DISCUSSION
In the present study, the clinical features of patients with normouricemia were characterized by having more frequent postoperative episodes and hemodialysis initiation and less frequent renal insufficiency and urinary stones. In addition, more pronounced inflammation, with fever and elevated WBC counts and CRP levels, was observed in the normouricemia group than in the hyperuricemia group. However, serum urate levels during an acute gout attack were not associated with recurrent gout attack.
Surgery has been known to be a risk factor for acute gout attack, related to starvation, catabolism, or dehydration [
9]. Interestingly, a previous research has shown that serum urate levels of patients with postoperative gout are significantly lower when compared with the preoperative serum urate levels [
10]. Moreover, in our study, serum urate levels of patients with postoperative acute gout attack were significantly lower during the acute gout attack (6.23 ± 2.87 mg/dL) than before the acute gout attack (8.99 ± 2.46 mg/dL) (
p < 0.001). In addition, postoperative acute gout attacks occur more often after gastrointestinal surgery than after other types of surgeries [
10]. Indeed, in the present study, patients with normouricemia more frequently underwent gastrointestinal surgery than those with hyperuricemia, although this finding was not statistically significant (11/20, 55% vs. 1/8, 12.5%;
p = 0.088). Several factors, such as administration of anesthetics, intestinal manipulation, and intravenous infusion of glucose or total parenteral nutrition, are associated with a marked increase in urinary excretion of serum urate during the postoperative period following abdominal surgery [
11-
14].
Serum urate reduction induce partial dissolution of tophi and released uric acid can activate a cascade of pro-inflammatory cytokines [
15]. Previous studies reported the development of acute gout attack after initiation of dialysis [
16,
17]. In our present study, normouricemia during acute attack was more frequently observed in patients with hemodialysis initiation (
Table 1); therefore, this can be explained by a rapid reduction of serum urate levels by hemodialysis.
Our findings showed that inflammatory activity, as assessed by the presence of fever and elevated CRP levels and WBC counts in the blood or joint fluid, was significantly higher in the normouricemia group than in the hyperuricemia group. A previous research found that the inflammatory process can play a role in the reduction of serum urate levels during an acute gout attack through urinary excretion of uric acid [
6]. It has been suggested that proinflammatory cytokines can induce the release of cortisol, which has uricosuric effect [
7,
18]. In the present study, the patients in the normouricemia group had significantly lower serum urate levels during an acute gout attack compared with previous serum urate levels (
Fig. 1). Thus, we can speculate that more inflammatory activity underlies the mechanisms responsible for the reduction of serum urate levels to be within the normal range.
A significantly lower rate of renal insufficiency was observed in the patients in the normouricemia group than in those in the hyperuricemia group (
Table 1). There are several factors that influence the development of hyperuricemia in renal function decline. These include decreased delivery of a filtered urate load to the renal tubule and increased reabsorption and/or decreased tubular secretion of uric acid [
19]. Recent studies have reported that urate transporters in the renal proximal tubule act on reabsorption and secretion of uric acid [
20-
22]. However, in patients with renal impairment, uric acid handling by renal urate transporters can be compromised and extrarenal urate transporters may play a greater role in determining serum urate levels [
23,
24]. Therefore, urate urinary excretion under certain conditions, such as those of surgery and inflammation, could occur more actively and efficiently in patients with normal kidney function than in those with renal insufficiency during an acute gout attack. This hypothesis might explain why normouricemia status is less likely to occur in patients with renal insufficiency.
The present study has shown that female sex is a risk factor for gout recurrence. Female hormone is associated with increased urinary excretion of uric acid; therefore, females are not generally affected by hyperuricemia before menopause [
25]. However, serum urate concentrations sharply increase after menopause, which leads to increased incidence of gout in postmenopausal women [
26]. Female patients with gout were found to be older, had more comorbidities including hypertension or renal insufficiency, and received diuretics more often [
27,
28]. In a previous study, hypertension, renal insufficiency, and use of diuretics were identified as risk factors of recurrent gout attacks [
29]. However, the effect of sex differences as well as hormones regarding the recurrence of gout attacks remain unclear. Therefore, it would be interesting to discover which factors are responsible for the elevated risk of gout recurrence in female patients.
In the present study, the presence of tophi and history of urinary stone were associated with the recurrence of gout attack. A previous study showed that serum urate levels were correlated with the number of tophi [
30]. In addition, serum urate levels act as a risk factor of urinary stone in a dose dependent manner [
31]. Thus, high urate burden in the presence of tophi or history of urinary stone may contribute to the recurrence of acute gout attack.
Diuretics increase serum urate levels by volume depletion and decrease in renal tubular secretion of uric acid [
32]. In a previous study, the use of loop diuretics or thiazide were associated with the incidence of gout attack [
33]. In addition, recent use of diuretics, especially thiazide, is an important risk factor for recurrent gout attack [
34]. Similarly, in our present study, the use of thiazide was associated with subsequent gout attacks.
Hyperuricemia has been reported to be closely linked to the development and recurrence of gout attack; thus, the reduction of serum urate levels is important for the reduction of future acute gout attacks [
35]. However, it is not well known whether normouricemia during an acute gout attack is associated with a lower risk of subsequent gout attack. In the present study, our finding showed that serum urate level during an acute gout attack was not associated with a different risk of subsequent gout attack as assessed by multivariate analysis (
Table 2) and IPTW analysis. Furthermore, the rate of initiation of a urate-lowering agent was not significantly different between the normouricemia and hyperuricemia groups. According to a previous study, 81% of gout patients with normouricemia at diagnosis subsequently developed hyperuricemia [
3]. In the present study, serum urate levels obtained both before and after the acute gout attack were available for 32 patients in the normouricemia group. Among these, only six patients (18.8%) showed persistent normouricemia, whereas the remaining 26 (81.3%) showed hyperuricemia at some point before and/or after the acute gout attack. These findings suggest that normouricemia during an acute gout attack may be a transient phenomenon of urate levels and is not associated with a lower risk of subsequent gout attack.
The present study has some limitations. Due to the retrospective design of the study, we could not analyze dietary food and the exact amount of alcohol intake, which can affect recurrent gout attacks and exclude the possibility that acute gout attack was not detected if the patients did not visit the clinic and some data may be missing. In addition, our findings have been obtained in patients with crystals confirmed by polarizing microscopy of the aspirated fluid that allow us to diagnose exactly in patients with normouricemia during acute attack, but the study population tended to be having a large-joint involvement thus it cannot be generalised.
In conclusion, approximately 40% patients with gout had normouricemia during an acute attack and the clinical features of these patients were characterized by a higher rate of postsurgical episodes, hemodialysis initiation, and inflammatory activity and a lower rate of renal insufficiency. The recurrence of subsequent gout attack was significantly associated with female sex, history of urinary stones, presence of tophi, and use of thiazide, but not with serum urate levels during the initial acute gout attack. Thus, careful diagnosis and follow-up should be considered in patients with gout symptoms regardless of serum urate levels during an acute gout attack.