Background/Aims: Non-alcoholic fatty liver disease is a spectrum of clinical conditions, including simple steatosis and non-alcoholic steatohepatitis (NASH). The aim of the study is to evaluate the tissue inhibitors of metalloproteinase-1 and 2 (TIMPs) as noninvasive predictors of NASH. Methods: Three groups were included in the study. Obese patients (n = 30) with normal liver enzymes were included in group I and obese patients (n = 30) with elevated liver enzymes with liver biopsy-based diagnosis of NASH were included in group II. Age-matched subjects (n = 30) formed the control as group III. The lipid profile, liver enzyme levels and levels of TIMPs were compared among all the patients and subjects. Results: Comparison of groups I and II showed significantly elevated levels of TIMP-1 and TIMP-2 in group II as compared to group I (p < 0.05). Similarly, comparison between groups II and III showed significantly increased levels of TIMP-1 and TIMP-2 in group II as compared to group III (p < 0.05). TIMP-1 (sensitivity 96.7%, specificity 100%) and TIMP-2 (sensitivity 93.3%, specificity 100%) showed high accuracy in NASH diagnosis. Conclusion: TIMP-1 and TIMP-2 may be considered noninvasive markers for the diagnosis of NASH.

1.
Kim CH, Younossi ZM: Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome. Cleve Clin J Med 2008;75:721-728.
2.
Machado MV, Cortez-Pinto H: Non-alcoholic fatty liver disease: what the clinician needs to know. World J Gastroenterol 2014;20:12956-12980.
3.
Dietrich P, Hellerbrand C: Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. Best Pract Res Clin Gastroenterol 2014;28:637-653.
4.
Grandison GA, Angulo P: Can NASH be diagnosed, graded, and staged noninvasively? Clin Liver Dis 2012;16:567-585.
5.
Petta S, Muratore C, Craxì A: Non-alcoholic fatty liver disease pathogenesis: the present and the future. Dig Liver Dis 2009;41:615-625.
6.
Fitzpatrick E, Dhawan A: Noninvasive biomarkers in non-alcoholic fatty liver disease: current status and a glimpse of the future. World J Gastroenterol 2014;20:10851-10863.
7.
Musso G, Cassader M, Olivetti C, Rosina F, Carbone G, Gambino R: Association of obstructive sleep apnoea with the presence and severity of non-alcoholic fatty liver disease. A systematic review and meta-analysis. Obes Rev 2013;14:417-431.
8.
Clark JM: The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol 2006;40(suppl 1):S5-S10.
9.
Miller MH, Walsh SV, Atrih A, Huang JT, Ferguson MA, Dillon JF: Serum proteome of nonalcoholic fatty liver disease: a multimodal approach to discovery of biomarkers of nonalcoholic steatohepatitis. J Gastroenterol Hepatol 2014;29:1839-1847.
10.
Musso G, Gambino R, Cassader M, Pagano G: Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011;43:617-649.
11.
Gori M, Arciello M, Balsano C: MicroRNAs in nonalcoholic fatty liver disease: novel biomarkers and prognostic tools during the transition from steatosis to hepatocarcinoma. Biomed Res Int 2014;2014:741465.
12.
Tapper EB, Krajewski K, Lai M, Challies T, Kane R, Afdhal N, et al: Simple non-invasive biomarkers of advanced fibrosis in the evaluation of non-alcoholic fatty liver disease. Gastroenterol Rep (Oxf) 2014;2:276-280.
13.
Kruger FC, Daniels CR, Kidd M, Swart G, Brundyn K, van Rensburg C, et al: APRI: a simple bedside marker for advanced fibrosis that can avoid liver biopsy in patients with NAFLD/NASH. S Afr Med J 2011;101:477-480.
14.
Sumida Y, Yoneda M, Hyogo H, Itoh Y, Ono M, Fujii H, et al: Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population. BMC Gastroenterol 2012;12:2.
15.
Walsh KM, Timms P, Campbell S, MacSween RN, Morris AJ: Plasma levels of matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinases -1 and -2 (TIMP-1 and TIMP-2) as noninvasive markers of liver disease in chronic hepatitis C: comparison using ROC analysis. Dig Dis Sci 1999;44:624-630.
16.
El-Gindy I, El Rahman AT, El-Alim MA, Zaki SS: Diagnostic potential of serum matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as non-invasive markers of hepatic fibrosis in patients with HCV related chronic liver disease. Egypt J Immunol 2003;10:27-35.
17.
Nagase H, Visse R, Murphy G: Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006;69:562-573.
18.
Okazaki I, Noro T, Tsutsui N, Yamanouchi E, Kuroda H, Nakano M, et al: Fibrogenesis and carcinogenesis in nonalcoholic steatohepatitis (NASH): involvement of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs). Cancers (Basel) 2014;6:1220-1255.
19.
Choi SH, Lee HJ, Jin YB, Jang J, Kang GY, Lee M, et al: MMP9 processing of HSPB1 regulates tumor progression. PLoS One 2014;9:e85509.
20.
Gaide Chevronnay HP, Selvais C, Emonard H, Galant C, Marbaix E, Henriet P: Regulation of matrix metalloproteinases activity studied in human endometrium as a paradigm of cyclic tissue breakdown and regeneration. Biochim Biophys Acta 2012;1824:146-156.
21.
Boeker KH, Haberkorn CI, Michels D, Flemming P, Manns MP, Lichtinghagen R: Diagnostic potential of circulating TIMP-1 and MMP-2 as markers of liver fibrosis in patients with chronic hepatitis C. Clin Chim Acta 2002;316:71-81.
22.
Leroy V, Monier F, Bottari S, Trocme C, Sturm N, Hilleret MN, et al: Circulating matrix metalloproteinases 1, 2, 9 and their inhibitors TIMP-1 and TIMP-2 as serum markers of liver fibrosis in patients with chronic hepatitis C: comparison with PIIINP and hyaluronic acid. Am J Gastroenterol 2004;99:271-279.
23.
Clark JM, Brancati FL, Diehl AM: Nonalcoholic fatty liver disease. Gastroenterology 2002;122:1649-1657.
24.
Bellentani S, Scaglioni F, Marino M, Bedogni G: Epidemiology of non-alcoholic fatty liver disease. Dig Dis 2010;28:155-161.
25.
Fan JG, Saibara T, Chitturi S, Kim BI, Sung JJ, Chutaputti A; Asia-Pacific Working Party for NAFLD: What are the risk factors and settings for non-alcoholic fatty liver disease in Asia-Pacific? J Gastroenterol Hepatol 2007;22:794-800.
26.
Cusi K: Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 2012;142:711-725.e6.
27.
Vernon G, Baranova A, Younossi ZM: Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011;34:274-285.
28.
Sattar N, Forrest E, Preiss D: Non-alcoholic fatty liver disease. BMJ 2014;349:g4596.
29.
Kasahara A, Hayashi N, Mochizuki K, Oshita M, Katayama K, Kato M, et al: Circulating matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as serum markers of fibrosis in patients with chronic hepatitis C. Relationship to interferon response. J Hepatol 1997;26:574-583.
30.
Li YW, Zhu CL, Gao RT, Pan JH: [Determinationand clinical significance of tissue inhibitorsof metalloproteinase-1 and -2 in serum of children with nonalcoholic fatty liver disease]. Zhongguo Dang Dai Er Ke Za Zhi 2010;12:455-458.
31.
Belo VA, Souza-Costa DC, Lana CM, Caputo FL, Marcaccini AM, Gerlach RF, et al: Assessment of matrix metalloproteinase (MMP)-2, MMP-8, MMP-9, and their inhibitors, the tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in obese children and adolescents. Clin Biochem 2009;42:984-990.
32.
Miele L, Forgione A, La Torre G, Vero V, Cefalo C, Racco S, et al: Serum levels of hyaluronic acid and tissue metalloproteinase inhibitor-1 combined with age predict the presence of nonalcoholic steatohepatitis in a pilot cohort of subjects with nonalcoholic fatty liver disease. Transl Res 2009;154:194-201.
33.
Younossi ZM, Page S, Rafiq N, Birerdinc A, Stepanova M, Hossain N, et al: A biomarker panel for non-alcoholic steatohepatitis (NASH) and NASH-related fibrosis. Obes Surg 2011;21:431-439.
34.
Yoneda M, Imajo K, Eguchi Y, Fujii H, Sumida Y, Hyogo H, et al: Noninvasive scoring systems in patients with nonalcoholic fatty liver disease with normal alanine aminotransferase levels. J Gastroenterol 2013;48:1051-1060.
35.
Pérez-Gutiérrez OZ, Hernández-Rocha C, Candia-Balboa RA, Arrese MA, Benítez C, Brizuela-Alcántara DC, et al: Validation study of systems for noninvasive diagnosis of fibrosis in nonalcoholic fatty liver disease in Latin population. Ann Hepatol 2013;12:416-424.
36.
McPherson S, Stewart SF, Henderson E, Burt AD, Day CP: Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut 2010;59:1265-1269.
37.
Xun YH, Fan JG, Zang GQ, Liu H, Jiang YM, Xiang J, et al: Suboptimal performance of simple noninvasive tests for advanced fibrosis in Chinese patients with nonalcoholic fatty liver disease. J Dig Dis 2012;13:588-595.
38.
McPherson S, Anstee QM, Henderson E, Day CP, Burt AD: Are simple noninvasive scoring systems for fibrosis reliable in patients with NAFLD and normal ALT levels? Eur J Gastroenterol Hepatol 2013;25:652-658.
39.
Maximos M, Bril F, Portillo Sanchez P, Lomonaco R, Orsak B, Biernacki D, et al: The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease. Hepatology 2015;61:153-160.
40.
Portillo-Sanchez P, Bril F, Maximos M, Lomonaco R, Biernacki D, Orsak B, et al: High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab 2015;100:2231-2238.
41.
Baršić N, Lerotić I, Smirčić-Duvnjak L, Tomašić V, Duvnjak M: Overview and developments in noninvasive diagnosis of nonalcoholic fatty liver disease. World J Gastroenterol 2012;18:3945-3954.
You do not currently have access to this content.