Kronik hepatit C hastalarında serum GRP78 düzeyleri anlamlı mı? Vaka-kontrol çalışması

Öz

Amaç: Glikozla düzenlenen protein 78 (GRP-78) dokudaki endoplazmik retikulum (ER) stresinin temel göstergelerinden birisidir. Hepatit C ile enfekte hastalarda karaciğerde ER stresinin geliştiği bilinmektedir. Bu çalışmada kronik hepatit C (KHC) hastalarında bir stres belirteci olarak daha önce incelenmemiş olan serum GRP78 düzeylerinin değerlendirilmesi amaçlanmıştır.

Yöntemler: Çalışmamız, Enfeksiyon Hastalıkları polikliniğimize başvuran Kronik Hepatit C (KHC) enfeksiyonu tanısı almış hasta grubu (n=60) ve ek kronik hastalığı olmayan sağlıklı kontrol (n=60) grubundan oluşan bir vaka kontrol çalışmasıdır. Serum GRP78 seviyesi Enzyme-Linked Immuno Sorbent Assay (ELISA) ile ölçülmüş, ardından GRP78 ile alanin aminotransferaz (ALT), aspartat aminotransferaz (AST), HCV-RNA düzeyleri arasında korelasyon analizi yapılmıştır.

Bulgular: KHC hastalarında HCV-RNA düzeyleri ile ALT ve AST düzeyleri arasında anlamlı bir ilişki izlenmiştir (sırasıyla P<0,001 ve P=0,008). Serum GRP78 hem kontrol hem de HCV alt gruplarında benzer seviyelerde saptanmıştır. Serum GRP78 seviyesi ile AST düzeyleri arasında anlamlı bir pozitif korelasyon saptanırken (P=0,046), serum ALT düzeyleri ile anlamlı bir ilişki saptanamamıştır.

Sonuç: HCV ile indüklenen karaciğer hasarında ER stresinin geliştiği gösterilmiş olmasına rağmen, sonuçlarımız kronik HCV enfeksiyonu sırasında serum GRP 78 düzeyinde anlamlı bir artış olmadığını göstermektedir.

Anahtar Kelimeler

• Glikozla düzenlenen protein78,Hepatit C enfeksiyonu,Endoplazmik retikulum stres

Are serum GRP78 levels significant in chronic hepatitis C patients? A case-control study

Abstract

Aims: Glucose-regulated protein 78 (GRP-78) is one of the basic markers of endoplasmic reticulum (ER) stress in tissues. It is known that ER stress develops in the livers of patients infected with hepatitis C. In this study, the aim was to assess serum GRP78 levels which have not previously been investigated as a stress marker in chronic hepatitis C patients (CHC).

Methods: This case control study includes patients with chronic hepatitis C (CHC) infection in our Infectious Diseases clinic (n=60) and a healthy control group without any additional chronic disease (n=60). Serum GRP78 levels were measured with enzyme-linked immunosorbent assay (ELISA), then correlation analysis was performed for serum GRP78 levels with alanine aminotransferase (ALT), aspartate aminotransferase (AST) and HCV-RNA levels.

Results: A significant positive correlation was observed between HCV-RNA, ALT and AST levels in CHC patients (P<0.001 and P=0.008, respectively). Serum GRP78 was identified at similar levels in both the control and HCV subgroups. While a significant positive correlation was identified between serum GRP78 and AST levels (P=0.046), no significant correlation was detected for serum ALT levels.

Conclusion: Though liver injury induced by HCV is shown to cause ER stress, our results showed there was no significant increase in serum GRP78 levels during chronic HCV infection.

Keywords

• Glucose-regulated protein 78,Hepatitis C infection,Endoplasmic reticulum stress

References

1. 1. Hanafiah KM, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013;57(4):1333-42.
2. 2. Messina JP, Humphreys I, Flaxman A, Brown A, Cooke GS, Pybus OG et al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology. 2015;61:77-87.
3. 3. Razavi H, Elkhoury AC, Elbasha E, Estes C, Pasini K, Poynard T, et al. Chronic hepatitis C virus (HCV) disease burden and cost in the United States. Hepatology. 2013;57:2164-70.
4. 4. El-Serag HB, Kanwal F, Davila JA, Kramer J, Richardson P. A new laboratory-based algorithm to predict development of hepatocellular carcinoma in patients with hepatitis C and cirrhosis. Gastroenterology. 2014;146:1249-55.
5. 5. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264-73.
6. 6. Düzgün A, Alaçam H, Okuyucu A. Endoplasmic reticulum stress and unfolded protein response. J Exp Clin Med. 2012;29:95-100.
7. 7. Asselah T, Bieche I, Mansouri A, Laurendeau I, Cazals-Hatem D, Feldmann G, et al. In vivo hepatic endoplasmic reticulum stress in patients with chronic hepatitis C. J Pathol. 2010;221(3):264-74.
8. 8. Welihinda AA, Tirasophon W, Kaufman RJ. The cellular response to protein misfolding in the endoplasmic reticulum. Gene Expression. 1999;7:293-300.

9. 9. Hosoi T, Ozawa K. Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities. Clinical Science. 2010;118(1):19-29.
10. 10. Hitomi J, Katayama T, Taniguchi M, Honda A, Imaizumi K, Tohyama M. Apoptosis induced by endoplasmic reticulum stress depends on activation of caspase-3 via caspase-12. Neuroscience Letters. 2004;357(2):127-30.
11. 11. Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β. Nature. 2000;403:98-103.
12. 12. Ullman E, Fan Y, Stawowczyk M, Chen HM, Yue Z, Zong WX. Autophagy promotes necrosis in apoptosis-deficient cells in response to ER stress. Cell Death Differ. 2008;15(2):422-5.
13. 13. Dara L, Ji C, Kaplowitz N. The contribution of endoplasmic reticulum stress to liver diseases. Hepatology. 2011;53(5):1752-63.
14. 14. Malhi H, Kaufman RJ. Endoplasmic reticulum stress in liver disease. J Hepatol. 2011;54(4):795-809.
15. 15. Yeganeh B, Moghadam AR, Alizadeh J, Wiechec E, Alavian SM, Hashemi M, et al. Hepatitis B and C virus-induced hepatitis: Apoptosis, autophagy, and unfolded protein response. World J Gastroenterol. 2015;21(47):13225-39.
16. 16. Aizawa Y, Seki N, Nagano T, Abe H. Chronic hepatitis C virus infection and lipoprotein metabolism. World J Gastroenterol. 2015;21(36):10299-313.
17. 17. Chan SW. Unfolded protein response in hepatitis C virus infection. Front Microbiol. 2014;5:1-17.
18. 18. Dash S, Srinivas C, Yucel A, Chandra PK, Ferraris P, Chen V, et al. Hepatitis C Virus Infection Induces Autophagy as a Prosurvival Mechanism to Alleviate Hepatic ER-Stress Response. Viruses. 2016;8:1-29.
19. 19. Khadir A, Kavalakatt S, Abubaker J, Cherian P, Madhu D, Al-Khairi I, et al. Physical exercise alleviates ER stress in obese humans through reduction in the expression and release of GRP78 chaperone. Metabolism. 2016;65(9):1409-20.
20. 20. Delpino A, Castelli M. The 78 kDa glucose-regulated protein (GRP78/BIP) is expressed on the cell membrane, is released into cell culture medium and is also present in human peripheral circulation. Biosci Rep. 2002;22:407-20.
21. 21. Ertuğrul G, Yanaral T. Living donor liver transplantation in hepatocellular carcinoma: A single-center experiences. J Surg Med. 2019;3(4):320-3.
22. 22. Khachatoorian R, French SW. Chaperones in hepatitis C virus infection. World J Hepatol. 2016;8(1):9-35.
23. 23. Chatterjee S, Cheng MF, Berger SJ, Berger NA. Induction of Mr 78,000 Glucose-regulated Stress Protein in Poly(Adenosine Diphosphate-Ribose) Polymerase- and Nicotinamide Adenine Dinucleotide-deficientV79 Cell Lines and Its Relation to Resistance to the Topoisomerase II Inhibitor Etoposide. Cancer Research. 1994;54:4405-11.
24. 24. Shuda M, Kondoh N, Imazeki N, Tanaka K, Okada T, Mori M, et al. Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. J Hepatol. 2003;38:605-14.
25. 25. McPherson S, Powell EE, Barrie HD, Clouston AD, McGuckin M, Jonsson JR. No evidence of the unfolded protein response in patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol. 2011;26:319-27.
26. 26. Gretch D, Corey L, Wilson J, dela Rosa C, Wilson R, Carithers R Jr, et al. Assessment of hepatitis C virus RNA levels by quantitative competitive RNA polymerase chain reaction: high-titer viremia correlates with advanced stage of disease. J Infect Dis. 1994;169:1219-25.
27. 27. Magrin S, Craxi A, Fabiano C, Simonetti RG, Fiorentino G, Marino L, et al. Hepatitis C viremia in chronic liver disease. Relationship to interferon-alpha or corticosteroid treatment. Hepatology. 1994;19:273-9.
28. 28. Karakuş A. The relationship of metabolic parameters and demographical characteristics in patients with naive chronic hepatitis C between viral load and histological factors [dissertation]. Eskişehir Osmangazi University School of Medicine, Department of Infectious Diseases and Clinical Microbiology; 2016.
29. 29. Zeuzem S, Alberti A, Rosenberg W, Marcellin P, Diago M, Negro F, et al. Review article: management of patients with chronic hepatitis C virus infection and "normal" alanine aminotransferase activity. Aliment Pharmacol Ther. 2006;24(8):1133-49.
30. 30. Giannini EG, Testa R, Savarino V. Liver enzyme alteration:a guide for clinicians. CMAJ. 2005;172:367-79.