Gout

Gout flares typically involve one joint at a time, with the second joint of the big toe (the metatarsophalangeal, or mTP joint) most commonly affected. MSU crystals can also form deposits (called tophi) in connective tissue outside joints, but these deposits are usually not as symptomatic as joint disease.

A frequent piece of advice for gout is a purine-restricted diet, as purines from the diet are broken down into uric acid and high purine meals tend to increase uric acid levels.^[22][23] Purine rich foods include meat (particularly organ meat), fish, and shellfish. Exactly how much purine restriction can lower uric acid levels may depend on baseline purine intake and degree of restriction and unfortunately there is limited well-conducted research on the topic. One study on people with hyperuricemia reported a 0.57 mg/dL drop in uric acid after 2 weeks on a low purine diet, however this study lacked a control group.^[24]

To make matters more complicated, there are several types of purines and some evidence indicates they are not all equal in their effects on uric acid levels.^[25] Because the amount of each purine type varies between foods, this means two foods might differ in their effect on uric acid even when purine levels are the same. One study, for example, found that the increase in uric acid 2-hours after eating a meal with either haddock (+0.34 mg/dL) or soybeans (+0.32 mg/dL) was greater than after a meal with beef liver (+0.15 mg/dL), despite a similar purine content between the three meals.^[22]

Average purine content of food groups

Fructose intake appears to increase uric acid levels, with one meta-analysis of randomized controlled trials reporting a 0.4 mg/dL reduction in uric acid when fructose was replaced with glucose and a 0.6 mg/dL reduction when sucrose was replaced with glucose.^[27]

The effect of fruit (a source of fructose) on uric acid is likely complicated. One study examined the impact of different fruits on uric acid in healthy women, reporting no effect of 300 grams of strawberries, 300 grams of kiwifruit, or 280 grams of red grapes and a possible reduction in uric acid following consumption of 280 grams of sweet cherries.^[28] Another study found no differences in fasting uric acid when women on an energy restricted diet consumed a diet high in fructose-rich fruit (delivering roughly 45 grams of fructose per day).^[29] However, in one study consuming 26.7 grams of fructose at on time from either 410 grams of apples, 170 mL of apple juice, or refined fructose all led to increases in uric acid, albeit in the short term (30 minutes after consumption).^[30] Another trial reported increases in uric acid following consumption of 5 apples (containing an estimated 63.9 grams of fructose) compared to eating plain bagels with the same carbohydrate content.^[31] Overall, the effect of fruit on uric acid may depend on quantity and type of fruit as well as the context in which it is consumed.

Excess body weight is associated with higher uric acid levels and risk of gout^[11] and diets that produce weight loss appear to reduce uric acid, with at least one noncontrolled study indicating diet-induced weight loss can reduce the rate of gout attacks.^[32] In another study, weight loss led to reductions in uric acid regardless of whether the diet was low fat, low carbohydrate, or a Mediterranean diet.^[33]

Milk and dairy products may reduce uric acid levels, with a couple of trials observing reductions in uric acid following the consumption of milk.^[34][35] However, one randomized, controlled trial found no effect of skim milk powder on uric acid or gout symptoms in people with gout, though there was an indication of benefits to some gout symptoms when two milk extracts (known as GMP and C600) were added the skim milk powder.^[36]

Two prospective cohort studies, one on men^[37] and the other on women,^[38] each found that higher coffee consumption was associated with a lower risk of developing gout. One Mendelian randomization study also observed that a genetically predicted increase in coffee consumption was linked to lower uric acid levels and a reduced risk of gout.^[39] However, the effect of coffee on gout has not yet been tested in clinical trials and at least one randomized controlled trial failed to find an effect of coffee (either caffeinated or decaffeinated) on uric acid levels.^[40]

Several clinical trials have observed a reduction in uric acid with increasing salt intakes, particularly when comparing low sodium intakes (1200–1380 mg per day) to either moderate or high sodium intakes.^[41][42][43] However, such studies have not yet been conducted on people with gout. Because some research suggests sodium in joints may increase the tendency of uric acid to crystallize,^[8] whether increasing salt intake will reduce the likelihood of gout remains uncertain.

Both extended fasting^[44] and very low carbohydrate diets^[45][46] have been at times shown to produce a rise in uric acid levels, in both cases potentially due to ketones inhibiting uric acid excretion. This effect may diminish over time.

Vitamin C may reduce uric acid, with one meta-analysis of 12 clinical trials^[47] reporting a reduction of 0.35 mg/dL in uric acid with supplemental vitamin C. However, the included studies had highly variable designs and populations. For example, many studies were performed on people performing moderate^[48][49] to high levels of exercise,^[50][51] including one study on ultramarathon runners.^[52] Results from these studies may not be applicable to most people at risk of gout. Only one randomized trial^[53] has investigated the effect of vitamin C on people with gout, but it compared vitamin C to a well established uric acid-lowering drug (allopurinol) rather than a placebo. This study reported a greater reduction in uric acid with allopurinol compared to 500 mg vitamin C and no reduction in uric with vitamin C compared to baseline. One large clinical trial on middle men observed a decrease in the risk of gout with supplementation, though there was no clear benefit among men with a BMI of 30 or higher.^[54] There are currently no randomized, placebo-controlled trials examining the effect of vitamin C among people with active gout.

Tart cherries have been suggested to lower uric acid, though findings from clinical trials have been mixed. In one study on women who did not have gout, consumption of tart cherry juice led to a 19.2% reduction in uric acid compared to a sugar matched placebo,^[55] whereas in a study on people with gout, consumption of various doses of tart cherry juice had no effect on uric acid levels or gout flares.^[2]

A limited number of trials have reported reductions in uric acid from various supplements, including phytic acid (aka inositol hexametaphosphate or IP6),^[56] a combination of glycine and tryptophan^[57], psyllium fiber,^[58] and probiotics.^[59]

The most important known cause of gout is elevated levels of uric acid in the blood, as the propensity of MSU crystals to develop in joints increases as uric acid levels rise.^[3] Although there is no precise level at which uric acid crystals form, a blood uric acid level above 6.8 mg/dL, clinically referred to as hyperuricemia, is often cited as the level at which gout risk rises dramatically. This is approximately the solubility of MSU in normal saline at 37℃.

In the Framingham Heart Study,^[4] the annual occurrence of gout was linearly associated with uric acid levels. In the study, after adjusting for potential confounders, high uric acid (7 to 7.9 mg/dL) was associated with 12 times the risk of gout in women and a 22 times the risk of gout among men compared to having low uric acid (<5 mg/dL), with risks continuing to rise as uric acid levels increased.

Figure 2: The association between uric acid levels and gout incidence

Uric acid levels and gout risk

The primary route of uric acid removal from the body is via urinary excretion. Uric acid in the blood is filtered into the kidneys, where most is reabsorbed back into the blood, with a smaller amount passed into urine. Reductions in uric acid excretion by the kidneys appears to be most responsible for hyperuricemia.^[5][6] A lesser pathway of uric acid removal (roughly 1/3 of uric acid excretion) is via the intestinal system.

Uric acid production, meanwhile, is the result of the metabolism of compounds called purines. These purines are derived both endogenously (in the body) from the breakdown of tissues and energy substrates as well as exogenously (outside the body) from eating foods containing purines and purine precursors.

While elevated uric acid is the primary cause of gout, many people with hyperuricemia do not develop gout, suggesting other factors play a role in the development of gout.^[7] In particular, the development of MSU crystals likely varies depending on a number of factors, including the temperature and pH of the gout-affected tissues.^[8] The body's inflammatory reaction to uric acid crystals is also an important determinant of the occurrence and severity of gout.

Genetic factors: Uric acid and gout both appear to have a genetic component, with uric acid levels estimated to be about 63% heritable.^[9] A number of genes have been identified that influence gout risk and/or uric acid levels (SLC2A9, SLC22A12, and ABCG2, among others), most of which appear to primarily affect uric acid excretion by the kidneys.^[10]

Body weight: Having overweight or obesity is associated with a much higher risk of gout,^[11] with one meta-analysis reporting people with obesity were 2.24 times more likely to develop gout.^[12]

Alcohol: Alcohol consumption can increase uric acid levels^[13] and is associated with a higher risk of gout.^[14] This effect may vary by the source of alcohol, as some research has observed an association between uric acid levels and intake of beer and liquor but not with wine.^[15][16]

Diet: One meta-analysis of observational studies reported that risk of gout was associated with an increased consumption of red meat, seafood, alcohol, and fructose.^[17] These foods were likewise associated with a higher risk of hyperuricemia. In general, this appears somewhat consistent with clinical research.

Medications: A number of drugs appear to increase uric acid and the risk of gout, including certain diuretics, immunosuppressant drugs, high doses of vitamin B3 (nicotinic acid), and low doses of aspirin.^[18]

Kidney disease: Kidney disease is strongly associated with elevated uric acid and gout, although the nature of this relationship is debated. Specifically, reductions in kidney function might increase uric acid levels, or increased uric acid might cause reduced kidney function, or possibly a mix of both.^[19]

Hypertension: Hypertension is associated with higher uric acid levels, possibly as a result of effects of high blood pressure on kidney function. However, as with kidney disease, this association could be backwards, with some research indicating uric acid may increase blood pressure.^[20][21]