Abstract
BackgroundElevated baseline circulating alanine aminotransferase (ALT) level has been demonstrated to be associated with an increased risk of the metabolic syndrome (MetS), but the nature of the dose-response relationship is uncertain.MethodsWe performed a systematic review and meta-analysis of published prospective cohort studies to characterize in detail the nature of the dose-response relationship between baseline ALT level and risk of incident MetS in the general population. Relevant studies were identified in a literature search of MEDLINE, EMBASE, and Web of Science up to December 2013. Prospective studies in which investigators reported relative risks (RRs) of MetS for 3 or more categories of ALT levels were eligible. A potential nonlinear relationship between ALT levels and MetS was examined using restricted cubic splines.ResultsOf the 489 studies reviewed, relevant data were available on 29,815 non-overlapping participants comprising 2,125 incident MetS events from five prospective cohort studies. There was evidence of a linear association (P for nonlinearity = 0.38) between ALT level and risk of MetS, characterised by a graded increase in MetS risk at ALT levels 6–40 U/L. The risk of MetS increased by 14% for every 5 U/L increment in circulating ALT level (95% CI: 12–17%). Evidence was lacking of heterogeneity and publication bias among the contributing studies.ConclusionsBaseline ALT level is associated with risk of the MetS in a linear dose-response manner. Studies are needed to determine whether the association represents a causal relationship.
Highlights
Metabolic syndrome (MetS) is characterized by a constellation of disorders, including high blood pressure, dyslipidemia, hyperglycemia, and abdominal obesity, and has been consistently shown to be strongly associated with type 2 diabetes[1,2] and cardiovascular disease.[1,3] The Third Report of the National Cholesterol Education Program – Adult Treatment Panel (NCEP-ATP) III has stressed the importance of targeted preventive approaches for individuals with the metabolic syndrome (MetS).[4]
Nonalcoholic fatty liver disease (NAFLD), commonly regarded as the hepatic component of the metabolic syndrome,[5,6] is a clinical condition characterised by hepatic steatosis with varying degrees of necroinflammation and fibrosis, and which develops in the absence of substantial alcohol intake.[5]
In a review published in a recent issue of PLoS ONE, Liu and colleagues[12] synthesized available prospective epidemiological data on the association between ALT and incident MetS and reported a multivariate adjusted relative risk (RR) (95% confidence interval) of 1.81 (1.49–2.14) for MetS in a comparison of top versus bottom category of baseline ALT level
Summary
This review was conducted using a predefined protocol and reported in accordance with PRISMA guidelines (Checklist S1).[13] We searched MEDLINE, EMBASE, and Web of Science electronic databases up to December 2013, for prospective (cohort, case-cohort or ‘‘nested case control’’) population-based studies reporting on the associations between ALT level and MetS risk. Observational cohort studies were included if they had at least one year of follow-up, assessed associations of ALT with incident MetS in adults, with samples measured at baseline, and recruited participants from approximately general populations (i.e., they did not select participants on the basis of confirmed pre-existing medical conditions such as MetS, diabetes mellitus, or known liver diseases at baseline). Studies which reported RRs with 95% confidence intervals (CIs) for at least three quantitative ALT categories were included. For studies that presented results separately according to subgroups (e.g., by sex), separate doseresponse trends were derived and a within-study summary estimate was obtained using a fixed effect analysis. Consistency of findings across studies was assessed by standard x2 and I2 statistics, with I2.50% considered to be important.[17,18] Evidence of publication bias was assessed using Begg’s funnel plots and Egger’s asymmetry test.[19,20] All analyses were performed using Stata release 12 (StataCorp, College Station, Texas)
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