People get gout because uric acid builds up in their blood until it crosses a critical threshold and forms sharp, needle-like crystals inside a joint. That threshold is about 6.8 mg/dL of uric acid in the blood, though crystals can form at even lower concentrations in cooler parts of the body like the big toe. The real question is why some people accumulate too much uric acid in the first place, and the answer involves genetics, kidney function, diet, alcohol, certain medications, and a few surprising quirks of human biology.
How Uric Acid Becomes a Crystal
Your body constantly breaks down compounds called purines, which come from the food you eat and from your own cells as they turn over. The final step in that breakdown is handled by an enzyme that converts purines into uric acid. In most mammals, another enzyme then breaks uric acid down further into a harmless substance. Humans lost the gene for that second enzyme millions of years ago, so uric acid is our metabolic dead end. It has to leave the body through the kidneys and, to a lesser extent, the gut.
When blood levels stay elevated long enough, uric acid begins crystallizing in joint fluid. The process happens in stages: uric acid molecules first clump into tiny fibril-like structures, then those fibrils ball together into larger clusters, and finally the outer surface of those clusters transforms into sharp, filament-shaped crystals that break off and scatter through the joint space. Your immune system treats those crystals like a foreign invader, triggering intense inflammation, swelling, and the severe pain characteristic of a gout attack.
Your Kidneys Are the Main Bottleneck
About two-thirds of uric acid leaves your body through the kidneys, making them the single biggest factor in whether levels stay safe or climb toward the danger zone. The kidney’s handling of uric acid is surprisingly complicated. Uric acid is first filtered freely into the kidney tubules, then mostly reabsorbed back into the blood, then secreted again into the tubules, and then partially reabsorbed a second time. The net result is that only a small fraction of the uric acid your kidneys filter actually makes it into your urine.
Any disruption to this process can tip the balance. Reduced kidney filtration (from chronic kidney disease, for instance) means less uric acid enters the tubules in the first place. Conditions that cause acidosis, such as diabetic ketoacidosis or heavy alcohol use, reduce the tubules’ ability to secrete uric acid. And genetic differences in the transport proteins lining those tubules can make some people naturally more efficient at reabsorbing uric acid back into the bloodstream, quietly raising levels over years.
Genetics Play a Larger Role Than Most People Realize
Several genes strongly influence your gout risk by controlling how your body moves uric acid in and out of cells. A large genome-wide study in the UK Biobank found that the strongest genetic signal for gout came from variants in a gene called ABCG2, which encodes a transporter protein responsible for pumping uric acid out of cells. Dysfunctional versions of this transporter lead to reduced uric acid excretion and higher blood levels. The second-strongest signal came from SLC2A9, a gene that controls uric acid reabsorption in the kidneys.
Beyond those two, researchers identified variants in at least three other urate transport genes that each independently affect gout risk. The overall pattern is clear: the gene pathways most strongly linked to gout are those involved in uric acid transport and metabolism. This is why gout runs in families, and why some people develop it despite eating a relatively healthy diet. Your genetic blueprint sets a baseline for how efficiently your body clears uric acid, and everything else layers on top of that.
What Food and Drink Actually Do
Diet matters, but not in the simplified way most people think. Yes, eating purine-rich foods (organ meats, shellfish, red meat) provides more raw material for uric acid production. But dietary purines account for a relatively modest share of total uric acid in the body. Your own cells generate purines constantly as part of normal DNA and RNA turnover.
Fructose is a more potent dietary trigger than many people realize, and the mechanism is different from purines. When your liver processes fructose, it rapidly uses up a molecule called ATP (your cells’ energy currency) without any built-in brake on the reaction. The speed of that first step outpaces the liver’s ability to keep up with the second step, so an intermediate product accumulates and intracellular energy stores drop. That energy depletion activates a pathway that accelerates purine breakdown, producing more uric acid and generating harmful oxidants in the process. Sugary drinks, fruit juices, and foods with added high-fructose corn syrup all deliver fructose rapidly enough to trigger this cascade.
Alcohol raises uric acid through multiple routes. Ethanol metabolism in the liver produces lactic acid, which competes with uric acid for excretion through the kidneys. Classic research showed that when heavy drinkers were given alcohol, their blood lactic acid and uric acid levels both rose while urinary uric acid excretion dropped. Beer compounds the problem because it’s also rich in purines from the brewing process. Spirits raise uric acid primarily through the lactic acid mechanism, while wine appears to have a smaller effect at moderate intake.
Why the Big Toe Gets Hit First
The base of the big toe is by far the most common site for a first gout attack, and temperature is a key reason. That joint sits at the far end of your circulation, where tissue temperature hovers around 32°C rather than the body’s core 37°C. This matters because uric acid’s solubility is temperature-dependent. Dropping from 37 to 35°C alone reduces the amount of uric acid that can stay dissolved from 6.8 to 6.0 mg/dL. At the big toe’s even cooler temperature, the saturation point is lower still.
The cooler temperature doesn’t just encourage crystal formation. Research shows it also amplifies the immune system’s inflammatory response to those crystals, making the attack more intense. This explains why gout tends to favor other cooler, peripheral joints as well: ankles, knees, wrists, and fingers. It also helps explain why attacks often strike at night, when body temperature naturally dips and peripheral joints cool further under bedcovers.
Medications That Raise Uric Acid
Certain common medications quietly push uric acid levels up. Thiazide diuretics, widely prescribed for high blood pressure, are among the best-documented culprits. Studies in healthy men showed that two weeks of thiazide use blunted the kidneys’ ability to excrete uric acid, likely by interfering with tubular secretion or increasing reabsorption. The risk appears dose-dependent: doses of 25 mg per day or higher (in hydrochlorothiazide equivalents) significantly increased the likelihood of needing gout treatment, roughly doubling the risk. Lower doses did not carry a statistically significant increase.
Low-dose aspirin also reduces uric acid excretion through the kidneys, as do certain drugs used after organ transplants. If you’re already genetically predisposed to higher uric acid levels, adding one of these medications can be the factor that tips you over the crystallization threshold.
Who Gets Gout and Why the Gap Exists
Gout is far more common in men than women. Among adults 65 and older globally, roughly 23.7 million cases were estimated in 2021, with men accounting for about 16.2 million of those and women about 7.5 million. The disease burden in older men is nearly double that of women of the same age, and incidence continues to climb with age.
The sex difference comes down largely to estrogen, which promotes uric acid excretion through the kidneys. Before menopause, women maintain lower uric acid levels and rarely develop gout. After menopause, that protective effect fades and women’s risk begins to converge with men’s, though it never fully catches up. This is why gout in women tends to appear a decade or more later than in men.
Obesity amplifies gout risk through several overlapping pathways. More body mass means more cell turnover and purine production. Excess fat tissue also promotes insulin resistance, which reduces the kidneys’ ability to clear uric acid. And the metabolic syndrome that often accompanies obesity, including high blood pressure requiring diuretics, creates a cascade of factors that each independently raise uric acid levels.
The Buildup Before the First Attack
One of the most important things to understand about gout is that it doesn’t start with the first painful flare. Uric acid levels can be elevated for years, even decades, before crystals accumulate enough to trigger symptoms. During this silent phase, crystals may already be depositing in joint tissue. The first attack typically happens when something tips the balance: a heavy meal, a night of drinking, dehydration, a new medication, surgery, or even a sudden illness. These triggers can cause a rapid shift in uric acid levels (either up or down), which destabilizes existing crystal deposits and provokes the immune response.
This is also why gout attacks can seem random or unpredictable. The underlying problem, persistent uric acid elevation, has been building quietly. The flare is just the moment the immune system finally reacts to a crystal load that’s been growing for a long time.