Current Pharmaceutical Design, 2008, 14, 1661-1665 1661

Acute Hepatitis C: Clinical Aspects, Diagnosis, and Outcome of Acute HCV Infection

P. Fabris1, V. M. Fleming2, M.T. Giordani and E. Barnes2,*

1
Department of Infectious Diseases and Tropical Medicine, S. Bortolo Hospital, Vicenza, Italy and 2Nuffield Department of Medi-
cine, University of Oxford, Oxford, UK

Abstract: Acute hepatitis C virus (HCV) infection is often a clinically silent infection, and is therefore rarely detected. A high index of
clinical suspicion in addition to careful serological and virological assessment is required to identify the disease, and to determine the
eventual clinical outcome after primary infection; the minority of acutely infected individuals spontaneously control viremia in long term
whilst the majority become persistently infected. Here, we describe the clinical presentation of acute HCV infection and the patterns of
viremia and liver alanine transaminase levels (ALT) observed. We discuss the serological and virological assessment and potential pit-
falls in accurately diagnosing acute HCV. Good prospective studies that identify host and virological factors that determine clinical
symptoms and disease outcome are difficult to perform due to the asymptomatic nature of infection, but some progress has been made in
this field. Host factors including gender, age at time of infection, prior resolution of infection, symptomatic infection and host immune
responses, and viral factors such as the nature of the infecting quasispecies and more speculatively viral genotype, are some features that
have been correlated with disease outcome. In spite of this, on an individual patient level, it is currently not possible to predict those that
will resolve infection. Identifying, in detail therefore, those factors that are responsible for viral control remains an important research
goal not only to aid clinical management but also to develop effective treatment and vaccination strategies.

Key Words: Acute hepatitis C, symptoms, signs, diagnosis, outcome, host, viral, factors.

CLINICAL ASPECTS OF ACUTE HCV INFECTION
The majority of acute HCV infections are asymptomatic. There-
fore, in most patients HCV infection is diagnosed several years
after exposure once chronicity is established, following routine
blood testing, or after the development of major complications. The
fact that most patients are asymptomatic means that large, robust
studies that assess prospectively both clinical signs and outcomes of
primary infection are lacking. Reports of the symptoms and out-
come of HCV infection are generally based on cross-sectional
analysis of people cohorts such as blood donors years after primary
infection, small outbreaks of HCV in a distinct clinical settings with
a single viral genotype [1, 2] or the assessment of patients who
present with clinical symptoms and/or abnormal liver function tests
[3]. An informative study by Cox et al. followed 179 people who
were actively using intravenous drugs. Of these, 62 developed pri-
mary HCV infection. Symptoms in all these were mild, and none
sought medical attention [4]. These findings are not necessarily
applicable to patients who become infected through alternative
routes, such as blood transfusion or needle-stick injuries and cer-
tainly there are many reports of patients presenting with sympto-
matic acute HCV infection, and rarely fulminant liver failure [5].
HCV Viremia
Following exposure to HCV, HCV RNA is usually detected in
serum 7-21 days later, and precedes the elevation in ALT under-
scoring the non-cytopathic nature of the virus. The peak levels of
HCV RNA are highly variable and have not been shown to corre-
late either with the degree of ALT elevation, the development of
jaundice or the outcome of HCV infection [4]. Patterns of viremia
after primary infection also vary widely between individuals and
may oscillate considerably during the early months of infection
within the same individual. An oscillating viral load may be a use-
ful indicator of acute infection and contrasts with viral loads seen in
long term chronic infection where viral loads are relatively stable.
A stable level of HCV RNA often occurs within the first 60 days
after the detection of viremia, but may not occur for up to a year in
those that develop persistent infection. Transient loss of HCV RNA
is commonly reported in those that ultimately develop persitent
*Address correspondence to this author at the Peter Medawar Building for
Pathogen Research, South Parks Rd, Oxford, OX1 3SY, UK; Tel: 01865
271199; E-mail: ellie.barnes@ndm.ox.ac.uk
infection. Similarly amongst individuals who resolve infection, the
timing at which HCV RNA is persistently undetectable varies
widely, but is typically said to occur at 3-4 months after infection,
but may take as little as 27 days [3] or as long as 620 days after the
detection of viremia [4]. No particular pattern of viremia has been
reported to clearly associate with the outcome of primary infection,
although in some patients viral clearance is associated with a fast
and continuous viral load decline (personal experience).
The heterogeneity in peak levels of viremia and clinical out-
come is most likely due to multiple factors such as the sequence of
the infecting viral strain, the viral titre in the infecting innoculum,
and the route of primary infection. Direct evidence for this in HCV
is lacking, although there is good indirect evidence from mouse
models of persistent viral infection, in particular lymphocytic
choriomeningitis virus (LCMV) [6]. LCMV is an RNA virus which
may cause liver inflammation in mice and which is able to set up
persitent infection, or be controlled to very low levels. LCMV in-
fection is controlled initially by innate immune mechanisms, such
as interferons. Mice lacking normal interferon pathways are highly
susceptible to infection [7]. However, the dose, route and, impor-
tantly, the kinetics of infection play an important role in defining
outcome [6]. Host differences in those infected with HCV, espe-
cially those that pertain to innate and adaptive immune responses
have been shown to crucially determine outcome and are discussed
in detail by Fitzmaurice and Klenerman in this edition.
ALT Levels
Similarly, the effect of acute HCV infection on levels of alanine
transaminase (ALT) between individuals is highly variable. ALT
levels typically rise 10-14 weeks after initial infection and can
reach more than 20 times the upper limits of normal [3]. However,
mild elevations of ALT are probably more common and may in-
crease above baseline in patients followed prospectively and yet
remain within the normal laboratory ALT limits [4].
Symptoms and Signs
Symptoms of acute infection, when they do occur, are undistin-
guishable from other causes of acute hepatitis, and begin several
weeks after primary infection following a rise in ALT levels that
signifies the onset of hepatocellular necrosis. The clinical syn-
drome, when it occurs, is generally less severe than acute hepatitis

1381-6128/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd.

1662 Current Pharmaceutical Design, 2008, Vol. 14, No. 17
A or B. Usually symptoms are mild and constitutional and include
nausea, flu-like symptoms (headache, muscle aches), and vomiting.
However abdominal pain, jaundice, and symptoms of cholestasis
such as itching, dark urine and pale stools also occur. Elevations of
bilirubin above pre-infection levels almost invariably occur, but the
incidence of overt jaundice is debated. Jaundice is said to occur in
as many as 50% of symptomatic acute hepatitis C patients [3]. This
is probably an overestimate, as the incidence of jaundice depends
on the criteria used to define acute hepatitis C. Studies which have
included very high ALT levels as an essential criteria for the diag-
nosis of acute HCV may over estimate the development of jaundice
during acute infection. The appearance of jaundice in acute HCV
reflects hepatic necrosis and the development of HCV specific
adaptive immune responses [8-10]. It has been suggested that the
presence of jaundice and/or symptoms may correlate directly with
an increased likelyhood of long-term HCV resolution [11, 12].
However, clearly symptomatic patients may develop persistent in-
fection, and conversely asymptomatic patients may eradicate virus
long-term, highlighting the complex interplay of multiple factors
that determine outcome from primary HCV infection (Table 1).
Table 1. Factors that Potentially Determine Outcome from Primary
HCV Infection
Host Related Viral Related
Gender Viral genotype
Age Viral quasispecies diversity
Symptomatic infection Transmission route
Immunological responses Size of inoculum or
- Innate responses viral load in inoculum
- HLA class I and II associations
- CD4+/CD8+ T cell responses
- Cytokine genetic polymorphisms
Coinfection
- HIV
- Schistosomiasis
Previous exposure to HCV
DIAGNOSIS OF HCV INFECTION
Serological, Virological and Biochemical Assessment
The gold standard for the diagnosis of acute infection is the
demonstration of sero-conversion from anti-HCV negative to anti-
HCV antibody positive status in an HCV RNA positive patient, or
the detection of HCV RNA in a patient very recently known to be
HCV-RNA negative, with a history of possible exposure to HCV
over recent weeks. However, many patients are already positive for
both HCV antibodies and HCV-RNA at the time of initial presenta-
tion. Therefore, seroconversion may be demonstrable only in pa-
tients routinely screened for anti-HCV, such as intra-venous drug
users or in individuals monitored following a well defined risk fac-
tor, such as needle stick injury.
HCV antibodies may be undetectable at presentation, despite
high levels of ALT. In these patients, especially those with no other
risk factors for hepatitis, HCV antibody testing should be repeated
and HCV-RNA should be measured by RT- PCR (reverse-
transcription polymerase chain reaction). The detection of HCV
RNA in this setting is not diagnostic of acute HCV however, and
may represent chronic infection; in some clinical scenarios, such as
in those with congenital deficits in immunoglobulin production,
patients with HIV infection, and renal dialysis patients sero-
conversion may be absent or very delayed and the diagnosis can be
made only by measuring HCV-RNA, in the presence of an appro-
priate clinical scenario.
Fabris et al.
Although very high ALT levels (>20 times upper limit of nor-
mal) have been used as one of the diagnostic criteria for acute HCV
[3], it is clear that patients may be acutely infected with minimal
increases in the ALT levels [4]. Furthermore many other factors
such as alcohol intake and other viral infections may be responsible
for a rise in transaminases. It has also been reported in a prospective
study conducted in prison inmates that transient HCV viremia can
be demonstrated, without anti-HCV sero-conversion at any time,
and without biochemical signs of liver damage [13]. This supports
the idea that as in other infections, a limited viral burden can be
eradicated by cellular immune responses. A patient who has detect-
able HCV antibodies but undetectable HCV RNA is most likely to
have had a previous exposure to HCV that has resolved, rather than
acute or persitent infection. However, repeat RNA testing should be
performed after several weeks to ensure that the patient is not
acutely infected at a time when the viral load is oscilating, or persis-
tently infected at very low viral titre so that HCV RNA is intermit-
tently positive.
Anti-HCV seroconversion typically occurs 4-10 weeks follow-
ing HCV infection. Humoral immune responses are generated
against multiple targets. During sero-conversion antibodies that
target the NS3 regions are first detected, followed by antibodies
against NS4 and NS5 regions [14]. HCV antibodies are detected
using enzyme immunoassays (EIA), where HCV specific antibodies
are “captured” on microtitre wells coated with viral antigens, and
detected using a colourimetric reaction. Third generation EIA’s
detect antibodies that target core, NS3, NS4 and NS5 proteins. EIAs
are automated, relatively cheap, are suitable for large sample num-
bers. A positive test should be repeated, ideally on a new sample
from the same patient, and HCV RNA testing performed to confirm
the presence of viremia. The presence of HCV specific antibodies
has also been determined using the RIBA (Recombinant Im-
munoblot) assay that demonstrates the appearance of antibodies
against multiple HCV antigens coated on a nitrocellulose strip.
Positive reactions are determined by counting the number of bands
on a strip. The RIBA assay may be “indeterminate” during the first
week (with antibodies positive to core and NS regions) of acute
infection. At later time points (ranging from 1 to 6 months) the
RIBA test becomes fully positive [11]. The RIBA test is not often
used in clinical practice as it is expensive and interpretation of the
test is partially subjective.
Anti-HCV IgM determination is not a useful marker in the di-
agnosis of acute HCV as it is present in patients with both acute and
chronic hepatitis C. Total HCV core antigen, one of the most con-
served products of viral genome has been assessed as an early puta-
tive marker of viremia. It is detectable in sera by using an EIA as-
say. Although there is a correlation between core antigen and HCV
viremia (1pg of core antigen is equivalent with 8,000 IU/mL HCV-
RNA) it has no role in the diagnosis of acute HCV, and is detected
1-2 days later than HCV RNA [15,16].
Ultrasound Scan and Acute Hepatitis C
Abdominal ultrasound Scan (US) is usually performed in pa-
tients presenting with a hepatitis of unknown aetiology, and is par-
ticularly useful where there is only a modest increase in ALT, as
commonly occurs in acute HCV, to exclude other liver pathology
such as tumour and cholelithiasis. There are some aspects that are
typical of acute hepatitis, but not specific for hepatitis C. During
acute hepatitis a ultrasound may reveal an enlarged liver. The
echostructure is conserved but the echogenicity is often increased.
The gall bladder wall is frequently thickened, secondary to the in-
flammatory process in the adjacent liver. Patients with highly ele-
vated serum liver enzymes are more likely to have gallbladder wall
thickening and disruption of planes between the muscular and se-
rosal layers than are patients with normal liver enzyme levels [17].
The most common finding at ultrasound in patients with acute
hepatitis is enlargement of lymphnodes located at the hepatic hilum,
Acute Hepatitis C
pancreatic area and lesser omentum [18]. Typically these nodes are
hyperechogenic at the centre with an hypoechogenic outer layer.
Lymphadenopathy is not specific for acute hepatitis and is also
reported in chronic HCV and HBV infections [19].
Histology
Liver biopsy in not indicated during acute hepatitis C. Serologic
tests, the pattern of ALT fluctuation and the serial determination of
HCV-RNA viral titre is generally diagnostic. However, a number of
liver biopsies have been performed during acute hepatitis C [20].
Histological findings in two patients biopsied in close temporal
proximity to the clinical presentation showed similar histologic
findings with mixed portal infiltrates with lymphocyte and neutro-
philis in addition to bile duct proliferation. The lobules showed
canalicular cholestasis and mild to moderate inflammation. Eight
weeks after presentation, biopsies demonstrated mild to moderate
portal and lobular lymphocyte infiltration. Similar findings were
also observed in a patient biopsied 18 weeks after presentation.
Therefore, liver biopsies performed early after acute hepatitis C
infection may have a cholestatic pattern, whereas later biopsies tend
to show mild non-specific portal and lobular lymphocytic inflam-
mation. The presence of significant fibrosis in a biopsy raises the
possibility that the diagnosis is chronic HCV with a “flare” in ALT
rather than acute infection, and the diagnosis of acute HCV should
be reviewed. Liver biopsy is also commonly performed in liver
transplant recipients where specific histological features may dis-
tinguish recurrent hepatitis C infection from acute cellular rejection
[21].
OUTCOME OF HCV INFECTION
The majority of patients infected with HCV develop persistent
infection. However, approximately 25% of patients will spontane-
ously resolve infection. Identifying those factors that are associated
with viral clearance remains an important goal in the research of
HCV with important implications for drug and vaccine design. The
outcome of HCV infection is determined by both host factors and
viral factors and are summarised in Table 1.
Host Factors
Several studies have shown that female gender is associated
with a higher rates of spontaneously clearance compared to male
individuals, possible due to an oestrogen-dependent mechanism [3,
11, 22, 23]. Older age at the time of infection is also associated with
an increased likelyhood of persistence [22].
A number of clinical observational and host immunogenetic
studies in both humans and chimpanzee models support the idea
that the host immune response crucially determines the outcome of
acute infection. These studies are discussed in detail by Fitzmaurice
and Klenerman in this edition. Patients with symptomatic acute
hepatitis C, in particular those with jaundice and high ALT levels,
appear to have a higher rate of spontaneous resolution compared to
those with clinically silent disease [11, 22]. It is thought that a ro-
bust anti-viral immune response targets infected hepatocytes result-
ing in liver necrosis and jaundice. In patients who resolve hepatitis
C in the absence of symptoms it is likely that cytokine mediated
viral clearance plays a particularly important role, as has been
shown for HBV infection [24]. The importance of the immune re-
sponse in resolving acute infection is further highlighted by the
high rates of chronicity seen in patients that are immunosuppressed
such as those with HIV infection or following liver transplantation
[25, 26]. The importance of an effective CD4+ and CD8+ T cell
response in mediating viral clearance is underscored by the clear
association of HLA class II [27, 28] and class I alleles [29] with
viral control. Furthermore, blocking CD4+ and CD8+ T cell subsets
in chimpanzee experiments prior to HCV infections has shown that
these subsets are an important component of viral control [30, 31].
In patients with Schistosoma mansoni co-infection, the rate of spon-
Current Pharmaceutical Design, 2008, Vol. 14, No. 17 1663
taneous clearance is virtually absent due to an impairment of HCV-
specific CD4+ response and the production of cytokines with a Th2
as opposed to a Th1 profile [32]. Host NK cell function may also
play an important role and it has been shown that homozygotes for
a polymorphism in the inhibitory NK cell receptor KIR2DL3 and
its HLA-C1 ligand were 2-3 fold more likely to clear HCV infec-
tion than heterozygotes for these alleles [33]. Variants of the immu-
nomodulatory cytokine IL-10 and IL19/IL20 have also been impli-
cated in the spontaneous resolution of HCV infection [34, 35]. Fi-
nally, assessing the rate of spontaneous resolution of HCV in intra-
venous drug users with serological evidence of prior HCV infec-
tion, suggests that the prior resolution of HCV may afford a degree
of protective immunity to subsequent infection [36].
Viral Factors
HCV is commonly classified into six major viral genotypes,
which share sequence homology of approximately 80%, and which
are located in geographically distinct regions [37]. A characteristic
feature of RNA viruses including HCV is the high degree of genetic
diversity generated during viral replication as the HCV RNA po-
lymerase lacks proof reading ability. Furthermore HCV replication
is extremely vigorous producing an estimated 10 trillions virions a
day [38]. Viral mutations are generated during each round of viral
replication, and so populations of genetically distinct viral strains
co-exist within the same individual (quasispecicies).
There is little quality data that allows any conclusions to be
drawn regarding HCV viral genotype in relation to viral clearance
following acute HCV infection. The rates of spontaneous resolution
of HCV have been derived from two kinds of studies. The first
involves HCV outbreaks from a single source, and therefore a sin-
gle viral genotype, making inter-genotypic comparisons within such
a study impossible. Although there a number of outbreaks of differ-
ent viral genotypes that could in theory be compared with each
other, the patients characteristics and transmission routes of infec-
tion in these cohorts are so different that meaningful comparison is
not possible [1, 22]. The second source of data is cross sectional
analysis of rates of spontaneous resolution defined as HCV anti-
body positivity in the absence of detectable viremia in comparison
to the rates of persistent viraemia within a defined population.
However, genotype is rarely defined in the spontaneous resolver
group so that the relevance of viral genotype cannot be determined.
It has been suggested that HCV genotype-3a has a higher rate of
spontaneous resolution than HCV genotype 1 in a cohort of German
prisioners where viral genotype was determined in patients with
resolved infection using the MUREX HCV serotyping assay (Ab-
bot, Germany) and compared to those with persistent infection [2].
HCV within any individual exists as a number of viral variants
(quasispecies), although in general a single strain dominates at any
one timepoint. In theory then, multiple quasispecies would be
transmitted to a new host during primary infection and further vari-
ants would be generated in the new host as a result of immune se-
lection or random mutation. Outbreak studies of acute HCV from a
single source result in diverse clinical outcomes, so clearly host
factors crucially determine outcome [1]. However, host and viral
factors cannot be dissociated as the distinct immunological reper-
toire in each host is likely to result in distinct viral populations.
A few studies have assessed the incoming viral population in a
small number of patients, in relation to the outcome of acute disease
[5, 39, 40]. These studies are restricted to the assessment of the
envelope proteins presumably because these proteins contain vari-
able regions that enable assessment of viral variants. There is cur-
rently no data assessing full length HCV viral sequence in relation
to disease outcome and it is not known therefore whether a particu-
lar sequence motif is associated with disease outcome. Such a sig-
nature has been sought by Ray et al. in the envelope region in a
small number of patients and was not detected [39].
1664 Current Pharmaceutical Design, 2008, Vol. 14, No. 17
It is likely that the generation of viral diversity contributes to
the outcome of acute infection. Farci et al. [5] assessed the number
of viral variants, genetic diversity and the evolution of viral variants
over time in twelve patients with acute HCV; three patients died
from fulminant hepatitis, three resolved infection in the first sixteen
weeks and six developed chronic infection of whom three had rap-
idly progressing liver disease. Viral diversity was examined early in
the course of infection prior to sero-conversion, and compared to
those obtained soon after seroconversion in relation to disease out-
come. This study suggested that the number of viral variants and
the genetic complexity before seroconversion did not relate to out-
come. However, viral diversity increased in individuals who devel-
oped chronic infection following seroconversion, but decreased in
those who resolved. This observation is supported by Ray et al.
who observed less genetic diversity at the time of sero-conversion
in 5 individuals who resolved infection, compared to ten who de-
veloped chronic infection following primary HCV [39]. The likely
explanation for this is that immune responses are more effective in
those who resolve infection and that genetic diversity of HCV
quasi-species declines as a result of the progressive clearance of
individual variants.
In summary then acute HCV is often a silent infection. The
diagnosis of acute HCV is frequently not straightforward and re-
quires repeat serological and virological testing. Some progress has
been made in identifying both host and viral factors that affect the
outcome of primary HCV infection. However, it is likely that the
outcome in any individual is determined by the complex interplay
of multiple host and viral factors. Further identification of factors
that determine outcome during acute infection and the way in which
these interact with one another remains an important goal and may
be key in developing both novel therapies and effective vaccination
strategies.
ABBREVIATIONS
ALT = Alanine transaminase
EIA = Enzyme immuno assay
HBV = Hepatitis B virus
HCV = Hepatitis C virus
HIV = Immunodeficiency virus
HLA = Human leukocyte antigen
Ig = Immunoglobulin
LCMV = Lymphocytic choriomeningitis virus
NK = Natural killer
NS = Non-structural
RIBA = Recombinant Immunoblot assay
RNA = Ribonucleic acid
RT- PCR = Reverse transcription-polymerase chain reaction
Th = T helper
US = Ultrasound
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