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N. V. Bergasa
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163© The Author(s), under exclusive license to Springer-Verlag London Ltd., part
of Springer Nature 2022
N. V. Bergasa (ed.), Clinical Cases in Hepatology,
https://doi.org/10.1007/978-1-4471-4715-2_6
Chapter 6
Chronic Hepatitis C
NoraV.Bergasa
A 50-year-old man was referred to the Hepatology clinic for evaluation of chronic hepa-
titis C diagnosed 10year prior to the referral. His risk factors included intravenous drug
use and multiple tattoos done in prison. He felt well. His exam was notable for absent
cutaneous stigmata of chronic liver disease, and several tattoos (Fig.
6.1). His hemo-
gram and liver function were normal, the serum alanine (ALT ) and aspartate (AST)
transaminase activities were twice the upper limit of normal consistently, with normal
bilirubin and coagulation prole. He was infected with genotype 1a, and his viral load
was 1million IU/L. He was immune to hepatitis A and B.His liver ultrasound was
normal. Liver disease workup done at the time of the rst clinic visit excluded other
causes of liver disease. This patient’s risk for viral hepatitis included tattoos done in
prison; of interest, he placed tattoos on both antecubital fossae to cover needle tracts
from his intravenous injection of drugs. He continued to use heroin intranasally. He
reported that the environment in which he lived was not supportive of his wish to stop
using illicit drugs and, thus, had decided to move to another state where he would seek
treatment for chronic HCV.
N. V. Bergasa (*)
Department of Medicine, H+H/Metropolitan, New York, NY, USA
New York Medical College, Valhalla, NY, USA
Hepatology, H+H/Woodhull, Brooklyn, NY, USA
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Etiology
The hepatitis C virus (HCV) belongs to the genus Hepacivirus of the Flaviviridae
family [1]. It is an RNA virus of 60nm in dimension, surrounded by a protein shell
that is further encased by a lipid envelope, in which two glycoproteins are anchored
[2]. The virus has a positive sense single-stranded RNA genome that consists of a
single open reading frame 9600 nucleotide bases long that produces one protein [1],
which is processed by proteases to generate ten polypeptides [3]. The structural
region is comprised of the core, E (envelope) 1, and E2, and the nonstructural region
of p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B. NS2 and NS4A function as
proteases, NS3 as a helicase protease, and NS5B as an RNA polymerase [4]. An
HCV antigen is considered to be encoded, at least in part, by an alternate reading
frame (ARF) overlapping the core-encoding region [5, 6]. The variabilities in the
NS5B region of the virus has led to the identication of several genotypes, 1 through
7, comprised of subtypes [7]. The HCV circulates in the form of quasispecies [8],
which are closely related genomes that result from mutations in the nucleotide
sequence [9, 10]; this characteristic allows the virus to survive different replication
environments including the appearance of neutralizing antibodies and cytotoxic T
Fig. 6.1 Tattoo on needle
tracts on the left
antecubital fossa of a
patient who had used
intravenous drugs. The
dragon alludes to the
phrase “chasing the
dragon”, which refers to
inhaling the vapor from a
heated solution of drugs
including heroin
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165
cells, contributing to the chronic state of the infection [11], and resistance to antivi-
ral drugs [12]. The virus replicates within the hepatocyte; the entry sites include the
CD81, highly sulfated heparan sulfate, the low-density lipoprotein receptor, and
scavenger receptor class B type I and claudin-1 [13, 14]. Hepatocyte specic factors
that facilitate the entrance of the virus and that have not been identied seem neces-
sary to explain the predilection for the hepatocyte as a site for replication [14];
however, there are experimental ndings to suggest that this virus also replicates in
cells outside the liver, including the peripheral mononuclear cells compartment
[15], central nervous system [16], and epithelial cells [17], including the small
intestine [18].
Genetics
Eighty to eighty-ve percent of subjects who acquire HCV infection develop
chronic disease. Factors associated with spontaneous HCV clearance included acute
clinical hepatitis and female gender [19], as concluded from an analysis of the
course of viral hepatitis from a group of studies that comprised 675 subjects, with a
rate of spontaneous resolution calculated to be 26% [19]. The genetic characteristics
of the host are relevant in the evolution of an HCV infection as distinct MHC class
I and II alleles have been reported in association with clearance of the virus in
human beings [20]. From a study of a group of patients infected from a single
source, the majority of subjects that cleared the infection exhibited A*03, B*27, and
Cw*01 more frequently than those who did not. The haplotypes associated with the
resolution of the infection were A*03-B*07-DRB1*15-DQB1*0602 and A*02-
B*27-Cw*01-DRB1*0101-DQB1*0501. The alleles A*03, DRB1*0101, *0401,
*15, and B*27 were reported to be associated with viral clearance, with the latter
exhibiting the strongest association. The haplotype A*01-B*08-Cw*07-
DRB1*03011-DQB1*0201 was reported in association with chronicity [20].
HLA-B 57 and HLA DRB1* have been associated with resolution in contrast to
HLA-B 08, which was reported in association with chronicity [21]. A group of
patients typed as HLA-B57 that had not been protected from developing chronic
hepatitis C was stated to have sequence variations in HLA-B 57-restricted T-cell
epitopes, which seem to have prevented HLA-B 57-mediated immune pressure
[21]. Along the same line, another study from this well-characterized group of
patients also revealed HLA-B27in association with chronicity and HCV clearance.
An HLA-B27 restricted hepatitis C virus (HCV)-specic CD8+ T cell epitope was
recognized in the majority of HLA-B27 positive women who had resolved the acute
HCV infection. In patients who had developed chronic hepatitis C, the viral sequence
was strongly associated with sequence variations within this epitope and expression
of HLA-B27, which was interpreted to suggest an allele-specic selection pressure
at the population level. It was further documented that the new viral epitopes are
escape mutations. These results identied HLA-B27 as having a fundamental role
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in HCV infection resolution, and evolution of the HCV in relationship to a dominant
CD8+ T cell epitope [22].
The genetic characteristics of the host also inuence the progression of chronic
hepatitis C to cirrhosis. In this regard, the polymorphism rs738409 GG genotype of
the patatin-like phospholipase domain-containing 3 (PNPLA3) encoding for the
I148M protein variant has been reported in signicant association with the stage of
brosis and presence of cirrhosis [23, 24].
Viral behavior is fundamental in determining the course of infection, including
the slow evolution of the heterogeneous viral population, dened as quasispecies,
correlating with the resolution, and viral escape mutations in epitopes targeted by
cytotoxic T lymphocytes associated with chronicity [24].
Changes in the sequence have been demonstrated to occur mainly within the
hypervariable region 1 of the E2 gene, conrmed to be temporarily related to anti-
body seroconversion, which has suggested that it is a behavior to escape immuno-
logical pressure from the immune system [11]. Acute infection associated with the
size of the inoculum, low and high, has both been associated with spontaneous reso-
lution. A single nucleotide polymorphism (rs12979860) in chromosome 19q13, 3
kilobases upstream of the IL28B gene, which encodes the type III interferon IFN-3,
and a high viral load in the acute infection (i.e., 7 log(10) IU/ml) were associated
with spontaneous viral clearance, as compared to subjects with the IL28B-T allele
in whom chronic infection prevailed [25]; this allele is also associated with sus-
tained virological response in association with treatment with interferon [26]. Other
genetic polymorphisms have been identied in association with clearance of the
hepatitis C virus infection, including genotype −509C in the gene that codes for
transforming growth factor (TGF)-β1 [27], and which suppresses the proliferation
and cytotoxicity of cells [28]. Genes encoding KIR2DL3, a receptor on the NK cell,
and its human leukocyte antigen C group 1 (HLA-C1) ligand also contribute to the
resolution of acute hepatitis C [29]. Over 50% of patients with genotype CC in the
gene that codes for IL 28B cleared an acute hepatitis C viral infection, in contrast to
those with genotypes CT, and TT, the least favorable genotype in association with
clearance [30].
What determines the outcome of the infection also relates to the manner in which
the host immune system handles the virus. Natural killer (NK) cells are fundamental
in response to viral infections. In hepatitis C, there is an activation of natural killer
cells during acute infection regardless of its outcome [31]. In the realm of NK cells,
the population of peripheral CD56(neg) NK cells was expanded in acute, resolved,
and chronic HCV infection. Increased frequency of HLA-C-binding KIR(+) NK
cells was documented in patients who had resolved the acute infection. There was a
reported increase in NKG2A(+) and CD94(+) NK cells in acute and chronic HCV
infection, but this was not documented in patients who had resolved the infection.
In addition, a decrease in the frequency of NKp30(+), NKp46(+), CD161(+), and
NKG2D(+) cells was reported in patients who in follow up, resolved the infection
[32]. Patients who did not develop hepatitis after documented exposure to the hepa-
titis C virus exhibited signs of natural killer (NK) T cell activation, increased serum
concentrations of chemokines, and NK cell responses with increased expression of
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CD122, NKp44, NKp46, and NKG2A, TRAIL and CD107a, and production of
gamma interferon. The NK response manifested itself earlier in the subjects who
did not develop hepatitis than in the one individual who did. The production of
interferon gamma by NK cells differed from what is documented to happen in
patients with chronic hepatitis C, whose NK cells fail to produce interferon gamma
appropriately. The degree of NKT cell activation and cytotoxicity was reported to
correlate with the specic HCV-T cell response expressed subsequently. There was
evidence of active replication in the absence of systemic viremia, as indicated by the
response of T cells targeting nonstructural proteins of the hepatitis C genome, which
require translation of viral RNA and hence, suggested replication. These ndings
tend to support the idea that a vigorous response by NKT cells is associated with a
subsequent effective T cell response and potential immunity against the hepatitis C
virus [33]. Also, in chronic infection, continued expansion in the NK population of
cells has been documented, with an increased presence of this type of cell in the
liver versus peripheral blood. The NK cells in the chronic stage of the infection were
reported to express tumor necrosis factor-related apoptosis-inducing ligand
(TRAIL), NKp44, NKG2C, and CD122 in contrast to a control group of non-
infected subjects. There was an increased frequency of CD107a expression indica-
tive of degranulation (i.e., cytotoxicity); however, no increase in interferon gamma
production of CD56(dim) NK cells was noted. The use of interferon alpha to stimu-
late invitro NK cells from infected and non-infected individuals was documented
to be associated with the NK phenotype of patients. These results were interpreted
to suggest that the exposure of NK cells to alpha interferon may contribute to the
liver injury associated with HCV infection via TRAIL and cytotoxicity, with the low
expression of gamma interferon contributing to chronicity [34]. In patients with
chronic hepatitis C, NKp46(High) NK cells displayed a greater cytolytic activity
and production of interferon gamma than NKp46(Dim) NK cells, and in vitro,
NKp46(High) NK cells blocked the production of HCV in the replicon system. An
increase in the density of NKp46(High) NK cells correlated inversely with hepatitis
C RNA load, suggesting an in situ and invivo antiviral effect and with hepatic bro-
sis, suggesting an antibrotic function of this type of NK cells [35]. The chemokine
CXCR3 receptor and its ligands have been reported as increased in chronic hepatitis
C.In further support of a role of NK cells in liver brosis in chronic hepatitis C is
the increase in the density of CXCR3(+)CD56Bright NK cells, which were docu-
mented to display impaired degranulation and impaired production of interferon
gamma in association with exposure to hepatic stellate cells [36]. Thus, emerging
data support the activation of innate immune responses after acute infection with the
hepatitis C virus and NK’s role in the evolution of hepatitis C virus infection and
potential mediation of liver brosis.
Spontaneous resolution of acute HCV infection is associated with the production
of neutralizing antibodies and the development of CD4+ and CD8+ T cells specic
to the virus [37]. In vitro studies by the use of an infectious retroviral HCV pseu-
doparticle model system with sera from subjects who had experienced acute HCV
after the receipt of contaminated immunoglobulin D [38] revealed that resolution of
infection was associated with high titers of neutralizing antibodies in the early
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phase, dened as the rst 6months after it, in contrast to what was reported from
patients who had developed chronic infection in whom low titers or absence of this
type of antibodies was documented [39]. Neutralizing antibodies, which were
recorded to cross-react with genotypes different from the one that caused the index
infection, decreased or disappeared after the resolution of the acute infection, con-
sistent with prior reports [40]; this peculiarity may be related to the absence of
protection from new HCV infections [41].
CD4+ T cells are considered essential in the clearance of the HCV in acute infec-
tion and prolonged protection against recurrent infections, as supported from stud-
ies of reinfection with HCV in chimpanzees in which CD4+ T cells had been
antibody-depleted. Persistence and immune evasion on a repeat exposure to the
HCV were reported in this model of the human disease in spite of functional CD8+
T cells [42]. In the initial stages of the infection, HCV-specic CD8+ T cells exhibit
a deciency in the production of interferon gamma [43]. In the subsequent stage,
interferon gamma is produced by HCV-specic CD8+ T cells [44]; this event coin-
cides with the appearance of HCV-specic CD4+ T cells, a decrease in viral load,
and an increase in serum activity of transaminases [44]. Ex vivo studies with cells
from patients with chronic hepatitis C and from those who recovered from the infec-
tion have been reported to reveal a signicantly greater response of HCV-specic
type-1 T-cell in patients who had recovered from the infection than in those who had
not. Chronicity of the infection was associated with a reversible CD4-mediated sup-
pression of HCV-specic CD8 T cells and with an increase in the number of CD4(+)
CD25(+) regulatory T cells in the material from patients with chronic infection able
to suppress HCV-specic type-1 CD8 T cells [45].
In contrast to the disappearance of antibodies, helper and cytotoxic T cell
responses characterized by interferon gamma production have been documented to
remain for years after the infection [40]. However, the characteristic features of T
cells have also been reported in patients who clear or fail to clear the virus on the
index infection. Clearance of the virus was stated to be associated with a production
of Th1 cytokines upon stimulation of CD4+ T cells by NS3 and NS4, nonstructural
proteins of the virus invitro, as compared to cells from patients who developed
chronic disease, which did not produce any Th1 cytokines [46]. In the liver, CD4+
FOXP3+ cells were abundant in the inammatory inltrate of samples from patients
with chronic hepatitis C virus infection [47].
T cell-mediated cytotoxic mechanisms also contribute to the response to an HCV
infection. Peripheral blood mononuclear cells from patients with resolved hepatitis
C viral infection were reported to exhibit a specic response to recombinant non-
structural viral protein 3 characterized by the production of interferon gamma. A
response was observed by peripheral mononuclear cells from some patients with
progression to chronic hepatitis C infection found from only a minority of samples
from patients with chronic infection [48]. A strong proliferative response to the
recombinant viral proteins core, E1, E2, NS3, NS4, and NS5 by peripheral T cells
was characteristic of cells derived from subjects who exhibited normalization of
serum activity of transaminases, a reection of hepatic inammation, in response to
an acute HCV infection, and viral clearance, than from cells derived from subjects
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who developed the chronic disease. T cells’ response to the viral proteins was
detected early in the course of the infection, suggesting that its magnitude deter-
mines the natural history of the infection, i.e., resolution or chronicity [49]. The loss
of specic CD4+ T cell proliferation in response to the virus has been associated
with recurrence of the disease, suggesting that for the infection to be permanently
controlled, the CD4+ cells must remain responsive to the viral proteins [49].
An important role of CD8+ T cells in the mediation of chronic hepatitis C has
also been identied and considered fundamental in the evolution of the acute HCV
infection. In this regard, it was demonstrated that in early HCV infection, a robust T
helper and cytotoxic response was characteristic; however, the cytotoxic activated
lymphocytes were decient in the production of interferon gamma, which gradually
increased as the viral load decreased. Hepatitis C responses from cytotoxic lympho-
cytes were more common in patients who cleared the virus than in those with
chronic disease [43].
The events that characterized the course of acute hepatitis C were: (i) the
appearance of hepatitis C virus specic T cells 1 month after infection, (ii) a
CD38+ IFN- gamma—CD8+ T cell response, in association with a decrease in
viral load, (iii) a robust CD4+ T cell response, and (iv) the appearance of CD
38-CD8+ T cells that produced interferon gamma, which coincided with a marked
decrease in viral load, not associated with an apparent increase in disease activity.
In patients in whom the viral infection became chronic, there was no substantial
T cell response or a response that was, although strong, transient [44]. A central
role of CD8+ T cells has been further suggested by the reported association
between protective HLA alleles, including HLA-B27, HLA-B57, and HLA-A3
and resolution of HCV infection in relationship with dominant CD8+ T cell epit-
opes [37, 50, 51].
The mechanism by which CD8+ T cells eliminate virus infected hepatocytes is
mostly non-cytolytic and mainly mediated by interferon gamma [52]. A fundamen-
tal role of CD8+ T cells has also been supported by an invitro study in which deple-
tion of CD4(+)CD25(+) T regulatory (T(reg)) cells from patients with chronic
hepatitis C was associated with increased HCV (and EBV) peptide driven expan-
sion and in the number of CD8(+) T cells expressing IFN-gamma; also, the suppres-
sive effect of CD4(+)CD25(+) regulatory T cells on CD8(+) T-cell proliferation was
not prevented by the addition of antibodies to IL-10 and to transforming growth
factor beta to block the expressed receptors by the CD8+T cells. These experiments
have supported the idea of a marked CD4(+)CD25(+) regulatory T-cell activity in
patients with chronic hepatitis C, associated with a suboptimal response to the HCV
by CD8+ T cells [53], consistent with the proper function of memory CD8+ T as a
prerequisite for protection from chronic hepatitis C [54].
It was also demonstrated that in early HCV infection a robust T helper and cyto-
toxic response was characteristic; however, the cytotoxic activated lymphocytes
were decient in the production of interferon gamma, which gradually increased as
the viral load decreased. Hepatitis C responses from cytotoxic lymphocytes were
more common in patients who cleared the virus, as compared to those with chronic
disease [43].
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Also, in patients who develop chronic hepatitis C, an abnormal function of CD8+
T cells, including their inability to produce IL-2, interferon gamma and other cyto-
kines, and to proliferate, has been documented [55, 56]. In this respect, studies on
the role of the immunoinhibitory receptor programmed death-1 (PD-1), which is
upregulated in dysfunctional virus specic CD8+ T cells, revealed that in the liver
of patients with chronic hepatitis C, HCV-specic CD8 T cells from chronically
HCV-infected patients expressed PD-1 intensely, exhibited dysfunctional behavior,
and were not responsive to the reparatory effect of PD-1/PD-L blockade. However,
in the periphery, CD8+ T cells expression was lower than that of the intrahepatic
cells and did exhibit a response to PD-1/PD-L blockade [57]. The expression of
PD-1in CD8+ T cells during the acute phase of the HCV infection was high, regard-
less of the course of the disease, i.e., resolution vs. chronicity, and subsequently
decreased, in association with differentiation of CD8+ T cells to a memory CD127+
phenotype and resolution of infection [58]. The degree of PD-1 expression in the
acute phase of the infection has also been reported to be signicantly higher on T
cells specically responsive to the HCV in patients who develop chronic hepatitis
than in those who resolve the infection [59].
IL-10, a cytokine that prevents inammation but that also has been reported to
facilitate viral prevalence, has been reported to contribute to the development of
chronic hepatitis C. In this context, intrahepatic CD8+ T cells responsive to the
hepatitis C virus produce IL-10 and not gamma interferon, and, although their pres-
ence was reported to prevent liver injury, these cells are not effective in eliminating
the virus [60]. In addition, CD8+ T cells that produce IL-10 were documented to be
present in the early stages of the acute infection and to prevail in chronic disease;
these ndings were reported to correlate with poor CD4+ effector function, and
with high viral load in acute infection. Although interleukin secretion in response to
the hepatitis C virus was high in patients without cirrhosis, the blockade of IL-10
was associated with an increased antiviral effect mediated by IFN-gamma, suggest-
ing that a proviral environment is facilitated by IL-10 [60].
An important role of CD8+ T cells has also been supported by an invitro study
in which depletion of CD4(+)CD25(+) T regulatory cells in samples from patients
with chronic viral hepatitis C was associated with increased HCV (and EBV) pep-
tide driven expansion and in the number of CD8(+) T cells expressing IFN-gamma;
also, the suppressive effect of CD4(+)CD25(+) regulatory T cells on CD8(+) T-cell
proliferation was not prevented by the addition of antibodies to IL-10 and to trans-
forming growth factor beta to block the expressed receptors by the CD8+ T cells.
These experiments have supported the idea of a marked CD4(+)CD25(+) regulatory
T-cell activity in patients with chronic hepatitis C, associated with a suboptimal
response to the HCV by CD8+ T cells [53], consistent with the proper function of
memory CD8+ T as a prerequisite for protection from chronic HCV infection [54].
Escaping CD8+ T cells by rapid mutations is another mechanism by which the HCV
survives in the body of the host. The lack of T cell receptor diversity does not allow
recognition of the mutant variant against which cellular activation and effector func-
tions would have been expected to occur, thus providing a way for the virus to
escape the immune system.
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Epidemiology
The World Health Organization (WHO) reports that every year 3–4 million people
contract hepatitis C virus infection [61]. Numbers as high as one hundred and fty
(150) million chronically infected individuals worldwide are quoted [61]. However,
there is uncertainty about the prevalence and incidence of this infection because
epidemiological studies come from certain parts of the globe only. Most impor-
tantly, statistics from vulnerable populations, including homeless and incarcerated
people, are not available. Yearly, the WHO reports that 350,000 people die from
chronic hepatitis C related complications [61]. In the United States, between 1999
and 2007, deaths from HCV increased signicantly to 15,106in a study that used
death certicates as sources of information [62]. In this regard, the generation of
baby boomers, comprised of individuals born from 1945 to 1965, is considered as
having been at risk for exposure, which, according to a Canadian group of investiga-
tors, concerns health care practices [63], and not the societal events that included
drug use and that affected that generation [64, 65]; this concern has led to the rec-
ommendation of the Centers for Disease Control and the United States Preventive
Task Force to screen persons from that generation and which now has been extended
to include subjects aged at least 18years [66].
The hepatitis C virus is transmitted by contaminated blood products, body uids,
and supplies used in procedures including injections; thus, the factors for hepatitis
C virus infection include: (i) blood transfusions given before 1992, and blood prod-
ucts, including factors, before 1987, (ii) organ transplantation before 1992, (iii)
injections with contaminated needles including those used for illicit drugs, or those
used by lay injectors, e.g., unsafe therapeutic injections, (iv) use of contaminated
needles such as injection of illicit drugs, (v) drug snorting, e.g., cocaine and heroin,
(vi) body piercing and tattoos done with contaminated needles or contaminated ink,
(vii) sex between men, multiple sexual partners, or sexual intercourse with an
infected partner 6months prior to clinical expression of the infection [67], (viii)
children born to HCV-positive mothers [68].
The prevention of hepatitis C virus infection concerns avoidance of high risk
behavior and practices, including unsafe injection practices, sharing sharp objects
of personal use, e.g., razors, sharing of drug paraphernalia, unprotected sex with
people with chronic hepatitis C, body piercing, acupuncture and tattoos with poten-
tially contaminated equipment.
Natural History
The clinical manifestation of acute hepatitis C is preceded by an incubation period
between 2weeks and 6months after inoculation with the virus.
Studies of populations at risk or analysis of stored samples from patients subse-
quently identied as having chronic hepatitis C have provided information on the
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