2015, Number 6
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Ann Hepatol 2015; 14 (6)
Correlation between serum cytokeratin-18 and the progression or regression of non-alcoholic fatty liver disease
Kawanaka M, Nishino K, Nakamura J, Urata N, Oka T, Goto D, Suehiro M, Kawamoto H, Yamada G
Language: English
References: 23
Page: 837-844
PDF size: 135.01 Kb.
ABSTRACT
Background. Diagnosis of non-alcoholic fatty liver disease (NAFLD) is limited by the need for liver biopsies.
Serum cytokeratin 18 (CK-18) levels have been investigated as potential biomarkers for the presence of NAFLD
and non-alcoholic steatohepatitis (NASH). Herein, we assessed the correlation between CK-18 levels
and NAFLD progression.
Material and methods. Serum CK-18 levels were estimated using the M30 antibody
enzyme-linked immunosorbent assay in 147 patients diagnosed with NAFLD. In 72 patients, disease progression
was evaluated by repeated liver biopsy, which was conducted after 4.3 ± 2.6 years. The relationship
between the CK-18 levels and liver histological findings was assessed.
Results. The CK-18 levels were useful
for identifying NAFLD patients with NAFLD activity scores (NAS) ≥ 5 (NAS ≥ 5
vs. ≤ 4: 675.1 U/L
vs. 348.7 U/L;
p ‹ 0.0001). A cut-off value of 375 U/L was calculated using the receiver operating characteristic curve
approach, with a specificity and sensitivity of 81.5 and 65%, respectively, for the diagnosis of NASH. Among
the 72 patients who underwent repeated liver biopsy, 11 patients with a progressed NAS also had significantly
increased serum CK-18 levels (p ‹ 0.01); in 30 patients with an improved NAS, there was a significant
improvement in the mean CK-18 levels (p ‹ 0.0001). The 31 patients with static NAS had static CK-18 levels.
Conclusions. In conclusion, serum CK-18 levels can predict NAS ≥ 5 in NAFLD patients. In NAFLD patients,
serum CK-18 levels reflect NAS values and correlate with histological changes, and they appear to be useful
indicators of progression and improvement.
REFERENCES
Wieckowska A, Feldstein AE. Diagnosis of nonalcoholic fatty liver disease: invasive versus noninvasive. Semin Liver Dis 2008; 28: 386-95.
Egichi Y, Hyogo H, Ono M, Mizuta T, Ono N, Fujimoto K, Chayama K, et al. Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2009 to 2010 in Japan: a multicenter large retrospective study. J Gastroenterol 2012; 47: 586-95.
Ekstedt M, Franzén LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, Kechagias S. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44: 865-73.
Rafiq N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T, Younossi ZM. Long-term follow up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol 2009; 44: 234-48.
Kawanaka M, Nishino K, Oka T, Urata N, Nakamura J, Goto D, Suehiro M, et al. A prospective study showing poor prognosis in Japanese NASH patients with fibrosis stage F3-4. Kawasaki Medical Journal 2012; 38: 119-27.
Shen J, Chan HL, Wong GL, Choi PC, Chan AW, Chan HY, Chim AM, et al. Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarker. J Hepatol 2012; 56: 1363-70.
Tamimi TI, Elgouhari HM, Alkhouri N, Yerian LM, Berk MP, Lopez R, Schauer PR, et al. An apoptosis panel for nonalcoholic steatohepatitis diagnosis. J Hepatol 2011; 54: 1224-9.
Shen J, Chan HL, Wong GL, Chan AW, Choi PC, Chan HY, Chim AM, et al. Assessment of non-alcoholic fatty liver disease using serum total cell death and apoptosis markers. Aliment Pharmacol Ther 2012; 36: 1057-66.
Yilmaz Y, Dolar E, Ulukaya E, Akgoz S, Keskin M, Kiyici M, Aker S, et al. Soluble forms of extracellular cytokeratin 18 may differentiate simple steatosis from nonalcoholic steatohepatitis. World J Gastroenterol 2007; 13: 837-44.
Feldstein AE, Alkhouri N, De Vito R, Alisi A, Lopez R, Nobili V. Serum cytokeratin-18 fragment levels are useful biomarkers for nonalcoholic steatohepatitis in children. Am J Gastroenterol 2013; 108: 1526-31.
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.
Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, 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.
Leers MP, Kölgen W, Björklund V, Bergman T, Tribbick G, Persson B, Björklund P, et al. Immunocytochemical detection and mapping of a cytokeratin 18 neo-epitope exposed during early apoptosis. J Pathol 1999; 187: 567-72.
Kliner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41: 1313-21.
Loomba R, Wesley R, Pucino F, Liang TJ, Kleiner DE, Lavine JE. Placebo in nonalcoholic steatohepatitis: insight into natural history and implications for future clinical trials. Clin Gastroenterol Hepatol 2008; 6: 1243-8.
Dowman JK, Tomlinson JW, Newsome PN. Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and nonalcoholic steatohepatitis. Aliment Pharmacol Ther 2011; 33: 525-40.
Kawanaka M, Nishino K, Nakamura J, Oka T, Urata N, Goto D, Suehiro M, et al. Usefulness of monitoring serum cytokeratin- 18 levels for evaluating long-term prognosis is patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease [Abstract]. Hepatology 2013; 474A.
Sumida Y, Yoneda M, Hyogo H, Yamaguchi K, Ono M, Fujii H, Eguchi Y, et al. A simple clinical scoring system using ferritin, fasting insulin, and type IV collagen 7S for predicting steatohepatitis in nonalcoholic fatty liver disease. J Gastroenterol 2011; 46: 257-68.
Omary MB, Ku NO, Strnad P, Hanada S. Toward unraveling the complexity of simple epithelial keratins in human disease. J Clin Invest 2009; 119: 1794-805.
Feldstein AE, Wieckowska A, Lopez AR, Liu YC, Zein NN, McCullough AJ. Cytokeratin-18 fragment levels as noninvasive biomarker for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 2009; 50: 1072-8.
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: 617-49.
Tsutsumi M, Tanaka N, Kawakubo M, Sheena Y, Horiuchi A, Komatsu M, Nagaya T, et al. Serum fragmented cytokeratin 18 levels reflect the histologic activity score of nonalcoholic fatty liver disease more accurately than serum alanine aminotransferase levels. J Clin Gastroenterol 2010; 44: 440-7.
Wong VW, Wong GL, Choi PC, Chan AW, Li MK, Chan HY, Chim AM, et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsy at 3 years. Gut 2010; 59: 969-74.