Simple Scores of Fibrosis and Mortality in Patients with NAFLD: A Systematic Review with Meta-Analysis

Noninvasive simple scores have been validated to assess advanced liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). We performed a systematic review with meta-analysis evaluating if NAFLD fibrosis score (NFS), AST to platelet ratio index (APRI), and Fibrosis-4 (FIB-4) score may also predict mortality. PubMed and EMBASE databases were searched until April 2018. Random-effects models were used to calculate pooled RRs of mortality for highest vs. lowest categories of exposure and to perform dose-response meta-analysis. Heterogeneity was assessed using the Q test and I2 statistic. Overall, eight studies were included in the systematic review; all of the eight studies provided data for NFS, while four provided data for APRI and FIB-4. When comparing the risk estimates for high (>0.676) vs. intermediate + low NFS (≤0.676), we found a nearly fourfold increase in mortality risk, with evidence of heterogeneity (RR = 3.85, 95% CI: 2.08, 7.11; I2 = 92%). At dose-response meta-analysis, compared to the midpoint of the lowest category of NFS (−2.5), the risk of mortality was about twofold higher for NFS = −0.5 (RR = 2.20, 95% CI: 1.31, 3.70) and more than fivefold higher for NFS = 1.5 (RR = 5.16, 95% CI: 2.02, 13.16). When comparing the risk estimates for high (>1.5) vs. medium + low APRI (≤1.5), we found a higher risk of mortality, without heterogeneity (RR = 3.61, 95% CI: 1.79, 7.28; I2 = 0%). Comparison of the risk estimates for high (>2.67) vs. medium + low FIB-4 (≤2.67) didn’t reveal a significantly higher risk of mortality, with heterogeneity (RR = 2.27, 95% CI: 0.72, 7.15; I2 = 85%). Dose-response analysis for APRI and FIB-4 was not considered conclusive due to the low number of studies. Based on the results of our meta-analysis, the measurement of NFS can be considered an accurate tool for the stratification of the risk of death in patients with NAFLD.


Supplementary
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

Protocol and registration
5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
2 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.
2 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.
2 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
2 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).
2 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.
2 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. 2

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.

NA
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means).

2,3
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.

2,3
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).

NA
Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, metaregression), if done, indicating which were pre-specified.

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.
3, Figure 1 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.
1,2, Table 1 Risk of bias within 19 Present data on risk of bias of each study and, if available, any outcome level NA studies assessment (see item 12).

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.

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).

7,8
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).

NA
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.

FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.