ORIGINAL ARTICLE

Nonalcoholic Fatty Liver Disease and Mean Platelet Volume A Systemic Review and Meta-analysis Shivank A. Madan, MD, MHA,* Febin John, MD,w and Capecomorin S. Pitchumoni, MD, MPH, MACGw

Background: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity, metabolic syndrome, and cardiovascular disease. Increased mean platelet volume (MPV), a marker of platelet activity, is associated with acute myocardial infarction, stroke, thrombosis, and increased mortality after myocardial infarction. The purpose of this study was to perform a meta-analysis to investigate the relationship between NAFLD and MPV. Methodology: A systematic search of MEDLINE (Ovid), PubMed, and CINAHL databases from 1950 to May 2014, complemented with manual review of references of published articles for studies comparing MPV in patients with and without NAFLD was done. Results were pooled using both fixed and random effects model. Results: Our analysis from pooling of data from 8 observational studies including 1428 subjects (NAFLD = 842 and nonNAFLD = 586) showed that MPV was significantly higher in patients with NAFLD than those without. The standardized mean difference in MPV between NAFLD and controls was 0.457 (95% confidence interval: 0.348-0.565, P < 0.001) using fixed and 0.612 (95% confidence interval: 0.286-0.938, P < 0.001) using random effects model. Conclusions: This study suggests that MPV is significantly higher in patients with NAFLD, indicating the presence of increased platelet activity in such patients. Future research is needed to investigate whether this increased MPV is associated with increased cardiovascular disease in patients with NAFLD. Key Words: nonalcoholic fatty liver disease, NAFLD, mean platelet volume, MPV

(J Clin Gastroenterol 2016;50:69–74)

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of NAFLD with MetS has led to increased interest in its role in CVS disease causation and progression.4,8 Platelets producing vasoactive and prothrombotic factors like IL-1b and CD40L play an important role in atherothrombosis.9,10 The efficacy of antiplatelet drugs in reducing CVS events further strengthens the belief in the atherothrombotic role of platelets.11 Mean platelet volume (MPV), a simple and inexpensive test, is commonly used to measure platelet size and is also a marker of platelet activity.9 MPV has been associated with CVS risk factors like diabetes,12 hypertension,13 and dyslipidemia.14 MPV is also associated with acute myocardial infarction,15–17 arterial and venous thrombosis,18 and ischemic strokes.19 Recent studies have evaluated MPV in patients with NAFLD.20–23 Whereas some studies have shown a significant association between MPV and NAFLD,21,23–25 others have not.20,22 This meta-analysis evaluates the relationship of NAFLD and MPV, by combining data from all the relevant cross-sectional and cohort studies. This is the first meta-analysis to our knowledge on this topic.

METHODS Search Strategy and Data Sources We did a systematic search of the scientific literature for all reported studies on the association of NAFLD and MPV. MEDLINE (Ovid), PubMed, and CINAHL databases were searched using predefined search terms (NAFLD, fatty liver, hepatic steatosis, NASH) AND (MPV, platelet). We restricted our search to articles published from 1950 up to May 2014 and published in English language. We also supplemented the electronic search in the database with manual review of bibliographies of the original articles on this topic.

onalcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the world,1 is characterized by the presence of hepatic steatosis and comprises a clinical spectrum ranging from simple steatosis (fatty liver) to nonalcoholic steatohepatitis (NASH) to cirrhosis.2,3 NAFLD is linked to metabolic syndrome (MetS) and various cardiovascular (CVS) risk factors like diabetes, hypertension, obesity, and dyslipidemia.4–7 The association

Study Selection: Inclusion and Exclusion Criteria

Received for publication December 23, 2014; accepted April 8, 2015. From the *Department of Medicine, Albert Einstein College of Medicine/Montefiore Medical Center, New York City, NY; and wRutgers Robert Wood Johnson Medical School /Saint Peters University Hospital Program, New Brunswick, NJ. S.A.M. and F.J. carried out the data collection and analysis. S.A.M., F.J., and C.S.P. were involved in selection of studies and writing of the manuscript. The authors declare that they have nothing to disclose. Reprints: Shivank A. Madan, MD, MHA, Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine/ Montefiore Medical Center, 3400 Bainbridge Avenue, 7th Floor, Bronx, NY 10467 (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

Data Extraction and Quality Assessment

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Our predefined search criteria included studies of patients with NAFLD (diagnosed either by imaging or liver biopsy), wherein one of the primary outcomes of comparison between patients with and without NAFLD was MPV. Only studies published in the English language and of adult population that provided clear information regarding population characteristics were included. Studies that did not have MPV as one of the primary outcomes as well as duplicate publications were excluded. Data were extracted by 2 reviewers independently using a standardized format. Data regarding lead author, year of publication, country of study (used as a surrogate for ethnicity), study population characteristics, and study setting were collected. Mean MPV with SD and number of www.jcge.com |

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

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subjects in both NAFLD cases and control groups were extracted either directly or calculated from the data provided in the original publication. One author was contacted directly to get additional information for meta-analysis as the original publication provided median MPV.25 Two reviewers independently assessed the quality of included studies using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool.26 QUADAS-2 tool was primarily used to assess the risk of bias and applicability judged as low, high, or unclear. There was a good consensus regarding study quality.

Statistical Analysis We used standardized mean difference (SMD) in MPV between NAFLD patients and controls as the primary measure of association. Both fixed and random effects models were used for pooling of data from the included studies. All quantitative variables were expressed as mean ± SD. All summary estimates were presented with 95% confidence intervals (CIs). All tests were 2-tailed and a value of P < 0.05 was considered statistically significant. Q statistic and I2 statistics (derived from Cochran Q statistic) were used to assess heterogeneity between the studies. The heterogeneity was considered significant when the P value was 50%. A sensitivity analysis was also performed, by omitting 1 study at a time, to investigate whether findings of this systemic review were dependent on any single study or any arbitrary confounding factors. The Begg and Mazumdar rank correlation test, which reported the Kendall t values, was used to assess any publication bias. All statistical analyses were performed with the comprehensive meta-analysis software by Biostat Inc., Englewood, NJ.

RESULTS Data Search Results Of the 168 records initially identified in search through databases, 133 were excluded in screening due to lack of appropriateness of topic. From the remaining 35 articles, 2 articles that were published in a language other than English and 5 review articles were excluded. Twenty-eight articles were reviewed in full length by 2 independent readers for appropriateness and inclusion/exclusion criteria. Seven studies measured MPV in subjects with NAFLD as one of the main endpoints. Manual review of bibliographies of the original articles on this topic yielded 1 additional study. Hence, of the potential publications identified, only 8 studies met all the inclusion/exclusion criteria, and were included in the final analysis. All the studies were suitable for the MPV meta-analysis. PRISMA flow diagram for search methodology is shown in Figure 1.

Study Characteristics Study characteristics are shown in Table 1. Whereas 2 studies reported using citrate as an anticoagulant,20,22 3 other studies used ethylene diamine tetra-acetic acid (EDTA)21,23,28 and the remaining 3 studies did not provide information on the type of anticoagulant used.24,25,27 The MPVs were determined within 1 hour of blood sampling for studies that used EDTA to prevent EDTA-induced platelet swelling.21,23,28 The diagnosis of NAFLD was made by detecting increased echogenicity on liver ultrasound (US)

FIGURE 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram showing the search methodology.

(n = 4)20,23,24,27 or by liver biopsy (n = 4).21,22,25,28 Sample sizes ranged from

Nonalcoholic Fatty Liver Disease and Mean Platelet Volume: A Systemic Review and Meta-analysis.

Nonalcoholic fatty liver disease (NAFLD) is linked to obesity, metabolic syndrome, and cardiovascular disease. Increased mean platelet volume (MPV), a...
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