Dose-response Relationship of Serum Uric Acid with Metabolic Syndrome and Non-alcoholic Fatty Liver Disease Incidence: A Meta-analysis of Prospective Studies

Emerging evidence has shown that serum uric acid (SUA) elevation might cause metabolic derangements, including metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD); however, magnitude of the risk has not been quantified. We searched PubMed, EMBASE, and ISI databases for relevant studies through 10 May 2015. Prospective studies reporting the risk of SUA elevation on the incidence of MetS/NAFLD were enrolled. Pooled HR of MetS was 1.55 (95%CI: 1.40–1.70) for the highest versus lowest SUA categories, and 1.05 (95%CI: 1.04–1.07) per incremental increased in SUA of 1 mg/dl. The pooled HR of MetS in younger women was higher than age-matched men and older women (1.17 vs. 1.05 and 1.04, respectively, P < 0.05). Individuals in the highest SUA category had a 40% greater risk of disease NAFLD occurrence. Dose-response increment of NAFLD events was 1.03 (95%CI: 1.02–1.05). A positive relationship with a linear trend for SUA elevation with MetS and NAFLD in different genders was examined by a dose-response meta-analysis (P < 0.001).SUA assay is useful in screening metabolic disorders for linear trend between its elevation and MetS/NAFLD incidence. SUA-lowering therapy is a potential strategy for preventing systemic/hepatic metabolic abnormalities.

Risk measures of metabolic syndrome/non-alcoholic fatty liver disease according to study specific mean dose of serum uric acid Figure S2 Forest plot of association between serum uric acid and individual metabolic syndrome components in prospective studies Risks were evaluated per standard deviation of uric acid elevation A represents the pooled uric acid-obesity association; B represents the uric acid-hyperlipemia association; C represents the uric acid-low-HDL-C association; D represents the uric acid-hypertension association; E represents the uric acid-hyperglycemia association. Figure S3 Forest plot of dose-response association between serum uric acid and metabolic syndrome/non-alcoholic fatty liver disease incidence in normouricemic subjects A represents serum uric acid-metabolic syndrome association; B represents serum uric acid-non-alcoholic fatty liver disease association.

4-5
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

5
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

4-5
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

4
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

5
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

5-6
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

6-7
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2 ) for each meta-analysis.

Section/topic # Checklist item Reported on page #
Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

RESULTS
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

7
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

7-8
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).

8-11
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

8-11
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.

8-11
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15).

DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

11-15
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).  How representative was the selected group in comparison with the general community population? (if yes, one star; no star if the participants were selected or selection of group was not described) 2. How representative was the group with elevated SUA level in comparison with the group within normal range? (if drawn from the same community, one star; no star if drawn from a different source or selection of group was not described) 3. Ascertainment of high risk group in exposure of high SUA concentration (if yes, one star) 4. Demonstration that the disease (MetS/NAFLD) outcome was not present at start of study (if yes, one star) Comparability 5. Comparison was controlled for age and gender (if yes, one star; no star was assigned if the two groups differed) 6. Comparison was controlled for alcohol intake, cigarette smoking, and baseline MetS components (one star was assigned as if two or more of these three characteristics were controlled for; no star was assigned if one or less characteristic was controlled for) Outcome assessment 7. Clearly defined disease (MetS/NAFLD) outcome by certain criteria (yes, one star for information ascertained in literature; no star if this information was not reported) 8. Adequate duration of follow-up for observation of ensuing disease (MetS/NAFLD) outcome (one star if duration of follow-up≥4 year) 9. Adequacy of follow-up of cohorts (one star if follow-up rate > 90%) Abbreviations: MetS, metabolic syndrome; NAFLD, non-alcoholic fatty liver disease; SUA, serum uric acid.  Total scores (maximum 9) 7 8 7 8 7 9 7 8 8 * NOS: Newcastle-Ottawa Scale "1" meant the study was corresponded to the NOS criteria, "0" meant the study wasn't corresponded to the NOS criteria Abbreviations: MetS, metabolic syndrome; NAFLD, non-alcoholic fatty liver disease; SUA, serum uric acid.