Abstract
Introduction
Non-alcoholic steatohepatitis (NASH) is a serious form of non-alcoholic fatty liver disease (NAFLD) that can progress to advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Differentiating between non-alcoholic fatty liver (NAFL) and NASH/advanced fibrosis is an important step in the management of NAFLD. Metabolic syndrome (MS) and its components are important risk factors for NAFLD, and NASH is thought to be the hepatic injury of MS. The prevalence of NASH among NAFLD patients with MS is thought to be high. In China, NAFLD is a relatively new public health concern, and the current prevalence of NASH among Chinese liver biopsy-proven NAFLD patients with and without MS is not known.
Methods
This multicenter, cross-sectional study will investigate the prevalence of NASH in approximately 480 Chinese NAFLD patients. Patients will be eligible for enrollment if they have biopsy-proven NAFLD and if their liver biopsies are available for rereading. For our analysis, patients will be stratified according to the presence/absence of MS, and the prevalence of NASH in the subgroups will be compared. Other possible tests that could indicate a risk of NASH, including transient elastography, ultrasonography, cytokeratin-18, liver function tests, and others, will be studied in an effort to derive a practical, noninvasive predictive model for NASH.
Discussion
Patients with NAFL who have MS may also have a very high risk of developing NASH. The present study will inform about the risk of NASH in Chinese liver biopsy-proven NAFLD patients with and without MS.
Trial Registration
This study registered at http://www.chictr.org.cn (registration number: ChiCTR-OOC-16007902).
Funding
Sanofi (China) Investment Co., Ltd.
Similar content being viewed by others
References
Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221–31.
Review Team, LaBrecque DR, Abbas Z, Anania F, Ferenci P, Khan AG, et al. World Gastroenterology Organisation global guidelines: nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Clin Gastroenterol. 2014;48:467–73.
Fan JG, Jia JD, Li YM, et al. Consensus report. Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010. J Dig Dis. 2011;12;38–44.
Fan J. Epidemiology of alcoholic and nonalcoholic fatty liver disease in China. J Gastroenterol Hepatol. 2013;28(Suppl 1):11–7.
Li ZZ, Xue P, Chen P, Chen L, Yan SP, Liu LY. Prevalence of nonalcoholic fatty liver disease in mainland of China: a meta-analysis of published studies. J Gastroenterol Hepatol. 2014;29:42–51.
Fung J, Lee CK, Chan M, Seto WK, Lai CL, Yuen MF, For the Hong Kong Liver Health Census Study Group. High prevalence of non-alcoholic fatty liver disease in the Chinese—results from the Hong Kong liver health census. Liver Int. 2015;35:542–9. doi:10.1111/liv.12619.
Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of noninvasive tests for liver disease severity. Ann Med. 2011;43:617–49.
Kim CH, Younossi ZM. Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome. Cleve Clin J Med. 2008;75:721–8.
Dam-Larsen S, Franzmann M, Andersen IB, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. 2004;53:750–5.
Dam-Larsen S, Becker U, Franzmann MB, Larsen K, Christoffersen P, Bendtsen F. Final results of a long-term, clinical follow-up in fatty liver patients. Scand J Gastroenterol. 2009;44:1236–43.
Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7:234–8.
Brunt EM, Tiniakos DG. Pathological features of NASH. Front Biosci. 2005;10:1475–84.
Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–9.
McCullough AJ. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin Liver Dis. 2004;8:521–33, viii.
Watanabe S, Hashimoto E, Ikejima K, et al. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hep Res. 2015;45:363–77.
Gill HK, Wu GY. Non-alcoholic fatty liver disease and the metabolic syndrome: effects of weight loss and a review of popular diets. Are low carbohydrate diets the answer? World J Gastroenterol. 2006;12:345–53.
Marchesini G, Brizi M, Morselli-Labate AM, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med. 1999;107:450–5.
Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–23.
Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35:373–9.
Marceau P, Biron S, Hould FS, et al. Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab. 1999;84:1513–7.
Ibrahim M, Singh C, Ganie MA, Alsayari K. NASH: the hepatic injury of metabolic syndrome: a brief update. Int J Health Sci. 2009;3:265–70.
Diehl AM, Clarke J, Brancati F. Insulin resistance syndrome and nonalcoholic fatty liver disease. Endocr Pract. 2003;9(Suppl 2):93–6.
Gupte P, Amarapurkar D, Agal S, et al. Non-alcoholic steatohepatitis in type 2 diabetes mellitus. J Gastroenterol Hepatol. 2004;19:854–8.
Pratt DS, Kaplan MM. Evaluation of abnormal liver enzyme results in asymptomatic patients. N Engl J Med. 2000;342:1266–71.
Bellentani S, Dalle Grave R, Suppini A, Marchesini G, Fatty Liver Italian Network. Behavior therapy for nonalcoholic fatty liver disease: the need for a multidisciplinary approach. Hepatology. 2008;47:746–54.
Wieckowska A, Zein NN, Yerian LM, Lopez AR, McCullough AJ, Feldstein AE. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology. 2006;44:27–33.
Feldstein AE, Wieckowska A, Lopez AR, Liu YC, Zein NN, McCullough AJ. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology. 2009;50:1072–8.
Chen J, Zhu Y, Zheng Q, Jiang J. Serum cytokeratin-18 in the diagnosis of non-alcoholic steatohepatitis: a meta-analysis. Hepatol Res. 2014;44:854–62.
Li YM, Fan JG, Wang BY, Lu LG, Shi JP, Niu JQ, et al. Chinese Association for the Study of Liver Disease. Guidelines for the diagnosis and management of alcoholic liver disease: update 2010: (published in Chinese on Chinese Journal of Hepatology. 2010;18:167–170). J Dig Dis. 2011;12:45–50.
Byrne CD, Targher G. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease: is universal screening appropriate? Diabetologia. 2016;59(6):1141–4.
Tapper EB, Sengupta N, Hunink MGM, Afdhal NH, Lai M. Cost-effective evaluation of nonalcoholic fatty liver disease with NAFLD fibrosis score and vibration controlled transient elastography. Am J Gastroenterol. 2015;110:1298–304.
Hamaguchi M, Kojima T, Itoh Y, et al. The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am J Gastroenterol. 2007;102:2708–15.
Liew P-L, Lee WJ, Lee YC, Wang HH, Wang W, Lin YC. Hepatic histopathology of morbid obesity: concurrence of other forms of chronic liver disease. Obesity Surg. 2006;16:1584–93.
Sattar N, Forrest E, Preiss D. Non-alcoholic fatty liver disease. BMJ. 2014;349:g4596.
Charlton M. Nonalcoholic fatty liver disease: a review of current understanding and future impact. Clin Gastroenterol Hepatol. 2004;2:1048–58.
van Hoek B, de Rooij BJ, Verspaget HW. Risk factors for infection after liver transplantation. Best Pract Res Clin Gastroenterol. 2012;26:61–72. doi:10.1016/j.bpg.2012.01.004.
Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology. 2010;52:79–104.
Ratziu V. Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol. 2013;10:676–85.
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–23.
Tolman KG, Dalpiaz AS. Treatment of non-alcoholic fatty liver disease. Ther Clin Risk Manag. 2007;3:1153–63.
Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898–906.
Seeff LB, Everson GT, Morgan TR, et al. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol. 2010;8:877–83.
Hernaez R, Lazo M, Bonekamp S, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology. 2011;54:1082–90.
Yoneda M, Yoneda M, Fujita K, et al. Transient elastography in patients with non-alcoholic fatty liver disease (NAFLD). Gut. 2007;56:1330–1.
Cusi K, Chang Z, Harrison S, et al. Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol. 2014;60:167–74.
Verma S, Jensen D, Hart J, Mohanty SR. Predictive value of ALT levels for non-alcoholic steatohepatitis (NASH) and advanced fibrosis in non-alcoholic fatty liver disease (NAFLD). Liver Int. 2013;33:1398–405.
Chen Z, Chen L, Dai H, Chen JH, Fang LZ. Relationship between alanine aminotransferase levels and metabolic syndrome in nonalcoholic fatty liver disease. J Zhejiang Uni Sci B. 2008;9:616–22.
Sheth SG, Flamm SL, Gordon FD, Chopra S. AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol. 1998;93:44–8.
Bril F, Ortiz-Lopez C, Lomonaco R, et al. Clinical value of liver ultrasound for the diagnosis of nonalcoholic fatty liver disease in overweight and obese patients. Liver Int. 2015;35:2139–46.
Mishra P, Younossi ZM. Abdominal ultrasound for diagnosis of nonalcoholic fatty liver disease (NAFLD). Am J Gastroenterol. 2007;102:2716–7.
Severson TJ, Besur S, Bonkovsky HL. Genetic factors that affect nonalcoholic fatty liver disease: a systematic clinical review. World J Gastroenterol. 2016;22:6742–56.
Bedossa P. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease. Hepatology. 2014;60(2):565–75.
Acknowledgments
Sponsorship and article processing charges for this study were funded by Sanofi (China) Investment Co., Ltd. We thank Lichuang Men from the Sanofi statistical team for his contributions to our study design. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Editorial support in the preparation of this publication was provided by Manette Williams (PhD) from Nucleus Shanghai and paid for by Sanofi. The authors, individually and collectively, are responsible for all content and editorial decisions and received no payment from Sanofi directly or indirectly (through a third party) related to the development of this publication.
Disclosures
Xu Zhengjie, Shi Junping, Jia Jidong, and Fan Jian-Gao declare that they have nothing to disclose. Yu Derong is an employee of Sanofi (China) Investment Co., Ltd Shanghai Branch. Zhu Lijuan is an employee of Sanofi (China) Investment Co., Ltd Shanghai Branch.
Compliance with Ethics Guidelines
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent will be waived in view of the retrospective nature of this study and that no sensitive patient data are involved. Amendments to the protocol will take effect only upon approval by the institutional review boards.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Enhanced content
To view enhanced content for this article go to http://www.medengine.com/Redeem/8AF6F060272CDA41.
Z.-J. Xu and J.-P. Shi are joint first authors.
Rights and permissions
About this article
Cite this article
Xu, ZJ., Shi, JP., Yu, DR. et al. Evaluating the Relationship Between Metabolic Syndrome and Liver Biopsy-Proven Non-Alcoholic Steatohepatitis in China: A Multicenter Cross-Sectional Study Design. Adv Ther 33, 2069–2081 (2016). https://doi.org/10.1007/s12325-016-0416-4
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12325-016-0416-4