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Abstract
Background The aim of this study was to compare the frequency and volume of dual energy CT (DECT) urate deposits in people with asymptomatic hyperuricaemia and symptomatic gout.
Methods We analysed DECT scans of the feet from asymptomatic individuals with serum urate ≥540 µmol/L (n=25) and those with crystal proven gout without clinically apparent tophi (n=33).
Results DECT urate deposits were observed in 6/25 (24%) participants with asymptomatic hyperuricaemia, 11/14 (79%) with early gout (predefined as disease duration ≤3 years) and 16/19 (84%) with late gout (p<0.001). DECT urate deposition was observed in both joints and tendons in the asymptomatic hyperuricaemia group, but significantly less frequently than in those with gout (p≤0.001 for both joint and tendon sites). The volume of urate deposition was also significantly lower in those with asymptomatic hyperuricaemia, compared with the early and the late gout groups (p<0.01 for both comparisons). Similar urate volumes were observed in the early and late gout groups.
Conclusions Although subclinical urate deposition can occur in people with asymptomatic hyperuricaemia, these deposits occur more frequently and at higher volumes in those with symptomatic gout. These data suggest that a threshold of urate crystal volume may be required before symptomatic disease occurs.
- Gout
- Arthritis
- Inflammation
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In the presence of urate concentrations above saturation levels (≥410 µmol/L, 6.8 mg/dL), monosodium urate (MSU) crystals form at physiological temperature and pH.1 The host response to MSU crystals leads to the clinical manifestations of gout, such as acute flares and tophaceous disease.2 ,3 In prospective observational studies, the risk of developing gout rises with increasing serum urate concentrations.4–6 For example, in the Normative Aging Study, the 5-year cumulative incidence rate for gout in men with baseline serum urate ≥540 µmol/L (9 mg/dL) was 19.8%.4 However, even in those with severe hyperuricaemia, not all individuals develop symptomatic gout.
Recent advanced imaging studies have reported that urate crystal deposition is present in some asymptomatic individuals with hyperuricaemia, suggesting that subclinical urate deposition occurs prior to presentation with symptomatic disease.7–11 It is currently unclear why some hyperuricaemic individuals with urate deposits on advanced imaging do not develop symptomatic gout. Sites of deposition may play a role, for example, periarticular deposition may not lead to clinically apparent disease. The amount of urate deposition may also influence the development of symptomatic disease.
Dual energy CT (DECT) is a recently developed advanced imaging modality that allows specific detection and volume measurement of urate crystals in people with gout.12 The aim of this study was to compare the frequency, sites and volume of DECT urate deposits in people with asymptomatic hyperuricaemia and symptomatic gout.
Patients and methods
In this cross-sectional study, DECT scans of both feet were prospectively obtained from asymptomatic individuals with severe hyperuricaemia, defined as serum urate ≥540 µmol/L (n=25), and those with crystal proven gout without clinically apparent tophi (n=33). The study was approved by the Northern A Health and Disability Ethics Committee (12/NTA/71) and all participants provided written informed consent.
Participants with asymptomatic hyperuricaemia were recruited from a community laboratory via a mailed invitation to individuals with serum urate concentrations ≥540 µmol/L. Participants with crystal proven gout were recruited from rheumatology clinics and via a laboratory mailed invitation to individuals with MSU crystals identified in synovial fluid. The study specifically focused on recruitment of those with early gout (predefined as onset of symptoms in the preceding 3 years). All participants attended a study visit in Auckland, New Zealand, where clinical details and DECT scans were obtained.
Asymptomatic individuals with normouricaemia according to local laboratories (all with serum urate ≤380 µmol/L, mean (SD) serum urate 330 (30) µmol/L, negative controls, n=10) and individuals with crystal proven tophaceous gout (positive controls, n=20) were also studied to optimise the DECT settings. These control participants were identified by public advertising and rheumatology clinics.
DECT scans of the feet were obtained by a dual X-ray tube 128 detector row scanner (Somatom Definition Flash, Siemens Medical, Erlangen, Germany), using protocols previously described.13 Two readers (a musculoskeletal radiologist (AJD) and a rheumatologist (ND), both experienced in DECT assessment), blinded to all clinical features including gout status and serum urate results, independently scored the scans for the presence and sites of urate deposition, and measured the urate volume in both feet using proprietary software (syngo DE Gout #MM, Siemens Medical). The online supplementary methods shows full details of DECT acquisition and scoring. Urate deposition was observed in no negative control participant and 18/20 (90%) positive control participants (mean volume (SD) 6.62 (10.65) cm3). Nail bed, skin, submillimeter, motion and beam hardening artefacts were excluded from the analysis and volume measurement.14 Inter-reader kappa for presence of urate deposition was 0.78, and intraclass correlation coefficient (95% CI) for urate volume was 1.00 (1.00 to 1.00). For the purposes of analysis, DECT urate deposits were considered present if scored by both readers.
The sample size was determined based on our previous conventional and dual energy CT studies in patients with gout.13 ,15–17 Data were analysed using SPSS V.20 (SPSS, Chicago, Illinois, USA) software. Means with SD and percentages were used to describe the clinical characteristics of patients. Reliability was assessed using agreement statistics including intraclass correlation coefficients. The gout group was separated into two groups: early gout (predefined as disease duration ≤3 years, n=14) and late gout (disease duration >3 years, n=19). Differences between groups were analysed using χ2 analysis, t tests and in the case of three groups, Kruskal–Wallis tests with Dunn's post hoc tests. 95% CI were calculated for proportions using the mid-P exact method on http://www.openepi.com. All tests were two tailed and p<0.05 was considered statistically significant.
Results
Clinical features
Table 1 shows the clinical features of the participants with asymptomatic hyperuricaemia and gout included in the analysis. There were no significant differences in age, sex, diuretic use or body mass index. Participants in the gout group were more likely to be of Pacific ethnicity and have chronic kidney disease. The mean serum urate was significantly higher in the asymptomatic hyperuricaemia group compared with the gout group, noting that 82% of the gout group was on urate-lowering therapy.
Clinical features of participants
DECT urate deposition: comparison between asymptomatic hyperuricaemia and entire gout group
DECT urate deposits were observed in 6/25 (24%) participants with asymptomatic hyperuricaemia, and 27/33 (82%) participants with gout (table 2). DECT urate deposition was observed in both joints and tendons in the asymptomatic hyperuricaemia group, but significantly less frequently than in the gout group (table 2). Urate deposition was observed at the first metatarsophalangeal joint site in two (8%) participants with asymptomatic hyperuricaemia, compared with 18/33 (54%) of the participants with gout.
Sites of urate deposition in the asymptomatic hyperuricaemia and gout groups
The volume of urate deposition was significantly lower in those with asymptomatic hyperuricaemia compared with those with gout (mean (SD) 0.023 (0.06) cm3 vs 0.62 (1.17) cm3, p=0.007). In those with urate deposits only, the volume of urate deposition was also significantly lower in those with asymptomatic hyperuricaemia compared with those with gout (mean (SD) 0.09 (0.10) cm3 vs 0.75 (1.26) cm3, p=0.012).
DECT urate deposition: comparison between asymptomatic hyperuricaemia and early gout
Of the 33 participants with non-tophaceous crystal proven gout, there were 14 participants with early gout. The mean (SD) disease duration in this group was 1.4 (1.0) years and 8 (57%) were on urate-lowering therapy.
DECT urate deposition was present at any site in 11/14 (79%) with early gout and 16/19 (84%) with late gout (compared with asymptomatic hyperuricaemia group p<0.001, figure 1A). DECT urate deposition was observed more frequently in both joints and tendons in the early gout group compared with the asymptomatic hyperuricaemia group (p<0.01 for both sites, figure 1B, C).
Comparison between asymptomatic hyperuricaemia (HU), early gout and late gout. (A) Frequency with any urate deposition. (B) Frequency with urate deposition at joint sites. (C) Frequency with urate deposition at tendon sites. (D) Urate volume. Negative controls with asymptomatic normouricaemia (NU) and positive controls with tophaceous gout (tophi) are shown in grey. The mean (SD) serum urate concentration for the normouricaemic negative control group was 330 (30) µmol/L, for the asymptomatic hyperuricaemia group was 590 (60) µmol/L, for the early gout was 460 (15) µmol/L, for the late gout was 420 (10) µmol/L and for positive control tophaceous gout group was 420 (13) µmol/L. **p<0.01, ***p<0.001.
The volume of urate deposition was significantly lower in those with asymptomatic hyperuricaemia compared with the early and late gout groups (p<0.01 for both, figure 1D). Similar urate volumes were observed in the early and late gout groups. In those with urate deposits only, there was a similar trend to lower volume of urate deposition in those with asymptomatic hyperuricaemia compared with the early gout group (mean (SD) 0.09 (0.10) cm3 vs 0.99 (1.14) cm3, p=0.074).
Discussion
This DECT study has confirmed that urate deposition can be detected in the feet of some asymptomatic individuals with severe hyperuricaemia. However, deposits occur more frequently and at higher volumes in symptomatic disease (even with recent onset of symptoms) compared with asymptomatic hyperuricaemia.
We observed that urate deposition occurs in both tendons and joints in those with asymptomatic deposition, suggesting that periarticular deposition alone cannot account for the lack of clinically apparent disease in those with asymptomatic hyperuricaemia. Our analysis was not able to assess factors such as the host inflammatory response to deposited crystals at intra-articular or periarticular sites that might play a role in presentation of symptomatic disease. However, our data do indicate that the volume of urate deposition may influence the development of symptomatic gout.
The relationship between serum urate and DECT deposition in symptomatic deposition is difficult to interpret, noting that most symptomatic individuals were on urate-lowering therapy. All participants with asymptomatic hyperuricaemia had serum urate concentrations (≥540 µmol/L) strongly associated with risk of developing symptomatic gout.4 Despite serum urate levels that were well above the recognised saturation concentrations,1 the majority of these individuals did not have evidence of urate deposition on DECT. This may reflect low sensitivity of DECT to detect very small concentrations of MSU crystals.18 ,19 Nevertheless, this finding does suggest that factors other than urate concentrations at a single time point contribute to formation of urate crystals in vivo. These factors may include the duration of exposure to high urate concentrations or the presence of local tissue factors that promote nucleation and/or growth of MSU crystals. These cross-sectional findings provide a rationale for longitudinal imaging studies of people with hyperuricaemia to understand what factors contribute to the development of urate crystal deposition in those with severe hyperuricaemia, and whether the presence or volume of urate crystal deposition predicts development of symptomatic disease or joint damage.20
In summary, although urate deposition can be detected by DECT in the feet in some asymptomatic individuals with severe hyperuricaemia, these deposits occur more frequently and at higher volumes in those with symptomatic gout. These data suggest that a threshold of urate crystal volume may be required before symptomatic disease occurs.
References
Supplementary materials
Lay summary
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Data supplement 1 - Online supplement
Footnotes
Handling editor Tore K Kvien
Contributors ND (the guarantor) accepts full responsibility for the work and the conduct of the study, had access to the data and controlled the decision to publish. ND conceived of the study. MEH coordinated the study. ND and AJD analysed the DECT scans. OA, PT, CF and AH assisted with participant recruitment and study visits. GDG assisted with statistical analysis and database management. LKS, AJD and FMM assisted with protocol development and interpretation of data. ND drafted the first version of the manuscript. All authors contributed to manuscript revisions and approved the final manuscript.
Funding This project was funded by the Health Research Council of New Zealand (13/668).
Competing interests ND has received consulting fees, speaker fees or grants from the following companies: Takeda, Teijin, Menorini, Ardea, AstraZeneca, Savient, Metabolex and Fonterra. LKS has received consulting fees from AstraZeneca. The other authors have no relevant conflicts of interest.
Patient consent Obtained.
Ethics approval Northern A Health and Disability Ethics Committee (12/NTA/71).
Provenance and peer review Not commissioned; externally peer reviewed.