Hyperuricemia: pathogenesis and modern mechanisms

Hyperuricemia is a persistently elevated serum uric acid concentration above the solubility limit of urate under physiological conditions. The saturation point for urate is approximately 6.8 mg/dL, which corresponds to approximately 400 μmol/L, at body temperature and physiological pH. Exceeding this threshold creates conditions for supersaturation and crystallization of monosodium urate in tissues and body fluids. [1]

In clinical practice, two approaches to determination are used: the distributional approach, which uses higher thresholds for women and men, and the pathophysiological approach, which relies on a crystallization threshold of approximately 6.0-6.8 mg/dL, regardless of gender. Some guidelines consider thresholds to be greater than 6.0 mg/dL for women and greater than 7.0 mg/dL for men, but the risk of crystallization increases at levels of approximately 6.8 mg/dL. [2]

Hyperuricemia is common worldwide and is increasing, particularly in high- and middle-income countries. Estimates vary by population, dietary habits, and ethnicity, with prevalence in individual samples ranging from 2.6% to 36%. The rise in hyperuricemia is associated with dietary changes, obesity, metabolic disorders, and population aging. [3]

The clinical significance of hyperuricemia extends beyond gout. Persistent elevated uric acid is associated with urolithiasis, hypertension, chronic kidney disease, and components of metabolic syndrome. Although causal relationships have not been proven in all cases, the body of evidence points to biological mechanisms that potentially involve oxidative stress, endothelial dysfunction, and low-grade inflammation. [4]

Where does uric acid come from: the biochemistry of purines

Uric acid is the end product of purine catabolism in humans. This breakdown pathway involves enzymes of the xanthine oxidase complex, which converts hypoxanthine and xanthine into uric acid. Humans lack uricase, so further oxidation of uric acid to allantoin does not occur, increasing the risk of its accumulation. Xanthine oxidase activity is associated with the formation of reactive oxygen species, which links hyperuricemia to oxidative stress. [5]

Substrates for uric acid formation are obtained in two ways: from exogenous dietary purines and from internal nucleotide metabolism processes, including increased adenosine triphosphate breakdown during fructose overload, tissue ischemia, and intense anaerobic conditions. Fructose consumption rapidly depletes intracellular adenosine triphosphate, increases inosine monophosphate levels, and stimulates de novo purine generation, leading to increased uric acid levels. [6]

Hormonal and signaling pathways also influence uric acid levels. Insulin resistance increases urate reabsorption in the proximal tubule, which explains the frequent association of hyperuricemia with metabolic syndrome and type 2 diabetes. Furthermore, alcohol increases lactic acidosis and competes with urate for tubular transporters, reducing its excretion. [7]

The contribution of exogenous purines depends on their source. High-purine foods and fructose-containing beverages increase the load on purine breakdown pathways, especially when combined with obesity and low physical activity. Moderate restriction of purine-rich foods and sugary beverages reduces the flow of substrates to xanthine oxidase. [8]

How the body eliminates uric acid: kidneys, intestines, and transporters

About two-thirds of urate is excreted by the kidneys and about one-third through the intestines. Renal excretion of urate is a sequence of filtration, almost complete reabsorption, then secretion, and final postscretory reabsorption. Key roles are played by the proximal tubular transporters URAT1, GLUT9, OAT1, and OAT3, as well as the tubular anion transporters NPT1 and NPT4. Disruptions in their function lead to "underexcretion" phenotypes, which predominate in hyperuricemia in most patients. [9]

Intestinal excretion of urate is primarily mediated by the ABCG2 protein, which is expressed in enterocytes. Decreased ABCG2 function reduces extracortical uric acid clearance and increases the intersystemic load on the kidneys, which contributes to hyperuricemia and the early onset of gout. The Q141K variant in ABCG2 is associated with early onset of the disease and high uric acid levels, emphasizing the importance of the intestinal excretion pathway. [10]

The SLC2A9 gene family, encoding the GLUT9 transporter, accounts for a significant portion of the interindividual variability in uric acid levels. SLC2A9 polymorphisms affect tubular urate reabsorption and are associated with the risk of hyperuricemia in different populations, while the contribution of specific loci may depend on ethnic origin. This explains the differences in the prevalence and severity of hyperuricemia between ethnic groups. [11]

Insulin and sodium also modulate transporter function, enhancing urate reabsorption in the proximal tubule. This effect is partially mediated through URAT1 and GLUT9, as well as through competition between organic anions in the tubular lumen. This links hyperuricemia with insulin resistance, diuretics, and conditions associated with lactate accumulation. [12]

Table 1. Main urate transporters and their role

Carrier	Gene	Localization	Main function	Clinical significance
URAT1	SLC22A12	Proximal tubule, apical membrane	Reabsorption of urate from the lumen	Target of uricosurics, variations increase the risk of "under-excretion"
GLUT9	SLC2A9	Proximal tubule, basolateral membrane	Export of urate from the cell into the blood	A major contributor to uric acid variability
ABCG2	ABCG2	Enterocytes of the small intestine	Intestinal excretion of urate	Defects reduce extracortical clearance, early onset of gout
OAT1 and OAT3	SLC22A6 and SLC22A8	Basolateral membrane	Uptake of urate and anions from the blood	Participate in the secretion of urate
NPT1 and NPT4	SLC17A1 and SLC17A3	Apical membrane	Secretion of urate into the lumen	Affect tubular excretion of urate

Source: Review and guidance publications on the pathophysiology of urate transporters. [13]

Factors and triggers that increase uric acid

Dietary factors include high intake of fructose, sugary beverages, and high-purine foods. Fructose accelerates the breakdown of adenosine triphosphate and stimulates de novo purine synthesis, and sugary beverages containing fructose are significantly associated with an increased risk of hyperuricemia and gout in population studies. Moderate limitation of such beverages and weight control reduce uric acid levels. [14]

Alcohol, especially beer, increases uric acid levels through a combination of two mechanisms: the high purine content of the beverage itself and the induction of lactic acidosis, which competes with urate for tubular transporters and reduces its excretion. Several studies have noted that beer has a more pronounced hyperuricemic effect than wine, which is associated with beer's richness in purine nucleosides. [15]

Medications often trigger hyperuricemia. Low doses of aspirin reduce urate excretion and increase its levels, while high doses have a uricosuric effect; thiazide and loop diuretics enhance urate reabsorption; cyclosporine reduces urate clearance and increases the risk of gout in transplant recipients. Consideration of medication load is a mandatory part of patient assessment. [16]

Metabolic conditions such as obesity, insulin resistance, hypertriglyceridemia, and non-alcoholic fatty liver disease form the basis for persistent hyperuricemia. Uric acid levels are positively correlated with metabolic syndrome components, and weight loss reduces daily urate excretion and blood levels. [17]

Table 2. The most common external and internal triggers of hyperuricemia

Category	Examples	Mechanism
Nutrition	Sweet drinks with fructose, organ meats, anchovies	Increased substrates for xanthine oxidase and stimulation of purine synthesis
Alcohol	Beer, spirits at high consumption	Beverage purines and lactic acidosis, competition with urate for transporters
Medicines	Low doses of acetylsalicylic acid, thiazides, loop diuretics, cyclosporine	Decreased tubular secretion and increased reabsorption of urate
Metabolic factors	Obesity, insulin resistance	Increased urate reabsorption, influence of hormonal regulation

Sources: contemporary reviews and original research. [18]

Genetics of hyperuricemia

Polymorphisms in urate transporter genes significantly contribute to the "under-excretion" phenotype. SLC2A9 variants are associated with urate levels in various populations and explain a significant portion of its variance. ABCG2 variants, particularly Q141K, reduce intestinal urate excretion and are associated with early-onset gout and persistent hyperuricemia. This confirms the central role of transporters in the pathogenesis of the disease. [19]

The impact of polymorphisms may depend on ethnicity, gender, and environmental factors. Studies show that the contribution of the same loci to fractional excretion of urate differs between Europeans and Polynesians, highlighting the need to consider population-specific data when interpreting genetic tests. Routine genotyping for hyperuricemia is currently limited, but in the future, it may help stratify risk and select targeted therapy. [20]

A combination of genetic predisposition and an unfavorable environment increases the likelihood of persistent hyperuricemia. Dietary habits, body weight, and medications can "uncover" genetic risk, especially in the presence of variants that reduce urate transport through the kidneys and intestines. This justifies comprehensive preventive strategies. [21]

Genetics also determines the safety of drug therapy. The HLA-B*58:01 allele increases the risk of severe skin reactions to allopurinol; testing is recommended in individuals of East Asian and African American descent before prescribing allopurinol, taking into account the population frequency of the allele. [22]

What Uric Acid Does to Tissues: Crystallization, Oxidative Stress, and Inflammation

When the saturation point is chronically exceeded, monosodium urate crystals form. Their deposition in joints and soft tissues leads to gouty inflammation with activation of the NLRP3 inflammasome and release of interleukin-1 beta. While acute gout is the clinical endpoint of the process, subclinical crystallization can be asymptomatic, maintaining chronic low-intensity inflammation. [23]

Xanthine oxidase activity is associated with the generation of reactive oxygen species. Xanthine oxidase inhibitors reduce the formation of reactive oxygen species and potentially improve endothelial function, which is considered one of the mechanisms of cardiorenal protection by reducing uric acid. These effects have been confirmed experimentally and, in part, by clinical data. [24]

Increased proximal tubular urate reabsorption is associated with adverse renal outcomes. Low fractional excretion of urate and low urinary urate-to-creatinine ratio correlate with a higher risk of chronic kidney disease progression, highlighting the pathogenic role of tubular urate overload.[25]

Thus, hyperuricemia affects tissues through two pathways: through the physicochemical crystallization of urates and through the biochemical effects of uric acid and xanthine oxidase, including oxidative stress and proinflammatory activation. This explains the association with gout, nephrolithiasis, and potentially with cardiometabolic disorders. [26]

Diagnosis: How to evaluate a patient

The first step is to confirm a persistent increase in uric acid levels with repeated measurements and assess the clinical context: gout symptoms, uric acid stones, comorbidities, medications, diet, and alcohol. It is important to remember that urate levels can fluctuate, and during an acute attack of gout, they are sometimes paradoxically low. [27]

Next, the type of hyperuricemia is assessed: whether "underexcretion" or "overproduction" predominates. This is done using the daily urate excretion and the fractional excretion of urate. Classically, a daily excretion of more than 800 mg per day on a low-purine diet indicates hyperuricosuria, while a low fractional excretion of urate indicates "underexcretion." In practice, the "underexcretion" phenotype is more common. [28]

Fractional excretion of urate helps stratify risk and select therapeutic targets. Low values of fractional excretion of urate are associated with worse renal outcomes, and its routine calculation is considered a useful tool for accurate diagnosis and monitoring. Urine acidity is also important, as acidic urine facilitates uric acid crystallization in the urinary tract. [29]

The examination concludes with an assessment of risk factors and comorbidities: obesity, hypertension, dyslipidemia, type 2 diabetes, chronic kidney disease, and medication effects. This forms a personalized lifestyle and medication plan and allows for the prioritization of interventions. [30]

Table 3. Diagnostic guidelines for hyperuricemia

Parameter	Thresholds and comments
Serum urate	The risk of crystallization increases from 6.8 mg/dL and above.
Daily excretion of urate	More than 800 mg per day on a low-purine diet indicates hyperuricosuria.
Fractional excretion of urate	Low values correspond to under-excretion and worse renal outcomes
Urine acidity	Low acidity promotes the formation of urate stones.
Medicinal influences	Diuretics, low doses of acetylsalicylic acid, cyclosporine, etc.

Sources: review and clinical publications. [31]

Correction tactics: lifestyle, drug interventions and new directions

Lifestyle modification is the cornerstone of the hyperuricemia strategy: weight loss, limiting sugary drinks containing fructose, and moderating the consumption of high-purine foods and alcohol, especially beer. These measures reduce the flow of substrates to xanthine oxidase and decrease tubular reabsorption of urate, improving overall balance. [32]

Pharmacotherapy is indicated for symptomatic hyperuricemia, primarily in gout and urate nephrolithiasis. Guidelines emphasize a "start low and titrate to target" strategy: allopurinol or febuxostat are started at low doses and gradually increased to achieve a target uric acid level of less than 6.0 mg/dL, and even lower in tophaceous gout. Anti-inflammatory prophylaxis is also prescribed during the titration period. [33]

The choice of drug class depends on the phenotype and comorbid conditions. Xanthine oxidase inhibitors reduce uric acid production and reactive oxygen species; uricosuric agents, which target URAT1, increase its excretion and are particularly appropriate in cases of "under-excretion." A combination of a xanthine oxidase inhibitor and uricosuric provides a more potent uric acid-lowering effect and is considered for severe forms and insufficient response to monotherapy. [34]

Sodium-glucose co-transporter type 2 inhibitors reduce uric acid by enhancing tubular excretion of urate and influencing cellular energy metabolism. Systematic reviews and meta-analyses show a modest but sustained reduction in uric acid levels and a reduced incidence of hyperuricemic events in patients receiving these drugs for cardiorenal indications. This opens an additional window of opportunity for patients with type 2 diabetes mellitus and chronic kidney disease. [35]

Table 4. Drug classes affecting uric acid levels

Class	Examples	Mechanism of influence	Practical notes
Xanthine oxidase inhibitors	Allopurinol, febuxostat	Decreased production of uric acid and reactive oxygen species	Start with a low dose, titrate to target, consider HLA-B*58:01
Urikosuriki URAT1	Probenecid, benzbromarone, verinurad in studies	Increased excretion of urate	Effective in cases of under-excretion; contraindications for nephrolithiasis are required
Combinations	Xanthine oxidase inhibitor plus uricosuric	Additive reduction in uric acid levels	Considered in resistant cases
Sodium glucose transporter type 2 inhibitors	Dapagliflozin and others	Increased fractional excretion of urate and metabolic effects	Additional benefit in patients with diabetes and chronic kidney disease

Sources: clinical guidelines and current research. [36]

Special clinical situations: chronic kidney disease and asymptomatic hyperuricemia

In chronic kidney disease, approaches differ for symptomatic and asymptomatic hyperuricemia. For patients with chronic kidney disease and symptomatic hyperuricemia, urate-lowering therapy is recommended, with priority given to xanthine oxidase inhibitors and careful dose titration. In asymptomatic hyperuricemia in patients with chronic kidney disease, current guidelines do not recommend initiating urate-lowering drugs to slow the progression of chronic kidney disease due to a lack of convincing evidence of benefit. [37]

Preventive non-pharmacological measures in patients with chronic kidney disease include limiting alcohol, meat products, and beverages containing fructose, as well as monitoring body weight and blood pressure. When symptomatic treatment of gout in the setting of chronic kidney disease is necessary, low-dose colchicine and glucocorticosteroids are preferred; non-steroidal anti-inflammatory drugs are used with caution. [38]

A separate clinical situation is hyperuricemia after organ transplantation during cyclosporine therapy. Such patients often experience decreased urate clearance and an increased risk of gout; treatment includes a review of immunosuppression, non-pharmacological measures, and urate-lowering drugs as indicated. [39]

Japanese guidelines recommend more active pharmacotherapy for asymptomatic hyperuricemia at levels of 8.0 mg/dL or greater in the presence of risk factors and 9.0 mg/dL or greater without them, reflecting differences between national clinical practices. These discrepancies are important to consider when interpreting international sources and planning patient management. [40]

Table 5. Asymptomatic hyperuricemia: discrepancies in recommendations

Situation	Recommendation
Chronic kidney disease, asymptomatic hyperuricemia	Do not initiate urate-lowering drugs to slow the progression of chronic kidney disease due to insufficient evidence
Symptomatic hyperuricemia in chronic kidney disease	Initiate urate-lowering therapy, preferably with xanthine oxidase inhibitors, with careful titration
Japan, asymptomatic hyperuricemia	Pharmacotherapy is possible at levels of 8.0 mg/dL with risk factors or 9.0 mg/dL without them.

Sources: current excerpts from clinical guidelines. [41]

Practical steps for the doctor and patient

Step one: Confirm persistently elevated uric acid levels and evaluate the clinical picture, including signs of gout, nephrolithiasis, and comorbidities. Be sure to review medications that increase urate and adjust them if possible. [42]

Step two: Calculate the fractional excretion of urate and, if indicated, estimate the daily excretion of urate to determine the phenotype and select treatment targets. Low fractional excretion of urate indicates underexcretion and poorer renal outcome, which justifies the use of uricosurics or combination therapy. [43]

Step three: implement non-drug measures—weight loss, reducing the consumption of fructose-sweetened beverages and alcohol, especially beer, and moderately limiting high-purine foods. These interventions serve as the basis even if drug therapy is prescribed. [44]

Step four: If indicated, initiate urate-lowering therapy at low doses and titrate to a target level of less than 6.0 mg/dL, using anti-inflammatory prophylaxis. In patients of East Asian and African descent, consider HLA-B*58:01 testing before starting allopurinol to reduce the risk of severe skin reactions. [45]

Summary table of thresholds and targets

Indicator	Meaning
Saturation point of urates	About 6.8 mg per dl
Clinical target level for gout	Less than 6.0 mg per dL, in the tophaceous form below
Daily excretion of urate	More than 800 mg per day on a low-purine diet - hyperuricosuria
Fractional excretion of urate	Low values indicate under-excretion and a worse renal prognosis.

Sources: clinical guidelines and reviews. [46]

Conclusion

Hyperuricemia results from an imbalance between urate formation and excretion, with underexcretion playing a leading role in most patients due to the specific urate transporters in the kidney and intestine. A modern approach combines phenotype assessment based on fractional excretion of urate, targeted lifestyle modifications, and individualized selection of urate-lowering therapy with titration to target levels. In specific situations, such as asymptomatic chronic kidney disease, pharmacotherapy is not indicated for its effect on progression, whereas in symptomatic cases, it is justified. Promising areas include optimization of combination strategies and the use of drugs that simultaneously improve cardiorenal outcomes and reduce uric acid. [47]