Hepatitis C pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian, Seyedmahdi Pahlavani, M.D. [2], Javaria Anwer M.D.[3]

## Overview[edit | edit source]

In isolated acute HCV infection, the host immune system stimulates the secretion of interferon alpha and the activation of natural killer cells, which is followed by the activation of the adaptive immune system. Chronic HCV is characterized by the impairment of these mechanisms. Eventually, chronic HCV infection leads to local inflammation and fibrogenesis, which cause hepatic injury and cirrhosis. Hepatocellular carcinoma, a known complication of chronic HCV infection, arises in cases of cirrhosis; the role of oncogenic proteins of HCV in the pathogenesis of hepatocellular carcinoma has yet to be elucidated.

## Transmission[edit | edit source]

The transmission of HCV can be defined as percutaneous, sexual, healthcare-associated, or maternal-infant in nature.

### Percutaneous Transmission[edit | edit source]

* Blood and blood components transfusion
* More than 90% of seronegative recipients who are transfused with blood from HCV-antibody positive donors will acquire infection.[1]
* Contaminated shared needles among intravenous drug users
* Before 1992, at least two-thirds of new HCV infections in the United States were associated with illicit drug use; the number has since decreased significantly.[2]
* Chronic hemodialysis
* The frequency of anti-HCV in patients on hemodialysis ranges from less than 10% in the United States to 55% to 85% in Jordan, Saudi Arabia, and Iran.[3]

### Sexual Transmission[edit | edit source]

* HCV RNA has been detected in semen and saliva.[4] People with multiple sexual partners and commercial sex workers have a high HCV prevalence.[5]

### Health care Associated[edit | edit source]

* Nosocomial transmission has been observed under several different conditions (e.g. needle stick, organ transplant, during surgery); now, however, because of infection control protocols, nosocomial transmission of HCV is rare except in cases of breach of protocols.[6][7]

### Maternal Infant Transmission[edit | edit source]

* Perinatal transmission frequency ranges from 0% to 4% in larger studies.[8][9]

## HCV Clearance and Persistence[edit | edit source]

Acute viral infection and HCV replication triggers the activation of host immune responses, first by secretion of type I interferon alpha (IFN-alpha) and activation of natural killer (NK) cells. Nonetheless, secretion of endogenous IFN does not seem to effectively inhibit HCV replication.[10][11][12]

HCV proteins play a crucial role in inhibiting IFN-alpha effectors, such as IFN regulatory factor-3 (IRF-3), double stranded RNA-dependent protein kinase (PKR), and the JAK-STAT signaling pathway.[13][14][15] More importantly, chronic carriage of HCV is associated with impaired activation of NK cells despite IFN-alpha secretion. It is believed that the cross-linking of CD81 and the envelope protein E2 of the virus is a key mechanism by which NK cells are inactivated and INF-gamma is not produced by these cells.[16]

The activation of IFN-gamma is a prerequisite for the appropriate clearance of HCV. When activation occurs normally, antibodies start to form 7-31 weeks later.[17][18][19][20] While most epitopes for antibodies have not been discovered yet, hypervariable region 1 (HVR1) of the E2 envelope glycoprotein was found to be a target for anti-HVR1 antibodies. Antibodies play a role in clearing the virus from the host. It is currently unknown whether "escape" mechanisms are present in HCV that favor persistent HCV infection despite an adequate antibody response.[17][18][19][20]

Similarly, the activation of the CD4+ and CD8+ T-cell response is required for viral clearance. This cellular response allows for the development of long-term immunity against HCV.[21] Studies also proved that delayed or inadequate activation of T-cell response is associated with persistence of infection. It is not known why T-cell response may fail in response to acute infection, but it is hypothesized that persistence might be related to viral inhibition of T-cell maturation, defective dendritic cells, and/or failure of interleukin (IL) 12 activation.[21][22][23][24][25][26]

## Liver Injury and Cirrhosis, and Hepatocellular Carcinoma[edit | edit source]

HCV is directly associated with hepatic steatosis, which is fat accumulation in the liver. It seems that core proteins may play a role in regulating lipid accumulation in hepatocytes, contributing to steatosis. However, steatosis is not observed in all genotypes of HCV infection; it is classically described in genotype 3, which perhaps is the only genotype that has a direct role in the development of steatosis irrespective of alcohol consumption or metabolic elements. Apart from steatosis, HCV per se has not been shown to have damaging effects on hepatocytes. The viral burden also does not seem to be directly related to the extent of liver injury.[27][28][29][30][31][32][33]

In chronic hepatitis C infections, the local immune response leads to portal lymphoid infiltration and chronic inflammation, which give way to bridging necrosis and degenerative lobular lesions.[16] Hepatic injury is directly associated with the degree of Th1 cytokine expression. The adaptive immune system, namely the cytotoxic T-cell response, injures infected cells as well as bystander cells. Nonetheless, it has not been confirmed whether the number of cytotoxic T cells is associated with the extent of liver injury.

Chronic inflammation ultimately leads to fibrogenesis due to deposition extracellular matrix elements in hepatic parenchyma. It is unknown whether viral components are directly responsible in the particular mechanism of hepatic cirrhosis in chronic HCV infection; although cirrhosis is definitely worsened in HCV patients who are also exposed to other risk factors, such as alcohol, obesity, and HIV.[16]

## Hepatocellular Carcinoma[edit | edit source]

Hepatocellular carcinoma (HCC) occurs following chronic HCV infection complicated by liver cirrhosis. The precise role of HCV components in the development of HCC is poorly understood. Pinpointing which viral protein is directly related to carcinogenesis has been difficult, but studies have shown that NS3, NS4B, and NS5A all have oncogenic properties.[34][35][36][37][38]

## Histology[edit | edit source]

Click on the arrow to view the pathologic findings in viral hepatitis: {{#ev:youtube|_hXvbpSxFZw}}

## Mechanisms involved in extra-hepatic manifestations[edit | edit source]

* Cryoglobulinemic vasculitis: Chronic antigen stimulation reduces the threshold for activation and proliferation of B-lymphocyte and induces Bcl-2 activation and t(14;18) translocation. It results in decreased apoptosis. As a result, CD21−CD27+ cells produce antibodies against the Fc portion of IgG, forming immune complexes that precipitate in small blood vessels.[39]
* B-cell lymphoma: A continuous HCV antigen stimulation and permanent genetic damage caused by viral proteins cause clonal proliferation of CD21−CD27+. It also down-regulates tumor-suppressive signals (such as, microRNA-26b). Oncogenic signals are further enhanced and additional tumor suppressor genes such as Bcl-6, p53, and β-catenin undergo mutation. Hence, the reduced levels of caspase 3, 7, and 9 reduce their sensitivity to Fas-induced apoptosis.[39]
* Cardiovascular disease: Local vascular damage is caused by an increased expression of adhesion molecules on endothelial surface. Smooth cells in the media proliferate and apoptosis is inhibited, with local macrophages producing proinflammatory cytokines and free radicals. These processes result in accelerated atherosclerosis, procoagulant effects, and lead to major cardiovascular events.[39]
* Chronic kidney disease: Direct HCV cytopathic effect, chronic inflammation from atherosclerosis and insulin resistance, endothelial and mesangial inflammation, and podocyte and tubular injury caise CKD. Cryoprecipitates deposit at glomeruli also manifested as type I membranoproliferative glomerulonephritis.[39]
* Type 2 diabetes: Caused by both hepatic and peripheral insulin resistance. In the liver, HCV leads to PI3K-AKT insulin-signaling pathway reduction via insulin receptor substrate 1 inhibition and impaired Glut2–mediated hepatic glucose intake. In the extrahepatic tissue, insulin resistance is a consequence of soluble endocrine mediators released by hepatocytes. Up-regulation of TNF, G6P, and resistin, with an imbalance in the adipocytokine profile, increases gluconeogenesis in these sites.[39]

## References[edit | edit source]

1. ↑ Vrielink H, van der Poel CL, Reesink HW, Zaaijer HL, Scholten E, Kremer LC, Cuypers HT, Lelie PN, van Oers MH (1995). "Look-back study of infectivity of anti-HCV ELISA-positive blood components". Lancet. 345 (8942): 95–6. PMID 7815889.
2. ↑ Alter MJ (1997). "Epidemiology of hepatitis C". Hepatology. 26 (3 Suppl 1): 62S–65S. doi:10.1002/hep.510260711. PMID 9305666.
3. ↑ Jadoul M, Barril G (2012). "Hepatitis C in hemodialysis: epidemiology and prevention of hepatitis C virus transmission". Contrib Nephrol. 176: 35–41. doi:10.1159/000333761. PMID 22310779.
4. ↑ Liou TC, Chang TT, Young KC, Lin XZ, Lin CY, Wu HL (1992). "Detection of HCV RNA in saliva, urine, seminal fluid, and ascites". J. Med. Virol. 37 (3): 197–202. PMID 1331308.
5. ↑ van Doornum GJ, Hooykaas C, Cuypers MT, van der Linden MM, Coutinho RA (1991). "Prevalence of hepatitis C virus infections among heterosexuals with multiple partners". J. Med. Virol. 35 (1): 22–7. PMID 1940879.
6. ↑ Martínez-Bauer E, Forns X, Armelles M, Planas R, Solà R, Vergara M, Fàbregas S, Vega R, Salmerón J, Diago M, Sánchez-Tapias JM, Bruguera M (2008). "Hospital admission is a relevant source of hepatitis C virus acquisition in Spain". J. Hepatol. 48 (1): 20–7. doi:10.1016/j.jhep.2007.07.031. PMID 17998149.
7. ↑ Alter MJ (2008). "Healthcare should not be a vehicle for transmission of hepatitis C virus". J. Hepatol. 48 (1): 2–4. doi:10.1016/j.jhep.2007.10.007. PMID 18023493.
8. ↑ Ohto H, Terazawa S, Sasaki N, Sasaki N, Hino K, Ishiwata C, Kako M, Ujiie N, Endo C, Matsui A (1994). "Transmission of hepatitis C virus from mothers to infants. The Vertical Transmission of Hepatitis C Virus Collaborative Study Group". N. Engl. J. Med. 330 (11): 744–50. doi:10.1056/NEJM199403173301103. PMID 8107740.
9. ↑ Zanetti AR, Tanzi E, Paccagnini S, Principi N, Pizzocolo G, Caccamo ML, D'Amico E, Cambiè G, Vecchi L (1995). "Mother-to-infant transmission of hepatitis C virus. Lombardy Study Group on Vertical HCV Transmission". Lancet. 345 (8945): 289–91. PMID 7530793.
10. ↑ Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV (2001). "Determinants of viral clearance and persistence during acute hepatitis C virus infection". J Exp Med. 194 (10): 1395–406. PMC 2193681. PMID 11714747.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
11. ↑ Thimme R, Bukh J, Spangenberg HC, Wieland S, Pemberton J, Steiger C; et al. (2002). "Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease". Proc Natl Acad Sci U S A. 99 (24): 15661–8. doi:10.1073/pnas.202608299. PMC 137773. PMID 12441397.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
12. ↑ Su AI, Pezacki JP, Wodicka L, Brideau AD, Supekova L, Thimme R; et al. (2002). "Genomic analysis of the host response to hepatitis C virus infection". Proc Natl Acad Sci U S A. 99 (24): 15669–74. doi:10.1073/pnas.202608199. PMC 137774. PMID 12441396.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
13. ↑ Katze MG, He Y, Gale M (2002). "Viruses and interferon: a fight for supremacy". Nat Rev Immunol. 2 (9): 675–87. doi:10.1038/nri888. PMID 12209136.CS1 maint: Multiple names: authors list (link)
14. ↑ Foy E, Li K, Wang C, Sumpter R, Ikeda M, Lemon SM; et al. (2003). "Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease". Science. 300 (5622): 1145–8. doi:10.1126/science.1082604. PMID 12702807.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
15. ↑ Blindenbacher A, Duong FH, Hunziker L, Stutvoet ST, Wang X, Terracciano L; et al. (2003). "Expression of hepatitis c virus proteins inhibits interferon alpha signaling in the liver of transgenic mice". Gastroenterology. 124 (5): 1465–75. PMID 12730885.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
16. ↑ 16.0 16.1 16.2 Pawlotsky JM (2004). "Pathophysiology of hepatitis C virus infection and related liver disease". Trends Microbiol. 12 (2): 96–102. doi:10.1016/j.tim.2003.12.005. PMID 15036326.
17. ↑ 17.0 17.1 Farci P, Alter HJ, Wong DC, Miller RH, Govindarajan S, Engle R; et al. (1994). "Prevention of hepatitis C virus infection in chimpanzees after antibody-mediated in vitro neutralization". Proc Natl Acad Sci U S A. 91 (16): 7792–6. PMC 44488. PMID 7519785.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
18. ↑ 18.0 18.1 Shimizu YK, Igarashi H, Kiyohara T, Cabezon T, Farci P, Purcell RH; et al. (1996). "A hyperimmune serum against a synthetic peptide corresponding to the hypervariable region 1 of hepatitis C virus can prevent viral infection in cell cultures". Virology. 223 (2): 409–12. doi:10.1006/viro.1996.0497. PMID 8806581.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
19. ↑ 19.0 19.1 Bartosch B, Dubuisson J, Cosset FL (2003). "Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes". J Exp Med. 197 (5): 633–42. PMC 2193821. PMID 12615904.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
20. ↑ 20.0 20.1 Puntoriero G, Meola A, Lahm A, Zucchelli S, Ercole BB, Tafi R; et al. (1998). "Towards a solution for hepatitis C virus hypervariability: mimotopes of the hypervariable region 1 can induce antibodies cross-reacting with a large number of viral variants". EMBO J. 17 (13): 3521–33. doi:10.1093/emboj/17.13.3521. PMC 1170689. PMID 9649423.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
21. ↑ 21.0 21.1 Bertoletti A, Ferrari C (2003). "Kinetics of the immune response during HBV and HCV infection". Hepatology. 38 (1): 4–13. doi:10.1053/jhep.2003.50310. PMID 12829979.
22. ↑ Bain C, Fatmi A, Zoulim F, Zarski JP, Trépo C, Inchauspé G (2001). "Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection". Gastroenterology. 120 (2): 512–24. PMID 11159892.CS1 maint: Multiple names: authors list (link)
23. ↑ Wedemeyer H, He XS, Nascimbeni M, Davis AR, Greenberg HB, Hoofnagle JH; et al. (2002). "Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection". J Immunol. 169 (6): 3447–58. PMID 12218168.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
24. ↑ Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P; et al. (2000). "Analysis of successful immune responses in persons infected with hepatitis C virus". J Exp Med. 191 (9): 1499–512. PMC 2213430. PMID 10790425.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
25. ↑ Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L; et al. (2002). "Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections". Nat Med. 8 (4): 379–85. doi:10.1038/nm0402-379. PMID 11927944.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
26. ↑ Kittlesen DJ, Chianese-Bullock KA, Yao ZQ, Braciale TJ, Hahn YS (2000). "Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation". J Clin Invest. 106 (10): 1239–49. doi:10.1172/JCI10323. PMC 381434. PMID 11086025.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
27. ↑ Poynard T, Ratziu V, McHutchison J, Manns M, Goodman Z, Zeuzem S; et al. (2003). "Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C." Hepatology. 38 (1): 75–85. doi:10.1053/jhep.2003.50267. PMID 12829989.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
28. ↑ Barba G, Harper F, Harada T, Kohara M, Goulinet S, Matsuura Y; et al. (1997). "Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets". Proc Natl Acad Sci U S A. 94 (4): 1200–5. PMC 19768. PMID 9037030.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
29. ↑ Rubbia-Brandt L, Quadri R, Abid K, Giostra E, Malé PJ, Mentha G; et al. (2000). "Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3". J Hepatol. 33 (1): 106–15. PMID 10905593.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
30. ↑ Serfaty L, Andreani T, Giral P, Carbonell N, Chazouillères O, Poupon R (2001). "Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C." J Hepatol. 34 (3): 428–34. PMID 11322205.CS1 maint: Multiple names: authors list (link)
31. ↑ Castéra L, Hézode C, Roudot-Thoraval F, Bastie A, Zafrani ES, Pawlotsky JM; et al. (2003). "Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies". Gut. 52 (2): 288–92. PMC 1774979. PMID 12524415.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
32. ↑ Sulkowski MS, Thomas DL (2003). "Hepatitis C in the HIV-Infected Person". Ann Intern Med. 138 (3): 197–207. PMID 12558359.
33. ↑ Pol S, Vallet-Pichard A, Fontaine H, Lebray P (2002). "HCV infection and hemodialysis". Semin Nephrol. 22 (4): 331–9. PMID 12118398.CS1 maint: Multiple names: authors list (link)
34. ↑ National Institutes of Health (2002). "National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C: 2002--June 10-12, 2002". Hepatology. 36 (5 Suppl 1): S3–20. doi:10.1053/jhep.2002.37117. PMID 12407572.
35. ↑ Ray RB, Lagging LM, Meyer K, Ray R (1996). "Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype". J Virol. 70 (7): 4438–43. PMC 190377. PMID 8676467.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
36. ↑ Sakamuro D, Furukawa T, Takegami T (1995). "Hepatitis C virus nonstructural protein NS3 transforms NIH 3T3 cells". J Virol. 69 (6): 3893–6. PMC 189112. PMID 7745741.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
37. ↑ Park JS, Yang JM, Min MK (2000). "Hepatitis C virus nonstructural protein NS4B transforms NIH3T3 cells in cooperation with the Ha-ras oncogene". Biochem Biophys Res Commun. 267 (2): 581–7. doi:10.1006/bbrc.1999.1999. PMID 10631105.CS1 maint: Multiple names: authors list (link)
38. ↑ Ghosh AK, Steele R, Meyer K, Ray R, Ray RB (1999). "Hepatitis C virus NS5A protein modulates cell cycle regulatory genes and promotes cell growth". J Gen Virol. 80 ( Pt 5): 1179–83. PMID 10355764.CS1 maint: Multiple names: authors list (link)
39. ↑ 39.0 39.1 39.2 39.3 39.4 Cacoub P, Desbois AC, Comarmond C, Saadoun D (November 2018). "Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis". Gut. 67 (11): 2025–2034. doi:10.1136/gutjnl-2018-316234. PMID 29703790.