The State-of-the-Art of Rheumatology Symposium

The model has evolved as recent studies have identified the many transporters that move urate across membranes in the proximal tubule in the kidney. If these transporters don’t work properly, then the individual under-excretes uric acid. These transporters are being actively investigated as drug targets.

Major shifts in the gout model have occurred as a result of an increased understanding of the role of inflammation in the pathophysiology of gout. We now know that urate crystals activate complement and macrophages. The activated macrophages appear to be the most important contributor to the gouty attack because they secrete interleukin 1.

The inflammatory model of gout is based largely upon the danger hypothesis work of Polly Matzinger, PhD, a senior investigator at the National Institutes of Health in Bethesda, Md. According to this hypothesis, antigen-presenting cells are activated by endogenous cellular alarm signals from distressed or injured cells. In the case of gout, the uric acid crystals activate dendritic cells and act as adjuvants, resulting in a significant inflammatory response.

Epidemiology of Gout

Nutrition science has also contributed to the evolution of thinking about gout. Purines and ethanol have long been known to elevate serum urate levels. One of the recent novel discoveries, however, is the effect of fructose consumption on urate levels.

As early as 1893 (and possibly even earlier), physicians noticed that patients who consumed large amounts of fruit had a higher incidence of gout. In The Principles and Practice of Medicine section on gout, Sir William Osler noted that, “The sugar should be reduced to a minimum. The sweeter fruits should not be taken.” We now know that the hepatic metabolism of fructose results in the synthesis of uric acid.

Epidemiologists have also noted that the incidence of gout began to rise at the same time as fructose consumption increased. Two-thirds of the fructose in the U.S. diet is derived from added sugars. Sweetened soft drinks represent the single biggest source of calories in the U.S. (10.6%). Moreover, the ingestion of fructose in the form of soft drinks correlates with serum uric acid levels. This correlation is present even after adjusting for other patterns of dietary consumption.

In contrast, individuals with a larger consumption of dairy products have a decreased risk for gout. This is true in patients who are relatively thin as well as those patients who are slightly heavier. Milk consumption decreases urate levels. Interestingly, soy milk causes urate levels to rise.