Changes in serum levels of cytokeratin-18 fragments in patients with chronic hepatitis C under antiviral therapy

Öz

Background and Aims: Cytokeratin-18 is the known substrate for caspases, which are encountered during hepatic and pancreatic acinar apoptosis. Studies performed in recent years have indicated that the cleavage level of serum cytokeratin-18 (M30 antigen) is correlated with hepatic fibrosis and disease severity in both chronic hepatitis C and non-alcoholic steatohepatitis. It was shown that antiviral therapy in chronic viral hepatitis C patients significantly reduced hepatocellular apoptosis and cytokeratin-18 is accepted as a reliable marker of hepatocyte apoptosis. Our aim was to determine the correlation between the cytokeratin-18 level and treatment response in patients with chronic viral hepatitis C. Materials and Methods: Sixty patients with chronic viral hepatitis C were included in the study. A 48-week course of peginterferon- ribavirin therapy was given to appropriate patients. Hepatitis C virus RNA was measured at 0, 12, and 24 weeks at the end of therapy and 72 weeks. In addition, cytokeratin-18 levels were measured at 0, 24, and 72 weeks. Results: The mean age of 60 patients was 52±10.9 years. While 31 (51.6%) of patients were in the sustained viral response group, 29 (8.4%) of patients were in the non-sustained viral response group. It was determined that while the cytokeratin-18 level at week 0 in the sustained viral response group was 243±21, the cytokeratin-18 level at week 24 was 115±12 U/L and the difference between the level of cytokeratin-18 at weeks 0 and 24 were 127±209 U/L (p: .014). While the cytokeratin-18 level at week 0 in the non- sustained viral response group was 270±14; at week 24, the cytokeratin-18 level was 136±19 U/L and the difference between cytokeratin-18 levels at weeks 0 and 24 was 136±156 U/L (p > .5). At week 72, the cytokeratin-18 level in the sustained viral response group was 109±38 and the difference between weeks 0 and 72 was 134±215 (p < .002). Conclusion: In chronic viral hepatitis C patients, there was a correlation between sustained viral response and cytokeratin-18, which is a marker of apoptosis. During treatment, it was found that there was a relationship between sustained viral response and the decrease in cytokeratin-18 levels. Thisfinding indicates that cytokeratin-18 level monitoring may be used as a predictive marker of sustained viral response.

Anahtar Kelimeler

• Chronic hepatitis C,cytokeratin-18,sustained viral response

Kronik hepatit C hastalarında antiviral tedavi ile serum sitokeratin-18 düzeylerinin değişimi

Öz

Giriş ve Amaç: Sitokeratin-18, hepatik ve pankreatit asiner apopitozisi sırasında ortaya çıkan kaspazların bilinen substuratıdır. Son zamanlarda yapılan çalışmalarda; serum sitokeratin-18 (M30 antijen) düzeyi ile non-alkolik steatohepatit ve kronik hepatit C’nin şiddeti ve hepatik fibrozis ile korelasyonu belirtilmiştir. Kronik viral hepatit C hastalarında, başarılı antiviral tedavi ile hepatosellüler apopitozisin anlamlı olarak azaldığı, hepatosit apopitozisini göstermede sitokeratin-18’in güvenilir bir markır olduğu gösterilmiştir. Bizim amacımız kronik viral hepatit C’li hastalarda sitokeratin-18 düzeyi ve tedavi yanıtı arasındaki korelasyonu belirlemektir. Gereç ve Yöntem: Kronik viral hepatit C tanısı alan 60 hasta çalışmaya alındı. Tedavi için uygun hastalara 48 hafta peginterferon- ribavirin tedavisi verildi. Tedavinin 0-12-24. haftalarında, tedavinin sonunda ve 72. haftada hepatitis C virusu RNA miktarı ölçüldü. Ayrıca tedavinin 0-24 ve 72. haftasında sitokeratin-18 düzeyleri ölçüldü. Bulgular: Altmış hastanın ortalama yaşı 52±10.9 yıl idi. Hastaların 31’i (%51,6) kalıcı viral yanıt grubunda iken, 29’u (%48,4) kalıcı viral yanıt elde edilemeyen grupta idi. Kalıcı viral yanıt grubunda 0. haftada sitokeratin-18 düzeyi 243±21 U/L iken, 24. haftada sitokeratin-18 düzeyi 115±12 U/L saptanmış olup 0. hafta ile 24. hafta arasındaki değişim 127±209 U/L bulunmuştur (p: 0.014). Kalıcı viral yanıt elde edilemeyen grupta 0. haftada sitokeratin-18 düzeyi 270±14 U/L iken, 24. haftada sitokeratin-18 düzeyi 133±19 U/L saptanmış olup 0. hafta ile 24. hafta arasındaki değişim 136±156 U/L bulunmuştur (p>0,5). Kalıcı viral yanıt grubunda, 72. haftada sitokeratin-18 düzeyi 109±38 saptanmış olup 0. hafta ile 72. hafta arasındaki değişim 134±215 bulunmuştur (p<0.002). Sonuç: Apopitozisin göstergesi olan sitokeratin-18 ile kronik viral hepatit C hastalarında kalıcı viral yanıt arasında korelasyon tespit edildi ve tedavi seyrinde sitokeratin-18 düzeyinde azalma ile kalıcı viral yanıt arasında ilişki bulunduğu gösterildi. Bu da sitokeratin-18 düzeylerinde azalmanın kalıcı viral yanıtı ön görmede bir parametre olarak kullanılabileceğini göstermektedir.

Anahtar Kelimeler

• Kronik viral hepatit C,sitokeratin-18,kalıcı viral yanıt

Kaynakça

1. 1. Poynard T, Yuen MF, Ratziu V, Lai CL. Viral hepatitis C. Lancet 2003;362:2095-100.
2. 2. McCaughan GW, Omata M, Amarapurkar D, et al. Asian Pacific Association for the Study of the Liver consensus statements on the diagnosis, management and treatment of hepatitis C virus infection. J Gastroenterol Hepatol 2007;22:615-33.
3. 3. Strnad P, Paschke S, Jang KH, Ku NO. Keratins: markers and modulators of liver disease. Curr Opin Gastroenterol 2012;28:209-16.
4. 4. Yagmur E, Trautwein C, Leers MP, et al. Elevated apoptosis-associated cytokeratin 18 fragments (CK18Asp386) in serum of patients with chronic liver diseases indicate hepatic and biliary inflammation. Clin Biochem 2007;40:651-5.
5. 5. Bantel H, Lugering A, Heidemann J, et al. Detection of apoptotic caspase activation in sera from patients with chronic HCV infection is associated with fibrotic liver injury. Hepatology 2004;40:1078-87.
6. 6. Kronenberger B, Zeuzem S, Sarrazin C, et al. Dynamics of apoptotic activity during antiviral treatment of patients with chronic hepatitis C. Antivir Ther 2007;12:779-87.
7. 7. Kronenberger B, Wagner M, Herrmann E, et al. Apoptotic cytokeratin 18 neoepitopes in serum of patients with chronic hepatitis C. J Viral Hepat 2005;12:307-14.
8. 8. Sgier C, Mullhaupt B, Gerlach T, et al. Effect of antiviral therapy on circulating cytokeratin-18 fragments in patients with chronic hepatitis C. J Viral Hepat 2010;17:845-50.

9. 9. Wei X, Wei H, Lin W, et al. Cell death biomarker M65 is a useful indicator of liver inflammation and fibrosis in chronic hepatitis B: A cross-sectional study of diagnostic accuracy. Medicine (Baltimore) 2017;96:e6807.
10. 10. Leers MP, Kolgen W, Bjorklund V, et al. Immunocytochemical detection and mapping of a cytokeratin 18 neo-epitope exposed during early apoptosis. J Pathol 1999;187:567-72.
11. 11. Oshima RG. Apoptosis and keratin intermediate filaments. Cell Death Differ 2002;9:486-92.
12. 12. Rosso C, Caviglia GP, Abate ML, et al. Cytokeratin 18-Aspartate396 apoptotic fragment for fibrosis detection in patients with non-alcoholic fatty liver disease and chronic viral hepatitis. Dig Liver Dis 2016;48:55-61.
13. 13. Volkmann X, Cornberg M, Wedemeyer H, et al. Caspase activation is required for antiviral treatment response in chronic hepatitis C virus infection. Hepatology 2006;43:1311-6.
14. 14. Parfieniuk-Kowerda A, Lapinski TW, Rogalska-Plonska M, et al. Serum cytochrome C and m30-neoepitope of cytokeratin-18 in chronic hepatitis C. Liver Int 2014;34:544-50.
15. 15. El-Zefzafy W, Eltokhy H, Mohamed NA, Abu-Zahab Z. Significance of serum cytokeratin-18 in prediction of hepatocellular carcinoma in chronic hepatitis C infected Egyptian patients. Open Access Maced J Med Sci 2015;3:117-23.