What are the common causes of hyperuricemia and the recommended management?

Causes of Elevated Uric Acid

Elevated uric acid results from either increased production or decreased renal excretion, with impaired kidney excretion being the dominant mechanism in most cases. 1, 2

Primary Mechanisms

Uric Acid Overproduction

• Increased purine biosynthesis, accelerated purine metabolism, or excessive dietary purine intake cause uric acid overproduction 1
• Rapid cell turnover in hematologic malignancies releases massive quantities of intracellular nucleic acids that are catabolized to uric acid 1
• Tumor lysis syndrome following chemotherapy causes acute, life-threatening uric acid overproduction from rapid cancer cell destruction 3, 1
• Screen specifically for overproduction using 24-hour urine collection in patients with gout onset before age 25 or history of kidney stones; values >1000 mg/day define overproduction 3, 1

Decreased Renal Excretion

• Impaired renal excretion is the dominant cause of hyperuricemia in most patients 2
• Intrarenal ischemia with lactate generation inhibits urate secretion by the anion-exchange transport system 4
• Genetic mutations in urate transporter 1 (URAT1) and uromodulin (UMOD) affect renal urate excretion 2
• Chronic kidney disease reduces uric acid clearance and is both a cause and consequence of hyperuricemia 5, 4

Medication-Induced Hyperuricemia

Eliminate non-essential medications that elevate serum urate as a first-line management step. 3, 1

• Thiazide and loop diuretics elevate serum urate by reducing renal excretion and should be discontinued when non-essential 3, 1
• Niacin and calcineurin inhibitors similarly elevate serum urate and warrant discontinuation if medically appropriate 3, 1
• 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 uric acid effects 3

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
• Purine-rich meats and seafood contribute to hyperuricemia through dietary purine load 1

Disease-Associated Hyperuricemia

Cardiovascular Conditions

• Heart failure patients develop hyperuricemia from loop diuretic use and renal dysfunction, with hyperuricemia conferring poor prognosis 1
• Chronic cyanotic heart disease causes abnormal urate clearance from reduced glomerular filtration rate and increased red blood cell turnover 1
• Hyperuricemia is independently associated with hypertension, coronary heart disease, heart failure, stroke, peripheral arterial disease, and cardiovascular mortality 5

Metabolic Disorders

• Metabolic syndrome and obesity are associated with hyperuricemia through hyperinsulinemia and increased uric acid production 6
• Hypothyroidism is associated with elevated uric acid levels 7

Genetic Disorders

• Familial juvenile hyperuricemic nephropathy, characterized by early onset hyperuricemia and renal failure, results from uromodulin mutations 2
• Various inherited disorders of urate transport cause primary hyperuricemia 8

Clinical Evaluation Approach

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

• Review and eliminate all non-essential medications that elevate serum urate, including thiazide and loop diuretics, niacin, and calcineurin inhibitors 3, 1
• 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 3, 1
• Do not use uricosuric drugs in overproducers, as increasing urinary uric acid excretion will precipitate nephrolithiasis and renal damage 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 3, 1

Important Clinical Caveats

• Serum uric acid behaves as a negative acute phase reactant, being temporarily lowered during episodes of acute inflammation and stress 3
• Individual patients with crystal-proven gout may have normal serum uric acid levels at the time of investigation, especially during acute attacks 3
• Hyperuricemia is a major risk factor for gout, but many people with high serum uric acid levels never develop gout 3