Author: valeria urzia
Date: 17/04/2012



Gout is a medical condition that usually presents with recurrent attacks of acute inflammatory arthritis (red, tender, hot, swollen joint). It is caused by elevated levels of uric acid in the blood, that may depend on diet. methabolic syndrome and/or renal damage.

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pubmedUric Acid


The prevalence of gout in the adult population was estimated to be 1.4 , with a peak of more than 7 in men over 75 years of age. This trend not only was observed in western population but appears to affect developing countries in Asia. Serum levels of urate are higher in men and this probably accounts for the fact that clinical gout is about five times more common in man that in women. (Developments in the scientific and clinical understanding in gout, 2008.)


Pathways of urate homeostasis. Hyperuricemia can lead to gout and possibly to cardiovascular effects, whereas hyperuricosuria may leads to uric acid crystal–induced pathologies.

Acute flares of gouty arthritis are characterized by warmth, swelling, redness and often severe pain. Pain frequently begins in the middle of the night or early morning. Gout attacks initially tend to occur in the lower extremities: midfoot, first metatarsophalangeal joint, ankle, knee. Over time, gout tends to include additional joints, including those of upper extremities. Patients may report fever and flulike malais. There may be a prolonged period before another attack occurs. During this time, the intercritical period, uric acid deposits may continue to increase silently.
Patients with chronic gout develop subcutaneous tophi. They are deposition of urate crystals in the tissue around joints and in other soft tissue structures. They are not usually hot or tender. Biopsy of a tophus reveals a chronic granulomatous inflammatory response around the sequestered crystals. If tophi are adjacent to bone, erosion into bone may occur.
(Clinical manifestations of hyperuricaemia and gout, 2008.)


Uric acid, a weak acid with a pk of 5.7, is the normal product of purine metabolism in humans and in plasma exist mainly in the form of urete. Uric acid is especially produced by tissues supplied with xantine-oxidase, particulay liver and small intestine. The production changes according to: purine content in diet, uric acid synthesis rate, purine degradation rate. The grater quantity (2/3) of urates are excreted by kidneys and the remaining (1/3) is removed by small intestine, where it is degraded by bacteria.
At physiological pH monosodium urate (MSU) crystallized when its plasma concentration exceeds its solubility, around 7 mg/dl. (normal plasma urate levels are between 3.3 and 6.9 mg/dl).
MSU are potent inducers of inflammation. Within the joint, they trigger a local inflammatory reaction, neutrophil recruitment and the production of pro-inflammatory cytokines as well as other inflammatory mediators. Experimentally, the uptake of MSU crystals by monocytes involves interactions with components of the innate immune system, namely Toll-like receptor (TLR-2, TLR-4) and CD14. Inercellulary, MSU crystals activate multiple processes that lead to the formation of NALP-3 inflammosome complex that in turn processes pro-interleukin IL-1 to yield mature IL-1 beta, with is then secreted. The subsequent recruitment of inflammatory leucocytes to the site, mediated most probably by endothelial activation, can account for the subsequent release of inflammatory mediators and the recognized inflammatory manifestation of acute gout.

Monosodium urate (MSU) crystals activate monocytes via the Toll-like receptor (TLR) pathway and the inflammasome. Binding to TLR and CD14 promotes phagocytosis and cell activation through MYD88-dependent signalling mechanisms. In the cytosol, MSU crystals induce the formation of the NALP-3 (NACHT, LRR, and pyrin domain-containing-3) inflammasome and lead to caspase-1 processing of pro-IL-1β. Activation of the endothelium by IL-1β increases trafficking of neutrophils to the inflammatory site. ASC, apoptosis-associated speck-like protein containing a caspase-associated recruitment domain; IL, interleukin; NF-κB, nuclear factor-kappa-B.

TLR-2 e TLR-4 are transmembrane receptors that, on binding to extracellular ligands, trigger cellular activation and proliferation. The second component is CD14, a pattern recognition molecule
found on the cell surface and in the circulation which serves to amplify the cellular response triggered by TLR-2 and TLR-4 ligands such us lipopolysaccharide.
MSU crystals are capable of triggering IL-1 beta release by its intaraction with a cytoplasmatic compelx called the “inflammosome”. IL-1 beta is released extracellulary after enzymatic processing of its precursor molecule pro-IL-1 by caspase-1. The activity of caspase-1 is itself tightly regulated
and requires the formation of homodimeric complex of pro-caspase-1 in the presence of cytoplasmatic protein ASC ( apoptosis-associated speck-like protein containing a caspase-associated recruitment domain [CARD] and a protein of the NALP family). Because of its ability to initiate IL-1 beta processing and secretion, this molecular complex has been named the inflammosome. A number of different inflammosomes of differing compositions have been described; one such NALP protein is NALP-3 (NACHT, LRR and pyrin domain-containing-3).
Therefore MSU crystals initiate an inflammatory cascade and the starting point is the release of active IL-1 beta from monocytes and macrophages.
Besides IL-1 beta, both IL-6 and TNF-alfa are also upregulated when monocytes are in contact with gouty tissues. The chemokines also play a central role in acute gounty inflammation, particularly in neutrophil recruitment. IL-8 and closely related chemokines, such as CXCL1, bind to receptor CXCR2 to promote neutrophil chemotaxis and can also affect angiogenesis.
MSU crystal also promote inflammation cells, as exemplified by MSU crystal-induced activation of classical pathway of complement (in vitro). The classical complement activation process does not require immunoglobulin, but is amplified by both C-rective protein and IgG. MSU crystals also activate the alternative pathway (in vitro) and, in this process, direct cleavage of C5 to C5a and C5b is triggered by the formation of a stable C5 convertase on the MSU crystal surface.
The formation of leucotrienes and arachidonic acid metabolities induced by MSU is largely accounted for by the effects of MSU crystal on neutrophils and platelets recruited to the inflammatory site.
(Mechanisms of inflammation in gout, 2010.)




Uric homeostasis depends on the balance between production and complex processes of secretion and reabsorption in the kidney tubule and excretion in the intestine. It is estimated that approximately 30% of uric acid excretion is by the intestine. Renal mechanisms of urate excretion account for the other 70% and are key to the understanding of hyperuricemia.
Most genes regulate serum acid level: they seem to be involved in regukating the renal excretion of uric acid and in susceptibility to gout.

Mechanisms of hyperuricaemia and gout. Major checkpoints in the regulation of urate metabolism and pathogenesis of gout are shown in relation to the genetic and environmental factors that influence susceptibility to gout. Factors impairing the excretion of urinary uric acid or purine salvage of urate are shown in red. Factors promoting retention of urinary urate or formation of serum urate are shown in green.

Genes that regulate uric acid excretion. The genes that have been implicated in the regulation of uric acid excretion are shown. Uric acid enters the renal tubule in exchange for monocarboxylate or dicarboxylate via OAT4, SLC5A8 and SLC5A12. Urate uptake is also mediated via SLC22A12 and apical SLC2A9. Urate exits the cell predominantly through SLC2A9 expressed on the basolateral aspect of the renal tubular cell.

Genes involved in the uric acid renal elimination, whose mutation can lead to a elimination decrease and thus hyperuricemia:

-SLC22A12: encodes URAT1 that is expressed on the apical membrane of renal tubular cells. Polymorfisms of this gene has been associated with raised serum urate levels and decreased fractonal urate excretion
-SLC2A9: is an important regulator of serum urate, uric acid excretion and gout. The effects of variation in SLC2A9 is most pronunced in famales and several variants at the SLC2A9 locus have also been shown to be associated with clinical gout. Heterozygous mutation in SLC2A9 associated with partial reduction in urate transport activity have been reported in individuals with hypouricaemia, most of whom were asyntomatic but same of whom developed nephrolithiasis or exercise-induced acute renal failure (EIARF). Recently, homozygous loss-of-function mutation have also been reported in individuals with hyporicaemia, nephrolithiasis or EIARF but even lower residual urate transport activity, high fractional excretion of uric acid and very low serum urate
concentration. SLC2A9 is expressed in the kidney, in the liver but also in articular chondrocytes, a major site of uric acid deposition in gout, raising the possibility that SLC2A9 might play a role in transporting urate within the joint.
-ABCG2: encodes a trasporter of the ATP-binding cassett (ABC) family which is expressed in the apical membrane of human kidney proxmal tubule cells and is known to transport purine nucleoside analogues.
-SLC17A3: encodes a sodium phosphate transporter (NPT4).
-SLC17A1: encodes a sodium phosphate transporter (NPT1).
Additional genes
-SLC22A11: encodes a solute transporeter in the same family as URAT1.
-PDZK1 and Na/H exchange regulatory factor-1 have been reported to interact directly with several key transporters complex at the apical membrane of renal tubular cells.
-LRRC16A: has been shown to be expressed in kidney and epithelial tissues and is a key inibitor of actine capping protein.

Genes involved in the uric acid endogen syntesis, whose mutation can lead to a elimination decrease and thus hyperuricemia:

-GCKR: is predominantly expressed in liver where it stabilizes and regulates glucokinase. It has been suggested that GCKR variants may cause hyperuricaemia by causing insuline resistance.

(Recent insights into the pathogenesis of hyperuricaemia and gout, 2009.)
(Developments in the scientific and clinical understanding in gout, 2008.)


The fructose intake and alcohol intake as well as dietary purine intake are associated with an increased risk of clinical gout.

Alcohol intake increase uric acid levels. This increase has been attributed to the increase of lactic acid alchohol mediated which can exchange with urate either in the kidney or liver (a similar phenomenon is observed in diabetic ketoacidosis).The renal handling of monocarboxylates such as lactate and urate depends on coupled Na/anion and urate/anion co-transporters (SLC5A8 and SLC5A12 expressed on the apical membrane of renal proximal tubular cells). However, given that beer consumption is a greater risk factor than consumption of spirits or wine it seems that there is at least as important a role for carbohydrate and purine content of beer in the aetiology of hyperuricaemia.

Fructose increase uric acid levels. This increase has been attributed to an increase in the degradation of purine metabolites (the effect is enhanced in patients with a history of gout).
The identification of SLC2A9 as a novel uric acid transporter when it had formerly been thought to be a fructose transporter fuelled speculation that a direct interaction of the two substrates may occur. SLC2A9 certainly transports both glucose and fructose although it is considerably more active as a urate transporter. The physiological significance of these observations is unclear but it is possible that dietary fructose enhances renal reuptake of uric acid and sustains the acute elevation of uric acid caused by fructose ingestion.

(Recent insights into the pathogenesis of hyperuricaemia and gout, 2009.)



Crystals may dissolve or became sequestered in the tissue. Monocytes mature into macrophages, changing their responsiveness to urate crystals and can begin to produce anti-iflammatory cytokines. In addition, some proteins that exude into the joint space with tha attack, such as apolopoprotein B, can coat the crystals and reduce their inflammatory properties.


Following an acute attack, the symptoms of gout arthritis may be gone, but the crystals are still present in the joint. Therefore, the patient remains at risk for subsequent flares and progressive disease. The crystals that remain in the joint are often associated with a low-grade persistent inflammation. It is not known why these crystals that remain in the joint fluid between attacks, some of which are phagocytized by white cells, do not initiate the whole cascade of inflammation. The reason may be related to the number of crystal presence, thier protein coating, or the nature of the resident synovial cells. Crystals may also persist as micro-tophi in the synovium. The key point is that low-grade inflammation persist and crystals remain in to the joint, which lead to progressive desease.
(The pathogenesis of gout, 2008.)


Gouty patients frequently develop nephrolithiasis: for the 40% it precedes the joint manifestation. Uric acid is the calculus core and around it calcium-oxalate precipitates. On the contrary, uric nephropathy is a late manifestation of severe gout. It is caracterized by crystals deposition surrounded by inflammatory cells in the renal interstice and it can causes chronic renal failure.


Hiperuricaemia is a common finding in patients with metabolic sindrome and an inverse correlation was noted between insulin resistance and decreased renal uric acid clearance, which is itself associated with elevated uricemia. Hyperuricaemia is also frequently observed in patients with cardiovascular desease.
Metabolic syndrome is a state of insulin resistance associated with elevated blood pressure, plasma glucose and triglyceride, decreased high-density lipoprotein cholesterol and abdominal obesity. Obesity, in particular visceral adiposity, is also positively associated with hyperuriceamia, which can be reduced by body weight loss.
The role of hyperuricemia in the pathogenesis of cardiovascular disease and metabolic syndrome remains controversial. There is increasing evidence of a cardioprotective effect of the xanthine oxidase inhibitor allopurinol in hyperuricaemic patients. Allopurinol has been shown to improve endothelial function , to be associated with decreased cardiovascular mortality and to reduce blood pressure. Importantly, it does not follow from this that hyperuricaemia is itself a cause of vascular morbidity. The endothelial effects of allopurinol have been shown to be independent of its uric acid lowering effect and mediated by a reduction in oxidative stress . This suggests that the generation of oxygen radicals by xanthine oxidase in the process of generating uric acid causes endothelial damage rather than hyperuricaemia per se. This is compatible with the long acknowledged role of uric acid as a powerful antioxidant and the demonstration that exogenous uric acid has been shown to have beneficial effects on endothelial function. In turn this may explain a protective effect on endothelial function of elevating levels of uric acid by increased renal reabsorption or reduced uricase degradation. However, a study conducted in rodents has been observed a possible pathogenic role of hyperuricemia in the genesis of endothelial damage: it seems that the uric acid mediated vasoconstriction leads to endothelial dysfunction, activation of the renin-angiotensin system, and hypertension. Critics argue that it is impossible to disentangle hyperuricaemia from hypertension and that hyperuricaemia is a surrogate marker for early subclinical renal disfuntion.

(Recent insights into the pathogenesis of hyperuricaemia and gout, 2009.)
(Uric acid transport and disease, 2010.)


The mainstay of treatment is represented by xanthine oxidase inhibition (predominantly with allopurinol) rather than uricosuric therapy which is used second line because of lesser efficacy or increased risk of side effects.
At the present time asymptomatic hyperuricaemia is not considered to be an indication for urate lowering therapy and in clinical practice, prophylactic treatment for gout is only introduced in patients who have had two or more attacks in a 12 month period.
The identification of alleles that increase the risk of gout could in the future be used in targeting high-risk patients for treatment, without the need for further attacks to occur. At present, however, the relative contribution of the different genes to uric acid variability has been estimated at between 0.12 and 3.53% and so it remains to be seen whether genetic screening would prove clinically valuable.

(Recent insights into the pathogenesis of hyperuricaemia and gout, 2009.)


These informations indicate that uric acid has complex chemical and biological effects. When hyperuricaemia leasds to the formation of microcrystals, it leads to joint and renal inflammation. Chronic inflammation (as in tophaceous gout) leads to bone and cartilage destruction, and chronic hyperuricaemia and hyperuricosuria in gouty patient are also frequently associated with tubulointerstitial fibrosis and glomerulosclerosis, signs of local renal inflammation. Part of this is explained by the activation of the NALP3 inflammosome to process and secrete IL-1 beta.and that In addition hyperuricaemia pro-oxidant or NO-reducing properties may explain the association among hyperuricaemia, hypertension, the matabolic syndrome and cardiovascular desease.

Valeria Urzia-Domenico Urzia

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