What is the etiology of hyperuricemia?

Etiology of Hyperuricemia

Hyperuricemia results from either decreased renal excretion of uric acid (the dominant cause in most cases) or increased production, with impaired renal clearance accounting for the majority of primary hyperuricemia. 1, 2

Primary Mechanisms

Decreased Renal Excretion (Most Common)

• Impaired renal uric acid excretion is the dominant cause of hyperuricemia, occurring when renal uric acid clearance falls below 6 mL/min under normal conditions where kidneys clear approximately 500 mg of uric acid daily. 3, 4

• Underexcretion is defined as renal uric acid clearance <6 mL/min, and this mechanism accounts for the majority of hyperuricemia cases in clinical practice. 3

• Uric acid has poor solubility at the distal tubular pH of approximately 5, with a pKa of 5.4-5.7, facilitating crystal formation when concentrations exceed approximately 15 mg/dL at this pH. 4, 3

• Genetic factors contribute to primary underexcretion, including mutations in urate transporter 1 (URAT1), an organic anion transporter with highly specific urate transport activity that exchanges uric acid with other organic anions. 2

• Uromodulin (UMOD) mutations cause familial juvenile hyperuricemic nephropathy, characterized by early-onset hyperuricemia and renal failure through impaired renal urate handling. 2

Increased Uric Acid Production

• Uric acid overproduction occurs through increased purine biosynthesis, accelerated purine metabolism, or excessive dietary purine intake, and is defined as 24-hour urinary uric acid excretion >1000 mg/day on a regular diet. 1, 3

• Screen specifically for overproduction in patients with gout onset before age 25 or those with a history of kidney stones using 24-hour urine collection; values >1000 mg/day define overproduction. 1

• Rapid cell turnover in hematologic malignancies (Burkitt's lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia) releases massive quantities of intracellular nucleic acids that are catabolized through hypoxanthine and xanthine to uric acid by xanthine oxidase. 4

• Tumor lysis syndrome following chemotherapy causes acute, life-threatening uric acid overproduction from rapid cancer cell destruction, with purine nucleic acids catabolized at rates that overwhelm the normal renal clearance capacity of 500 mg/day. 4, 1, 3

Secondary Causes

Medication-Induced Hyperuricemia

• Thiazide and loop diuretics elevate serum urate by reducing renal excretion and should be discontinued when non-essential, as they are prime examples of drugs causing hyperuricemia. 1, 3

• Niacin and calcineurin inhibitors (cyclosporine, tacrolimus) similarly elevate serum urate and warrant discontinuation if medically appropriate. 1, 3

• Low-dose aspirin (≤325 mg daily) modestly elevates serum urate but should not be discontinued for cardiovascular prophylaxis, as the cardiovascular benefits outweigh the modest effect on uric acid. 1

Dietary and Lifestyle Factors

• High-fructose corn syrup consumption increases uric acid synthesis, with 1 gram of fructose per kilogram of body weight raising serum uric acid by 1-2 mg/dL within 2 hours. 1

• Alcohol intake, particularly beer and spirits, increases uric acid production and reduces renal excretion with a dose-response relationship for gout flares. 1, 3

• Purine-rich meats and seafood (organ meats such as liver and kidney, shellfish) contribute to hyperuricemia through dietary purine load. 1, 3

Comorbid Conditions

• Chronic kidney disease (CKD) causes hyperuricemia through reduced glomerular filtration rate, with approximately 70% of uric acid excreted by the kidneys, creating a bidirectional relationship where CKD both causes and results from hyperuricemia. 5, 6

• Heart failure patients develop hyperuricemia from loop diuretic use and renal dysfunction, with hyperuricemia conferring poor prognosis in this population. 1

• Chronic cyanotic heart disease causes abnormal urate clearance from reduced glomerular filtration rate and increased red blood cell turnover, occasionally leading to symptomatic gout. 1

• Metabolic syndrome and obesity are strongly associated with hyperuricemia, probably as a consequence of insulin resistance and the effects of insulin to reduce urinary urate excretion. 5

• Hypertension is commonly associated with hyperuricemia, occurring in approximately 25% of hypertensive patients, with metabolic syndrome present in 40% of these cases. 3, 6

• Hypothyroidism and pesticide exposure are additional risk factors associated with elevated risk of hyperuricemia. 7

Clinical Approach to Etiology Determination

• Calculate estimated glomerular filtration rate (eGFR) to assess renal function, as this determines both the cause and management approach, distinguishing renal insufficiency as a contributor. 1, 3

• Review and eliminate all non-essential medications that elevate serum urate, including thiazide and loop diuretics, niacin, and calcineurin inhibitors as a first-line diagnostic and therapeutic step. 1, 3

• Obtain 24-hour urine uric acid collection in patients with gout onset before age 25 or history of kidney stones to distinguish overproducers (>1000 mg/day) from underexcretors, as this fundamentally changes management. 1, 3

• Do not use uricosuric drugs in overproducers, as increasing urinary uric acid excretion will precipitate nephrolithiasis and renal damage in this population. 1

• Consider rheumatology referral for unclear etiology of hyperuricemia, refractory symptoms despite appropriate therapy, difficulty reaching target uric acid levels, or multiple adverse events from urate-lowering therapy. 1

Important Clinical Caveats

• Serum uric acid behaves as a negative acute-phase reactant, with levels transiently falling during episodes of acute inflammation or physiological stress, which can mask underlying hyperuricemia. 1, 3

• Patients with crystal-proven gout may present with normal serum uric acid concentrations during an acute attack (approximately 10% of cases), owing to the negative acute-phase effect, so clinicians should not rely solely on a single uric acid measurement. 1, 3

• Although hyperuricemia is a major risk factor for gout, many individuals with elevated serum uric acid levels never develop clinical gout, highlighting that hyperuricemia alone is not a disease but a biochemical abnormality requiring clinical context. 1