Elevated uric acid as a risk factor

Introduction

Uric acid (UA) is the end-product of endogenous and exogenous purine mononucleotide catabolism, catalysed by the enzyme xanthine oxidoreductase (XOR). XOR has two isoforms, xanthine dehydrogenase (XDH) and xanthine oxidase (XO) [1]. Two thirds of serum uric acid (SUA) [2] are excreted by the kidneys, one third by the small intestine. UA remote sensing and signalling theory hypothesises that SUA levels are regulated by the synergic interaction between the gut microbiome, renal urate transporters, and intestinal urate transporters [3]. However, the mechanisms involved in the regulation of intracellular UA levels remain not fully explained [4].

Hyperuricaemia is defined as SUA ≥6.0 mg/dL in women and ≥7.0 mg/dL in men [5]. From the discovery of hyperuricaemia as the cause of gout in the 19th century, several epidemiological and genetic studies have shown an association between high SUA levels and the incidence of several cardiovascular (CV) diseases and risk factors [6]. The treatment of hyperuricaemia is recommended for all symptomatic patients, namely those with gout, tophi, urate nephrolithiasis, or severe comorbidities [5]. The target for long-term SUA treatment is 6.0 mg/dL. Some studies suggest that people with asymptomatic hyperuricaemia should be treated only if their calculated CV risk at 10 years is high or very high, or if they have high SUA levels (>8 mg/dL). However, international guidelines/consensus documents recommend not to treat asymptomatic hyperuricaemia under any circumstances [5].

Thus, debate persists regarding the benefit of treating asymptomatic hyperuricaemia. However, clinically silent joint UA deposits have been found in almost one third of individuals with asymptomatic hyperuricaemia [7]. Furthermore, asymptomatic hyperuricaemia has been shown to be an independent risk factor for several CV diseases, such as coronary artery disease [7]. The beneficial effects of urate-lowering therapies on CV risk reduction have still to be fully clarified in large randomised controlled studies.

The reasons for hyperuricaemia

The prevalence of hyperuricaemia is increasing worldwide, with high-income countries being more affected. Hyperuricaemia may occur when there is an excessive production or, more commonly, a decreased excretion of UA [8]. Degradation of purines, such as during ATP, DNA, and RNA breakdown, can increase SUA levels. High-purine diets (e.g., meat, seafood) or aliments rich in fructose, alcohol, and sodium are known to increase SUA levels [1, 9]. An increased activity of aldose reductase and XO, such as during dehydration and ischaemia, leads to a rise in SUA and intracellular UA [1, 10]. Defects in other enzymes of purine metabolism (e.g., adenosine monophosphate deaminase) may also be responsible for an increase in SUA levels [1, 11]. Additionally, hyperuricaemia can result from proximal renal tubules’ increased reabsorption or decreased secretion of UA, a condition that may be caused by hypothyroidism, metabolic acidosis, or treatment with certain drugs (e.g., beta-blockers) [10].

An impaired kidney function may be responsible for SUA accumulation, although some studies have shown that hyperuricaemia may precede the development of kidney injury [11, 12]. Finally, gut microbiome and multiple transport proteins of both kidney and gut may play a role in the development of hyperuricaemia [3].

Hyperuricaemia and cardiovascular disease

The association between UA and CV disease has been demonstrated for several conditions and even for UA levels in the normal to high range (from 5.2 to 6 mg/dL) [6]. Hyperuricaemia has been shown to predict the development of hypertension, metabolic syndrome, chronic kidney disease, and type 2 diabetes [7, 10]. Furthermore, a few trials demonstrated that UA-lowering therapies can reduce blood pressure and insulin resistance and may exert nephroprotective effects [7, 10].

Hyperuricaemia increased the risk for heart failure development and was associated with worse outcomes in a meta-analysis of 32 studies [13]. Additionally, another study showed an association between hyperuricaemia and the prevalence of atrial fibrillation [14]. The Mendelian randomisation study by Kleber and colleagues demonstrated that for each mg/dL increase in genetically predicted SUA there was a hazard ratio (HR) of 1.77 and 2.41 for CV death and sudden cardiac death, respectively [15]. Hyperuricaemia has also been associated with the development and outcome of coronary artery disease, being an independent risk factor for coronary artery disease [7].

The Italian URRAH (Uric Acid Right for Heart Health) multicentre study has recently shown that, in a cohort of more than 20,000 outpatients, SUA was associated with all-cause and CV mortality, with an optimal SUA cut-off point for CV mortality of 5.6 mg/dL [2]. Although the causality of the relationship between UA and CV disease remains partially unproven, several mechanisms have been proposed to explain how hyperuricaemia may play a role in the development and progression of CV disease. Some mechanisms, such as UA-induced endothelial dysfunction, oxidative stress, and systemic inflammation, are shared with other CV risk factors [7, 10].

Thus, hyperuricaemia may increase the CV risk synergically acting on the same pathophysiologic mechanisms of other risk factors, such as hypertension and diabetes, eventually inducing endothelial dysfunction and atherosclerosis. We believe that CV risk is a complex entity that has to be evaluated with a holistic approach, treating all risk factors equally as parts of the same process [6, 10].

When and how to treat hyperuricaemia

Both international and European guidelines on the management of hyperuricaemia recommend allopurinol as the first-line drug, with initial recommended dosage varying from 50 mg to 200 mg, titrating till 300-600 mg daily [5]. The second-line drug is another XO inhibitor, febuxostat. Both drugs inhibit XO activity, reducing the production of UA from xanthine, which in turn is produced by purine catabolism [5]. However, the non-purine XO inhibitor febuxostat has been shown to be unsafe in patients at high CV risk [9].

Allopurinol is safe and well tolerated, although severe hypersensitivity reactions may occur, especially in the Asian population who carry the HLA B58 allele [12, 16]. Allopurinol has been shown to reduce the CV risk and ameliorate the CV outcomes not only through its hypouricaemic effect but also suppressing the production of reactive oxygen species and attenuating the endothelial dysfunction [7]. In fact, high XO levels are able to induce oxidative stress, systemic inflammation and endothelial dysfunction [9]. As previously stated, allopurinol has also been demonstrated to reduce blood pressure and insulin resistance. In patients who do not reach the treatment target (SUA <6 mg/dL) with allopurinol, or do not tolerate the treatment with XO inhibitors, other hypouricaemic medications can be prescribed.

Uricosuric agents act on renal proximal tubule transporters, reducing UA reabsorption. Lesinurad is an oral selective inhibitor of URAT1 and OAT4 urate transporters; probenecid and benzbromarone only inhibit URAT1 [9, 16]. Probenecid cannot be prescribed if chronic kidney disease or blood dyscrasias are present, while benzbromarone causes hepatotoxicity [16]. SUA can also be lowered by recombinant uricases such as pegloticase and rasburicase, which metabolise uric acid into allantoin. These drugs are parentally administered and well tolerated, although some individuals may develop anaphylactic reactions and antibodies against these agents, limiting their effectiveness [12, 17].

In a recent meta-analysis, UA-lowering medicines were shown to reduce the incidence of major adverse cardiovascular events (MACE), significantly reducing the all-cause mortality [18]. However, further randomised controlled studies are needed to answer definitively the question of whether SUA reduction would have beneficial effects on CV outcomes in the general population and in cohorts at higher risk of CV disease.

Conclusions

Hyperuricaemia is often an under-recognised CV risk factor. In experimental models, UA has been shown to induce endothelial dysfunction, oxidative stress, and systemic and local inflammation. On the other hand, epidemiological and genetic studies have shown significant associations between hyperuricaemia and several CV diseases, such as hypertension, metabolic syndrome, heart failure, coronary artery disease, diabetes, and chronic kidney disease. A few trials have demonstrated a clear benefit of UA-lowering therapies on CV outcomes.

It is recommended to treat symptomatic hyperuricaemia with a target level of serum UA ≤6 mg/dL. However, the level of evidence is not sufficient to recommend treatment in asymptomatic individuals without significant comorbidities. Further randomised controlled studies are warranted to clarify better the role of UA as an independent CV risk factor and to assess the beneficial effects of UA-lowering therapies on CV outcomes.