Hepatitis C pathophysiology: Difference between revisions

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== The Virus ==
==Characteristics==
{{main|Hepatitis C virus}}
Hepatitis C virus (HCV) is a member of the genus ''Hepacivirus'' that belongs to the ''Flaviviridae'' family. It is an enveloped, single-stranded RNA virus that measures approximately 60 nm in diameter.  
[[Image:Em_flavavirus-HCV_samp1c.jpg|left|thumb]]
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]]''.
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== Transmission ==


[[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]]]
[[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]]]


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.
==Mode of Transmission==
HCV is primarily transmitted by blood. Exposure to blood is observed primarily in healthcare settings, such as in blood transfusions, surgical procedures, needle injuries, and hemodialysis. Also, the role of intravenous drug use has recently emerged as a great risk for viral transmission after the relatively successful control of nosocomial HCV transmission.<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>


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>
==Life Cycle==
Humans are considered the only natural hosts for HCV. The full life cycle of the virus is poorly understood due to difficulty to culture ''in vitro''. The expression of E1-E2, two important envelope glycoprotein complexes, on the surface of HCV allows the virus to interact with host-ell molecules (glycosaminoglycans) by acting as ligands for cellular receptors, such as tetraspanin CD81, scavenger receptor class B type I (SR-BI), and mannose binding lectins DC-SIGN and L-SIGN. This interaction is believed to have a crucial role in cell recognition and cellular tropism.<ref name="pmid11602769">{{cite journal| author=Op De Beeck A, Cocquerel L, Dubuisson J| title=Biogenesis of hepatitis C virus envelope glycoproteins. | journal=J Gen Virol | year= 2001 | volume= 82 | issue= Pt 11 | pages= 2589-95 | pmid=11602769 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11602769  }} </ref><ref name="pmid11356980">{{cite journal| author=Penin F, Combet C, Germanidis G, Frainais PO, Deléage G, Pawlotsky JM| title=Conservation of the conformation and positive charges of hepatitis C virus E2 envelope glycoprotein hypervariable region 1 points to a role in cell attachment. | journal=J Virol | year= 2001 | volume= 75 | issue= 12 | pages= 5703-10 | pmid=11356980 | doi=10.1128/JVI.75.12.5703-5710.2001 | pmc=PMC114285 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11356980  }} </ref><ref name="pmid12867431">{{cite journal| author=Barth H, Schafer C, Adah MI, Zhang F, Linhardt RJ, Toyoda H et al.| title=Cellular binding of hepatitis C virus envelope glycoprotein E2 requires cell surface heparan sulfate. | journal=J Biol Chem | year= 2003 | volume= 278 | issue= 42 | pages= 41003-12 | pmid=12867431 | doi=10.1074/jbc.M302267200 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12867431  }} </ref><ref name="pmid9794763">{{cite journal| author=Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R et al.| title=Binding of hepatitis C virus to CD81. | journal=Science | year= 1998 | volume= 282 | issue= 5390 | pages= 938-41 | pmid=9794763 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9794763  }} </ref><ref name="pmid12913001">{{cite journal| author=Bartosch B, Vitelli A, Granier C, Goujon C, Dubuisson J, Pascale S et al.| title=Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor. | journal=J Biol Chem | year= 2003 | volume= 278 | issue= 43 | pages= 41624-30 | pmid=12913001 | doi=10.1074/jbc.M305289200 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12913001  }} </ref><ref name="pmid12761383">{{cite journal| author=Hsu M, Zhang J, Flint M, Logvinoff C, Cheng-Mayer C, Rice CM et al.| title=Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. | journal=Proc Natl Acad Sci U S A | year= 2003 | volume= 100 | issue= 12 | pages= 7271-6 | pmid=12761383 | doi=10.1073/pnas.0832180100 | pmc=PMC165865 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12761383  }} </ref><ref name="pmid12356718">{{cite journal| author=Scarselli E, Ansuini H, Cerino R, Roccasecca RM, Acali S, Filocamo G et al.| title=The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. | journal=EMBO J | year= 2002 | volume= 21 | issue= 19 | pages= 5017-25 | pmid=12356718 | doi= | pmc=PMC129051 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12356718  }} </ref><ref name="pmid12609975">{{cite journal| author=Lozach PY, Lortat-Jacob H, de Lacroix de Lavalette A, Staropoli I, Foung S, Amara A et al.| title=DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2. | journal=J Biol Chem | year= 2003 | volume= 278 | issue= 22 | pages= 20358-66 | pmid=12609975 | doi=10.1074/jbc.M301284200 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12609975  }} </ref><ref name="pmid12634366">{{cite journal| author=Pöhlmann S, Zhang J, Baribaud F, Chen Z, Leslie GJ, Lin G et al.| title=Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR. | journal=J Virol | year= 2003 | volume= 77 | issue= 7 | pages= 4070-80 | pmid=12634366 | doi= | pmc=PMC150620 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12634366  }} </ref> The exact mechanism by which viral genome enters the host cell is poorly understood, but it is believed to be via receptor-mediated endocytosis. Then envelope glycoproteins utilize pH-dependent mechanisms to mediate fusion of the viral envelope using endosomal membrane.<ref name="pmid12913001">{{cite journal| author=Bartosch B, Vitelli A, Granier C, Goujon C, Dubuisson J, Pascale S et al.| title=Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor. | journal=J Biol Chem | year= 2003 | volume= 278 | issue= 43 | pages= 41624-30 | pmid=12913001 | doi=10.1074/jbc.M305289200 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12913001  }} </ref><ref name="pmid12761383">{{cite journal| author=Hsu M, Zhang J, Flint M, Logvinoff C, Cheng-Mayer C, Rice CM et al.| title=Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. | journal=Proc Natl Acad Sci U S A | year= 2003 | volume= 100 | issue= 12 | pages= 7271-6 | pmid=12761383 | doi=10.1073/pnas.0832180100 | pmc=PMC165865 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12761383  }} </ref> As soon as it is released into the cytoplasm, the viral nucleocapsid uncoats by unknown mechanisms.


=== Methods of transmission ===
Template HCV RNA allows viral replication to take place and protein synthesis is thus facilitated. Cap-independent protein translation takes place when ribosomal 40S subunit binds to internal ribosome entry site (IRES).<ref name="pmid1310759">{{cite journal| author=Tsukiyama-Kohara K, Iizuka N, Kohara M, Nomoto A| title=Internal ribosome entry site within hepatitis C virus RNA. | journal=J Virol | year= 1992 | volume= 66 | issue= 3 | pages= 1476-83 | pmid=1310759 | doi= | pmc=PMC240872 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1310759  }} </ref> IRES is a stem-loop structure that is located at the 5' untranslated region (UTR) of the virus and the initial 30-40 nucleotides of the viral core-encoding region.<ref name="pmid1310759">{{cite journal| author=Tsukiyama-Kohara K, Iizuka N, Kohara M, Nomoto A| title=Internal ribosome entry site within hepatitis C virus RNA. | journal=J Virol | year= 1992 | volume= 66 | issue= 3 | pages= 1476-83 | pmid=1310759 | doi= | pmc=PMC240872 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1310759  }} </ref> Nonetheless, full polyprotein translation also requires the use of 80S ribosomes and the viral 3' UTR, both of which presumably play a role in regulation of the translational process.


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.
Translation is accompanied by co-translational processes and followed by post-translational processes; all of which yield a total of 10 mature proteins.<ref name="pmid7679746">{{cite journal| author=Grakoui A, Wychowski C, Lin C, Feinstone SM, Rice CM| title=Expression and identification of hepatitis C virus polyprotein cleavage products. | journal=J Virol | year= 1993 | volume= 67 | issue= 3 | pages= 1385-95 | pmid=7679746 | doi= | pmc=PMC237508 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7679746  }} </ref>


; Injection drug use


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 following proteins are produced:
====Structural Proteins:====
*Core (C) protein<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>


; Drug use by nasal inhalation (Drugs which are "snorted")
*Envelope 1 (E1) glycoprotein<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>


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>
*Envelope 2 (E2) glycoprotein<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>


; Blood products


[[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.
C, E1, and E2 are separated by the remaining 7 non-structural proteins by the activity of p7, a small membrane polypeptide that belongs to viroporin family.<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 3 proteins are released by the activity of signal peptidases mediated by the host cell.  


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.
====Non-Structural (NS) Proteins:====
*NS2: Zn-dependent proteinase<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><ref name="pmid14752815">{{cite journal| author=Penin F, Dubuisson J, Rey FA, Moradpour D, Pawlotsky JM| title=Structural biology of hepatitis C virus. | journal=Hepatology | year= 2004 | volume= 39 | issue= 1 | pages= 5-19 | pmid=14752815 | doi=10.1002/hep.20032 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14752815  }} </ref>


; Iatrogenic; medical or dental exposure
*NS3: Serine-dependent proteinase, helicase, and NTPase<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><ref name="pmid14752815">{{cite journal| author=Penin F, Dubuisson J, Rey FA, Moradpour D, Pawlotsky JM| title=Structural biology of hepatitis C virus. | journal=Hepatology | year= 2004 | volume= 39 | issue= 1 | pages= 5-19 | pmid=14752815 | doi=10.1002/hep.20032 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14752815  }} </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.
*NS4A: Cofactor NS3 proteinase<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><ref name="pmid14752815">{{cite journal| author=Penin F, Dubuisson J, Rey FA, Moradpour D, Pawlotsky JM| title=Structural biology of hepatitis C virus. | journal=Hepatology | year= 2004 | volume= 39 | issue= 1 | pages= 5-19 | pmid=14752815 | doi=10.1002/hep.20032 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14752815  }} </ref>


; Occupational exposure to blood
*NS4B: Membrane anchor<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><ref name="pmid14752815">{{cite journal| author=Penin F, Dubuisson J, Rey FA, Moradpour D, Pawlotsky JM| title=Structural biology of hepatitis C virus. | journal=Hepatology | year= 2004 | volume= 39 | issue= 1 | pages= 5-19 | pmid=14752815 | doi=10.1002/hep.20032 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14752815  }} </ref>


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.
*NS5A: Regulation of RNA polymerase activity and inhibition of antiviral activity of interferon<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><ref name="pmid14752815">{{cite journal| author=Penin F, Dubuisson J, Rey FA, Moradpour D, Pawlotsky JM| title=Structural biology of hepatitis C virus. | journal=Hepatology | year= 2004 | volume= 39 | issue= 1 | pages= 5-19 | pmid=14752815 | doi=10.1002/hep.20032 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14752815  }} </ref>


; Recreational exposure to blood
*NS5B: RNA-dependent RNA polymerase<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><ref name="pmid14752815">{{cite journal| author=Penin F, Dubuisson J, Rey FA, Moradpour D, Pawlotsky JM| title=Structural biology of hepatitis C virus. | journal=Hepatology | year= 2004 | volume= 39 | issue= 1 | pages= 5-19 | pmid=14752815 | doi=10.1002/hep.20032 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14752815  }} </ref>


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.
*p7: Separation of structural from non-structural proteins and possible formation of ion channel<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><ref name="pmid14752815">{{cite journal| author=Penin F, Dubuisson J, Rey FA, Moradpour D, Pawlotsky JM| title=Structural biology of hepatitis C virus. | journal=Hepatology | year= 2004 | volume= 39 | issue= 1 | pages= 5-19 | pmid=14752815 | doi=10.1002/hep.20032 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14752815  }} </ref>


; 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>
Non-structural proteins NS3 to NS5B play an important role in the formation of a replication complex that includes an intracellular "membranous web", at least partially derived from host endoplasmic reticulum.<ref name="pmid12021330">{{cite journal| author=Egger D, Wölk B, Gosert R, Bianchi L, Blum HE, Moradpour D et al.| title=Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex. | journal=J Virol | year= 2002 | volume= 76 | issue= 12 | pages= 5974-84 | pmid=12021330 | doi= | pmc=PMC136238 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12021330  }} </ref> The replication complex is responsible for synthesis template negative-strand RNA and consequent synthesis of its positive-strand counterpart. These RNA molecules are then enclosed in new virions.


; Body piercings and tattoos
===Formation of Nucleocapsid and Envelope===
New HCV nucleocapsid is formed by the action of core protein C along with viral genomic positive-strand RNA.<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 envelope of the newly formed nucleocapsid is later formed by budding action into the lumen of the endoplasmic reticulum. Nonetheless, envelope glycoproteins do not yet mature early on at this stage. When new virions are exported outside the host cell, via cellular secretory mechanisms, glycoproteins of the envelope finally mature.<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>


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>


==Histology==
==Histology==

Revision as of 00:35, 28 July 2014

Characteristics

Hepatitis C virus (HCV) is a member of the genus Hepacivirus that belongs to the Flaviviridae family. It is an enveloped, single-stranded RNA virus that measures approximately 60 nm in diameter.

CDC figures for sources of infection in the US. Source

Mode of Transmission

HCV is primarily transmitted by blood. Exposure to blood is observed primarily in healthcare settings, such as in blood transfusions, surgical procedures, needle injuries, and hemodialysis. Also, the role of intravenous drug use has recently emerged as a great risk for viral transmission after the relatively successful control of nosocomial HCV transmission.[1]

Life Cycle

Humans are considered the only natural hosts for HCV. The full life cycle of the virus is poorly understood due to difficulty to culture in vitro. The expression of E1-E2, two important envelope glycoprotein complexes, on the surface of HCV allows the virus to interact with host-ell molecules (glycosaminoglycans) by acting as ligands for cellular receptors, such as tetraspanin CD81, scavenger receptor class B type I (SR-BI), and mannose binding lectins DC-SIGN and L-SIGN. This interaction is believed to have a crucial role in cell recognition and cellular tropism.[2][3][4][5][6][7][8][9][10] The exact mechanism by which viral genome enters the host cell is poorly understood, but it is believed to be via receptor-mediated endocytosis. Then envelope glycoproteins utilize pH-dependent mechanisms to mediate fusion of the viral envelope using endosomal membrane.[6][7] As soon as it is released into the cytoplasm, the viral nucleocapsid uncoats by unknown mechanisms.

Template HCV RNA allows viral replication to take place and protein synthesis is thus facilitated. Cap-independent protein translation takes place when ribosomal 40S subunit binds to internal ribosome entry site (IRES).[11] IRES is a stem-loop structure that is located at the 5' untranslated region (UTR) of the virus and the initial 30-40 nucleotides of the viral core-encoding region.[11] Nonetheless, full polyprotein translation also requires the use of 80S ribosomes and the viral 3' UTR, both of which presumably play a role in regulation of the translational process.

Translation is accompanied by co-translational processes and followed by post-translational processes; all of which yield a total of 10 mature proteins.[12]


The following proteins are produced:

Structural Proteins:

  • Core (C) protein[13]
  • Envelope 1 (E1) glycoprotein[13]
  • Envelope 2 (E2) glycoprotein[13]


C, E1, and E2 are separated by the remaining 7 non-structural proteins by the activity of p7, a small membrane polypeptide that belongs to viroporin family.[13] The 3 proteins are released by the activity of signal peptidases mediated by the host cell.

Non-Structural (NS) Proteins:

  • NS3: Serine-dependent proteinase, helicase, and NTPase[13][14]
  • NS5A: Regulation of RNA polymerase activity and inhibition of antiviral activity of interferon[13][14]
  • NS5B: RNA-dependent RNA polymerase[13][14]
  • p7: Separation of structural from non-structural proteins and possible formation of ion channel[13][14]


Non-structural proteins NS3 to NS5B play an important role in the formation of a replication complex that includes an intracellular "membranous web", at least partially derived from host endoplasmic reticulum.[15] The replication complex is responsible for synthesis template negative-strand RNA and consequent synthesis of its positive-strand counterpart. These RNA molecules are then enclosed in new virions.

Formation of Nucleocapsid and Envelope

New HCV nucleocapsid is formed by the action of core protein C along with viral genomic positive-strand RNA.[13] The envelope of the newly formed nucleocapsid is later formed by budding action into the lumen of the endoplasmic reticulum. Nonetheless, envelope glycoproteins do not yet mature early on at this stage. When new virions are exported outside the host cell, via cellular secretory mechanisms, glycoproteins of the envelope finally mature.[13]



Histology

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

References

  1. ↑ 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.
  2. ↑ Op De Beeck A, Cocquerel L, Dubuisson J (2001). "Biogenesis of hepatitis C virus envelope glycoproteins". J Gen Virol. 82 (Pt 11): 2589–95. PMID 11602769.
  3. ↑ Penin F, Combet C, Germanidis G, Frainais PO, Deléage G, Pawlotsky JM (2001). "Conservation of the conformation and positive charges of hepatitis C virus E2 envelope glycoprotein hypervariable region 1 points to a role in cell attachment". J Virol. 75 (12): 5703–10. doi:10.1128/JVI.75.12.5703-5710.2001. PMC 114285. PMID 11356980.
  4. ↑ Barth H, Schafer C, Adah MI, Zhang F, Linhardt RJ, Toyoda H; et al. (2003). "Cellular binding of hepatitis C virus envelope glycoprotein E2 requires cell surface heparan sulfate". J Biol Chem. 278 (42): 41003–12. doi:10.1074/jbc.M302267200. PMID 12867431.
  5. ↑ Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R; et al. (1998). "Binding of hepatitis C virus to CD81". Science. 282 (5390): 938–41. PMID 9794763.
  6. ↑ 6.0 6.1 Bartosch B, Vitelli A, Granier C, Goujon C, Dubuisson J, Pascale S; et al. (2003). "Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor". J Biol Chem. 278 (43): 41624–30. doi:10.1074/jbc.M305289200. PMID 12913001.
  7. ↑ 7.0 7.1 Hsu M, Zhang J, Flint M, Logvinoff C, Cheng-Mayer C, Rice CM; et al. (2003). "Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles". Proc Natl Acad Sci U S A. 100 (12): 7271–6. doi:10.1073/pnas.0832180100. PMC 165865. PMID 12761383.
  8. ↑ Scarselli E, Ansuini H, Cerino R, Roccasecca RM, Acali S, Filocamo G; et al. (2002). "The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus". EMBO J. 21 (19): 5017–25. PMC 129051. PMID 12356718.
  9. ↑ Lozach PY, Lortat-Jacob H, de Lacroix de Lavalette A, Staropoli I, Foung S, Amara A; et al. (2003). "DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2". J Biol Chem. 278 (22): 20358–66. doi:10.1074/jbc.M301284200. PMID 12609975.
  10. ↑ Pöhlmann S, Zhang J, Baribaud F, Chen Z, Leslie GJ, Lin G; et al. (2003). "Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR". J Virol. 77 (7): 4070–80. PMC 150620. PMID 12634366.
  11. ↑ 11.0 11.1 Tsukiyama-Kohara K, Iizuka N, Kohara M, Nomoto A (1992). "Internal ribosome entry site within hepatitis C virus RNA". J Virol. 66 (3): 1476–83. PMC 240872. PMID 1310759.
  12. ↑ Grakoui A, Wychowski C, Lin C, Feinstone SM, Rice CM (1993). "Expression and identification of hepatitis C virus polyprotein cleavage products". J Virol. 67 (3): 1385–95. PMC 237508. PMID 7679746.
  13. ↑ 13.00 13.01 13.02 13.03 13.04 13.05 13.06 13.07 13.08 13.09 13.10 13.11 13.12 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.
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 Penin F, Dubuisson J, Rey FA, Moradpour D, Pawlotsky JM (2004). "Structural biology of hepatitis C virus". Hepatology. 39 (1): 5–19. doi:10.1002/hep.20032. PMID 14752815.
  15. ↑ Egger D, Wölk B, Gosert R, Bianchi L, Blum HE, Moradpour D; et al. (2002). "Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex". J Virol. 76 (12): 5974–84. PMC 136238. PMID 12021330.

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