase in blood pressure and increased salt sensitivity. These changes allowed for an increase in blood pressure that may have provided an evolutionary advantage. With the marked increases in sodium consumption in modern times, it is postulated that elevated serum urate levels may now contribute to nephrosclerosis and hypertension.8 This theory is highly innovative but is still not proven, though work is proceeding rapidly in this area. A recent investigation performed in adolescents with new-onset hypertension showed that treatment with allopurinol actually resulted in a decline in blood pressure measurements.9