What Causes Gout
Gout is caused by the accumulation and deposition of monosodium urate (MSU) crystals in joints and tissues, which occurs when serum uric acid levels persistently exceed 6.8 mg/dL, leading to hyperuricemia and subsequent inflammatory arthritis. 1
Underlying Pathophysiology
The fundamental mechanism involves either:
- Reduced renal clearance of uric acid (most common cause) 2
- Overproduction of uric acid (less frequent) 2
When serum urate persistently exceeds the saturation point of 6.8 mg/dL, extracellular fluids become supersaturated, causing MSU crystal formation and deposition in joints, cartilage, bones, tendons, bursae, and soft tissues 1, 3. The inflammatory response to these crystal deposits produces the clinical manifestations of gout 2, 4.
Major Risk Factors
Modifiable Risk Factors
- Obesity and overweight status 1
- Alcohol consumption (particularly beer and spirits) 1
- Diet rich in purines (meat, seafood, high-fructose foods and drinks) 1, 5
- Diuretic use 1
Non-Modifiable Risk Factors
- Male sex (men are disproportionately affected) 1, 5
- Age (prevalence increases with age: up to 7% in men over 65,3% in women over 85) 1
- Family history 6
Associated Comorbidities
The EULAR guidelines emphasize systematic assessment for comorbidities, as gout strongly associates with metabolic and cardiovascular conditions: 7, 6
- Chronic kidney disease (increases gout risk 4.95-fold; RR 4.95% CI 4.28-5.72) 6
- Hypertension 1, 6
- Diabetes mellitus 1, 4
- Cardiovascular disease (coronary artery disease, heart failure) 6, 4
- Metabolic syndrome (constellation of insulin resistance, hypertension, obesity, dyslipidemia) 4
Secondary Causes
Gout may be secondary to:
- Hematologic malignancies (acute and chronic leukemia, polycythemia vera, multiple myeloma) 8
- Rapid tissue breakdown (chemotherapy, tumor lysis) 8
- Renal dialysis 8
- Psoriasis 8
Critical Clinical Pitfall
A common diagnostic error is assuming hyperuricemia alone causes gout or that normal serum uric acid excludes gout. 6 The EULAR guidelines specifically warn that serum uric acid may be normal during acute gout attacks, as urate is being deposited into tissues 6. Conversely, most adults with hyperuricemia remain asymptomatic throughout their lives and never develop clinical gout 2.
Genetic and Metabolic Factors
Rare genetic conditions like Lesch-Nyhan syndrome (deficiency of hypoxanthine-guanine phosphoribosyltransferase) cause massive uric acid overproduction and severe early-onset gout 8, 9. Environmental and genetic factors interact to determine individual susceptibility to developing symptomatic gout from hyperuricemia 9.