Excerpt from the Paleodiet Update :
Gout: The Real Dietary Causes
It has been known for almost 40 years that fructose ingestion or infusions result in hyperuricemia (elevated blood uric acid levels)21-24. However, this information has seemingly been buried in the medical literature, since clinical nutrition texts make few or no dietary recommendations for gout patients to reduce dietary sources of fructose. Fructose stimulates synthesis of AMP and GMP (see Figure 4) which are ultimately converted to uric acid by the liver, thereby elevating plasma uric acid levels24, 25. Only fructose causes this effect, as experimental 3,000 kcal day diets consisting entirely of glucose in obese patients did not increase plasma uric acid levels, whereas a high sucrose (table sugar) diet did26. Because sucrose is composed of the two simple sugars, glucose and fructose, then the digestion of sucrose in the gut to its two component sugars shows that fructose alone is responsible for inducing hyperuricemia.
In the US diet the two primary sources of fructose are from the digestion of sucrose and from foods containing high fructose corn syrup. Figure 5 shows the total consumption of all refined sugars in the U.S. from 1970 to 2000. Note that total fructose consumption (from both the metabolism of sucrose and high fructose corn syrup) has increased from 51.5 lbs in 1970 to 64.9 lbs in 2000 – an increase of 26%.
Figure 5. Annual per capita consumption of refined sugars in the U.S 1970-20001.
Fructose causes hyperuricemia by lowering the inorganic phosphate (Pi) content of the liver. High levels of Pi in the liver normally slow the metabolism of GMP and AMP into uric acid (see Figure 4). Fructose is an unusual sugar in that it enters liver metabolism (glycolysis) after the PFK regulatory step, thereby causing unregulated phosphorylation of fructose to fructose 1-P which in turn lowers both liver ATP and Pi27. Further, because fructose bypasses the PFK regulatory step, it increases blood lactic acid which is an inhibitor of uric acid excretion by the kidneys28. Consequently, fructose ingestion either from high fructose corn syrup or from sucrose enhances uric acid production and also slows it excretion. To add insult to injury, long term ingestion of table sugar (sucrose) and high fructose corn syrup, because they are high glycemic load carbohydrates, will chronically elevate blood insulin concentrations and frequently result in insulin resistance1. Numerous studies conclusively show that insulin is a potent inhibitor or uric acid excretion by the kidneys29-31. Taken together, these basic and well established biochemical facts indicate that sucrose, high fructose corn syrup and all high glycemic load carbohydrates play a central role in causing gout. Diseases of hyperuricemia are tightly coupled with metabolic syndrome diseases because both categories of diseases result, in part, from chronically elevated insulin.
There is one final dietary key which completes the picture. In addition to fructose, sucrose and high glycemic load carbohydrates, excessive consumption of alcoholic beverages may also promote gout symptoms by simultaneously increasing uric acid production and slowing its excretion. The metabolism of alcohol (ethanol) like that of fructose reduces the liver stores of ATP and Pi by uncoupling oxidation from phosphorylation and thereby increases uric acid synthesis from AMP and GMP32. A by product of alcohol metabolism is lactic acid which once again inhibits uric acid excretion in the kidneys by competitively inhibiting uric acid secretion in the proximal tubules11.
The Supporting Evolutionary Evidence
As you Paleo Diet Newsletter readers are well aware, whenever a complex diet/disease question arises, insight into the problem can almost always be gained by framing the question in an evolutionary perspective. In the case of gout, the recommendation to limit high purine meats is completely contrary to the anthropological evidence showing that animal food was the staple of hunter gatherer diets, typically comprising more than 50% of total daily energy33, 34. In ancestral hominins, animal food based diets have an ancient origin dating back at least 2.5 million years, as evidenced by stone tool cut marks present on fossilized bones of prey animals (Figure 6). We can also infer that animal food was the staple of Homo erectus living 1.77 million years ago in what is now the Dmanisi archeological site 36 in the Republic of Georgia. Because of the seasonal scarcity or absence of plant foods at 40 degrees North latitude, these ancestral hominins almost certainly were highly dependent upon animal foods for many months during the year (Figure 7).
Figure 6. The earliest evidence for meat and marrow extraction dating to 2.5 million years ago35.
Given our ancient heritage of meat based diets, it is paradoxical that high purine meats would still cause a crippling disease after more than 2 million years of evolutionary experience. A more likely evolutionary scenario would be that natural selection must have been operative in selecting genes to overcome any deleterious effects of excessive dietary purine. Let’s take a look at the evidence.
Almost all animals except humans don’t ever get gout because they have an enzyme called uricase which converts uric acid into a substance called allantoin, which is 5-10 times more soluble than uric acid and thus more easily eliminated by the kidneys11. Modern humans and great apes cannot synthesize uricase because, over the course of evolution, they have experienced mutations which have inactivated the uricase gene. Chimps and other great apes maintain much higher blood uric acid levels than do other animals capable of synthesizing uricase, however chimps and other great apes apparently do not ever develop gout in the wild, presumably because they consume a near vegetarian diet without additional purines from meat11.
Figure 7. The earliest evidence of fossilized hominins living outside of Africa at the Dmanisi archaeological site in the Republic of Georgia.
As early hominins began to increasingly include more and more purine containing animal foods into their diets37, blood concentration of uric acid almost certainly must have been higher than their more vegetarian predecessors, thereby increasing the incidence of gout. Because gout impairs mobility, mortality must have increased in individuals susceptible to gout. Hence, natural selection would have rapidly weeded out individuals who were most susceptible to gout and selected for those who could tolerate a high meat diet without developing gout symptoms. In support of this evolutionary scenario is a metabolic adaptation present in humans which lowers uric acid synthesis despite a high dietary purine intake.
Take a look at Figure 4 one more time. As the purine precursors, GMP and AMP, are ultimately converted to uric acid there are a couple of key intermediary steps along the way. AMP is converted to hypoxanthine and then to xanthine and finally to uric acid. GMP is converted to xanthine and then to uric acid. Both the conversion of hypoxanthine to xanthine and xanthine to uric acid are regulated by an enzyme called xanthine oxidase. Humans avoid the overproduction of uric acid in the face of increasing dietary purine intake from meats by decreasing the activity of xanthine oxidase38. Compared to other animals, xanthine oxidase activity is almost 100 times lower in humans39. This evolutionary adaptation has occurred because the gene coding for xanthine oxidase (more specifically xanthine oxidoreductase) has been repressed40.
So there you have it. The evolutionary model originally predicted that a meat based diet should not increase the risk for gout. Now we have genetic and biochemical evidence supporting the evolutionary model. The final corroborative link would be experimental evidence. If you put gout patients on a meat based, high protein diet, reduce refined sugars and high glycemic load carbohydrates, what do you think will happen. What might the evolutionary paradigm predict? Let’s take a look.
The Proof Is In The Pudding (A Clinical Trial)
As is the case with many diet related diseases, the dogma has been so well established that it is difficult to unlearn what was once known to be the absolute truth. Nothing could be a better example of this lesson than the dietary dogma for treating gout. It took until the year 2000 before anyone ever tried putting gout patients on a high protein, low glycemic load diet to see what would happen41. Low and behold this program normalized serum uric acid concentrations in 7 of 12 gout patients and significantly decreased gout attacks. The authors concluded their paper by saying "Current dietary recommendations for gout may need re-evaluation".
Epilogue
Six years have now come and gone since this revolutionary clinical trial has been conducted. You might think that the rheumatology community would jump onto this band wagon as fast as a hot knife through butter. Ah, we should be so lucky – not in our wildest dreams. There has not been a single corroborative or follow up study, and the misconception that a high purine, meat based diet causes gout continues to be spread in prestigious world wide medical journals13.
