Evaluation of C-reactive protein levels in the differentiation of non-alcoholic steatohepatitis and simple liver steatosis

Abstract

Aim: Non-alcoholic fatty liver disease (NAFLD) is a broad-spectrum disease that has increased in recent years due to increased sedentary life and obesity. It was aimed to determine C-reactive protein (CRP) levels, its association with simple steatosis and non-alcoholic steatohepatitis (NASH) and its diagnostic value in this study. Methods: A total of 165 patients had a diagnosis of fatty liver disease (simple steatosis group and NASH group) and 99 healthy controls without liver disease were included in the study. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, direct bilirubin, CRP levels were evaluated and ultrasonographic evaluation of liver was performed in all groups. Histopathological evaluation was performed by biopsy in 65 patients who were thought to have NASH. Results: AST and ALT values were found to be significantly higher in the NASH group than the other groups. CRP levels were detected lowest in control group and highest in NASH group (p <0.001). AST values were also found to be significantly higher in patients with fibrosis grade 3-4 compared to the control group. Conclusion: Our study showed that CRP level is a suitable marker for differentiation of simple steatosis and NASH.

Keywords

• Non-alcoholic fatty liver disease
• C-reactive protein
• non-alcoholic steatohepatitis

Non-alkolik steatohepatit ve basit karaciğer yağlanması ayrımında C-reaktif protein düzeylerinin değerlendirilmesi

Öz

Amaç: Non-alkolik yağlı karaciğer hastalığı (NAFLD), artan sedanter hayat ve obezite nedeniyle son yıllarda artış gösteren geniş spektrumlu bir hastalıktır. Bu çalışmada, C-reaktif protein (CRP) düzeylerinin, basit steatoz ve non-alkolik steatohepatit (NASH) ile ilişkisini ve tanısal değerini belirlemek amaçlanmıştır. Metodlar: Yağlı karaciğer hastalığı tanısı alan 165 hasta (basit steatoz grubu ve NASH grubu) ve karaciğer hastalığı olmayan 99 sağlıklı kontrol çalışmaya dahil edildi. Tüm gruplarda aspartat aminotransferaz (AST), alanin aminotransferaz (ALT), total bilirubin, direkt bilirubin, CRP düzeyleri değerlendirildi ve karaciğerin ultrasonografik değerlendirmesi yapıldı. NASH olduğu düşünülen 65 hastada biyopsi ile histopatolojik değerlendirme yapıldı. Bulgular: AST ve ALT değerleri NASH grubunda diğer gruplara göre anlamlı olarak yüksekti. CRP düzeyleri kontrol grubunda en düşük, NASH grubunda en yüksek saptandı (p <0.001). Fibrozis derecesi 3-4 olan hastalarda kontrol grubu ile kıyaslandığında, AST değerinin anlamlı düzeyde yüksek olduğu saptandı. Sonuç: Çalışmamız, CRP düzeyinin basit steatoz ve NASH ayrımı için uygun bir belirteç olduğunu göstermiştir.

Anahtar Kelimeler

• Non-alkolik yağlı karaciğer hastalığı
• C-reaktif protein
• non-alkolik steatohepatit

References

1. Adams LA, Angulo P. Recent concepts in non-alcoholic fatty liver disease. Diabet Med 2005;22:1129-33.
2. Torres DM, Harrison SA. Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology 2008;134:1682-8.
3. Zois CD, Baltayiannis GH, Bekiari A, Goussia, A., Karayiannis, P., Doukas, M., Demopoulos, D., Mitsellou, A., Vougiouklakis, T., Mitsi, V., Tsianos, E. V. Steatosis and steatohepatitis in postmortem material from Northwestern Greece. World J Gastroenterol 2010;16:3944-9.
4. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P.. The natural history of nonalcoholic fatty liver disease: A population-based cohort study. Gastroenterology 2005;129:113-21.
5. Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003;98:960-7.
6. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 2004;114:147-52.
7. Lazo M, Clark JM. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis 2008;28:339-50.
8. Zimmermann E, Anty R, Tordjman J, Verrijken A, Gual P, Tran A, Iannelli A, Gugenheim J, Bedossa P, Francque S, Le Marchand-Brustel Y, Clement K, Van Gaal L, Sørensen TIA, Jess T. C. C reactive protein levels in relation to various features of non-alcoholic fatty liver disease among obese patients. J Hepatol 2011;55(3):660-5.

9. Massaro KS, Costa SF, Leone C, Chamone DA. Procalcitonin (PCT) and C-reactive protein (CRP) as severe systemic infection markers in febrile neutropenic adults. BMC Infect Dis 2007;7:137.
10. Rodriguez-Hernandez H, Simental-Mendia LE, Rodriguez-Ramirez G, Reyes-Romero MA. Obesity and inflammation: epidemiology, risk factors, and markers of inflammation. Int J Endocrinol 2013:678159.
11. Uchihara M, Izumi N. High-sensitivity C-reactive protein (hs-CRP): A promising biomarker for the screening of non-alcoholic steatohepatitis (NASH) Nihon Rinsho 2006;64:1133-8.
12. Nigam P, Bhatt SP, Misra A, Vaidya M, Dasgupta J, Chadha DS. Non-alcoholic fatty liver disease is closely associated with sub-clinical inflammation: A case-control study on Asian Indians in North India. J Hepatol 2006;44:1167-74.
13. Fierbinteanu-Braticevici C, Dina I, Petrisor A, Tribus L, Negreanu L, Carstoiu C. Noninvasive investigations for nonalcoholic fatty liver disease and liver fibrosis. World J Gastroenterol 2010;16:4784-91.
14. Yoneda M, Mawatari H, Fujita K, ida H, Yonemitsu K, Kato S, Takahashi H, Kirikoshi H, Inamori M, Nozaki Y, Abe Y, Kubota K, Saito S, Iwasaki T, Terauchi Y, Togo S, Maeyama S, Nakajima A. High-sensitivity C-reactive protein is an independent clinical feature of nonalcoholic steatohepatitis (NASH) and also of the severity of fibrosis in NASH. J Gastroenterol 2007;42:573-82.
15. Ariz U, Mato JM, Lu SC, Lu SC, Mato JM, Martínez-Chantar ML. Nonalcoholic steatohepatitis, animal models, and biomarkers: what is new? Methods Mol Biol 2010;593:109136.
16. Chiang CH, Huang CC, Chan WL, Chen JW, Leu HB. The severity of non-alcoholic fatty liver disease correlates with high sensitivity C-reactive protein value and is independently associated with increased cardiovascular risk in healthy population. Clin Biochem 2010;43:1399-404.
17. Kuppan G, Anjana RM, Deepa M, Paramasivam P, Chandrakumar S, Kaliyaperumal V, Mohan V. Inflammatory markers in relation to nonalcoholic fatty liver disease in urban South Indians. Diabetes Technol Ther 2012;14:152-8.
18. Genc H, Dogru T, Kara M, Tapan S, Nuri EC, Acikel C, Karslioglu Y, Bagci S. Association of plasma visfatin with hepatic and systemic inflammation in nonalcoholic fatty liver disease. Ann Hepatol 2013;12:548-55.
19. Lambert M, Delvin EE, Paradis G, O'Loughlin J, Hanley JA, Levy E. C-reactive protein and features of the metabolic syndrome in a population-based sample of children and adolescents. Clin Chem 2004;50:1762-8.
20. Festa A, D’Agostino R Jr., Howard G, Mykkänen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000; 102: 42-7.
21. Park SH, Kim BI, Yun JW Kim JW, Park DI, Cho YK, Sung IK, Park CY, Sohn CI, Jeon WK, Kim H, Rhee EJ, Lee WY, Kim SW. Insulin resistance and C reactive protein as independent risk factors for non-alcoholic fatty liver disease in non-obese Asian men. J Gastroenterol Hepatol 2004;19(6):694-8.
22. Targher G, Bertolini L, Rodella S, Lippi G, Franchini M, Zoppini G, Muggeo M, Day CP. NASH predicts plasma inflammatory biomarkers independently of visceral fat in men. Obesity (Silver Spring) 2008;16:1394-9.
23. Oruc N, Ozutemiz O, Yuce G, Akarca US, Ersoz G, Gunsar F, Batur Y. Serum procalcitonin and CRP levels in non-alcoholic fatty liver disease: A case control study. BMC Gastroenterol 2009;9:16.
24. Fierbinteanu-Braticevici C, Baicus C, Tribus L, Papacocea R. Predictive factors for nonalcoholic steatohepatitis (NASH) in patients with nonalcoholic fatty liver disease (NAFLD). J Gastrointestin Liver Dis 2011;20:153-9.
25. Hamirani YS, Katz R, Nasir K, Zeb, I., Blaha, M. J., Blumenthal, R. S., Kronmal, R. N., Budoff, M. J. Association between inflammatory markers and liver fat: The Multi Ethnic Study of Atherosclerosis. J Clin Exp Cardiolog 2014;5:1000344.
26. Maleki I, Rastgar A, Hosseini V, Taghvaei T. High sensitive CRP and pentraxine 3 as noninvasive biomarkers of nonalcoholic fatty liverdisease. Eur Rev Med Pharmacol Sci 2014;18:1583-90.
27. Haukeland JW, Damås JK, Konopski Z, Løberg EM, Haaland T, Goverud I, Torjesen PA, Birkeland K, Bjøro K, Aukrust P. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol 2006;44:1167-74.
28. Tarantino G, Finelli C. Pathogenesis of hepatic steatosis: the link between hypercortisolism and non-alcoholic fatty liver disease. World J Gastroenterol 2013;19: 6735-43.
29. Feingold KR, Grunfeld C. Role of cytokines in inducing hyperlipidemia. Diabetes 1992; 41 Suppl 2:97-101.
30. Kumar R, Prakash S, Chhabra S, Singla V, Madan K, Gupta SD, Panda SK, Khanal S, Acharya SK. Association of pro-inflammatory cytokines, adipokines & oxidative stress with insulin resistance & non-alcoholic fatty liver disease. Indian J Med Res 2012;136:229-36.
31. Kim JH, Baik HW, Yoon YS, Joung HJ, Park JS, Park SJ, Jang EJ, Park SW, Kim SJ, Kim MJ, Jeon DO, Cho HJ, Lee SJ, Im SG, Jang SK. Measurement of antioxidant capacity using the biological antioxidant potential test and its role as a predictive marker of metabolic syndrome. Korean J Intern Med 2014;29:31-9.
32. Malhi H, Kaufman RJ. Endoplasmic reticulum stress in liver disease. J Hepatol 2011;54:795-809.
33. Foroughi M, Maghsoudi Z, Khayyatzadeh S, Ghiasvand R, Askari G, Iraj B. Relationship between non-alcoholic fatty liver disease and inflammation in patients with non-alcoholic fatty liver. Adv Biomed Res 2016;5:28.
34. Lee J, Yoon K, Ryu S, Chang Y, Kim H-R. High-normal levels of hs CRP predict the development of non-alcoholic fatty liver in healthy men. PLoS One 2017;24;12:e0172666.
35. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, Mills PR, Keach JC, Lafferty HD, Stahler A, Haflidadottir S, Bendtsen F. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2015;149:389-97.