Abstract

Egypt has a high prevalence of HCV infection which causes hepatic fibrosis. Assessment of the degree of hepatic fibrosis is essential for decision of antiviral therapy. Untill now, liver biopsy is the gold standard for assessment of hepatic fibrosis but it is an invasive procedure. The aim of this study was to assess the utility of serum autotaxin level as a marker of liver fibrosis in chronic hepatitis C patients in comparison with liver biopsy.Sixty HCV patients with hepatic fibrosis confirmed with liver biopsy and20 healthy subjects were inrolled in the current study.Lab assessment included CBC, fasting serum glucose, liver and kidney function tests, serum AFP, hepatitis markers (HCVAb, HBsAg), PCR for HCV RNA and serum autotaxin (using sandwich ELISA).Results revealed that serum ATX levels were significantly increased in HCV group versus control group and were positively correlated with the stage of fibrosis. Serum autotaxin level at cutoff value (<115.8 ng/ml) was the best parameter in detection of F0 with AUC (0.79), at a cutoff value (≥180.3 ng/ml) was the best parameter in detection of advanced fibrosis (≥ F3) with AUC (0.82) and at a cutoff value (≥189.2 ng/ml) was the best parameter in detection of F4 with AUC (0.85).

It was concluded that serum autotaxin level is a valuable test for exclusion of fibrosis and detection of advanced fibrosis and cirrhosis but lacks discrimination of intermediate fibrosis stages.

Keywords: Hepatitis C, autotaxin, hepatic fibrosis.

 1.      Palmeri ML, Wang MH, Rouze NC,  Abdelmalek MF, Guy CD, Moser B, Diehl AM, et al. Noninvasive evaluation of hepatic fibrosis using acoustic radiation force-based shear stiffness in patients with nonalcoholic fatty liver disease. Journal of Hepatology 2011; 55(3): 666-672.

2.      Ibrahim WS and Mandour EM. Correlation of Liver Biopsy with Liver Enzymes and PCR among Egyptian Patients with Chronic Hepatitis C. Academic Journal of Cancer Research 2014; 7 (2): 59-64.

3.      Friedman SL. Liver fibrosis from bench to bedside. J Hepatol2003; 38(1): 38-53.

4.      Lauer GM and Walker BD. Hepatitis C virus infection. N Engl J Med 2001; 345(1): 41-52.

5.      Boursier J, Isselin G, Fouchard-Hubert I, Oberti F, Dib N, Lebigot J,  Bertrais S, et al. Acoustic radiation force impulse: a new ultrasonographic technology for the widespread noninvasive diagnosis of liver fibrosis. European journal of gastroenterology &hepatology 2010; 22(9):1074-84.

6.      Leroy V, Hilleret MN, Sturm N,  Trocme C, Renversez JC, Faure P, Morel F, et al. Prospective comparison of six non-invasive scores for the diagnosis of liver fibrosis in chronic hepatitis C. J Hepatol 2007; 46(5): 775–782.

7.      Nakanaga K, Hama K and Aoki J. Autotaxin--an LPA producing enzyme with diverse functions. Journal of biochemistry 2010; 148(1):13-24.

8.      Ikeda H   and Yatomi Y. Autotaxin in liver fibrosis.ClinChimActa 2012; 413(23-1

9.      Koike S, Yutoh Y, Keino-Masu K,  Noji S, Masu M and Ohuchi H.Autotaxin is required for the cranial neural tube closure and establishment of the midbrain–hindbrain boundary during mouse development. DevDyn 2011; 240(2): 413-421.

10.  Brindley DN. Lipid phosphate phosph-atases and related proteins: signaling functions in development, cell division, and cancer. J Cell Biochem 2004; 92(5):900-912.

11.  Ikeda H, Nagashima K, Yanase M,  Tomiya T, Arai M, Inoue Y, Tejima K, et al. Involvement of Rho/Rho kinase pathway in regulation of apoptosis in rat hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 2003; 285(5): 880–886.

12.  Tanaka M, Okudaira S, Kishi Y,  Ohkawa R, Iseki S, Ota M, Noji S, Yatomi Y, Aoki J, Arai H. Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid. J BiolChem 2006; 281(35): 25822–25830.

13.  Jansen S, Andries M, Vekemans K, Vanbilloen H, Verbruggen A, Bollen M.Rapid clearance of the circulating metastatic factor autotaxin by the scavenger receptors of liver sinusoidal endothelial cells. Cancer Lett 2009; 284 (2): 216–221.

14.  Watanabe N, Ikeda H, Nakamura K , Ohkawa R, Kume Y, Aoki J, Hama K, et al. Both plasma lysophosphatidic acid and serum autotaxin levels are increased in chronic hepatitis C. J ClinGastroenterol 2007; 41(6): 616–623.

15.  Pleli T, Martin D, Kronenberger B, Brunner F, Köberle V, Grammatikos G, Farnik H, et al. Serum autotaxin is a parameter for the severity of liver cirrhosis and overall survival in patients with liver cirrhosis--a prospective cohort study. PLoS One 2014; 9(7): e103532. 

16.  Nustad K, Paus E, Kierulf B andBørmer OP.Specificity and affinity of 30 monoclonal antibodies against alpha-fetoprotein.TumourBiol 1998;19(4):293-300.

17.  Butler JE, Spradling JE, Suter M, Dierks SE, Heyermann H, Peterman JH.The immunochemistry of sandwich ELISAs--I. The binding characteristics of immunoglobulins to monoclonal and polyclonal capture antibodies adsorbed on plastic and their detection by symmetrical and asymmetrical antibody-enzyme conjugates. Molecular immunology 1986; 23(9): 971-82.

18.  Wai CT, Greenson JK, Fontana RJ,Kalbfleisch JD, Marrero JA,  Conjeevaram HS, Lok AS. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic HCV. Hepatology 2003; 38(2): 518-526.

19.  Poynard T and Bedossa P. Age and platelet count: a simple index for predicting the presence of histological lesions in patients with antibodies to hepatitis C virus. METAVIR and CLINIVIR Cooperative Study Groups. J Viral Hepat 1997; 4(3):199-208.

20.  Bedossa P and Poynard T.An algorithm for the grading of activity in chronic hepatitis C. for the METAVIR Cooperative Study Group.Hepatology 1996; 24: 289-293.

21.  Perrakis  A and Moolenaar WH. Autotaxin: structure-function and signaling.  J Lipid Res 2014; 55(6): 1010–1018.

22.  Benesch MG, Ko YM, McMullen TPand Brindley DN.Autotaxin in the crosshairs: taking aim at cancer and other inflammatory conditions. FEBS Lett 2014; 588(16): 2712-2727.

23.  Nakagawa H, Ikeda H, Nakamura K, Ohkawa R, Masuzaki R, Tateishi R, Yoshida H, et al. Autotaxin as a novel serum marker of liver fibrosis. Clinica ChimicaActa 2011; 412(13-14):1201-1206.

24.  Rockey DC, Boyles JK, Gabbiani G and Friedman SL.  Rat hepatic lipocytes express smooth muscle actin upon active-tion in vivo and in culture. J Submicrosc CytolPathol 1992; 24(2):193–203.

25.  Yamaoka K, Nouchi T, Marumo F and Satoc C.  Alpha-smooth-muscle actin expression in normal and fibrotic human livers. Dig Dis Sci1993; 38(8): 1473–1479.

26.  Tanaka M, Okudaira S, Kishi Y, Ohkawa R, Iseki S, Ota M, Noji S, et al.Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid. J BiolChem2006; 281(35):25822–25830.

27.  Garcı ´a-Paga´nJC, Gracia-SanchoJ and BoschJ. Functional aspects on the pathophysiology of portal hypertension in cirrhosis.J Hepatol  2012; 57(2):458–461.

28.  Ezzat WM,Ragab HM, El MaksoudNA,  Abdulla NA, Yasser A and Elhosary YA. Validity of Autotaxin as a Novel Diagnostic Marker for Liver Fibrosis in Egyptian Chronic HCV Patients. Maced J Med Sci2013; 6(4): 359-364.

29.  Fouad SA, Esmat S, Omran D,  Rashid L and Kobaisi MH. Non-invasive assessment of hepatic fibrosis in Egyptian patients with chronic hepatitis C virus infection. World J Gastroenterology 2012; 18(23): 2988-2994.

30.  Attallah AM, El-Far M, Omran MM, Farid K, Albannan MS and El-Dosoky I. Noninvasive Diagnosis of Liver Fibrosis and Cirrhosis in Chronic Hepatitis C Patients. Journal of clinical laboratory analysis 2013; 27(2): 121-129.

31.  Lackner C, Struber G, Liegl B, Leibl S, Ofner P, Bankuti C, Bauer B, et al. Comparison and validation of simple noninvasive tests for prediction of fibrosis in chronic hepatitis C. Hepatology 2005; 41(6):1376-1382.

32.  Cadranel JF and Philippe M.Prothrombin index decrease: a useful and reliable marker of extensive fibrosis. Eur J Gastroenterol Hepatol 2002; 14(10): 1057-1059.

33.  Mistry PK and Jain D.Haematological disorders of the liver. In: Dooley JS, Lok ASF, Burroughs AK and Heathcote EJ(eds.).Sherlock’s Diseases of The Liver and Biliary System. 12th ed. United Kingdom: Blackwell Publishing Ltd, 2011, p. 48-69.

34.  Coverdale SA, Samarasinghe DA, Lin R, Kench J, Byth K, Khan MH, Crewe E, et al. Changes in antipyrine clearance and platelet count, but not conventional liver tests, correlate with fibrotic change in chronic hepatitis C: value for predicting fibrotic progression. Am. J. Gastroenterol 2003; 98(6): 1384-1390.

35.  Friedman SL, Mantin P and Munoz SJ. Laboratory methods for evalution of the patients with liver disease. In: Zakim D, Boyer TD(eds.).A textbook of liver diseases. Philadelphia: saunder, 2002, p. 661-708.

36.  Elias E. Jaundice and cholestasis. In: Dooley JS, Lok ASF, Burroughs AK and Heathcote EJ (eds.).Sherlock’s Diseases of The Liver and Biliary System.12th ed. Blackwell Publishing Ltd, 2011, p.234-256.

37.  Omran MM, Farid K, Emran TM and Attallah AA. Fibro α-score as a simple and useful non-invasive test for predicting significant liver fibrosis in chronic hepatitis C patients. Arab Journal of Gastroenterology 2011; 12(2):74-79.

38.  Taketa K.  Alpha fetoprotein: reevaluation in hepatology. Hepatology 1990; 12(6): 1420-1432.

39.  Adinolfi LE, Utili R, Andreana A, Tripodi MF, Marracino M, Gambardella M,  Giordano M, et al. Serum HCV RNA levels correlate with histological liver damage and concur with steatosis in progression of chronic hepatitis C. Dig Dis Sci. 2001; 46(8): 1677-1683.

40.  Magrin S, Craxi  A, Fabiano C,  Simonetti RG, Fiorentino G, Marino L, Diquattro O, et al.Hepatitis C viremia in chronic liver disease: relationship to interferon-alpha or corticosteroid treatment. Hepatology 1994; 19(2): 273-279.

41.  Nousbaum, JB, Pol S, Nalpas B, Landais P, Berthelot P and Bréchot C. Hepatitis-C-virus-type 1b (II) infection in France and Italy. Collaborative Study Group.Ann. intern. Med 1995; 122(3): 161-168.

42.  Shahid M, Idrees M, Nasir B, Raja AJ, Raza SM, Amin I, Rasul A,  et al. Correlation of biochemical markers and HCV RNA titers with fibrosis stages and grades in chronic HCV-3a patients. Eur J Gastroenterol Hepatol 2014; 26(7): 788-794.