The management of hyperuricemia: back to the pathophysiology of uric acid

Paleopathology, a perspective for comprehension

Paleopathology, the science that studies ancient human diseases, was extensively concerned with gout, as this arthritis was among the earliest diseases to be recognized as a clinical entity. The study of the disease recognition and of cures used by ancient peoples could also provide useful hints to the comprehension of pathophysiological pathways involved.

Hippocrates first referred to the disease as an “arthritis of the rich”, noting the link with an indulgent lifestyle, as opposed to rheumatism, an “arthritis of the poor”. Galen associated gout with debauchery and indulgence, but also recognized a hereditary trait, that had previously been referred to by the Roman senator Seneca¹.

The role of excess dietary purines (derived from meat, seafood, and beer) was later accepted and further illustrated by the disparity between the incidence of gout in Asia and Europe. Traditional Asian diets, based on rice and vegetables, are low in purines, and gout has been relatively rare in these cultures¹. Antonie van Leeuwenhoek (1632–1723), one of the pioneers of microscopy, was the first to describe the appearance of the crystals from a gouty tophus, although their chemical composition was unknown at that time¹. The English chemist Woollaston demonstrated urate in a tophus from his own ear in 1797, and in his volume of 1859 “The Nature and Treatment of Gout and Rheumatic Gout”, the English physician Alfred Garrod stated that “the deposited urate of soda may be looked upon as the cause, and not the effect, of the gouty inflammation”¹. As early as the 2nd century AD, the Cappadocian physician Aretaeus recognized that gout could be inherited. In the 19th century, Sir Archibald Garrod (the son of Sir Alfred Garrod) suggested that gout be included among disorders that could result from inborn errors of metabolism¹.

Monosodium urate crystal deposition

Gout has now been long recognized as a crystal-induced arthritis, in which monosodium urate (MSU) crystals precipitate within joints and soft tissues and elicit an inflammatory response. The disease is nonetheless heterogeneous in its clinical presentation patterns, due to the interaction of many different mechanisms such as the genesis of elevated serum urate, the processes leading to crystal formation and growth, and the inflammatory pathways activated by MSU crystals. The susceptibility to form MSU crystals is a consequence of excessive blood levels of soluble urate, one of the final products of the metabolic breakdown of purine nucleotides. Hyperuricemia is typically defined as occurring above the saturation point of MSU (serum urate levels >6.8 mg/dL), at which point the risk of crystallization increases² (Figure 1). In gout, deposition of MSU crystals within joints and connective tissue engenders highly inflammatory but localized responses⁴.

Figure 1. Mechanisms of hyperuricemia. On the left, overproduction of urate through the purine degradation pathway is a minor contributor to serum urate concentrations. Underexcretion of urate is the dominant cause of hyperuricemia in people with gout. In the center, major components of the renal proximal tubule urate transportasome are clustered according to their role as reuptake transporters of urate from filtered urine or as secretory transporters. On the right, in the gut, variants in ABCG2 with reduced function block excretion and contribute to underexcretion. Reproduced with permission³.

The baseline risk factor for hyperuricemia, in humans as well as in some other primates, is mutational inactivation of the gene for uricase. This enzyme in other mammals degrades urate to the more soluble molecule allantoin². However, additional factors are required to produce hyperuricemia, including decreased renal excretion of urate, excessive cell and purine turnover (as happens in the presence of leukemias, hemolytic anemias, and other conditions), purine dietary intake, and/or primary urate overproduction².

Urate excretion

Since the serum uric acid (SUA) level is balanced between hepatic production and excretion mainly through the kidney, a decrease in the excretion rate of urate results in hyperuricemia⁵. Although renal handling of urate is not yet fully understood, it is known that approximately 90% of glomerularly filtrated urate is reabsorbed at proximal tubular cells by uptake from the urinary lumen and is secreted to blood vessels⁶. Several transporter proteins, expressed in the apical membranes of the proximal tubular cells, are involved in urate uptake, including: urate–anion exchanger URAT1 (also called SLC22A12, solute carrier family 22 member 12) mainly expressed in the renal cortex; organic anion transporter (OAT) 4 that mediates uptake of uric acid from the renal tubule; and OAT 10, a low affinity reuptaker of uric acid⁷. Many drugs may alter SUA levels by interfering with urate transporters, as shown for OAT1, OAT3, OAT4, and MRP4^6,8.

Crystal formation

Little is indeed known about the process of MSU crystal formation (Figure 2). Physicochemical factors play an important role, but other less well established factors must also be operative, as epidemiological observations suggest. Although the presence of hyperuricemia is essential for the formation of crystals, only a fraction of hyperuricemia patients develop gout – ranging from 2 to 36% of patients in studies with approximately 5–10 years of follow-up – suggesting that not all hyperuricemias undergo MSU crystal formation^10,11.

Figure 2. SUA, oxidative stress and cardiovascular disease, a comprehensive hypothesis. Borghi and Cicero⁹.

Conversely, patients are sometimes observed to have a normal SUA level (≤6.0 mg/dL) at the time of an acute gout attack, indicating that the relationship between SUA level and acute MSU crystallization is complex¹². Thus, local and/or systemic biological environments are likely to modulate MSU solubility, precipitation, and/or stability¹².

Inflammation

Once formed, MSU crystals activate complement, and resident tissue macrophages, which secrete inflammatory cytokines including IL-1β. These mediators promote a neutrophilic influx that is the well known pathophysiologic feature of acute gout². Upon infiltration, neutrophils are activated by the crystals they encounter, producing additional pro-inflammatory mediators such as the arachidonic acid products PGE2 and LTB4. Interestingly, it was observed that MSU crystals can persist in the joint fluid between attacks, suggesting that the inflammatory potential of MSU crystals may be modulated by synovial fluid elements².

Association of hyperuricemia has been described with cardiovascular diseases, metabolic syndrome and renal disease. Inflammation is believed to be a major link between hyperuricemia and comorbid conditions¹³. The causal role of uric acid in such diseases, the possible role of urate lowering therapies, and the safe target level of SUA are debated. A prospective cohort study in postmenopausal women found that SUA level was associated with: coronary endothelial dysfunction (CED); inflammatory markers such as neutrophil count (p = .02); and high-sensitivity C-reactive protein levels (p = .006) among patients with CED, but not among those without CED¹⁴.

Xanthine oxidoreductase

In primates and in humans, the molybdopterin-flavin enzyme xanthine oxidoreductase (XOR) catalyzes the final steps in purine catabolism: oxidation of hypoxanthine to xanthine and xanthine to uric acid. XOR is transcribed as a single gene product, xanthine dehydrogenase (XDH). During inflammatory conditions, post-translational modification by oxidation of critical cysteine residues or limited proteolysis converts XDH to xanthine oxidase (XO). Reactive oxygen species (ROS) production is connected with XO activity but it is known that XDH displays partial oxidase activity under conditions in which NAD + levels are diminished, such as the ischemic/hypoxic microenvironment encountered in vascular inflammation. This same inflammatory milieu leads to enhanced XO levels and thus increased XO-derived ROS. Several inflammatory cytokines (TNF-α, IL-1β, IFN-γ) as well as hypoxia are noted to induce XOR expression. In particular, vascular endothelial cells respond to hypoxia, cytokine stimulation and shear stress by upregulating XOR and exporting the enzyme to the circulation^15,16.

Endothelial dysfunction

Increased XO activity was correlated with increased XO-derived ROS formation resulting in activation of redox-dependent cell signaling reactions and alterations in vascular endothelial function. In addition, it is known that uric acid reduces NO production in endothelial cells, thus impairing vasodilation¹⁷. The clinical relevance of such mechanisms was exemplified by numerous studies in which XO inhibition attenuated vascular dysfunction in conditions including congestive heart failure, sickle cell anemia and diabetes¹⁸. Disparity between XO inhibitor drugs was observed regarding the activity on XO when bound to vascular endothelial cell glycosaminoglycans (GAGs)¹⁹. The impact of gout and SUA on mortality and risk for coronary heart disease and cardiovascular events was first shown by epidemiological observations^19–21. Nevertheless, it was observed that uric acid is a powerful scavenger of free radicals and provides 60% of free-radical scavenging capacity in plasma. Although the antioxidant effect of uric acid suggests that it might have protective effects, high SUA concentration was associated with obesity and insulin resistance, and hyperuricemia has even been proposed as a component of metabolic syndrome²². XO inhibition has indeed been proven to improve endothelial dysfunction independently of uric acid lowering²³. Therefore, the safe target level of SUA is debated²⁴.

Heritability of hyperuricemia

Hyperuricemia and hyperuricosuria have been shown to have a familial inheritance and to cluster within families, heritability ranging from 39 to 45% in families of studies carried out in South America. In addition, genetic loci contributing to renal urate excretion measure were found both in adults and in children^25,26. Nonetheless, heterogeneity of clinical patterns was found in the presence of common genetic substrates in twin studies²⁷. Models that quantified the relative contribution of genetic and environmental factors on phenotypic variance showed that individual variability in gout was substantially influenced by environmental factors shared between co-twins and not by genetic factors. In contrast, individual differences in hyperuricemia were influenced significantly by genetic factors²⁷.

GWASs (Genome-wide association studies) examine a wide set of genetic variants in many individuals to evaluate the association of a variant with a trait²⁸. A GWAS involving more than 140,000 participants of European ancestry identified 28 genetic loci that encode urate transporters and affect serum urate concentrations²⁵. A few GWASs with gout as an outcome have been done, finding unclear results, but candidate gene studies have provided evidence that genes involved in NLRP3 inflammasome activation and activity are causal in gout^29,30.

Therapeutic approaches in history

Paleopathology, in addition to describing the condition of gout and the discovery of its relationship with tophi and urate serum levels, reported several therapeutic approaches to the disease. Diet has long been recognized as a major causative factor in the pathogenesis of hyperuricemia and gout, but dietary restriction or modification as a means of controlling gout and hyperuricemia has been and continues to be largely neglected. The first use as a selective and specific treatment for gout of colchicine, an alkaloid derived from Colchicum autumnale, is attributed to the Byzantine physician Alexander of Tralles in the 6th century AD¹. Uricosuric agents, which enhance the renal clearance of urate, were first used at the end of the 19th century. See (1877), in his attempt to treat gout, was able to induce uricosuria and resolution of tophi in a patient with gout by administering large doses of salicylates¹. Salicylates were not long used for treating patients with gout because of the toxicity and impracticality of high dose therapy that is needed because of the mechanism of action of the drug¹. A recent important historical advance in the treatment of hyperuricemia was the development of xanthine oxidase inhibitors: which are effective in reducing plasma and urinary urate levels; have been shown to reverse the development of tophaceous deposits¹; and seem to have beneficial effects on vessel wall inflammation independent of SUA level control²³.

Conclusions

An international symposium, held in Bologna in December 2016, provided insight into the novel findings about the pathophysiology of hyperuricemia. This supplement contains literature reviews based on the symposium lectures. The articles will present a new study approach, based on genetic principles, along with the latest evidence on associations of hyperuricemia with cardiovascular and renal diseases, and advances in urate lowering therapy. These perspectives are examined with the aim of identifying therapeutic interventions directed not only to arthritis but also to the whole spectrum of symptoms linked to hyperuricemia.

Transparency

Declaration of funding

This editorial was funded by Fondazione Menarini.

Declaration of financial/other relationships

C.B. has disclosed that he has received sponsorship and speaker’s bureau fees from Menarini.

CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no relevant financial or other relationships to disclose.

Acknowledgements

Editorial assistance for this supplement was provided by Content Ed Net funded by Fondazione Menarini.