miRNAs in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis
Author(s): ,
Manuel Romero-Gómez
University of Seville, Seville, Spain
Corresponding author. Address: Digestive Diseases Unit, Virgen del Rocío University Hospital, Institute of Biomedicine of Seville, University of Seville, Avda Manuel Siurot s/n, Sevilla 41013, Spain. Tel.: +34 671535780; fax: +34 955 923 101.
Rocío Gallego-Durán
Institute of Biomedicine of Seville, Sevilla, Spain
Rocío Muñoz-Hernández
Institute of Biomedicine of Seville, Sevilla, Spain
Ángela Rojas
Institute of Biomedicine of Seville, Sevilla, Spain
Rocío Montero-Vallejo
University of Seville, Seville, Spain
Antonio Gil-Gómez
University of Seville, Seville, Spain
Javier Ampuero
University of Seville, Seville, Spain
Chang-Hai Liu
University of Seville, Seville, Spain
EASL LiverTree™. Romero Gomez M. 12/01/18; 256743
Prof. Manuel Romero Gomez
Prof. Manuel Romero Gomez
Contributions Biography
Journal Abstract
Graphical abstract

Graphical abstract

miRNA-34a, miRNA-122 and miRNA-192 helped to distinguish NAFLD and NASH severity. The correlation of miRNA expression between serum and liver tissue was inconsistent. miRNA-122 showed moderate accuracy to distinguish NAFLD from healthy controls. miRNA-34a showed moderate accuracy to distinguish NASH from NAFL.

Background & Aims

microRNAs (miRNAs) are deregulated in non-alcoholic fatty liver disease (NAFLD) and have been proposed as useful markers for the diagnosis and stratification of disease severity. We conducted a meta-analysis to identify the potential usefulness of miRNA biomarkers in the diagnosis and stratification of NAFLD severity.


After a systematic review, circulating miRNA expression consistency and mean fold-changes were analysed using a vote-counting strategy. The sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio and area under the curve (AUC) for the diagnosis of NAFLD or non-alcoholic steatohepatitis (NASH) were pooled using a bivariate meta-analysis. Deeks’ funnel plot was used to assess the publication bias.


Thirty-seven studies of miRNA expression profiles and six studies of diagnostic accuracy were ultimately included in the quantitative analysis. miRNA-122 and miRNA-192 showed consistent upregulation. miRNA-122 was upregulated in every scenario used to distinguish NAFLD severity. The miRNA expression correlation between the serum and liver tissue was inconsistent across studies. miRNA-122 distinguished NAFLD from healthy controls with an AUC of 0.82 (95% CI 0.75–0.89), and miRNA-34a distinguished non-alcoholic steatohepatitis (NASH) from non-alcoholic fatty liver (NAFL) with an AUC of 0.78 (95% CI 0.67–0.88).


miRNA-34a, miRNA-122 and miRNA-192 were identified as potential diagnostic markers to segregate NAFL from NASH. Both miRNA-122, in distinguishing NAFLD from healthy controls, and miRNA-34a, in distinguishing NASH from NAFL, showed moderate diagnostic accuracy. miRNA-122 was upregulated in every scenario of NAFL, NASH and fibrosis.

Lay summary

microRNAs are deregulated in non-alcoholic fatty liver disease. The microRNAs, miRNA-34a, miRNA-122 and miRNA-192, were identified as potential biomarkers of non-alcoholic fatty liver and non-alcoholic steatohepatitis, at different stages of disease severity. The correlation between miRNA expression in the serum and in liver tissue was inconsistent, or even inverse.

Non-alcoholic fatty liver disease, miRNA, Expression profile, Diagnostic accuracy
[1]. M.A. Konerman - Pharmacotherapy for NASH: current and emerging
[2]. G. Cholankeril - Nonalcoholic fatty liver disease: epidemiology, natural history, and diagnostic challenges
[3]. S.A. Harrison - NASH, from diagnosis to treatment: where do we stand?
[4]. E.K. Spengler - Recommendations for diagnosis, referral for liver biopsy, and treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
[5]. M. Blachier - The burden of liver disease in Europe: a review of available epidemiological data
[6]. S. Agrawal - Non-alcoholic fatty liver disease: east versus west
[7]. Q.M. Anstee - The genetics of NAFLD
[8]. M. Romero-Gomez - Treatment of NAFLD with diet, physical activity and exercise
[9]. E.T. Oni - A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care?
[10]. S. De Minicis - From NAFLD to NASH and HCC: pathogenetic mechanisms and therapeutic insights
[11]. E. Fabbrini - Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications
[12]. A. Lonardo - Epidemiological modifiers of non-alcoholic fatty liver disease: focus on high-risk groups
[13]. R.J. Wong - Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States
[14]. N. Rafiq - Long-term follow-up of patients with nonalcoholic fatty liver
[15]. A.J. Sanyal - Endpoints and clinical trial design for nonalcoholic steatohepatitis
[16]. A.J. Sanyal - Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop
[17]. E.M. Brunt - Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings
[18]. D.E. Kleiner - Histology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in adults and children
[19]. M. Arrese - Circulating microRNAs: emerging biomarkers of liver disease
[20]. P.S. Mitchell - Circulating microRNAs as stable blood-based markers for cancer detection
[21]. M. Weiland - Small RNAs have a large impact: circulating microRNAs as biomarkers for human diseases
[22]. C.J. Pirola - Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis
[23]. D. Povero - Novel molecular mechanisms in the development of non-alcoholic steatohepatitis
[24]. K. Sato - Exosomes in liver pathology
[25]. D. Moher - Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
[26]. J.P.T. Higgins - Cochrane handbook for systematic reviews of interventions
[27]. P.F. Whiting - QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies
[28]. O.L. Griffith - Meta-analysis and meta-review of thyroid cancer gene expression profiling studies identifies important diagnostic biomarkers
[29]. S.K. Chan - Meta-analysis of colorectal cancer gene expression profiling studies identifies consistently reported candidate biomarkers
[30]. J.P. Higgins - Measuring inconsistency in meta-analyses
[31]. J.B. Reitsma - Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews
[32]. J.J. Deeks - The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed
[33]. O. Cheung - Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression
[34]. R. Gallego-Durán - P0969: Role of epigenetic factors in non-alcoholic steatohepatitis development
[35]. A.L. Simao - Mirna-339-3p is increased in human and experimental models of Nafld and targeted by Tudca in insulin-resistant muscle cells
[36]. N. Elfimova - 1255 miR-101 in steatosis and steatohepatitis of non-alcoholic fatty liver disease (NAFLD)
[37]. P. Handa - MicroRNA profiling in plasma of patients uncovers unique microRNA signatures associated with liver inflammation, cirrhosis, nonalcoholic steatohepatitis and hepatocellular carcinoma that predict the progression of Primary Sclerosing Cholangitis
[38]. Z.M. Younossi - Hepatic signature expression of miR-199a-5p, miR-21-3p, miR-224-5p, and miR-150-5p detected by NextSeq technology are independently associated with fibrosis in non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD)
[39]. R. Srivastava - Role of integrated microrna-mRNA network in human hepatic fat accumulation and non-alcoholic fatty liver disease
[40]. S. Cermelli - Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease
[41]. X.L. Liu - Disease-specific miR-34a as diagnostic marker of non-alcoholic steatohepatitis in a Chinese population
[42]. Y. Tan - A pilot study of serum microRNAs panel as potential biomarkers for diagnosis of nonalcoholic fatty liver disease
[43]. H. Zhang - Serum levels of microRNAs can specifically predict liver injury of chronic hepatitis B
[44]. M. Celikbilek - Circulating microRNAs in patients with non-alcoholic fatty liver disease
[45]. C. Sun - MiR-21 regulates triglyceride and cholesterol metabolism in non-alcoholic fatty liver disease by targeting HMGCR
[46]. B. Zhuge - MiR-150 deficiency ameliorated hepatosteatosis and insulin resistance in nonalcoholic fatty liver disease via targeting CASP8 and FADD-like apoptosis regulator
[47]. Y. Guo - A micro-RNA expression signature for human NAFLD progression
[48]. R.E. Castro - MiR-34a/SIRT1/p53 is suppressed by ursodeoxycholic acid in the rat liver and activated by disease severity in human non-alcoholic fatty liver disease
[49]. D. Dattaroy - Micro-RNA 21 inhibition of SMAD7 enhances fibrogenesis via leptin-mediated NADPH oxidase in experimental and human nonalcoholic steatohepatitis
[50]. Y. Xu - A metabolic stress-inducible miR-34a-HNF4alpha pathway regulates lipid and lipoprotein metabolism
[51]. P.P. Becker - Performance of Serum microRNAs -122, -192 and -21 as Biomarkers in Patients with Non-Alcoholic Steatohepatitis
[52]. X. Loyer - Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARalpha expression
[53]. N.C. Salvoza - Association of circulating serum miR-34a and miR-122 with dyslipidemia among patients with non-alcoholic fatty liver disease
[54]. H. Yamada - Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver
[55]. G. Lendvai - Elevated miR-33a and miR-224 in steatotic chronic hepatitis C liver biopsies
[56]. T. Auguet - MiR33a/miR33b and miR122 as possible contributors to hepatic lipid metabolism in obese women with nonalcoholic fatty liver disease
[57]. P. Muangpaisarn - Serum microRNA-34a is potential biomarker for inflammation in nonalcoholic fatty liver disease
[58]. J. Latorre - Decreased lipid metabolism but increased FA biosynthesis are coupled with changes in liver microRNAs in obese subjects with NAFLD
[59]. D. Povero - Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-gamma
[60]. I.P. Pogribny - Difference in expression of hepatic microRNAs miR-29c, miR-34a, miR-155, and miR-200b is associated with strain-specific susceptibility to dietary nonalcoholic steatohepatitis in mice
[61]. T. Fu - Aberrantly elevated microRNA-34a in obesity attenuates hepatic responses to FGF19 by targeting a membrane coreceptor beta-Klotho
[62]. H. Xu - Liver-enriched transcription factors regulate microRNA-122 that targets CUTL1 during liver development
[63]. H. Miyaaki - Significance of serum and hepatic microRNA-122 levels in patients with non-alcoholic fatty liver disease
[64]. I. Iino - Effect of miR-122 and its target gene cationic amino acid transporter 1 on colorectal liver metastasis
[65]. A.P. Lewis - Regulation and biological function of the liver-specific miR-122
[66]. C. Esau - MiR-122 regulation of lipid metabolism revealed by in vivo antisense targeting
[67]. T. Babak - Probing microRNAs with microarrays: tissue specificity and functional inference
[68]. W. Filipowicz - The liver-specific microRNA miR-122: biology and therapeutic potential
[69]. M. Boeri - MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer
[70]. D. Povero - Circulating extracellular vesicles with specific proteome and liver microRNAs are potential biomarkers for liver injury in experimental fatty liver disease
[71]. Y. Fu - Circulating microRNA-101 as a potential biomarker for hepatitis B virus-related hepatocellular carcinoma
[72]. T. Katsumi - Discrepant expression of mir-139-5p between serum and liver in patients with primary biliary cirrhosis, and its possible cellular origin
[73]. A. Krek - Combinatorial microRNA target predictions
[74]. M. Zhu - Integrated analysis of hepatic mRNA and miRNA profiles identified molecular networks and potential biomarkers of NAFLD
[75]. F. Sato - Intra-platform repeatability and inter-platform comparability of microRNA microarray technology
[76]. F. Leti - High-throughput sequencing reveals altered expression of hepatic microRNAs in nonalcoholic fatty liver disease-related fibrosis
[77]. C.C. Pritchard - MicroRNA profiling: approaches and considerations
[78]. P. Mestdagh - A novel and universal method for microRNA RT-qPCR data normalization
[79]. J. Ampuero - Editorial: looking for patients at risk of cirrhosis in the general population-many needles in a haystack
[80]. M. Romero-Gomez - Detecting liver fat from viscoelasticity: how good is CAP in clinical practice? The need for universal cut-offs
[81]. L. Chang-Hai - Diagnostic accuracy of SCCA and SCCA-IgM for hepatocellular carcinoma: A meta-analysis
[82]. R. Ao - Altered microRNA-9 expression level is directly correlated with pathogenesis of nonalcoholic fatty liver disease by targeting Onecut2 and SIRT1
[83]. A. Zarrinpar - Serum microRNAs explain discordance of non-alcoholic fatty liver disease in monozygotic and dizygotic twins: a prospective study
[84]. Y. Zhang - Upregulation of miR-15b in NAFLD models and in the serum of patients with fatty liver disease
[85]. J. Vega-Badillo - Hepatic miR-33a/miR-144 and their target gene ABCA1 are associated with steatohepatitis in morbidly obese subjects
[86]. K. Okamoto - A series of microRNA in the chromosome 14q32.2 maternally imprinted region related to progression of non-alcoholic fatty liver disease in a mouse model
[87]. Y. Wang - MiR-130a-3p attenuates activation and induces apoptosis of hepatic stellate cells in nonalcoholic fibrosing steatohepatitis by directly targeting TGFBR1 and TGFBR2
[88]. M. Lopez-Riera - New microRNA biomarkers for drug-induced steatosis and their potential to predict the contribution of drugs to non-alcoholic fatty liver disease
[89]. G. Hanin - MiRNA-132 induces hepatic steatosis and hyperlipidaemia by synergistic multitarget suppression
[90]. M. Tran - Loss of miR-141/200c ameliorates hepatic steatosis and inflammation by reprogramming multiple signaling pathways in NASH
[91]. Q. Xu - MiRNA-103: molecular link between insulin resistance and nonalcoholic fatty liver disease
[92]. W. Yang - NFE2 induces miR-423-5p to promote gluconeogenesis and hyperglycemia by repressing the hepatic FAM3A-ATP-Akt pathway
[93]. L. Wang - Decreased MiR-155 level in the peripheral blood of non-alcoholic fatty liver disease patients may serve as a biomarker and may influence LXR activity
[94]. Y. Wang - MiR-181b regulates steatosis in nonalcoholic fatty liver disease via targeting SIRT1
[95]. S.C. Cazanave - A role for miR-296 in the regulation of lipoapoptosis by targeting PUMA
[96]. B. Li - Aberrant miR199a-5p/caveolin1/PPARalpha axis in hepatic steatosis
[97]. J. Guo - Reduced miR-200b and miR-200c expression contributes to abnormal hepatic lipid accumulation by stimulating JUN expression and activating the transcription of srebp1

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies