Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies

Dear Sir,

Very recently Xi and co-workers published a huge review on any possible relationship between serum uric acid and several clinical conditions involving also the cardio-renal and metabolic systems. They conclude that an indisputable causative role for uric acid can be established only for gout while all the other evidence should be considered with caution. I basically agree with this conclusion since there is no doubt that hyper-uricemia and gout are strictly related, but I am not so convinced that the interpretation of the possible effects of uric acid beyond gout can be explained by using the plasma levels as discriminatory tool.

In particular the same serum level of uric acid can be found in patients bearing to a completely different pathophysiological pathway since serum uric acid is the final result of the balance between production and excretion.

Second, those who are affected by a condition of overproduction of uric acid usually have some functional over expression of xanthine-oxidase and associated oxidative strass that can selectively contribute to the cardio-renal and metabolic settings. The identification of these subjects will be a mandatory goal for the near future since they will probably be the target of cardiovascular prevention by xanthine-oxidase inhibitors.

Third, the studies of Mendelian randomisation included in the manuscript are focused exclusively on the importance of SNP involved in renal transport of uric acid, a mechanism that is significantly altered in patients with gout but is probably only minimally involved in cardiovascular, renal and metabolic diseases. The same procedure of spontaneous randomisation applied to genetic polymorphisms involving xanthine-oxidase have given completely different results leading to a possibility that serum uric levels per se are only partially representative of the negative effects of uric acid in some important populations of patients.

Fourth, the many adjustments that have been applied to the observational data should be re-considerd after the demonstration that elevated levels of uric acid can precede some of the adjusting factors (e.g hypertension) leading to an unfair conclusion in therms of causative role.

Finally, the threshold level for the different conditions related to uric acid seems to be largely different ranging from 4-5 mg/dl for cardio-metabolic diseases to 6-5 for gout. Most of the cross-sectional data have been analysed by considering as a threshold for elevated serum uric acid levels those qualifying for the diagnosis of gout (usually > 7 mg/dl) so attributing to the normal range a remarkable proportion of patients with an increased risk of cardio-metabolic disease with a consequent reduction in the discriminatory power of the analysis.

For all these reasons we do not believe the the puzzling interpretation of the role of serum uric acid beyond gout can be inspired by any huge analysis and review of all the available literature; more attention should be paid to the possibility of going beyond the plasma phenotype. Any comprehensive paper that does not consider the heterogeneity of the phenotype will have only the effect of increasing the uncertainty and reducing the probability to find a solution (if any) to a very interesting and unresolved problem.