Increased ascites natural killer cells in patients with chronic hepatitis B cirrhosis using lamivudine: A pilot study

Öz

Background and Aims: Natural killer cells play a direct role in liver injury and fibrogenic response. Peripheral blood natural killer cells have been studied widely in chronic liver diseases. We aimed to evaluate the ascites natural killer cell frequency and its significance in chronic hepatitis B related cirrhosis. Materials and Methods: Overall, 30 patients [23 males] with decompensated chronic hepatitis B cirrhosis with ascites were included. Patients with a recent ascites infection history and other etiologic factors besides chronic hepatitis B infection were excluded. After defining the demographic characteristics of the cases, we divided patients according to their Child-Turcotte-Pugh classification scores into two groups, and their natural killer (CD3−/CD16+/CD56+) cell frequencies in peripheral blood and ascites were studied using flow cytometry. Finally, we compared the natural killer cell frequencies in peripheral blood and ascites between the Child-Turcotte-Pugh classification groups based on lamivudine use. Results: Median lamivudine usage duration was 60 months, interquartile range 18.7–93 months in Child-Turcotte-Pugh B and 7.5 months, interquartile range 2.2–21 months in Child-Turcotte-Pugh C (p = 0.053). Ascites natural killer cells were significantly increased in lamivudine users of Child-Turcotte-Pugh B (p = 0.049), whereas no change was observed in peripheral blood - natural killer frequency in patients using lamivudine in the Child-Turcotte-Pugh B and C groups (p = 0.574 and p = 0.174, respectively). Conclusion: Long-term lamivudine use might have increased the ascites natural killer frequency, whereas no change was observed in the peripheral blood - natural killer cell frequency in patients with chronic hepatitis B cirrhosis, suggesting a potential role of antivirals in ascites natural killer cell response.

Anahtar Kelimeler

• Chronic hepatitis B,cirrhosis,ascites,natural killer cells

Kronik hepatit B’ye bağlı sirozda lamivudin kullanımı ile artan asit natural killer hücreleri: Pilot çalışma

Öz

Giriş ve Amaç: Natural killer hücreler karaciğer hasarı ve fibrojenik cevapta doğrudan rol alırlar. Kronik karaciğer hastalıklarında periferik kanda natural killer hücreleri bir çok çalışmada araştırılmıştır. Amacımız asit natural killer sıklığını ve bunun kronik hepatit B’ye bağlı sirozdaki önemini araştırmaktı. Gereç ve Yöntem: Otuz erişkin (23 erkek) ardışık asitle dekompanse kronik hepatit B sirotik hasta çalışmaya alındı. Son zamanlarda asit infeksiyon öyküsü olanlar ve kronik hepatit B etiyolojisi dışında etiyolojik faktörü bulunan hastalar çalışmaya alınmadı. Olguların demografik özellikleri tanımlandıktan sonra Child-Turcotte-Pugh puanlarına göre iki gruba ayrıldılar. Bu olguların asit ve kan örneklerinde akım sitometrisi ile natural killer hücre sıklıkları araştırıldı. Daha sonra Child-Turcotte-Pugh B ve C grupları içinde lamivudine kullanımına göre natural killer hücre sıklıklarını karşılaştırdık. Bulgular: Lamivudin kullanım medyan süresi Child-Turcotte-Pugh B’de 60 ay, çeyrekler arası açıklık (18.7-93), Child-Turcotte-Pugh C’de 7.5 ay, çeyrekler arası açıklık (2.2-21) idi (p=0.053). Asit natural killer hücreleri Child-Turcotte-Pugh B grubunda lamivudin kullananlarda, kullanmayanlara göre belirgin olarak artarken (p=0.049), periferik kan natural killer hücrelerinde her iki grup arasında farklılık saptamadık (sırasıyla p=0.574 ve p=0.174). Sonuç: Uzun dönem lamivudin kullanımı kronik hepatit B’ye bağlı sirozda periferik kan natural killer hücre sıklığında değişiklik oluşturmamakta iken, asitte natural killer hücre sıklığını arttırmış olabilir. Bu durum asit natural killer hücrelerinin antivirallere cevapta potansiyel rollerinin olduğunu düşündürmektedir.

Anahtar Kelimeler

• Kronik hepatit B,siroz,asit,natural killer hücreleri,lamivudin

Kaynakça

1. 1- Lin J, Wu JF, Zhang Q, Zhang HW, Cao GW. Virus-related liver cirrhosis: molecular basis and therapeutic options. World J Gastroenterol 2014;20:6457-69.
2. 2- Gao B, Radaeva S. Natural killer and natural killer T cells in liver fibrosis. Biochim Biophys Acta 2013; 1832:1061-9.
3. 3- Melhem A, Muhanna N, Bishara A, et al. Antifibrotic activity of NK cells in experimental liver injury through killing of activated HSC. J Hepatol 2006;45:60-71.
4. 4- Notas G, Kisseleva T, Brenner D. NK and NKT cells in liver injury and fibrosis. Clin Immonol 2009;130:16-26.
5. 5- Lv J, Jin Q, Sun H, et al. Antiviral treatment alters the frequency of activating and inhibitory receptor-expressing natural killer cells in chronic hepatitis B virus infected patients. Mediators Inflamm 2012;2012:804043.
6. 6- Tjwa ET, van Oord GW, Biesta PJ, et al. Restoration of TLR3-activated myeloid dendritic cell activity leads to improved natural killer cell function in chronic hepatitis B virus infection. J Virol 2012;86:4102-9.
7. 7- Oliviero B, Varchetta S, Paudice E, et al. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology 2009;137:1151-60.
8. 8- Scott-Algara D, Mancini-Bourgine M, Fontaine H, Pol S, Michel ML. Changes to the natural killer cell reportoire after therapeutic hepatitis B DNA vaccination. PLoS One 2010;18:e8761.

9. 9- Kiyici M, Nak SG, Budak F, et al. Lymphocyte subsets and cytokines in ascitic fluid of decompensated cirrhotic patients with and without spontaneous ascites infection. J Gastroenterol Hepatol 2006;21:963-9.
10. 10- Runyon BA, Morrissey RL, Hoefs JC, Wyle FA. Opsonic activity of human ascitic fluid: a potentially important protective mechanism against spontaneous bacterial peritonitis. Hepatology 1985;5:634-7.
11. 11- Mal F, Huu TP, Bendahou M, et al. Chemoattractant and opsonic activity in ascetic fluid. A study in 47 patients with cirrhosis or malignant peritonitis. J Hepatol 1991;12:45-9.
12. 12- Llach J, Rimola A, Navasa M, et al. Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascetic fluid protein concentration. Hepatology 1992;16:724-7.
13. 13- Gao B, Radaeva S, Jeong WI. Activation of natural killer cells inhibits liver fibrosis: a novel strategy to treat liver fibrosis. Expert Rev Gastroenterol Hepatol 2007;1:173-80.
14. 14- Glassner A, Eisenhardt M, Kramer B, et al. NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner. Lab Invest 2012;92:967-77.
15. 15- Shabani Z, Bagheri M, Zare-Bidaki M, et al. NK cells in hepatitis B virus infection: a potent target for immunotherapy. Arch Virol 2014;159:1555-65.
16. 16- Li WJ, Jiang YF, Jin QL, et al. Immunologic characterization of posthepatitis cirrhosis caused by HBV and HCV infection. J Biomed Biotechnol 2010; 2010:138237.
17. 17- Zheng Q, Zhu YY, Chen J, et al. Activated natural killer cells accelerate liver damage in patients with chronic hepatitis B virus infection. Clin Exp Immunol 2015;180:499-508.
18. 18- Zhang QF, Shao JY, Yin WW, et al. altered immune profiles of natural killer cells in chronic hepatitis b patients: a systematic review and meta-analysis. PLoS One 2016;11:0160171.
19. 19- Kweon YO, Goodman ZD, Dienstag JL, et al. Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B. J Hepatol 2001;35:749-55.
20. 20- Peng CY, Chien RN, Liaw YF. Hepatitis B virus-related decompensated liver cirrhosis: benefits of antiviral therapy. J Hepatol 2012;57:442-50.
21. 21- Shi J, Zhao J, Zhang X, et al. Activated hepatic stellate cells impair NK cell anti-fibrosis capacity through a TGF-β-dependent emperipolesis in HBV cirrhotic patients. Sci Rep 2017;7:44544.
22. 22- Kramer B, Korner C, Kebschull M, et al. Natural killer p46High expression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis. Hepatology 2012;56:1201-13.
23. 23- Zhao J, Li Y, Jin L, et al. Natural killer cells are characterized by the concomitantly increased interferon-γ and cytotoxicity in acute resolved hepatitis B patients. PLoS One 2012;7:e49135.
24. 24- Stegmann KA, Björkström NK, Veber H, et al. Interferon alpha induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection. Gastroenterology 2010;138:1885-97.