In this study we demonstrated that single-point sUA measurements are unreliable in hyperuricemia classification. About 21% of participants initially normouricemic were found to be hyperuricemic on subsequent checkups. In addition, nearly half of hyperuricemic participants were normouricemic on subsequent checkups. Our findings could influence the way studies using serum urate as an enrollment criteria or outcome are conducted or planned. Our study differed from previous examinations in its calculation of a threshold for screening sUA level more helpful in ruling out future hyperuricemia.
We used 6.8 mg/dL as our threshold for hyperuricemia, as this is related to the physiologic saturation at which urate begins to precipitate. We found a sUA threshold < 6.0 mg/dL, reliable in ruling out subsequent hyperuricemia, as the conversion rate was just over 7%. Our somewhat small number of subjects did not allow us to calculate a comparable threshold value above which persistent hyperuricemia appears to be more likely. A second sUA measurement did not add reliability in excluding future hyperuricemia, as there was no significant difference in the conversion rates between those with one initial value below threshold and those with two values below threshold.
There has been a paucity of published data on the rate of conversion from normouricemia to hyperuricemia and from hyperuricemia to normouricemia after an initial laboratory check in the absence of intervention.
A 2004 study examined the serum urate levels and 24-h urinary uric acid levels monthly for a 12-month period in 12 healthy men on self-selected diets, without medications known to effect urate levels, as well as abstinence from alcohol 7 days prior to measurement of levels. Seven of the twelve subjects (58.3%) had transient hyperuricemia at some point during the study period . A similarly designed study found that 10/12 subjects experienced transient hyperuricemia at some point during the course of 1 year . The Framingham heart study concluded that a higher percentage of the male population had hyperuricemia when considering four biennial determinations rather than a single determination .
The mean coefficient of variation for sUA was also examined in these two similar studies [15, 19]. Our mean coefficient of 8.5% was comparable to the findings of the 2004 study (9%, with a range of 5–12%) , and is less than that found in the second study mentioned (17.5%, with a range of 15–22%) .
In addition to variation over months, it has also been demonstrated that uric acid levels fluctuate over the course of a single day . Serum urate levels were significantly higher when measured in the morning than when measured in the afternoon, with a decrease of up to 30% seen in a subgroup of diabetic patients . In contrast to this, other studies have found that the serum urate levels are lowest when measured in the morning [21, 22]. The factors driving diurnal variations in serum urate are not fully understood, but changes in the variation may be impacted by gender, age and diet . Differences in uric acid levels have also been shown to be associated with hypertension with “non-dipping profiles” (absence of significant decrease in blood pressure during sleep), suggesting that there may be interplay between sUA and blood pressure determiners [23,24,25].
The cause of the variation in sUA found by our study and previous studies is likely multifactorial. Multiple elements are known to affect sUA levels, including diet and medications. Intake of alcohol, purine-rich foods (including seafood and organ meats such as liver), xylitol and fructose have all been associated with increased serum urate. Medications that increase urate include low-dose aspirin, pyrazinamide, cytotoxic chemotherapy, diuretics (particularly loop and thiazide diuretics), immunosuppressants such as cyclosporine and tacrolimus, nicotinic acid, testosterone, levodopa and theophylline [26, 27]. Lead exposure also increases urate and can cause saturnine gout . Disease processes that increase serum urate include renal failure, polycythemia vera, chronic myeloid leukemia and other hematologic malignancies, genetic diseases such as Lesch Nyhan, and any malady that results in acidemia . Alternately, medications that can decrease SUA levels include losartan, amlodipine, fenofibrate and high dose aspirin .
Even though our study participants were part of a clinical trial and sUA measurements were collected in a relatively short time frame (12–14 weeks), the observed variability in sUA levels could possibly be a result of subtle factors such as time of day, diet, changes in weight, renal function and undisclosed use of medications. As more data becomes available regarding the degree to which these variables affect sUA, a more standardized protocol for checking sUA may become common practice, such as checking sUA early in the morning, prior to any meals.
This variability in sUA may also influence treatment guidelines for gout in the future. Perhaps in part due to increased recognition of the imprecision of a single spot serum urate level, there is controversy regarding the choice between titration of urate lowering therapy to minimize acute intermittent symptoms and the treat-to-target approach with specified urate goals [29, 30]. However, because our study population excluded individuals with gout, our ability to extrapolate in this regard is limited.
Our study has a number of limitations. The initial screening sUA was not standardized with regards to time of day as the rest of the measurements were, and not all the subsequent measurements occurred during the targeted time frame. This discrepancy could account for some of the measured variability in sUA levels, as urate concentration is highest in the morning . However, in current clinical practice it is not standard of care to draw sUA levels at a specified time of day, and sUA levels measured at different times are often compared to one another to assess response to treatment. In this sense, our analysis may more accurately represent variability in sUA often demonstrated in clinical practice. The diet of the participants also likely had an impact on the sUA variation. We attempted to mitigate this effect by asking participants to fast prior to measurements, but this overall likely remains a factor in urate variation both in our study and in the general population.
The young age of our participants could limit generalizability to older populations. We used the same definition for hyperuricemia in both males and females, due to the physiologic precipitation of urate at this level; we also attempted to control for changes in urate due to hormonal fluctuations by timing our sample collections at similar points in the menstrual cycles of our participants.
The sample size was relatively small, but our study may prompt future studies with larger numbers of participants. Additionally, the cohort examined was from a single center. Further validation from additional study cohorts, or a multi-center analysis is likely warranted.
A total of 13 study participants presented with an initial sUA in the hyperuricemic range, which could make the conclusions obtained from that group imprecise. This small sub-population size could be the reason why a threshold sUA level above which conversion to hyperuricemia is less likely could not be proposed. Additionally, the enrollment criteria of the parent SURPHER study requiring an initial sUA of ≥5.0 mg/dL for men and ≥ 4.0 mg/dL for women does limit our ability to evaluate serum urate variability in these individuals with very low sUA levels .
Several of the measurements of sUA took place outside of the planned 2-to-4 week intervals to maintain consistency in relation to the menstrual cycles of the subjects. This could have limited our ability to compare measurements between subjects, but our demonstrated variability in sUA over time remains valid despite this limitation.
The presence of placebo and allopurinol dosing in between analyzed measurements could have affected our results, though we attempted to minimize these effects by confirming dissipation of the effects of allopurinol by examining carry-over effects with a two sample t-test.
There was also exclusion of 14 out of 99 individuals who did not complete all required sUA checks, which could affect our data if the reason for these omissions were associated with factors affecting serum urate fluctuations.
Participants did receive monetary compensation for their participation in the trial, which could have influenced the characteristics of the study population .