5. Hyperuricemia and Hypertension: A Cause or Effect?
Inflammation remains the principal suspect linking gout and cardiovascular diseases. Mechanisms whereby serum urate levels could contribute to the development of hypertension are partly related to the uric acid’s primary effect on the kidney. These mechanisms include activating the renin–angiotensin–aldosterone system (RAAS) and the disposition of urate crystals in the urinary lumen. Additional evidence suggests that elevated serum uric acid can decrease nitric oxide production, causing endothelial injury and dysfunction. It is well established that monosodium urate crystals can activate the NLRP3 inflammasome cascade and the production of inflammatory cytokines such as IL-1 beta and IL-8
[30][47]. Although uric acid is predominantly eliminated through the kidney, new evidence has reported that urate crystals can deposit in the coronary artery among gout patients
[31][48]. The deposition of urate crystals in the aorta and main arteries was associated with a higher coronary calcium score and can trigger an inflammatory response like the observed response in the kidney. Beyond the joints, these observations support the hypothesis that high serum urate levels could deposit into soft tissues and extraarticular regions, which can then become pro-oxidants, increasing the inflammatory burden and the development of the multiple comorbidities observed in patients with gout or hyperuricemia
[32][49].
Hypertension is an epidemic affecting more than 30% of adults worldwide
[33][50]. While genetics may contribute to the development of hypertension, the contribution has been limited, suggesting that the external environment plays a significant role in developing hypertension compared with genetics. Moreover, a growing body of evidence has repeatedly reported on the association between elevated urate levels (hyperuricemia) and hypertension. For example, a cross-sectional study determined that each 1 mg/dL increase in serum urate contributes to a 20% increased prevalence of hypertension in a general population not treated with hyperuricemia and hypertension
[34][51].
Hyperuricemia is an independent risk factor for multiple cardiovascular disease risk factors, which can, collectively, elevate the risk of cerebrovascular events. Nonetheless, the direct role of uric acid levels in developing stroke events is inconclusive
[35][36][53,54].
The incidence and prevalence of hypertension and obesity were minimal in specific populations until Westernization and the adoption of a Western diet
[37][38][57,58]. Additionally, the immigration of select population subgroups, Filipinos and Japanese, has been linked to earlier gout onset, higher gout and hypertension rates, and higher mean urate levels than their native home residents
[38][39][40][41][42][43][25,58,59,60,61,62]. These observations support the hypothesis that dietary changes from a traditional diet to a Westernized diet enriched with fatty meats may be responsible for the increased prevalence of gout, high serum urate levels, and increased incidence of hypertension and diabetes.
6. Uric Acid and Neurodegenerative Diseases: The Antioxidant Hypothesis
The old hypothesis that the chemical structure of uric acid could mimic specific brain stimulants, such as caffeine or methylxanthine, may have provided selective advantages to early hominoids
[44][63]. To this hypothesis, the loss of uricase activity in early hominoids has caused an increase in uric acid levels in the brain, which could have given rise to quantitative and qualitative intelligence among early hominoids. Indeed, limited studies have shown that urate plasma levels may be associated with higher intelligence
[44][45][46][63,64,65].
Multiple epidemiological studies have examined the association between serum urate levels, gout diagnosis, and brain-related diseases
[47][48][66,67]. Specifically, the associations between urate levels or gout and Alzheimer’s disease (AD) and Parkinson’s disease (PD) have been a focal point in recent studies
[49][50][51][68,69,70]. However, the results of these studies have been conflicting or showing no association
[52][53][71,72]. Partly, these inconclusive findings have been attributed to the study design, not accounting for uric acid level confounders, and the varying degrees of disease progression among study subjects
[54][73]. While the transport of uric acid into the brain remains elusive, uric acid is produced in the human brain
[50][69]. Urate production in the brain has paved a path for a great deal of research into whether uric acid could exert antioxidant activity, protecting the brain from developing neurodegenerative diseases by mitigating the burden of oxidative stress sequelae. Uric acid can function as an antioxidant and block peroxynitrite, which could be beneficial in slowing the progression of PD and multiple sclerosis (MS)
[55][56][57][74,75,76]. Lower uric acid levels have been linked with a greater risk of developing PD, the severity of motor features, and faster progression of both motor and non-motor features
[50][69]. This observation has led to the hypothesis that raising uric acid may provide a neuroprotective effect in PD patients
[58][77].
To assess the causality between uric acid and PD, a Mendelian randomization approach was used to systematically evaluate the inherent risk of lower urate levels and disability requiring dopaminergic treatment in early PD patients. Genotyping 808 patients for three loci across the
SLC2A9 (rs6855911, rs7442295, and rs16890979), cumulative scores of the risk alleles were created based on the total number of minor alleles across the three loci
[59][78]. Serum urate levels were 0.69 mg/dL lower among individuals with ≥4
SLC2A9 minor alleles versus those with ≤2 minor alleles
[59][78]. A 5% increased risk of PD progression with a 0.5 mg/dL decrease in serum urate was observed. However, the hazard ratio for the progression to disability requiring dopaminergic treatment, though increased with the
SLC2A9 score, was not statistically significant (
p = 0.056)
[59][78].
The role of uric acid levels in mild cognitive impairment (MCI), a common diagnosis that precedes the development of clinical AD, has been extensively investigated. While asymptomatic hyperuricemia can go undiagnosed and rarely treated, exploring the association between hyperuricemia and neurodegenerative diseases may be confounded by recall bias, disease misdiagnosis, and secondary causes of hyperuricemia. Nonetheless, patients with gout are considered to have the highest uric acid burden and represent the extreme phenotype of hyperuricemia. Therefore, the association between gout diagnosis and the risk of neurodegenerative diseases has been of significant interest in neurodegenerative disease research.
7. Hyperuricemia and Innate Immune System: Acquired Protection?
Selective advantages to developing hyperuricemia in distinct population groups may have been driven by natural selection. This natural selection advantage may partly explain the inherently increased predisposition for hyperuricemia or gout among select population groups, especially when challenged by unprecedented environmental threats or culturally altering events. Besides being a naturally occurring antioxidant, urate levels may have enabled humans to survive crucial environmental stressors and pathogenic threats. When crystallized, urate may trigger the innate immune response. For this reason, monosodium urate crystals are considered a critical natural endogenous immune response trigger. With infectious diseases being one of the strongest drivers of natural selection, it is presumed that genes associated with raising urate may have been selected during major depopulation events. This theory may partly explain the genetic predisposition for hyperuricemia/gout and the higher mean uric acid levels in the Pacific and Oceania regions compared with whites and the Western world
[39][60][61][62][63][25,87,88,89,90].
Historically, exposure to pathogenic or parasitic infections such as malaria has pressured the human genome of distinct populations to develop disorders like sickle-cell disease and glucose-6-phosphate dehydrogenase deficiency as a survival switch. Therefore, it is plausible that the inherent risk of hyperuricemia could be considered another adaptation to protect against malaria or other pathogens that threatened our ancestors. Urate levels released from erythrocytosis because of malaria infection have been shown to activate the host’s inflammatory response, facilitating the detection of the parasite
[60][87].
8. Uric Acid: A Therapeutic Target or Disease Bystander?
Uric acid levels are the strongest predictor of developing gout via the deposition of monosodium urate crystals in and around the joints. The chronic suppression of uric acid levels is the hallmark of reducing the MSU crystal burden and preventing future gout flares. While different treatment modalities have been developed to lower serum urate, most treatments are focused on inhibiting uric acid production. In the advanced forms of gout, the recombinant form of uricase has been used to reduce the tophi burden or if the patient is not responsive to available treatments.
While numerous experimental and clinical studies support the role of uric acid as an independent cardiovascular risk factor, a handful of studies also suggested that lowering serum urate may improve blood pressure. These studies included pre-hypertensive obese
[64][95], hypertensive adolescents
[65][96], hypertensive children on an angiotensin-converting enzyme inhibitor
[66][97], and adults with asymptomatic hyperuricemia
[67][68][98,99].
A growing body of evidence also suggests that urate-lowering therapy does not affect blood pressure. A crossover single-center study enrolled ninety-nine participants randomized to 300 mg of allopurinol or placebo over four weeks
[69][100]. There was no difference in the change in blood pressure between the groups; however, the allopurinol group had a decrease in uric acid and improved endothelial function, estimated as flow-mediated dilation
[69][100]. What is noteworthy is that the study participants were relatively young (28 years old), had relatively normal systolic blood pressure (123.6 mm Hg), and had a relatively normal uric acid level at baseline (5.9 mg/dL)
[69][100].
With gout and hyperuricemia being associated with increased sterile inflammation, earlier reports suggested that the use of allopurinol in patients with hyperuricemia can significantly reduce inflammatory biomarkers
[67][98]. A recent study showed that urate-lowering therapy, mainly allopurinol, was significantly associated with lower hs-CRP, LDL, and total cholesterol levels in patients with gout compared with those not receiving urate-lowering therapy
[70][102]. These results support that patients optimally treated for gout can garner added benefits above and beyond reduced uric acid burden. Although urate-lowering therapy was not associated with lowering blood pressure, a high chronic kidney disease diagnosis in patients receiving allopurinol was observed
[70][102]. Overall, the study suggested that uric acid may be a remediable risk factor to lower the atherogenic disease burden in patients with gout
[70][102]
9. Summary
The loss of activity mutations in the uricase gene may have been protective in situations of famine and food scarcity; thus, it rapidly took over the ancestral population, likely driven by harsh environmental factors during the Miocene era. In modern times, this adaptation is possibly leading to a state of hyperuricemia, increasing the risk of gout and other cardiometabolic disorders. Today, all humans are considered uricase knockouts. Loss of the uricase enzyme resulted in the inability to regulate uric acid effectively. The adaptation to famine and food scarcity in early hominoids dictated crucial changes to obtain and conserve energy for survival. In contrast to animal experiments and observational studies, targeting uric acid levels for therapeutic purposes beyond the purpose of gout remains conflicting.
As hyperuricemia and gout animal models continue to be instrumental in advancing the field of gout and uric acid metabolism, it is equally important to recognize that animal models are inherently predisposed to eliminating uric acid. Therefore, the effects of raising uric acid levels in animal models may not reflect the outcomes seen in human studies. Additionally, the sex effect on uric acid levels reinforces the need for adequate and robust analyses by sex.
While genetics play a significant role in developing hyperuricemia or gout, it is equally important to recognize that the same genetics are therapeutic targets to modify uric acid metabolism. Genetic polymorphisms have been implicated in the racial difference in gout prevalence and may also contribute to the heterogeneity in response to urate-lowering or urate-elevating therapies. Therefore, genetic investigations into uric acid metabolism in clinical trials need to be considered in designing the study. Finally, as described earlier, uric acid levels are the culmination of endogenous cellular processes and external dietary sources; therefore, accounting for dietary and lifestyle habits in uric acid levels may minimize the effect of study confounders.