What causes an increase in uric acid levels (Hyperuricemia)?

From the Guidelines

Hyperuricemia is primarily caused by a combination of genetic, nutritional, and lifestyle factors, including diet, obesity, hypertension, diabetes mellitus, metabolic syndrome, and renal and cardiovascular diseases.

Key Factors Contributing to Hyperuricemia

• Genetic polymorphisms of renal transporters of urate: These genetic variations can affect how the body processes and eliminates uric acid, leading to increased levels in the blood 1.
• Nutritional factors: Certain dietary choices, such as high intake of purine-rich foods, fructose, and alcohol, can increase uric acid production and contribute to hyperuricemia 1.
• Obesity and metabolic syndrome: These conditions are associated with increased uric acid production and decreased uric acid excretion, leading to hyperuricemia 1.
• Hypertension, diabetes mellitus, and renal and cardiovascular diseases: These conditions can also contribute to hyperuricemia, possibly due to decreased uric acid excretion or increased production 1.

Relationship Between Uric Acid Levels and Gout

• Higher serum uric acid levels are associated with an increased risk of gout: Studies have shown that higher serum uric acid levels are associated with an increased risk of gout, with a threshold of around 6 mg/dL (360 mmol/L) often used as a cut-off point for increased risk 1.
• Uric acid levels can fluctuate during acute gout attacks: Uric acid levels may be normal or even low during acute gout attacks, possibly due to increased renal excretion or other factors 1.

Management of Hyperuricemia

• Urate-lowering therapy (ULT): ULT is often used to manage hyperuricemia and prevent gout attacks, with a goal of reducing serum uric acid levels to below 6 mg/dL (360 mmol/L) 1.
• Lifestyle modifications: Dietary changes, weight loss, and exercise can also help manage hyperuricemia and reduce the risk of gout attacks 1.

From the Research

Causes of Hyperuricemia

• Hyperuricemia occurs when uric acid (UA) production exceeds UA excretion 2
• The kidney plays a dominant role in UA excretion, with approximately 70% of daily produced UA being excreted by the kidneys, and the remaining 30% being excreted from the intestine 2
• Increased urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) expression, and glycolytic disturbances due to insulin resistance may be associated with the development of hyperuricemia in metabolic syndrome 2

Factors Contributing to Hyperuricemia

• Massive urate overproduction, usually occurring acutely due to tumor lysis, rhabdomyolysis, or some other cause of rapid nucleic acid turnover or tissue destruction, can cause acute renal failure 3
• Chronic urate overproduction is more likely to be associated with stones or gout than with acute renal failure 3
• Hyperuricemia is associated with metabolic syndrome, diabetes, hypertension, and kidney and cardiovascular diseases 4, 5

Mechanisms of Hyperuricemia

• Monosodium urate (MSU) crystals induce an inflammatory reaction, which is recognized by toll-like receptors (TLRs) and activates NALP3 inflammasome 6
• Soluble uric acid can also mediate the generation of free radicals and function as a pro-oxidant 6
• The elevation of uric acid in blood is mainly due to an increase in its intake or a defect in its secretion 5
• The mechanisms of renal damage go beyond the deposition of crystals at the tubular level, and also contribute to the production of chemotactic cytokines, cell proliferation, and inflammation 5