Advertisement

Journal of Gastroenterology

, Volume 42, Issue 7, pp 573–582 | Cite as

High-sensitivity C-reactive protein is an independent clinical feature of nonalcoholic steatohepatitis (NASH) and also of the severity of fibrosis in NASH

  • Masato Yoneda
  • Hironori Mawatari
  • Koji Fujita
  • Hiroshi Iida
  • Kyoko Yonemitsu
  • Shingo Kato
  • Hirokazu Takahashi
  • Hiroyuki Kirikoshi
  • Masahiko Inamori
  • Yuichi Nozaki
  • Yasunobu Abe
  • Kensuke Kubota
  • Satoru Saito
  • Tomoyuki Iwasaki
  • Yasuo Terauchi
  • Shinji Togo
  • Shiro Maeyama
  • Atsushi Nakajima
Liver, Pancreas, and Biliary Tract

Abstract

Background

The changes in nonalcoholic fatty liver disease (NAFLD) range over a wide spectrum, extending from steatosis to steatohepatitis (NASH). However, it has remained difficult to differentiate between NASH and nonprogressive NAFLD by clinical examination. We investigated the interrelationships between serum high-sensitivity C-reactive protein (hs-CRP) and the pathogenesis and progression of NASH.

Methods

Hs-CRP was measured in 100 patients with histologically verified NAFLD (29 with steatosis and 71 with NASH), and a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was performed to measure the intrahepatic mRNA expressions of CRP and interleukin (IL)-6.

Results

The results of a multiple regression analysis revealed that in comparison with cases of steatosis, hs-CRP was significantly elevated (P = 0.0048) in cases of NASH. Furthermore, among patients with NASH, hs-CRP was significantly elevated in those with advanced fibrosis compared with that in those with mild fibrosis (P = 0.0384), even after adjustment for age, sex, presence of diabetes, body mass index, visceral fat area, subcutaneous fat area, homeostasis model assessment for insulin resistance, high-density lipoprotein cholesterol, triglyceride, and low-density lipoprotein cholesterol. The results of the RT-PCR analysis showed that intrahepatic mRNA expression of CRP, but not IL-6, was increased in patients with NASH compared with those with steatosis (P = 0.0228).

Conclusions

This is the first report to demonstrate consistent and profound elevation of hs-CRP in cases of NASH compared with in cases of simple nonprogressive steatosis. Our results suggest that hs-CRP may be a clinical feature that not only distinguishes NASH from simple nonprogressive steatosis but also indicates the severity of hepatic fibrosis in cases of NASH.

Key words

NASH NAFLD CRP fibrosis 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Angulo, P 2002Nonalcoholic fatty liver diseaseN Engl J Med18122131CrossRefGoogle Scholar
  2. 2.
    Farrell, GC 2003Non-alcoholic steatohepatitis: what is it, and why is it important in the Asia-Pacific region?J Gastroenterol Hepatol1812438PubMedCrossRefGoogle Scholar
  3. 3.
    Diehl, AM, Goodman, Z, Ishak, KG 1988Alcohollike liver disease in nonalcoholics. A clinical and histologic comparison with alcohol-induced liver injuryGastroenterology95105662PubMedGoogle Scholar
  4. 4.
    Ludwig, J, Viggiano, TR, McGill, DB, Oh, BJ 1980Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed diseaseMayo Clin Proc554348PubMedGoogle Scholar
  5. 5.
    Hui, JM, Hodge, A, Farrell, GC, Kench, JG, Kriketos, A, George, J 2004Beyond insulin resistance in NASH: TNF-alpha or adiponectin?Hepatology404654PubMedCrossRefGoogle Scholar
  6. 6.
    Chitturi, S, Abeygunasakera, S, Farrell, GC, Holmes-Walker, J, Hui, JM, Fung, C,  et al. 2002NASH and insulin hypersecretion and specific association with the insulin resistance syndromeHepatology353739PubMedCrossRefGoogle Scholar
  7. 7.
    Ridker, PM, Hennekens, CH, Buring, JE, Rifai, N 2000C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in womenN Engl J Med34283643PubMedCrossRefGoogle Scholar
  8. 8.
    Koenig, W, Sund, M, Frohlich, M, Fischer, HG, Lowel, H, Doring, A,  et al. 1999C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984–92Circulation9923742PubMedGoogle Scholar
  9. 9.
    Danesh, J, Whincup, P, Walker, M, Lennon, L, Thomson, A, Appleby, P,  et al. 2000Low grade inflammation and coronary heart disease: prospective study and updated meta-analysesBMJ321199204PubMedCrossRefGoogle Scholar
  10. 10.
    Ridker, PM, Rifai, N, Rose, L, Buring, JE, Cook, NR 2002Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular eventsN Engl J Med347155765PubMedCrossRefGoogle Scholar
  11. 11.
    Yudkin, JS, Stehouwer, CD, Emeis, JJ, Coppack, SW 1999C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?Arterioscler Thromb Vasc Biol1997278PubMedGoogle Scholar
  12. 12.
    Hak, AE, Stehouwer, CD, Bots, ML, Polderman, KH, Schalkwijk, CG, Westendorp, IC,  et al. 1999Associations of C-reactive protein with measures of obesity, insulin resistance, and subclinical atherosclerosis in healthy, middle-aged womenArterioscler Thromb Vasc Biol19198691PubMedGoogle Scholar
  13. 13.
    Yamada, S, Gotoh, T, Nakashima, Y, Kayaba, K, Ishikawa, S, Nago, N,  et al. 2001Distribution of serum C-reactive protein and its association with atherosclerotic risk factors in a Japanese population. Jichi Med School Cohort StudyAm J Epidemiol153118390PubMedCrossRefGoogle Scholar
  14. 14.
    Mulhall, BP, Ong, JP, Younossi, ZM 2002Non-alcoholic fatty liver disease: an overviewJ Gastroenterol Hepatol17113643PubMedCrossRefGoogle Scholar
  15. 15.
    Angulo, P, Lindor, KD 2002Non-alcoholic fatty liver diseaseJ Gastroenterol Hepatol17S18690PubMedCrossRefGoogle Scholar
  16. 16.
    Park, SH, Kim, BI, Yun, JW, Park, DI, Cho, YK, Sung, IK,  et al. 2004Insulin resistance and C-reactive protein as independent risk factors for non-alcoholic fatty liver disease in non-obese Asian menJ Gastroenterol Hepatol196948PubMedCrossRefGoogle Scholar
  17. 17.
    Kurioka, S, Murakami, Y, Nishiki, M, Sohmiya, M, Koshimura, K, Kato, Y 2002Relationship between visceral fat accumulation and anti-lipolytic action of insulin in patients with type 2 diabetes mellitusEndocr J4945964PubMedCrossRefGoogle Scholar
  18. 18.
    Hanley, AJ, Williams, K, Festa, A, Wagenknecht, LE, D'Agostino, RB,Jr, Haffner, SM 2005Liver markers and development of the metabolic syndrome: the insulin resistance atherosclerosis studyDiabetes5431407PubMedCrossRefGoogle Scholar
  19. 19.
    Iwasaki, T, Nakajima, A, Yoneda, M, Terauchi, Y 2006Relationship between the serum concentrations of C-reactive protein and parameters of adiposity and insulin resistance in patients with type 2 diabetes mellitusEndocr J5334556PubMedCrossRefGoogle Scholar
  20. 20.
    Alberti, KG, Zimmet, PZ 1998Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultationDiabet Med1553953PubMedCrossRefGoogle Scholar
  21. 21.
    Ridker, PM, Cushman, M, Stampfer, MJ, Tracy, RP, Hennekens, CH 1997Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy menN Engl J Med3369739PubMedCrossRefGoogle Scholar
  22. 22.
    Ridker, PM, Rifai, N, Clearfield, M, Downs, JR, Weis, SE, Miles, JS,  et al. 2001Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary eventsN Engl J Med344195965PubMedCrossRefGoogle Scholar
  23. 23.
    Ridker, PM, Rifai, N, Pfeffer, MA, Sacks, FM, Moye, LA, Goldman, S,  et al. 1998Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) InvestigatorsCirculation9883944PubMedGoogle Scholar
  24. 24.
    Promrat, K, Lutchman, G, Uwaifo, GI, Freedman, RJ, Soza, A, Heller, T,  et al. 2004A pilot study of pioglitazone treatment for nonalcoholic steatohepatitisHepatology3918896PubMedCrossRefGoogle Scholar
  25. 25.
    Bugianesi, E, Gentilcore, E, Manini, R, Natals, S, Vanni, E, Villanova, N,  et al. 2005A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver diseaseAm J Gastroenterol100108290PubMedCrossRefGoogle Scholar
  26. 26.
    Matthews, DR, Hoskër, JP, Rudenski, AS, Naylor, BA, Treacher, DF, Tumer, RC 1985Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in manDiabetologia284129PubMedCrossRefGoogle Scholar
  27. 27.
    Ono, T, Shiga, N, Taneda, Y 1999The fasting-plasma glucose range in which insulin resistance measured by homeostasis model assessment correlates with euglycemic clampingJ Jpn Diabetes Soc42100511Google Scholar
  28. 28.
    Katsuki, A, Sumida, Y, Urakawa, H, Gabazza, EC, Murashima, S, Morioka, K,  et al. 2002Neither homeostasis model assessment nor quantitative insulin sensitivity check index can predict insulin resistance in elderly patients with poorly controlled type 2 diabetes mellitusJ Clin Endocrinol Metab8753325PubMedCrossRefGoogle Scholar
  29. 29.
    Yoshizumi, T, Nakamura, T, Yamane, M, Islam, AH, Menju, M, Yamasaki, K,  et al. 1999Abdominal fat: standardized technique for measurement at CTRadiology2112836PubMedGoogle Scholar
  30. 30.
    Teli, MR, James, OF, Burt, AD, Bennett, MK, Day, CP 1995The natural history of nonalcoholic fatty liver: a follow-up studyHepatology2217149PubMedCrossRefGoogle Scholar
  31. 31.
    Matteoni, CA, Younossi, ZM, Gramlich, T, Boparai, N, Liu, YC, McCullough, AJ 1999Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severityGastroenterology11614139PubMedCrossRefGoogle Scholar
  32. 32.
    Hui, JM, Kench, JG, Chitturi, S, Sud, A, Farell, GC, Byth, K,  et al. 2003Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis CHepatology384207PubMedCrossRefGoogle Scholar
  33. 33.
    Brunt, EM 2001Nonalcoholic steatohepatitis: definition and pathologySemin Liver Dis21316PubMedCrossRefGoogle Scholar
  34. 34.
    Odbileg, R, Konnai, S, Usui, T, Ohashi, K, Onuma, M 2005Quantification of llama inflammatory cytokine mRNAs by real-time RT-PCRJ Vet Med Sci671958PubMedCrossRefGoogle Scholar
  35. 35.
    Sattar, N, Gaw, A, Scherbakova, O, Ford, I, O'Reilly, DS, Haffner, SM,  et al. 2003Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention StudyCirculation1084149PubMedCrossRefGoogle Scholar
  36. 36.
    Lorenzo, C, Okoloise, M, Williams, K, Stern, MP, Haffner, SM 2003The metabolic syndrome as predictor of type 2 diabetes: the San Antonio heart studyDiabetes Care2631539PubMedCrossRefGoogle Scholar
  37. 37.
    Rutter, MK, Meigs, JB, Sullivan, LM, D'Agostino, RB,Sr, Wilson, PW 2004C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring StudyCirculation1103805PubMedCrossRefGoogle Scholar
  38. 38.
    Sanyal, AJ 2002Treatment of non-alcoholic fatty liver diseaseJ Gastroenterol Hepatol17S3858PubMedCrossRefGoogle Scholar
  39. 39.
    Ridker, PM, Stampfer, MJ, Rifai, N 2001Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial diseaseJAMA28524815PubMedCrossRefGoogle Scholar
  40. 40.
    Park, SH, Jeon, WK, Kim, SH, Kim, HJ, Park, DI, Cho, YK,  et al. 2006Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adultsJ Gastroenterol Hepatol2113843PubMedCrossRefGoogle Scholar
  41. 41.
    Liangpunsakul, S, Chalasani, N 2005Unexplained elevations in alanine aminotransferase in individuals with the metabolic syndrome: results from the third National Health and Nutrition Survey (NHANES III)Am J Med Sci3291116PubMedCrossRefGoogle Scholar
  42. 42.
    Clark, JM, Diehl, AM 2003Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosisJAMA28930004PubMedCrossRefGoogle Scholar
  43. 43.
    Friedman, LS, Dienstag, JL, Watkins, E, Hinkle, CA, Spiers, JA, Rieder, SV,  et al. 1987Evaluation of blood donors with elevated serum alanine aminotransferase levelsAnn Intern Med10713744PubMedGoogle Scholar
  44. 44.
    Haukeland, JW, Damas, JK, Konopski, Z, Loberg, EM, Haaland, T, Goverud, I,  et al. 2006Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2J Hepatol44116774PubMedCrossRefGoogle Scholar
  45. 45.
    Baumann, H, Gauldie, J 1990Regulation of hepatic acute phase plasma protein genes by hepatocyte stimulating factors and other mediators of inflammationMol Biol Med714759PubMedGoogle Scholar
  46. 46.
    Expert Panel on Detection2001Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)JAMA285248697CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 2007

Authors and Affiliations

  • Masato Yoneda
    • 1
  • Hironori Mawatari
    • 1
  • Koji Fujita
    • 1
  • Hiroshi Iida
    • 1
  • Kyoko Yonemitsu
    • 1
  • Shingo Kato
    • 1
  • Hirokazu Takahashi
    • 1
  • Hiroyuki Kirikoshi
    • 1
  • Masahiko Inamori
    • 1
  • Yuichi Nozaki
    • 1
  • Yasunobu Abe
    • 1
  • Kensuke Kubota
    • 1
  • Satoru Saito
    • 1
  • Tomoyuki Iwasaki
    • 2
  • Yasuo Terauchi
    • 2
  • Shinji Togo
    • 3
  • Shiro Maeyama
    • 4
  • Atsushi Nakajima
    • 1
  1. 1.Division of GastroenterologyYokohama City University HospitalYokohamaJapan
  2. 2.Division of Endocrinology and MetabolismYokohama City University Graduate School of MedicineYokohamaJapan
  3. 3.Division of Gastroenterological SurgeryYokohama City University Graduate School of MedicineYokohamaJapan
  4. 4.Kitakashiwa Rehabilitation HospitalKashiwaJapan

Personalised recommendations