Subscribe to RSS
DOI: 10.1055/s-0035-1547233
A Nonclassical Monocyte Phenotype in Peripheral Blood is Associated with Nonalcoholic Fatty Liver Disease: A Report from an EMIL Subcohort
Publication History
received 24 September 2014
accepted 04 February 2015
Publication Date:
08 April 2015 (online)
![](https://www.thieme-connect.de/media/hmr/201601/lookinside/thumbnails/2014-09-0287_10-1055-s-0035-1547233-1.jpg)
Abstract
Nonalcoholic fatty liver disease (NAFLD) as the prototypic hepatic manifestation of metabolic syndrome is an independent risk factor for cardiovascular disease. Our study was designed to investigate the association between NAFLD and alteration in monocyte subsets as hallmark of cardiovascular disease. Seventy-three “Echinococcus Multilocularis and other medical diseases in Leutkirch” (EMIL) population-based cohort participants (mean observation period 11 years) were selected to study their monocyte phenotype by multiparameter flow cytometry. NAFLD was diagnosed using standard ultrasound based criteria excluding other causes of fatty liver disease. Three monocyte subsets (“classical” CD14++ CD16–, “intermediate” CD14++ CD16+, “nonclassical” CD14+CD16++ monocytes), and surface markers (CD36 and CD9) were determined. Classical risk markers covering inflammatory and dysmetabolic characters were also determined. Forty-three out of 73 subjects revealed a stable clinical phenotype, namely 17 subjects revealed NAFLD, whereas 26 subjects showed no fatty liver disease. Compared to the nonfatty liver group, the nonclassical monocyte fraction (p=0.049), total monocyte fraction and count were increased in NAFLD probands (p=0.028, and 0.035, respectively), while classical monocyte fraction (p=0.034) was decreased. Total monocyte fraction, nonclassical monocyte fraction, and waist circumstance were independent risk factors for NAFLD. The nonclassical monocyte fraction and classical monocyte fraction were significantly correlated with waist-to-hip ratio. This pilot long-term follow-up study suggests that nonclassical monocyte fraction and total monocyte fraction might have potential as a prognostic and modifiable biomarker in NFALD patients. This novel marker set might therefore be of interest to monitor druggable inflammatory pathways in individuals with hepatic manifestation of the metabolic syndrome.
* These authors contributed equally to this work.
Supporting Information
- for this article is available online at http://www.thieme-connect.de/products
- Supporting Information
-
References
- 1 Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 2012; 142: 711-725
- 2 Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 1221-1231
- 3 Lerchbaum E, Pilz S, Grammer TB, Boehm BO, Stojakovic T, Obermayer-Pietsch B, Maerz W. The fatty liver index is associated with increased mortality in subjects referred to coronary angiography. Nutr Metab Cardiovasc Dis 2013; 23: 1231-1238
- 4 Kotronen A, Yki-Jaervinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol 2008; 28: 27-38
- 5 Vanni E, Bugianesi E, Kotronen A, De Minicis S, Yki-Jaervinen H, Svegliati-Baroni G. From the metabolic syndrome to NAFLD or vice versa?. Dig Liver Dis 2010; 42: 320-330
- 6 Hazlehurst JM, Tomlinson JW. Non-alcoholic fatty liver disease in common endocrine disorders. Eur J Endocrinol 2013; 169: R27-R37
- 7 Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med 2014; 371: 1131-1141
- 8 Biswas SK, Mantovani A. Orchestration of metabolism by macrophages. Cell Metab 2012; 15: 432-437
- 9 ÓHartaigh B, Bosch JA, Thomas GN, Lord JM, Pilz S, Loerbroks A, Kleber ME, Grammer TB, Fischer JE, Boehm BO, Maerz W. Which leukocyte subsets predict cardiovascular mortality? From the LUdwigshafen RIsk and Cardiovascular Health (LURIC) Study. Atherosclerosis 2012; 224: 161-169
- 10 Kim HL, Chung GE, Park IY, Choi JM, Hwang SM, Lee JH, Kim D. Elevated peripheral blood monocyte fraction in nonalcoholic fatty liver disease. Tohoku J Exp Med 2011; 223: 227-233
- 11 Haenle MM, Brockmann SO, Kron M, Bertling U, Mason RA, Steinbach G, Boehm BO, Koenig W, Kern P, Piechotowski I, Kratzer W. Overweight, physical activity, tobacco and alcohol consumption in a cross-sectional random sample of German adults. BMC Public Health 2006; 6: 233
- 12 Physical status: the use and interpretation of anthropometry . Report of a WHO Expert Committee. World Health Organ Tech Rep Ser 1995; 854: 1-452
- 13 Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, Tiribelli C. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol 2006; 6: 33
- 14 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419
- 15 Heimbeck I, Hofer TP, Eder C, Wright AK, Frankenberger M, Marei A, Boghdadi G, Scherberich J, Ziegler-Heitbrock L. Standardized single-platform assay for human monocyte subpopulations: Lower CD14+CD16++ monocytes in females. Cytometry A 2010; 77: 823-830
- 16 Hamaguchi M, Kojima T, Itoh Y, Harano Y, Fujii K, Nakajima T, Kato T, Takeda N, Okuda J, Ida K, Kawahito Y, Yoshikawa T, Okanoue T. The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am J Gastroenterol 2007; 102: 2708-2715
- 17 Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013; 10: 330-344
- 18 Smith K. Liver disease: Kupffer cells regulate the progression of ALD and NAFLD. Nat Rev Gastroenterol Hepatol 2013; 10: 503
- 19 Wan J, Benkdane M, Teixeira-Clerc F, Bonnafous S, Louvet A, Lafdil F, Pecker F, Tran A, Gual P, Mallat A, Lotersztajn S, Pavoine C. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology 2014; 59: 130-142
- 20 Sakaguchi S, Takahashi S, Sasaki T, Kumagai T, Nagata K. Progression of alcoholic and non-alcoholic steatohepatitis: common metabolic aspects of innate immune system and oxidative stress. Drug Metab Pharmacokinet 2011; 26: 30-46
- 21 Mikita J, Dubourdieu-Cassagno N, Deloire MS, Vekris A, Biran M, Raffard G, Brochet B, Canron MH, Franconi JM, Boiziau C, Petry KG. Altered M1/M2 activation patterns of monocytes in severe relapsing experimental rat model of multiple sclerosis. Amelioration of clinical status by M2 activated monocyte administration. Mult Scler 2011; 17: 2-15
- 22 Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol 2013; 13: 709-721
- 23 Grip O, Bredberg A, Lindgren S, Henriksson G. Increased subpopulations of CD16(+) and CD56(+) blood monocytes in patients with active Crohn’s disease. Inflamm Bowel Dis 2007; 13: 566-572
- 24 Horelt A, Belge KU, Steppich B, Prinz J, Ziegler-Heitbrock L. The CD14+CD16+ monocytes in erysipelas are expanded and show reduced cytokine production. Eur J Immunol 2002; 32: 1319-1327
- 25 Kawanaka N, Yamamura M, Aita T, Morita Y, Okamoto A, Kawashima M, Iwahashi M, Ueno A, Ohmoto Y, Makino H. CD14+, CD16+ blood monocytes and joint inflammation in rheumatoid arthritis. Arthritis Rheum 2002; 46: 2578-2586
- 26 Soares G, Barral A, Costa JM, Barral-Netto M, Van Weyenbergh J. CD16+ monocytes in human cutaneous leishmaniasis: increased ex vivo levels and correlation with clinical data. J Leukoc Biol 2006; 79: 36-39
- 27 Wildgruber M, Lee H, Chudnovskiy A, Yoon TJ, Etzrodt M, Pittet MJ, Nahrendorf M, Croce K, Libby P, Weissleder R, Swirski FK. Monocyte subset dynamics in human atherosclerosis can be profiled with magnetic nano-sensors. PLoS One 2009; 4: e5663
- 28 Kashiwagi M, Imanishi T, Tsujioka H, Ikejima H, Kuroi A, Ozaki Y, Ishibashi K, Komukai K, Tanimoto T, Ino Y, Kitabata H, Hirata K, Akasaka T. Association of monocyte subsets with vulnerability characteristics of coronary plaques as assessed by 64-slice multidetector computed tomography in patients with stable angina pectoris. Atherosclerosis 2010; 212: 171-176
- 29 Rogacev KS, Seiler S, Zawada AM, Reichart B, Herath E, Roth D, Ulrich C, Fliser D, Heine GH. CD14++ CD16+ monocytes and cardiovascular outcome in patients with chronic kidney disease. Eur Heart J 2011; 32: 84-92
- 30 Heine GH, Ulrich C, Seibert E, Seiler S, Marell J, Reichart B, Krause M, Schlitt A, Koehler H, Girndt M. CD14(++ )CD16+ monocytes but not total monocyte numbers predict cardiovascular events in dialysis patients. Kidney Int 2008; 73: 622-629
- 31 Yang J, Zhang L, Yu C, Yang XF, Wang H. Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases. Biomark Res 2014; 2: 1
- 32 Rogacev KS, Ulrich C, Bloemer L, Hornof F, Oster K, Ziegelin M, Cremers B, Grenner Y, Geisel J, Schlitt A, Koehler H, Fliser D, Girndt M, Heine GH. Monocyte heterogeneity in obesity and subclinical atherosclerosis. Eur Heart J 2010; 31: 369-376
- 33 Armutcu F, Akyol S, Ucar F, Erdogan S, Akyol O. Markers in nonalcoholic steatohepatitis. Adv Clin Chem 2013; 61: 67-125