Hepatitis C pathophysiology: Difference between revisions

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__NOTOC__
{{Hepatitis C}}
{{Hepatitis C}}
{{CMG}}; '''Assistant Editor-In-Chief:''' Nina Axiotakis [mailto:naxiotak@oberlin.edu]
{{CMG}}; '''Associate Editor(s)-In-Chief:''' [[User:YazanDaaboul|Yazan Daaboul]], [[User:Sergekorjian|Serge Korjian]], {{MehdiP}}, {{JA}}
== The Virus ==
==Overview==
{{main|Hepatitis C virus}}
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.


The '''''Hepatitis C virus''''' ('''HCV''') is a small (50 [[metre#SI prefixes|nm]] in size), enveloped, single-stranded, positive sense [[RNA]] virus in the families ''[[Flaviviridae]]''.
==Transmission==


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


[[Image:Sources of Infection for Persons with Hepatitis C (CDC) US.png|thumb|450px|left|CDC figures for sources of infection in the US. [http://www.cdc.gov/ncidod/diseases/hepatitis/c/plan/HCV_infection.htm Source]]]
===Percutaneous Transmission===
*Blood and blood components transfusion
**More than 90% of seronegative recipients who are transfused with blood from HCV-antibody positive donors will acquire infection.<ref name="pmid7815889">{{cite journal |vauthors=Vrielink H, van der Poel CL, Reesink HW, Zaaijer HL, Scholten E, Kremer LC, Cuypers HT, Lelie PN, van Oers MH |title=Look-back study of infectivity of anti-HCV ELISA-positive blood components |journal=Lancet |volume=345 |issue=8942 |pages=95–6 |year=1995 |pmid=7815889 |doi= |url=}}</ref>
*Contaminated shared needles among [[intravenous drug use (recreational)|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.<ref name="pmid9305666">{{cite journal |vauthors=Alter MJ |title=Epidemiology of hepatitis C |journal=Hepatology |volume=26 |issue=3 Suppl 1 |pages=62S–65S |year=1997 |pmid=9305666 |doi=10.1002/hep.510260711 |url=}}</ref>
*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.<ref name="pmid22310779">{{cite journal |vauthors=Jadoul M, Barril G |title=Hepatitis C in hemodialysis: epidemiology and prevention of hepatitis C virus transmission |journal=Contrib Nephrol |volume=176 |issue= |pages=35–41 |year=2012 |pmid=22310779 |doi=10.1159/000333761 |url=}}</ref>


The hepatitis C virus (HCV) is transmitted by blood-to-blood contact. In developed countries, it is estimated that 90% of persons with chronic HCV infection were infected through transfusion of unscreened blood or blood products or via injecting drug use or by inhalational drug use. In developing countries, the primary sources of HCV infection are unsterilized injection equipment and infusion of inadequately screened blood and blood products.
===Sexual Transmission===
*HCV RNA has been detected in semen and saliva.<ref name="pmid1331308">{{cite journal |vauthors=Liou TC, Chang TT, Young KC, Lin XZ, Lin CY, Wu HL |title=Detection of HCV RNA in saliva, urine, seminal fluid, and ascites |journal=J. Med. Virol. |volume=37 |issue=3 |pages=197–202 |year=1992 |pmid=1331308 |doi= |url=}}</ref> People with multiple sexual partners and commercial sex workers have a high HCV prevalence.<ref name="pmid1940879">{{cite journal |vauthors=van Doornum GJ, Hooykaas C, Cuypers MT, van der Linden MM, Coutinho RA |title=Prevalence of hepatitis C virus infections among heterosexuals with multiple partners |journal=J. Med. Virol. |volume=35 |issue=1 |pages=22–7 |year=1991 |pmid=1940879 |doi= |url=}}</ref>


Although injection drug use and receipt of infected blood/blood products are the most common routes of HCV infection, ''any'' practice, activity, or situation that involves blood-to-blood exposure can potentially be a source of HCV infection. The virus may be [[sexually transmitted disease|sexually transmitted]], although this is rare, and usually only occurs when a second [[STD]] makes blood contact more likely.<ref>''[http://www.plannedparenthood.org/sexual-health/std/hepatitis.htm What is hepatitis?]'', [[Planned Parenthood]], accessed May 15, 2007</ref>
===Health care Associated===
*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.<ref name="pmid17998149">{{cite journal |vauthors=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 |title=Hospital admission is a relevant source of hepatitis C virus acquisition in Spain |journal=J. Hepatol. |volume=48 |issue=1 |pages=20–7 |year=2008 |pmid=17998149 |doi=10.1016/j.jhep.2007.07.031 |url=}}</ref><ref name="pmid18023493">{{cite journal |vauthors=Alter MJ |title=Healthcare should not be a vehicle for transmission of hepatitis C virus |journal=J. Hepatol. |volume=48 |issue=1 |pages=2–4 |year=2008 |pmid=18023493 |doi=10.1016/j.jhep.2007.10.007 |url=}}</ref>


=== Methods of transmission ===
===Maternal Infant Transmission ===
*Perinatal transmission frequency ranges from 0% to 4% in larger studies.<ref name="pmid8107740">{{cite journal |vauthors=Ohto H, Terazawa S, Sasaki N, Sasaki N, Hino K, Ishiwata C, Kako M, Ujiie N, Endo C, Matsui A |title=Transmission of hepatitis C virus from mothers to infants. The Vertical Transmission of Hepatitis C Virus Collaborative Study Group |journal=N. Engl. J. Med. |volume=330 |issue=11 |pages=744–50 |year=1994 |pmid=8107740 |doi=10.1056/NEJM199403173301103 |url=}}</ref><ref name="pmid7530793">{{cite journal |vauthors=Zanetti AR, Tanzi E, Paccagnini S, Principi N, Pizzocolo G, Caccamo ML, D'Amico E, Cambiè G, Vecchi L |title=Mother-to-infant transmission of hepatitis C virus. Lombardy Study Group on Vertical HCV Transmission |journal=Lancet |volume=345 |issue=8945 |pages=289–91 |year=1995 |pmid=7530793 |doi= |url=}}</ref>


Several activities and practices have been identified as potential sources of exposure to the hepatitis C virus. Anyone who may have been exposed to HCV through one or more of these routes should be screened for hepatitis C.
==HCV Clearance and Persistence==
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 cells|natural killer (NK) cells]]. Nonetheless, secretion of endogenous IFN does not seem to effectively inhibit HCV [[replication]].<ref name="pmid11714747">{{cite journal| author=Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV| title=Determinants of viral clearance and persistence during acute hepatitis C virus infection. | journal=J Exp Med | year= 2001 | volume= 194 | issue= 10 | pages= 1395-406 | pmid=11714747 | doi= | pmc=PMC2193681 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11714747  }} </ref><ref name="pmid12441397">{{cite journal| author=Thimme R, Bukh J, Spangenberg HC, Wieland S, Pemberton J, Steiger C et al.| title=Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. | journal=Proc Natl Acad Sci U S A | year= 2002 | volume= 99 | issue= 24 | pages= 15661-8 | pmid=12441397 | doi=10.1073/pnas.202608299 | pmc=PMC137773 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12441397  }} </ref><ref name="pmid12441396">{{cite journal| author=Su AI, Pezacki JP, Wodicka L, Brideau AD, Supekova L, Thimme R et al.| title=Genomic analysis of the host response to hepatitis C virus infection. | journal=Proc Natl Acad Sci U S A | year= 2002 | volume= 99 | issue= 24 | pages= 15669-74 | pmid=12441396 | doi=10.1073/pnas.202608199 | pmc=PMC137774 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12441396  }} </ref>


; Injection drug use
HCV proteins play a crucial role in inhibiting [[IFN-α|IFN-alpha]] effectors, such as IFN regulatory factor-3 (IRF-3), double stranded RNA-dependent [[protein kinase]] (PKR), and the [[JAK-STAT signaling pathway]].<ref name="pmid12209136">{{cite journal| author=Katze MG, He Y, Gale M| title=Viruses and interferon: a fight for supremacy. | journal=Nat Rev Immunol | year= 2002 | volume= 2 | issue= 9 | pages= 675-87 | pmid=12209136 | doi=10.1038/nri888 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12209136  }} </ref><ref name="pmid12702807">{{cite journal| author=Foy E, Li K, Wang C, Sumpter R, Ikeda M, Lemon SM et al.| title=Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. | journal=Science | year= 2003 | volume= 300 | issue= 5622 | pages= 1145-8 | pmid=12702807 | doi=10.1126/science.1082604 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12702807  }} </ref><ref name="pmid12730885">{{cite journal| author=Blindenbacher A, Duong FH, Hunziker L, Stutvoet ST, Wang X, Terracciano L et al.| title=Expression of hepatitis c virus proteins inhibits interferon alpha signaling in the liver of transgenic mice. | journal=Gastroenterology | year= 2003 | volume= 124 | issue= 5 | pages= 1465-75 | pmid=12730885 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12730885  }} </ref> 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.<ref name="pmid15036326">{{cite journal| author=Pawlotsky JM| title=Pathophysiology of hepatitis C virus infection and related liver disease. | journal=Trends Microbiol | year= 2004 | volume= 12 | issue= 2 | pages= 96-102 | pmid=15036326 | doi=10.1016/j.tim.2003.12.005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15036326  }} </ref>


Those who currently or have used [[drug injection]] as their delivery route for illicit drugs are at increased risk for getting hepatitis C because they may be sharing needles or other drug paraphernalia (includes cookers, cotton, spoons, water, etc.), which may be contaminated with HCV-infected blood. An estimated 60% to 80% of all IV drug users in the United States have been infected with HCV. [[Harm reduction]] strategies are encouraged in many countries to reduce the spread of hepatitis C, through education, provision of clean needles and syringes, and safer injecting techniques.
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.<ref name="pmid7519785">{{cite journal| author=Farci P, Alter HJ, Wong DC, Miller RH, Govindarajan S, Engle R et al.| title=Prevention of hepatitis C virus infection in chimpanzees after antibody-mediated in vitro neutralization. | journal=Proc Natl Acad Sci U S A | year= 1994 | volume= 91 | issue= 16 | pages= 7792-6 | pmid=7519785 | doi= | pmc=PMC44488 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7519785  }} </ref><ref name="pmid8806581">{{cite journal| author=Shimizu YK, Igarashi H, Kiyohara T, Cabezon T, Farci P, Purcell RH et al.| title=A hyperimmune serum against a synthetic peptide corresponding to the hypervariable region 1 of hepatitis C virus can prevent viral infection in cell cultures. | journal=Virology | year= 1996 | volume= 223 | issue= 2 | pages= 409-12 | pmid=8806581 | doi=10.1006/viro.1996.0497 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8806581  }} </ref><ref name="pmid12615904">{{cite journal| author=Bartosch B, Dubuisson J, Cosset FL| title=Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes. | journal=J Exp Med | year= 2003 | volume= 197 | issue= 5 | pages= 633-42 | pmid=12615904 | doi= | pmc=PMC2193821 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12615904  }} </ref><ref name="pmid9649423">{{cite journal| author=Puntoriero G, Meola A, Lahm A, Zucchelli S, Ercole BB, Tafi R et al.| title=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. | journal=EMBO J | year= 1998 | volume= 17 | issue= 13 | pages= 3521-33 | pmid=9649423 | doi=10.1093/emboj/17.13.3521 | pmc=PMC1170689 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9649423  }} </ref> 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.<ref name="pmid7519785">{{cite journal| author=Farci P, Alter HJ, Wong DC, Miller RH, Govindarajan S, Engle R et al.| title=Prevention of hepatitis C virus infection in chimpanzees after antibody-mediated in vitro neutralization. | journal=Proc Natl Acad Sci U S A | year= 1994 | volume= 91 | issue= 16 | pages= 7792-6 | pmid=7519785 | doi= | pmc=PMC44488 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7519785  }} </ref><ref name="pmid8806581">{{cite journal| author=Shimizu YK, Igarashi H, Kiyohara T, Cabezon T, Farci P, Purcell RH et al.| title=A hyperimmune serum against a synthetic peptide corresponding to the hypervariable region 1 of hepatitis C virus can prevent viral infection in cell cultures. | journal=Virology | year= 1996 | volume= 223 | issue= 2 | pages= 409-12 | pmid=8806581 | doi=10.1006/viro.1996.0497 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8806581  }} </ref><ref name="pmid12615904">{{cite journal| author=Bartosch B, Dubuisson J, Cosset FL| title=Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes. | journal=J Exp Med | year= 2003 | volume= 197 | issue= 5 | pages= 633-42 | pmid=12615904 | doi= | pmc=PMC2193821 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12615904  }} </ref><ref name="pmid9649423">{{cite journal| author=Puntoriero G, Meola A, Lahm A, Zucchelli S, Ercole BB, Tafi R et al.| title=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. | journal=EMBO J | year= 1998 | volume= 17 | issue= 13 | pages= 3521-33 | pmid=9649423 | doi=10.1093/emboj/17.13.3521 | pmc=PMC1170689 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9649423  }} </ref>


; Drug use by nasal inhalation (Drugs which are "snorted")
Similarly, the activation of the [[CD4+]] and [[CD8+ T cells|CD8+]] T-cell response is required for viral clearance. This cellular response allows for the development of long-term immunity against HCV.<ref name="pmid12829979">{{cite journal| author=Bertoletti A, Ferrari C| title=Kinetics of the immune response during HBV and HCV infection. | journal=Hepatology | year= 2003 | volume= 38 | issue= 1 | pages= 4-13 | pmid=12829979 | doi=10.1053/jhep.2003.50310 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12829979  }} </ref> Studies also proved that delayed or inadequate activation of [[T cell|T-cell]] response is associated with persistence of infection. It is not known why [[T cell|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 12|interleukin (IL) 12]] activation.<ref name="pmid12829979">{{cite journal| author=Bertoletti A, Ferrari C| title=Kinetics of the immune response during HBV and HCV infection. | journal=Hepatology | year= 2003 | volume= 38 | issue= 1 | pages= 4-13 | pmid=12829979 | doi=10.1053/jhep.2003.50310 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12829979  }} </ref><ref name="pmid11159892">{{cite journal| author=Bain C, Fatmi A, Zoulim F, Zarski JP, Trépo C, Inchauspé G| title=Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection. | journal=Gastroenterology | year= 2001 | volume= 120 | issue= 2 | pages= 512-24 | pmid=11159892 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11159892  }} </ref><ref name="pmid12218168">{{cite journal| author=Wedemeyer H, He XS, Nascimbeni M, Davis AR, Greenberg HB, Hoofnagle JH et al.| title=Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection. | journal=J Immunol | year= 2002 | volume= 169 | issue= 6 | pages= 3447-58 | pmid=12218168 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12218168  }} </ref><ref name="pmid10790425">{{cite journal| author=Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P et al.| title=Analysis of successful immune responses in persons infected with hepatitis C virus. | journal=J Exp Med | year= 2000 | volume= 191 | issue= 9 | pages= 1499-512 | pmid=10790425 | doi= | pmc=PMC2213430 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10790425  }} </ref><ref name="pmid11927944">{{cite journal| author=Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L et al.| title=Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. | journal=Nat Med | year= 2002 | volume= 8 | issue= 4 | pages= 379-85 | pmid=11927944 | doi=10.1038/nm0402-379 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11927944  }} </ref><ref name="pmid11086025">{{cite journal| author=Kittlesen DJ, Chianese-Bullock KA, Yao ZQ, Braciale TJ, Hahn YS| title=Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation. | journal=J Clin Invest | year= 2000 | volume= 106 | issue= 10 | pages= 1239-49 | pmid=11086025 | doi=10.1172/JCI10323 | pmc=PMC381434 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11086025  }} </ref>


Researchers have suggested that the transmission of HCV may be possible through the nasal inhalation (insuffulation) of illegal drugs such as cocaine and crystal methamphetamine when straws (containing even trace amounts of mucus and blood) are shared among users.<ref name=Thompson_1996>{{cite journal |author=Thompson S, Hernberger F, Wale E, Crofts N |title=Hepatitis C transmission through tattooing: a case report |journal=Aust N Z J Public Health |volume=20 |issue=3 |pages=317-8 |year=1996 |id=PMID 8768424}}</ref>
==Liver Injury and Cirrhosis, and Hepatocellular Carcinoma==
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 [[Hepatocyte|hepatocytes]]. The viral burden also does not seem to be directly related to the extent of liver injury.<ref name="pmid12829989">{{cite journal| author=Poynard T, Ratziu V, McHutchison J, Manns M, Goodman Z, Zeuzem S et al.| title=Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. | journal=Hepatology | year= 2003 | volume= 38 | issue= 1 | pages= 75-85 | pmid=12829989 | doi=10.1053/jhep.2003.50267 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12829989  }} </ref><ref name="pmid9037030">{{cite journal| author=Barba G, Harper F, Harada T, Kohara M, Goulinet S, Matsuura Y et al.| title=Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. | journal=Proc Natl Acad Sci U S A | year= 1997 | volume= 94 | issue= 4 | pages= 1200-5 | pmid=9037030 | doi= | pmc=PMC19768 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9037030  }} </ref><ref name="pmid10905593">{{cite journal| author=Rubbia-Brandt L, Quadri R, Abid K, Giostra E, Malé PJ, Mentha G et al.| title=Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. | journal=J Hepatol | year= 2000 | volume= 33 | issue= 1 | pages= 106-15 | pmid=10905593 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10905593  }} </ref><ref name="pmid11322205">{{cite journal| author=Serfaty L, Andreani T, Giral P, Carbonell N, Chazouillères O, Poupon R| title=Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C. | journal=J Hepatol | year= 2001 | volume= 34 | issue= 3 | pages= 428-34 | pmid=11322205 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11322205  }} </ref><ref name="pmid12524415">{{cite journal| author=Castéra L, Hézode C, Roudot-Thoraval F, Bastie A, Zafrani ES, Pawlotsky JM et al.| title=Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies. | journal=Gut | year= 2003 | volume= 52 | issue= 2 | pages= 288-92 | pmid=12524415 | doi= | pmc=PMC1774979 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12524415  }} </ref><ref name="pmid12558359">{{cite journal| author=Sulkowski MS, Thomas DL| title=Hepatitis C in the HIV-Infected Person. | journal=Ann Intern Med | year= 2003 | volume= 138 | issue= 3 | pages= 197-207 | pmid=12558359 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12558359  }} </ref><ref name="pmid12118398">{{cite journal| author=Pol S, Vallet-Pichard A, Fontaine H, Lebray P| title=HCV infection and hemodialysis. | journal=Semin Nephrol | year= 2002 | volume= 22 | issue= 4 | pages= 331-9 | pmid=12118398 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12118398  }} </ref>


; Blood products
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.<ref name="pmid15036326">{{cite journal| author=Pawlotsky JM| title=Pathophysiology of hepatitis C virus infection and related liver disease. | journal=Trends Microbiol | year= 2004 | volume= 12 | issue= 2 | pages= 96-102 | pmid=15036326 | doi=10.1016/j.tim.2003.12.005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15036326  }} </ref> 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 cell|cytotoxic T cells]] is associated with the extent of liver injury.


[[Blood transfusion]], blood products, or [[organ transplantation]] prior to implementation of HCV screening (in the U.S., this would refer to procedures prior to 1992) is a decreasing risk factor for hepatitis C.
[[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]].<ref name="pmid15036326">{{cite journal| author=Pawlotsky JM| title=Pathophysiology of hepatitis C virus infection and related liver disease. | journal=Trends Microbiol | year= 2004 | volume= 12 | issue= 2 | pages= 96-102 | pmid=15036326 | doi=10.1016/j.tim.2003.12.005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15036326  }} </ref>


The virus was first isolated in 1989 and reliable tests to screen for the virus were not available until 1992. Therefore, those who received blood or blood products prior to the implementation of screening the blood supply for HCV may have been exposed to the virus. Blood products include clotting factors (taken by [[hemophilia]]cs), immunoglobulin, Rhogam, platelets, and plasma. In 2001, the Centers for Disease Control and Prevention reported that the risk of HCV infection from a unit of transfused blood in the United States is less than one per million transfused units.
==Hepatocellular Carcinoma==
[[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.<ref name="pmid12407572">{{cite journal| author=National Institutes of Health| title=National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C: 2002--June 10-12, 2002. | journal=Hepatology | year= 2002 | volume= 36 | issue= 5 Suppl 1 | pages= S3-20 | pmid=12407572 | doi=10.1053/jhep.2002.37117 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12407572  }} </ref><ref name="pmid8676467">{{cite journal| author=Ray RB, Lagging LM, Meyer K, Ray R| title=Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. | journal=J Virol | year= 1996 | volume= 70 | issue= 7 | pages= 4438-43 | pmid=8676467 | doi= | pmc=PMC190377 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8676467  }} </ref><ref name="pmid7745741">{{cite journal| author=Sakamuro D, Furukawa T, Takegami T| title=Hepatitis C virus nonstructural protein NS3 transforms NIH 3T3 cells. | journal=J Virol | year= 1995 | volume= 69 | issue= 6 | pages= 3893-6 | pmid=7745741 | doi= | pmc=PMC189112 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7745741  }} </ref><ref name="pmid10631105">{{cite journal| author=Park JS, Yang JM, Min MK| title=Hepatitis C virus nonstructural protein NS4B transforms NIH3T3 cells in cooperation with the Ha-ras oncogene. | journal=Biochem Biophys Res Commun | year= 2000 | volume= 267 | issue= 2 | pages= 581-7 | pmid=10631105 | doi=10.1006/bbrc.1999.1999 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10631105  }} </ref><ref name="pmid10355764">{{cite journal| author=Ghosh AK, Steele R, Meyer K, Ray R, Ray RB| title=Hepatitis C virus NS5A protein modulates cell cycle regulatory genes and promotes cell growth. | journal=J Gen Virol | year= 1999 | volume= 80 ( Pt 5) | issue=  | pages= 1179-83 | pmid=10355764 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10355764  }} </ref>


; Iatrogenic; medical or dental exposure
==Histology==
Click on the arrow to view the pathologic findings in viral hepatitis:
{{#ev:youtube|_hXvbpSxFZw}}
==Mechanisms involved in extra-[[hepatic]] manifestations==
*[[Cryoglobulinemia|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]].<ref name="pmid29703790">{{cite journal |vauthors=Cacoub P, Desbois AC, Comarmond C, Saadoun D |title=Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis |journal=Gut |volume=67 |issue=11 |pages=2025–2034 |date=November 2018 |pmid=29703790 |doi=10.1136/gutjnl-2018-316234 |url=}}</ref>
*[[B-cell lymphoma]]: A continuous HCV [[antigen]] stimulation and permanent [[genetic]] damage caused by [[virus|viral]] [[proteins]] cause clonal proliferation of CD21−CD27+. It also down-regulates [[tumor]]-suppressive signals (such as, microRNA-26b). [[cancer|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]].<ref name="pmid29703790">{{cite journal |vauthors=Cacoub P, Desbois AC, Comarmond C, Saadoun D |title=Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis |journal=Gut |volume=67 |issue=11 |pages=2025–2034 |date=November 2018 |pmid=29703790 |doi=10.1136/gutjnl-2018-316234 |url=}}</ref>
* [[CVS|Cardiovascular]] [[disease]]: Local [[vessel|vascular]] damage is caused by an increased expression of adhesion molecules on [[endothelium|endothelial]] surface. Smooth cells in the media proliferate and [[apoptosis]] is inhibited, with local [[macrophages]] producing [[inflammation|proinflammatory]] [[cytokines]] and free radicals. These processes result in accelerated [[atherosclerosis]], procoagulant effects, and lead to major cardiovascular events.<ref name="pmid29703790">{{cite journal |vauthors=Cacoub P, Desbois AC, Comarmond C, Saadoun D |title=Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis |journal=Gut |volume=67 |issue=11 |pages=2025–2034 |date=November 2018 |pmid=29703790 |doi=10.1136/gutjnl-2018-316234 |url=}}</ref>
*[[Chronic kidney disease]]: Direct [[HCV]] cytopathic effect, [[chronic]] [[inflammation]] from [[atherosclerosis]] and [[insulin resistance]], [[endothelium|endothelial]] and mesangial [[inflammation]], and [[podocyte]] and tubular [[injury]] caise [[CKD]]. [[Cryoprecipitates]] deposit at [[glomeruli]] also manifested as type I [[membranoproliferative glomerulonephritis]].<ref name="pmid29703790">{{cite journal |vauthors=Cacoub P, Desbois AC, Comarmond C, Saadoun D |title=Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis |journal=Gut |volume=67 |issue=11 |pages=2025–2034 |date=November 2018 |pmid=29703790 |doi=10.1136/gutjnl-2018-316234 |url=}}</ref>
*[[Type 2 diabetes]]: Caused by both hepatic and peripheral [[insulin]] resistance. In the [[liver]], [[HCV]] leads to [[phosphatidylinositol 3-kinase|PI3K]]-AKT insulin-signaling pathway reduction via [[insulin]] receptor substrate 1 inhibition and impaired [[Sodium-glucose transport proteins|Glut2]]–mediated [[hepatic]] [[glucose]] intake. In the extra[[hepatic]] tissue, [[insulin]] resistance is a consequence of soluble endocrine mediators released by [[hepatocytes]]. Up-regulation of [[tumor necrosis factor|TNF]], [[glucose 6-phosphate|G6P]], and [[resistin]], with an imbalance in the adipocytokine profile, increases [[gluconeogenesis]] in these sites.<ref name="pmid29703790">{{cite journal |vauthors=Cacoub P, Desbois AC, Comarmond C, Saadoun D |title=Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis |journal=Gut |volume=67 |issue=11 |pages=2025–2034 |date=November 2018 |pmid=29703790 |doi=10.1136/gutjnl-2018-316234 |url=}}</ref>


People can be exposed to HCV via inadequately or improperly sterilized medical or dental equipment. Equipment that may harbor contaminated blood if improperly sterilized includes needles or syringes, hemodialysis equipment, oral hygiene instruments, and jet air guns, etc. Scrupulous use of appropriate sterilization techniques and proper disposal of used equipment can reduce the risk of iatrogenic exposure to HCV to virtually zero.
; Occupational exposure to blood
Medical and dental personnel, first responders (e.g., firefighters, paramedics, emergency medical technicians, law enforcement officers), and military combat personnel can be exposed to HCV through accidental exposure to blood through accidental needlesticks or blood spatter to the eyes or open wounds. Universal precautions to protect against such accidental exposures significantly reduce the risk of exposure to HCV.
; Recreational exposure to blood
Contact sports and other activities, such as "slam dancing" that may result in accidental blood-to-blood exposure are potential sources of exposure to HCV.
; Sexual exposure to blood
Sexual transmission of HCV is considered to be rare.  The CDC does not recommend the use of condoms between discordant couples (where one partner is positive and the other is negative); however, because of the high prevalence of hepatitis C, this small risk may translate into a non-trivial number of cases transmitted by sexual routes.  Vaginal penetrative sex is believed to have a lower risk of transmission than sexual practices that involve higher levels of trauma to anogenital mucosa (anal penetrative sex, fisting, use of sex toys).<ref name="Hanh2007">{{cite journal | author=Hahn JA | year=2007 | journal=J Infect Dis | volume=195 | pages=1556&ndash;9 | title=Sex, Drugs, and Hepatitis C Virus }}</ref>
; Body piercings and tattoos
Tattooing dyes, ink pots, stylets and piercing implements can transmit HCV-infected blood from one person to another if proper sterilization techniques are not followed. Tattoos or piercings performed before the mid 1980s, "underground,"  or non-professionally are of particular concern since sterile techniques in such settings may have been or be insufficient to prevent disease.
; Shared personal care items
Personal care items such as razors, toothbrushes, cuticle scissors, and other manicuring or pedicuring equipment can easily be contaminated with blood. Sharing such items can potentially lead to exposure to HCV.
HCV is ''not'' spread through casual contact such as hugging, kissing, or sharing eating or cooking utensils.
=== Vertical transmission ===
[[Vertical transmission]] refers to the transmission of a communicable disease from an infected mother to her child during the birth process. Mother-to-child transmission of hepatitis C has been well described, but occurs relatively infrequently. Transmission occurs only among women who are HCV RNA positive at the time of delivery; the risk of transmission in this setting is approximately 6 out of 100. Among women who are both HCV and HIV positive at the time of delivery, the risk of HCV is increased to approximately 25 out of 100.
The risk of vertical transmission of HCV does ''not'' appear to be associated with method of delivery or breast feeding.
=== Co-infection with HIV ===
Approximately 350,000, or 35% of patients in the USA infected with HIV are also infected with the hepatitis C virus, mainly because both viruses are blood-borne and present in similar populations. In other countries co-infection is less common, and this is possibly related to differing drug policies. HCV is the leading cause of chronic liver disease in the USA. It has been demonstrated in clinical studies that HIV infection causes a more rapid progression of chronic hepatitis C to cirrhosis and liver failure. This is not to say treatment is not an option for those living with co-infection.
==Clinical Stages==
===Acute Hepatitis C===
Acute hepatitis C refers to the first 6 months after infection with HCV. Between 60% to 70% of people infected develop no symptoms during the acute phase. In the minority of patients who experience acute phase symptoms, they are generally mild and nonspecific, and rarely lead to a specific diagnosis of hepatitis C. Symptoms of acute hepatitis C infection include decreased appetite, fatigue, [[abdominal pain]], [[jaundice]], [[itching]], and flu-like symptoms.
The hepatitis C virus is usually detectable in the blood within one to three weeks after infection, and antibodies to the virus are generally detectable within 3 to 12 weeks. Approximately 20-30% of persons infected with HCV clear the virus from their bodies during the acute phase as shown by normalization in [[liver function tests]] ([[LFTs]]) such as [[alanine transaminase]] ([[ALT]]) & [[aspartate transaminase]] ([[AST]]) normalization, as well as plasma HCV-RNA clearance (this is known as ''spontaneous viral clearance''). The remaining 70-80% of patients infected with HCV develop [[chronic (medicine)|chronic]] hepatitis C, i.e., infection lasting more than 6 months.
Previous practice was to not treat acute infections to see if the person would spontaneously clear; recent studies have shown that treatment during the acute phase of genotype 1 infections has a greater than 90% success rate with half the treatment time required for chronic infections, but that the majority of acute hepatitis C is cleared. <ref name=Jaeckel><!--
-->{{cite journal | author = Jaeckel E, Cornberg M, Wedemeyer H, Santantonio T, Mayer J, Zankel M, Pastore G, Dietrich M, Trautwein C, Manns MP | title = Treatment of acute hepatitis C with interferon alfa-2b | journal = New England Journal of Medicine | year = 2001 | month = Nov | volume = 345 | issue = 20 | pages = 1452-1457 | id = PMID 11794193 }}</ref>
=== Chronic Hepatitis C ===
Chronic hepatitis C is defined as infection with the hepatitis C virus persisting for more than six months. Clinically, it is often asymptomatic (without jaundice) and it is mostly discovered accidentally.
The natural course of chronic hepatitis C varies considerably from one person to another. Virtually all people infected with HCV have evidence of inflammation on liver biopsy, however, the rate of progression of liver scarring (fibrosis) shows significant variability among individuals. Recent data suggests that among untreated patients, roughly one-third progress to liver [[cirrhosis]] in less than 20 years. Another third progress to [[cirrhosis]] within 30 years. The remainder of patients appear to progress so slowly that they are unlikely to develop [[cirrhosis]] within their lifetimes. Factors that have been reported to influence the rate of HCV disease progression include age (increasing age associated with more rapid progression), gender (males have more rapid disease progression than females), alcohol consumption (associated with an increased rate of disease progression), HIV coinfection (associated with a markedly increased rate of disease progression), and fatty liver (the presence of fat in liver cells has been associated with an increased rate of disease progression).
Symptoms specifically suggestive of liver disease are typically absent until substantial scarring of the liver has occurred. However, hepatitis C is a systemic disease and patients may experience a wide spectrum of clinical manifestations ranging from an absence of symptoms to a more symptomatic illness prior to the development of advanced liver disease. Generalized signs and symptoms associated with chronic hepatitis C include [[fatigue]], marked [[weight loss]], flu-like symptoms, [[muscle pain]], [[joint pain]], intermittent low-grade [[fever]]s, [[itching]], sleep disturbances, [[abdominal pain]] (especially in the right upper quadrant), appetite changes, [[nausea]], [[diarrhea]], [[dyspepsia]], cognitive changes, [[depression]], [[headache]]s, and mood swings.
Once chronic hepatitis C has progressed to [[cirrhosis]], signs and symptoms may appear that are generally caused by either decreased liver function or increased pressure in the liver circulation, a condition known as portal hypertension. Possible signs and symptoms of liver [[cirrhosis]] include [[ascites]] (accumulation of fluid in the abdomen), bruising and bleeding tendency, bone pain, [[varices]] (enlarged veins, especially in the stomach and esophagus), fatty stools ([[steatorrhea]]), [[jaundice]], and a syndrome of cognitive impairment known as [[hepatic encephalopathy]].
Liver function tests show variable elevation of [[ALAT]], [[AST]] and [[GGTP]] and periodically they might show normal results. Usually [[prothrombin]] and [[serum albumin|albumin]] results are normal. The level of elevation of liver tests do not correlate well with the amount of liver injury on biopsy. Viral genotype and viral load also do not correlate with the amount of liver injury. Liver biopsy is the best test to determine the amount of scarring and inflammation. Radiographic studies such as ultrasound or [[CT scan]] do not show liver injury until it is fairly advanced.
Chronic hepatitis C, more than other forms of hepatitis, is diagnosed because of extrahepatic manifestations associated with the presence of HCV such as [[thyroiditis]] (inflammation of the thyroid) with hyperthyreosis or hypothyreosis, [[porphyria cutanea tarda]], [[cryoglobulinemia]] (a form of [[vasculitis]]) <!--
  --><ref name="pascual">{{cite journal | author = Pascual M, Perrin L, Giostra E, Schifferli J | title = Hepatitis C virus in patients with cryoglobulinemia type II. | journal = J Infect Dis | volume = 162 | issue = 2 | pages = 569-70 | year = 1990 | id = PMID 2115556}}</ref><!--
--> and [[glomerulonephritis]] (inflammation of the kidney), specifically [[membranoproliferative glomerulonephritis]] ([[MPGN]]) <!--
  --><ref name="johnson">{{cite journal | author = Johnson R, Gretch D, Yamabe H, Hart J, Bacchi C, Hartwell P, Couser W, Corey L, Wener M, Alpers C | title = Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. | journal = N Engl J Med | volume = 328 | issue = 7 | pages = 465-70 | year = 1993 | id = PMID 7678440}}</ref>.  Hepatitis C is also associated with sicca syndrome, [[thrombocytopenia]], [[lichen planus]], [[diabetes mellitus]] and with B-cell [[lymphoproliferative disorder]]s.<!--
--><ref name=Extrahepatic>{{cite journal | author = Zignego AL, Ferri C, Pileri SA, Caini P, Bianchi FB; for the Italian Association of the Study of Liver (A.I.S.F.) Commission on Extrahepatic Manifestations of HCV infection | title = Extrahepatic manifestations of Hepatitis C Virus infection: A general overview and guidelines for a clinical approach | journal = Dig Liver Dis. | volume = | issue = | pages = E-publication | year = 2006 | id = PMID 16884964}}</ref>
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}


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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

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

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

Percutaneous Transmission

  • 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

  • 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

  • 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

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

HCV Clearance and Persistence

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

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

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

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

Mechanisms involved in extra-hepatic manifestations

References

  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.
  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.
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  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.
  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.
  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.
  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.
  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.
  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.
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  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.
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