Hyperuricemia (HUA) is a chronic metabolic disorder caused by purine metabolism dysfunction. Clinically, it can be classified into two types: primary and secondary. Primary hyperuricemia is often caused by congenital abnormalities in purine metabolism and is typically associated with conditions such as obesity, type 2 diabetes, dyslipidemia, hypertension, atherosclerosis, and coronary heart disease. Secondary hyperuricemia often results from certain systemic diseases or the use of specific medications.
Etiology and Pathogenesis
Uric acid is the end product of purine metabolism in the human body. Uric acid has two main sources: endogenous, which accounts for about 80% of total body uric acid, arises from internal synthesis or nucleic acid degradation, while exogenous sources, accounting for approximately 20%, come from purine-containing foods. Under normal circumstances, the production and excretion of uric acid in the body remain in dynamic balance. Any factors leading to excessive uric acid production and/or reduced excretion can result in hyperuricemia.
Primary Hyperuricemia
Reduced Uric Acid Excretion
Approximately 80%–90% of HUA cases involve uric acid excretion dysfunction, which may include:
- Decreased secretion by renal tubules, which is the most significant contributor.
- Reduced glomerular filtration.
- Increased reabsorption by renal tubules.
- Precipitation of urate crystals.
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Increased Uric Acid Production
This is caused by congenital abnormalities of purine metabolism, including:
- Inactivation of the uricase gene, which is a primary reason humans are susceptible to HUA.
- Genetic defects in key enzymes involved in uric acid synthesis.
- Genetic defects in key ion channels responsible for uric acid transport.
Mixed Type
Some patients exhibit a combination of the above two factors.
Secondary Hyperuricemia
Common causes include:
- Certain hereditary diseases such as type I glycogen storage disease and Lesch-Nyhan syndrome.
- Certain hematological diseases, such as leukemia, multiple myeloma, lymphoma, and excessive uric acid production during chemotherapy or radiotherapy for malignant tumors.
- Chronic kidney disease, in which reduced tubular secretion of uric acid contributes to elevated uric acid levels.
- Certain medications like furosemide, etacrynic acid, pyrazinamide, and aspirin, which inhibit uric acid excretion and lead to HUA.
Clinical Manifestations
Hyperuricemia is often discovered incidentally during physical examinations, when laboratory tests reveal transient or persistent elevation of serum uric acid levels. This is referred to as asymptomatic HUA. Many patients exhibit comorbidities such as obesity, type 2 diabetes, dyslipidemia, hypertension, atherosclerosis, and coronary heart disease. The progression from elevated uric acid levels to the onset of arthritis symptoms can take several years to decades. Approximately 5%–12% of patients with HUA eventually develop gout, presenting with recurrent acute gouty arthritis, interstitial nephritis, and tophi formation. In severe cases, joint deformities or uric acid urinary stones can occur.
Laboratory and Other Examinations
Serum Uric Acid Measurement
This is performed on fasting blood samples taken under a normal purine diet, and analyzed using the uricase method.
Urinary Uric Acid Measurement
This is performed on urine samples collected under a normal purine diet and measured using enzymatic colorimetry.
Urine pH
This is determined using a compound pH indicator method.
Diagnosis and Subclassification
Diagnostic Criteria
Hyperuricemia is diagnosed when fasting serum uric acid levels exceed the upper normal limit on two separate occasions under a normal purine diet. Diagnostic thresholds are as follows:
- Serum uric acid > 420 μmol/L (7 mg/dl) in men and postmenopausal women.
- Serum uric acid > 360 μmol/L (6 mg/dl) in premenopausal women.
Subclassification
After following a low-purine diet for five days, 24-hour urinary uric acid excretion levels are measured:
- Uric acid excretion < 600 mg (3.6 mmol) indicates decreased uric acid excretion type.
- Uric acid excretion ≥ 800 mg (4.8 mmol) indicates excessive uric acid production type.
- Intermediate levels indicate mixed type.
Considering the impact of renal function on uric acid excretion, the fractional excretion of uric acid (FEUA) can be calculated using creatinine clearance (Ccr):
- FEUA (%) = (serum creatinine × 24-hour urinary uric acid) / (serum uric acid × 24-hour urinary creatinine).
- FEUA < 7% indicates impaired uric acid excretion.
- FEUA between 7% and 12% indicates mixed type hyperuricemia.
- FEUA > 12% indicates increased uric acid production.
Differential Diagnosis
A detailed medical history is essential to rule out other systemic diseases and various medications that may cause elevated serum uric acid levels. Secondary hyperuricemia or gout usually exhibits the following characteristics:
- It is more frequently observed in children, adolescents, women, and elderly individuals.
- The degree of hyperuricemia tends to be more severe.
- About 40% of patients demonstrate increased 24-hour urinary uric acid excretion.
- Renal involvement is common, with higher rates of gouty nephropathy and uric acid stones, sometimes leading to acute renal failure.
- Symptoms of gouty arthritis are often mild or atypical.
- A clear history of related medication use is usually present.
Treatment
Treatment Objectives:
- To control hyperuricemia and prevent urate crystal deposition.
- To address hyperuricemia-associated metabolic and cardiovascular risk factors.
- To prevent the formation of uric acid stones and protect renal function.
Lifestyle Modifications
Lifestyle changes play a central role in the management of hyperuricemia. A healthy diet, smoking cessation, alcohol abstinence, regular exercise, and weight control are key components. The diet should primarily consist of low-purine foods such as grains, fruits, vegetables, milk, dairy products, and eggs. Purine-rich foods, including high-fructose beverages, organ meats, sardines, anchovies, rich meat-based broths, beer, seafood, meat, and legumes, need to be strictly limited. Protein intake should be restricted to about 1 gram per kilogram of ideal body weight per day. Increased water intake is recommended to ensure a daily urine output greater than 2,000 ml, which aids in uric acid excretion. It is also necessary to avoid triggering factors and to actively manage related medical conditions.
Treatment for Asymptomatic Hyperuricemia
Although only 5%–12% of hyperuricemia cases eventually progress to gout, hyperuricemia is associated with various conventional cardiovascular risk factors. Multiple epidemiological studies have confirmed hyperuricemia as an independent risk factor for cardiovascular events and coronary artery disease-related mortality. Furthermore, hyperuricemia can increase the incidence of new-onset kidney diseases and impair renal function. Therefore, the screening and management of hyperuricemia should be taken seriously.
Drug treatment is recommended when the serum uric acid level exceeds 480 μmol/L (8 mg/dl) in asymptomatic HUA patients with cardiovascular risk factors or cardiovascular diseases (including hypertension, impaired glucose tolerance or diabetes, dyslipidemia, coronary artery disease, stroke, heart failure, or abnormal renal function). In the absence of cardiovascular risk factors or diseases, drug treatment is recommended when serum uric acid levels exceed 540 μmol/L (9 mg/dl). Approximately 90% of hyperuricemia cases are caused by reduced uric acid excretion, while only about 10% arise from increased uric acid production. Treatment plans should take into account the indications and contraindications of medications, as well as the classification of hyperuricemia.
Target Levels for Asymptomatic Hyperuricemia Treatment
The goal of uric acid-lowering therapy is to promote the dissolution of crystals and prevent their formation. This necessitates lowering serum uric acid levels below the saturation point of monosodium urate. As a result, serum uric acid should remain below 360 μmol/L (6 mg/dl).
Urine Alkalization
Uric acid is less soluble in acidic environments. When the urine pH is below 6.0, alkalization may be necessary to prevent urate deposition and the formation of stones. This can be achieved through the use of citrate preparations or sodium bicarbonate. Citrate preparations, such as potassium citrate, may be prescribed for patients with uric acid stones, cystine stones, or hypocitraturia, at a typical dose of 9–10 g/day. Sodium bicarbonate can be administered at a dose of 0.5–1.0 g three times daily, but excessive dosages or prolonged use should be avoided to prevent complications such as metabolic alkalosis, hypertension, and hyperkalemia. During treatment, urine pH needs to be monitored, with an optimal range of 6.2–6.8.
Uricosuric Agents
The mechanism of action of these drugs involves inhibiting urate transporter 1 (URAT1) at the brush border of renal proximal tubular cells, reducing tubular reabsorption of uric acid and promoting its excretion in urine, thereby lowering serum uric acid levels. These medications are suitable for patients with normal renal function and limited daily urinary uric acid excretion. Common drugs in this category include benzbromarone, probenecid, and sulfinpyrazone. Benzbromarone is a potent and commonly used uricosuric agent in clinical practice. The starting dose for adults is 25–50 mg/day, taken after breakfast, with dosage adjustments to 50–100 mg/day based on serum uric acid levels after 1–3 weeks. In cases of renal insufficiency (Ccr < 60 ml/min), the dose should be reduced to 50 mg/day. Adverse effects may include gastrointestinal discomfort, diarrhea, and skin rashes. Relative contraindications include 24-hour urinary uric acid excretion > 600 mg (3.6 mmol) or the presence of uric acid stones.
Xanthine Oxidase Inhibitors (XOIs)
These drugs work by competitively inhibiting xanthine oxidase, thereby blocking the conversion of hypoxanthine and xanthine to uric acid, effectively reducing uric acid production. They lower serum uric acid concentrations, mobilize urate deposits in tissues, and help dissolve tophi. Common medications in this category include allopurinol, febuxostat, oxipurinol, and topiroxostat.
Allopurinol
Adult starting doses of 50 mg once or twice daily are typically increased weekly by 50–100 mg, reaching 200–300 mg/day, divided into 2–3 doses. Serum uric acid levels are monitored every two weeks for dose adjustments, with a maximum dose of 600 mg/day. For patients with impaired renal function (Ccr < 60 ml/min), the dose should be adjusted to 50–100 mg/day. Allopurinol is contraindicated when Ccr < 15 ml/min.
Febuxostat
Doses of 20–80 mg/day may be used.
Common adverse reactions to allopurinol include hypersensitivity, which ranges from mild (e.g., skin rash) to severe (e.g., delayed vasculitis, exfoliative dermatitis), the latter being potentially fatal and a contraindication. HLA-B*5801 allele carriers are at significantly increased risk for allopurinol hypersensitivity syndrome (AHS) and must test negative for this allele before initiating therapy. Impaired renal function also increases the likelihood of severe hypersensitivity reactions. Additional adverse effects include liver damage, progressive declines in blood cell counts, diarrhea, headache, nausea, and vomiting. Some studies suggest an increased risk of cardiovascular mortality in gout patients treated with febuxostat.
Uricase Agents
These medications catalyze the conversion of uric acid to the more water-soluble allantoin, which is excreted renally, thereby reducing serum uric acid levels.
Rasburicase
This drug is used in acute hyperuricemia, particularly chemotherapy-induced cases or those associated with high-risk tumor lysis syndrome. It is administered prior to or at the early stages of chemotherapy.
Pegloticase
Recombinant uricase, such as polyethylene glycol-uricase (pegloticase), is used for refractory hyperuricemia.
Adverse effects include hypersensitivity reactions, hemolysis, and methemoglobinemia. These medications are intended for the treatment and prevention of acute hyperuricemia in patients with hematologic malignancies and high-risk tumor lysis syndrome, especially those with chemotherapy-induced hyperuricemia.
Adjunctive Uric Acid-Lowering Agents
Losartan is useful for hyperuricemia in hypertensive patients.
Fenofibrate is suitable for hyperuricemia in patients with hypertriglyceridemia.
SGLT2 inhibitors or dual SGLT1/SGLT2 inhibitors, such as sotagliflozin, exhibit mild uric acid-lowering effects in patients with type 2 diabetes and hyperuricemia.
Avoidance of Uric Acid-Elevating Medications
Drugs that can elevate serum uric acid levels include diuretics (especially thiazides), corticosteroids, insulin, cyclosporine, tacrolimus, nicotine, pyrazinamide, and niacin. Aspirin has a bidirectional effect on uric acid excretion: at low doses (< 2 mg/kg), it reduces uric acid excretion, while at high doses (> 3 mg/kg), it promotes uric acid excretion.
Management of Comorbidities and Complications
Attention to metabolic abnormalities and cardiovascular risk factors associated with hyperuricemia is critical. These include dyslipidemia, hypertension, hyperglycemia, fatty liver, and obesity.
Prognosis
The overall prognosis of hyperuricemia is good, with only 5%–12% of cases progressing to gout. This proportion significantly decreases with effective treatment. Researchers, using untargeted metabolomics technology, have identified seven biomarkers—uracil, glycocholic acid, betaine, trigonelline, piperideine, myristic acid, and arachidonic acid—and established a risk prediction model to assess the likelihood of hyperuricemia patients developing gout.
Studies indicate that 8.4%–13.3% of hyperuricemia patients have concomitant chronic kidney disease, 30.3%–47.2% have hypertension, 67% have lipid metabolism disorders, and 12.2% have diabetes. Hyperuricemia is an independent risk factor for metabolic abnormalities and cardiovascular events and requires significant attention for prevention and management.