Our story begins a very long time ago, somewhere between 11 and 16 million years ago, an era better known as the Middle Miocene epoch. Dogs and bears made their first appearances. The evolution of horses was galloping along over the landmass that became North America. In the western interior of North America, a great outpouring of lava formed the Columbia River basalt plateau, which became part of the American northwest landmass. On the other side of the planet, the Alps continued their ascent. In the midst of all this geophysical tumult, another critical event was taking shape: the enzyme uricase began to disappear in hominids.
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Explore This IssueJanuary 2013
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There appears to have been three critical mutations in the uricase gene in humans, chimpanzees, and gorillas that led to the demise of the enzyme.1 Two were nonsense mutations, involving codons 33 and 187, and the third was a mutation in the splice acceptor signal of exon 3. The mutation of codon 33 is thought to be responsible for the major loss of uricase function. The promoter region of the gene had probably been degraded in the evolutionary process by previous mutations and, over time, humans and some other higher primates lost all uricase activity. Perhaps this seminal event should be considered to be the “Big Bang” in the rheumatology universe. After all, without it there would be no podagra, hot swollen ankles, or sore insteps. I suspect that most rheumatology consult services would have withered with the loss of such a sizable portion of their clinical revenue!
Gout is a wonderful disease to study. Its superficial simplicity (molecular formula of C5H4N4O3) belies its complicated role in human biology. Despite our greater understanding of the pathogenesis of gout, many patients are misdiagnosed or treated inappropriately. Acute pain, redness, and swelling in a lower extremity joint, a raised serum urate, and voila, the diagnosis is made. Really? Who needs a polarizing microscope? Certainly not the majority of practitioners who diagnose gout. In the U.S., it is estimated that rheumatologists perform fewer than 2% of all office visits for gout, compared with primary care doctors who see 70% and cardiologists who manage 10% of gout sufferers. I suspect that allopurinol is one of the most widely misunderstood drugs prescribed by nonrheumatologists. Perhaps each prescription should contain a package insert advising the patient to confirm its use with a rheumatologist.