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natural history of acute HCV infection [69, 70]. In one such study, it was docu-
mented that 85% of patients presented with clinical ndings of acute hepatitis, and
of those, 52% exhibited spontaneous clearance of the virus, measured by reverse
transcriptase (RT) polymerase chain reaction (PCR) [71], the concentration of
which uctuates during the acute phase of the infection, varying from hundreds to
millions of international units per ml [72], within 12weeks of the determined time
of infection, in contrast to the patients who developed chronic hepatitis C, who had
stable serum RNA concentrations [72], and who did not have any clinical manifes-
tations [70], further supporting the idea of a host-specic response in the determina-
tion of the course of the infection [20]. The development of anti-HCV antibodies
measured by documented antibody seroconversion by enzyme immunoassay (EIA)
and recombinant immunoblot assay occurs in the majority of patients after acute
HCV [69]. In transfusion associated acute hepatitis C, it was documented that anti-
bodies appeared 22weeks after infection, or 15 weeks after the onset of clinical
hepatitis [69], and persist over many years. In patients in whom the infection
resolves itself, the antibody has been documented to disappear after 4years [69].
Most patients who resolve the acute hepatitis C infection clear the virus within
6months [72, 73]. Thus, chronic hepatitis C has been dened as the presence of the
hepatitis C RNA in serum 6months after infection. However, the spontaneous clear-
ance of the virus has been documented up to 2years after the time of infection [74].
The resolution of acute hepatitis C virus infection has been reported in association
with race, being less common in individuals of the black race, versus non-black
subjects [74]. Approximately 75–85% of patients develop chronic infection, 60 to
70% chronic liver disease, and 5–20% cirrhosis over 20–30years [68, 72, 75], with
up to 4% per year proceeding to decompensated disease and hepatocellular carci-
noma (HCC) [76].
The natural history of chronic hepatitis C (and chronic hepatitis B) was studied
over 8.4years in a representative sample from individuals from Northern Italy. It
was documented that progression to cirrhosis was 4.5 per 1000 person-year, and the
development of hepatocellular carcinoma 2.0 per 1000 person-year; the intake of
alcohol was reported as an independent predictor of cirrhosis with a rate ratio of 4.5,
with a 95% condence interval (CI) ranging from 1.02 to 41.2 and a death rate of
8.53 (95% CI 1.40–24.61) for increments by 30g/day of alcohol intake at base-
line [77].
By the use of the METAVIR score system, a study that included 2235 patients
with chronic hepatitis C documented that patients with chronic hepatitis C could be
categorized as slow brosers, dened as patients infected for more than 20years,
and liver histology not exhibiting septa brosis (F0 or F1), rapid brosers, dened
as patients who had developed cirrhosis (F4) before the age of 50years, and inter-
mediate brosers (F2 or F3, by inference); this nding suggested that progression
was not “universal” or “inevitable” [75]. Age older than 40years at the time of
infection, male gender, and alcohol intake of more than 50g/day were identied in
association with disease progression, the latter being associated with an increase in
the progression of brosis of 34% [75]. The median expected time to cirrhosis was
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30years, with 33% of patients having an expected time to cirrhosis of fewer than
20years, and with 31% not progressing to cirrhosis at all, or not progressing for at
least 50years [75].
A study that included 33 patients who were infected from a common source
revealed chronic hepatitis in the majority of the liver samples obtained 17 and
19years after the infection with little progression over the 2year period; only one
patient had developed cirrhosis [78]. From the same group of patients, a non-
aggressive course was documented 22years of after infection [79].
Steatosis is documented to accelerate disease progression in association with
chronic hepatitis C genotype 3 [80] and to impede response to antiviral therapy [80].
Steatosis was reported in signicant association with brosis, infection with geno-
type 3 hepatitis C virus, high body mass index (BMI), alcohol use, and age [80]. In
patients with chronic hepatitis C coinfected with the human immunodeciency
virus and who had a high BMI, diabetes and hepatic steatosis were associated with
brosis; in addition, persistently increased serum activity of transaminases related
to brosis progression, which occurred over 2.5years [81].
In a study published in 1997 that included 2235 patients with chronic hepatitis C,
factors identied with disease progression were age older than 40 at the time of
infection, alcohol intake of at least 50g/day, and male gender. The median time to
progression to cirrhosis was 30years from infection, with a range from 28 to 32. In
men infected after age 40, cirrhosis could be established after 13years of the infec-
tion. In women, cirrhosis could be established 42years after the infection in the
absence of alcohol use. Thirty-three percent of patients who were not treated had an
expected median time to cirrhosis of 20years, with 31% not expected to progress to
cirrhosis for at least 50years [75]. In regard to cirrhosis, the polymorphism rs738409
GG genotype of the patatin-like phospholipase domain-containing 3 (PNPLA3)
encoding for the I148M protein variant was reported in signicant association with
the stage of brosis and presence of cirrhosis [23, 24], supporting a role of genetic
predisposition to the progression of the disease.
Clinical Manifestations
20 to 30% of patients with acute hepatitis C have symptoms, fatigue being the
most common. A subgroup of women who acquired hepatitis C virus from a
common source [68, 74, 82] was studied at the time of the infection and 22years
afterward [79]. Jaundice was reported at the time of the infection by 20.6% of
those who did not have hepatitis C viral RNA by polymerase chain reaction
(PCR) at the time of the follow-up study [74], versus 3.4% of those in whom
hepatitis C RNA was detected. These ndings suggested that jaundice may pre-
dict the resolution of acute hepatitis C.Other signs include choluria and acholic
stools. Other symptoms include arthralgia, anorexia, abdominal pain, nausea,
and vomiting.
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Physical Exam
In general, the physical exam in patients with acute hepatitis C would be notable for
jaundice, in cases of hyperbilirubinemia. In patients with chronic hepatitis C, the
ndings depend on the degree of liver disease; patients may or may not exhibit
cutaneous stigmata of liver disease and signs of decompensation, including ascites
and edema.
Acute hepatitis C is associated with increased activity of ALT, usually higher
than 400IU/ml, and rarely in the thousands. Hyperbilirubinemia may be present.
Patients with chronic hepatitis C can have a normal liver prole, e.g., ALT activity;
66% of patients with chronic hepatitis C 20years after the infection were reported
to have increased serum activity of ALT (>40IU/l) [79]. The serum activity of ALT
can uctuate throughout the disease; in a prospective study, this pattern was docu-
mented in 21% of patients with chronic hepatitis C over several years [79]. A uc-
tuating pattern has also been reported, emphasizing the importance of screening for
hepatitis C virus infection regardless of a normal liver prole [66]. As the disease
progresses and cirrhosis ensues, serum AST activity increases over that of the ALT
as it happens in most chronic liver diseases [83, 84]. Increased activity of alkaline
phosphatase, and gamma glutamyl transpeptidase, in association with increased
activity of transaminases, is the prole typical of advanced disease.
Hyperbilirubinemia, hypoalbuminemia, and coagulopathy are features of hepatic
dysfunction, as in that from other etiologies. Thrombocytopenia is a sign of hyper-
splenism, from portal hypertension; however, it can be seen in patients with chronic
hepatitis C without portal hypertension, considered to be an effect of the virus per
se, with normalization of platelet count after successful antiviral therapy. In chronic
hepatitis C, there is also suppression of all hematological cell lines, characteristic of
liver disease in general.
Several methods have been developed to test antibodies in blood and in saliva.
The methodology includes enzyme immunoassay (EIA), enhanced chemilumines-
cence immunoassay (CIA), microparticle enzyme immunoassay (MEIA), recombi-
nant immunoblot assay (RIBA), and chemiluminescent microparticle immunoassay
(CMIA) [85–87]; the presence of hepatitis C RNA can be qualitatively and quanti-
tatively detected by polymerase chain reaction (PCR) methodology [87].
Anti-hepatitis C antibodies (anti-HCV) can be detected in serum 4–10 weeks
after infection with the hepatitis C virus, with a 96% detectability 6months after the
infection [69, 88]. Anti-HCV tends to persist. However, a rate of antibody loss has
been reported as 0.6 per 100 person-years [88].
Testing for genotype in patients with chronic hepatitis C has been necessary as
the duration of treatment has varied according to the genotype [89]. The presence of
anti-HCV antibodies should be followed by testing for serum HCV RNA, and when
appropriate, e.g., in the face of acute hepatitis, the latter should be repeated over
several weeks. The absence of anti-HCV antibodies in the presence of infection, i.e.,
a false negative result, can occur when the viral titer is low, as in very early stages
of infection, or in persons who are immunocompromised. Thus, the presence of risk
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factors in a subject with absent anti-HCV antibody requires repeat testing, including
HCV-RNA [90].
Antinuclear antibodies, anti-smooth muscle antibodies, and anti-liver/kidney
microsomal type 1 antibodies can be detected in the serum of patients with chronic
hepatitis C with a reported wide prevalence of approximately 20 to 40% in some
series [91, 92]. The presence of non-organ specic autoantibodies has not been
consistently associated with the stage of liver disease. In some studies, serum auto-
antibodies have been associated with a high degree of inammation and brosis,
and elevated serum concentrations of gamma globulins [93, 94]. However, in other
studies, including an observational study that included 24,306 patients [95], the
presence of autoantibodies in chronic hepatitis C has been documented to correlate
with histology, decision to start standard antiviral therapy, or response to it [92, 95].
The interpretation of the clinical relevance of autoantibodies has to be individual-
ized [95], especially, if a diagnostic procedure, e.g., liver biopsy, or treatment for
another liver disease, e.g. autoimmune hepatitis, is considered based on serum auto-
antibody prole.
Differential Diagnosis
Causes of hepatitis, including viral, autoimmune, metabolic, and toxic (e.g., drug-
induced), must be excluded in patients who present with increase serum activity of
transaminases, with or without hyperbilirubinemia. Identifying risk factors is fun-
damental for prompt diagnosis, which is conrmed by laboratory ndings, i.e.,
serum hepatitis C RNA.
Histology
Some of the features documented from liver histology in acute hepatitis C include
conuent liver necrosis, sinusoidal inammatory inltrates, steatosis, dense portal
lymphoid aggregates, and bile duct injury, i.e., the Poulsen–Christoffersen lesions
[96, 97], the latter having been documented to portend evolution to chronic liver
disease in one study [96].
The principal histological ndings that have been reported in chronic hepatitis C
include portal and lobular inammation, and interface hepatitis, steatosis, lymphoid
aggregates, and bile duct injury, apoptotic and Mallory bodies, steatosis, bile duct
lesions, and lymphoid cell follicles within portal tracts (Fig.6.2) [79, 98–100].
The bile duct lesion of hepatitis, most commonly seen in chronic hepatitis C, is
characterized by swelling, vacuolization, and irregular nuclei, with a basement
membrane that appears ruptured, lymphocytes, some plasma cells, and neutrophils,
invading the bile ducts; the lesion is reminiscent of the orid bile duct lesion of
primary biliary cholangitis (PBC); however, it is not considered to lead to bile duct
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destruction and ductopenia in most cases, as happens in PBC.This bile duct lesion
of hepatitis, and mostly of chronic hepatitis C, i.e., the Poulsen–Christoffersen
lesion [101], has been documented to represent diverticular bile duct lesions that
may represent Hering ducts and groups of periportal liver cells that have escaped the
piecemeal necrosis [102].
Early immunohistochemical studies documented the constitution of the lym-
phoid aggregates or follicles, characteristic of chronic hepatitis C, as functional
lymphoid follicles that contain activated B cells in the midst of a follicular dendritic
cell network, and a mantle zone of B cells, surrounded by a T cell zone, consisting
of CD4-positive helper T cells and CD8-positive suppressor/cytotoxic T cells [103,
104] some of which expressed CD25 and IL-2 receptor, as well as human leukocyte
antigen DR, suggesting an activated state [104]. The necrotic inammatory inltrate
that comprised the necrosis, piecemeal type (currently known as interface) in the
samples studied was composed of CD4 helper T cells, and those identied in the
lobule were predominantly CD8 suppressor/cytotoxic T cells [103]. The character-
istics of the hepatic lymphoid follicles were reported as similar to those found in
autoimmune diseases. They suggested that a component of the liver injury in chronic
hepatitis C may be immune mediated [103, 104]. One immunohistochemical study
of liver tissue from patients with chronic hepatitis C (and B) documented the cel-
lular inammatory inltrate to be comprised of T lymphocytes, 50% of which was
CD4CD45RO(+), consistent with activated cells, and 25% CD8CD45RO(+), and of
B lymphocytes, 15% of which was CD20(+)CD45RA (+), and 10% of which was a
combination of CD20(−)CD45RA(+) and NK cells. Most cells in the portal area
expressed HLA class II molecules suggesting a response to antigen presentation,
i.e., the HCV [104].
Foxp3 is a member of the forkhead transcription factors group, which regulates
the development and function of regulatory T cells, CD4(+)CD25(+)Treg (Tregs)
[105]; these cells are a key suppressive component of the immune system [106]. The
presence of activated CD4+FoxP3+ Treg, as evidenced by the expression of
Fig. 6.2 Liver histology in
a patients with chronic
hepatitis C displaying
interface hepatitis (arrow)
(Hematoxylin and Eosin
stain)
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CD45RO, CCR7, CTLA-4, and HLA-DR, has been documented in the livers of
patients with chronic hepatitis C and limited brosis, suggesting that this type of
cell may decrease brogenesis by suppression of an immunological response to the
virus [107]. In this context, intrahepatic FoxP3
+
CD4
+
regulatory T cells were docu-
mented to produce IL-8in patients with chronic hepatitis C [107]. An increase in the
number of activated GARP-positive IL-8(+) Tregs was identied close to areas of
brosis in liver tissue from patients with chronic hepatitis C.In addition, it was
reported that Tregs increased the expression of markers of brosis including TIMP1,
MMP2, TGF-beta1, alpha-SMA, collagen, and CCL2 in primary human hepatic
stellate cells (HSC) studied exvivo, an effect that was blocked by anti-IL-8 antibod-
ies; these ndings were interpreted to support the idea that, in addition to mediating
immune response to the HCV infection, Foxp3(+)CD4(+) Tregs contribute to the
development of brosis [108]. Further characterization of intrahepatic mononuclear
cells documented the presence of intrahepatic CD4(+)FoxP3(+)T cells within the
inammatory inltrate in close association with a few CD8(+)FoxP3(+)T cells; this
nding has suggested that the inhibition of CD8+ T cell is mediated by cell to cell
contact. Advanced brosis was associated with a reduction in the FoxP3(+)/CD8(+)
cell ratio because of a low number of FoxP3 cells [109]. Activated CD4+FoxP3+
Treg lymphocytes, as evidenced by the expression of CD45RO, CCR7, CTLA-4,
and HLA-DR, have been documented in the livers of patients with chronic hepatitis
C and limited brosis, suggesting that this type of cell may decrease the brosis
process in association with this viral infection [107].
Fibrosis in chronic hepatitis is exhibited as portal to portal bridges of collagen,
and also as central to central and as central to portal, known as passive septa, which
is considered to result from bouts of necrosis in zone 3, and repair of episodes of
intra-acinar necrosis [110]. The contraction of brous septa is associated with nod-
ule formation, changing the liver’s architecture, which denes cirrhosis; the asso-
ciation with nodules, incomplete or complete, with necroinammatory activity, is
termed active cirrhosis [110].
Several non-invasive tests and indices have been developed or derived to predict
the presence of brosis in the liver of patients with chronic hepatitis C, including the
platelet count, age-platelet index, aspartate aminotransferase-platelet ratio index
(APRI), FibroIndex, FibroTest, Forns index, and for identication of cirrhosis, the
platelet count, age-platelet index, and Hepascore [111]. Examination of liver histol-
ogy by liver biopsy is the gold standard to assess the presence and degree of liver
disease, including brosis and cirrhosis [112].
Extrahepatic Manifestations
Extrahepatic manifestations of chronic hepatitis C have been reported in 38–76% of
patients, and they include cryoglobulinemia complicated by systemic vasculitis,
sicca syndrome, lymphoproliferative diseases, and lichen planus [113]. The associa-
tion with sarcoidosis has been documented in case reports [114, 115]. An
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association between cardiomyopathy and chronic hepatitis C was supported by the
recovery of cardiac function in a patient with chronic hepatitis C treated with anti-
viral therapy that was associated with sustained virological response [116]. This
association was initially reported in Japan [117–119]. However, it was not con-
rmed in studies from Italy [120], Brazil [121], nor Brooklyn, NewYork [122],
which has suggested a racial, ethnic, and/or genetic predisposition to this potential
complication of chronic hepatitis C.
Cryoglobulinemia is the presence of serum immunoglobulin that precipitates
invitro at temperatures lower than 37°C, and dissolves itself after rewarming [123].
The cryoglobulins are classied into three types, based on their composition. Type
I tends to be composed of monoclonal immunoglobulin IgM or IgG, type II is a
mixture of monoclonal IgM with rheumatoid factor activity, which binds to the Fc
portion of IgG, and type III, a combination of polyclonal IgM and IgG [123, 124].
The prevalence of HCV in cryoglobulinemia has been reported to be between 30%
to nearly 100% [123, 125], with the development of cryoglobulinemic vasculitis in
10–15% of patients [125]. Non-enveloped HCV core protein has been documented
in the cryoprecipitate of type II mixed cryoglobulinemia [126]. In patients with
chronic hepatitis C, serum cryoglobulins have been documented with an annual
incidence of 3%, and most commonly, in patients with advanced disease [113, 123,
127, 128]. The pathogenesis of cryoglobulinemia in chronic hepatitis C seems to
concern the tropism of the hepatitis C virus for lymphoid tissue. The E2 protein of
the hepatitis C envelope interacts with an extracellular loop of tetraspanin CD81, a
protein expressed by hepatocytes and B and T cells [129], which has been proposed
to mediate the proliferation and clonal expansion of B lymphocytes.
The manifestations of cryoglobulinemia-associated vasculitis include rash, pal-
pable purpura, and chronic ulcers, fatigue, arthralgia, motor-sensory axonopathy,
arterial hypertension, glomerulonephritis, and nephrotic syndrome [129]. As the
hepatitis C virus is considered the stimulus of B cells [130], the treatment aims to
eradicate the virus.
The association of lymphoma with chronic hepatitis C was also documented
from a retrospective cohort study of subjects who attended US Veterans Affairs
health care facilities from 1997 to 2004 and that included 146,394 individuals. The
hazard risk for non-Hodgkin’s lymphoma was 1.21, with a 95% condence interval
(CI) between 1.07 and 1.37, and a hazard ratio of 2.72 (95% CI 2.00–3.72) both
signicantly higher than in the group of patients without chronic hepatitis C [131].
This report followed a published meta-analysis from which the pooled relative risk
(RR) for all NHL among all patients with chronic hepatitis C was 2.5, (95% CI
2.1–3, and a pooled RR of 2.5 (95% CI, 2.1–3.1) and a pooled RR of 2.0 (95% CI,
1.8–2.2) from case control and cohort studies, respectively [132].
There is literature suggesting an association between chronic hepatitis C and
diabetes mellitus type 2; however, analysis of population-based data from the
U.S.National Health and Nutrition Examination Survey from 1999 to 2010, which
included 15,128 subjects, documented a lack of association between hepatitis C
antibody in serum and pre-diabetes or diabetes [133].
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There is literature reporting an association between chronic hepatitis C infection
and porphyria cutanea tarda (PCT) [134–138]. PCT is characterized by skin fragil-
ity, erythema, bullae, erosions, hypertrichosis, and milia in sun-exposed areas and
by increased concentration of porphyrins in the urine [139]. PCT is classied as
type I, comprising 75–80% of the cases, dened as an acquired deciency limited to
the hepatocyte of uroporphyrinogen decarboxylase (UROD), a key enzyme in the
synthesis of heme, type II, hereditary, comprising 20–25% of the cases, and charac-
terized by a decreased activity of UROD in all tissues by approximately 50%, and
type III, also hereditary, for which the genetic defect has not been described, com-
prising less than 1% of the cases, and characterized by a decrease in UROD hepato-
cyte activity [134, 139]. A reduction of activity of UROD in the liver in the absence
of decreased protein levels of UROD has suggested that an inhibitor of UROD is
made in the hepatocytes; in support of this idea seems to be the nding of normal
protein concentration of UROD in association with reduction of enzyme activity.
Studies in a mouse model of PCT have lent support to this line of thinking by reveal-
ing the inhibitor of recombinant human URO-D (rhURO-D) to be uroporphometh-
ene; however, the identity of the inhibitor has not been consistently conrmed [140].
An inhibitor of rhURO-D was also isolated from the cytosol of hepatocytes obtained
from liver samples from patients with PCT.These results have suggested that the
clinical expression of PCT is due to the iron dependent oxidation of uroporphyrino-
gen to uroporphomethene, a competitive inhibitor of URO-D [134, 141], suggesting
that iron itself may contribute to the pathophysiology of PCT [134].
A meta-analysis that included 2167 patients from 50 studies documented the
prevalence of hepatitis C RNA in serum of 50% [137]. The prevalence of chronic
hepatitis C in PCT varied according to the type of porphyria, 57% for the sporadic
form (Type I), and 26% for the familial form (Type II) [137]. From another meta-
analysis, the prevalence of chronic hepatitis C in PCT was reported as 17% in
Northern Europe, 20% in Australia and New Zealand, and 65% in Southern Europe,
and 94% (16 of 17 PCT) in a study from one hospital in Indianapolis, Indiana in the
United States [142]. These results have suggested that the HCV contributes to the
pathogenesis of PCT [137, 142]. Infection with the HCV alone does not seem suf-
cient to trigger PCT [143]; however, the HCV may alter porphyrin metabolism
facilitating the clinical expression of PCT in patients predisposed to it and with this
type of viral hepatitis. How the hepatitis C virus mediates the events that result in
PCT has been a matter of speculation; in this regard, it has been proposed that iron
may be the factor that predisposes PCT in patients with chronic hepatitis C, in which
iron has been reported as a factor contributing to liver injury [144] as also reported
for PCT.In this context, it has been suggested that high iron content in PCT is sec-
ondary to abnormal regulation of hepcidin, a protein made in the hepatocyte, which
regulates iron absorption in human beings. Infection with the HCV was reported to
be associated with decreased hepcidin expression [145], which has suggested a
mechanism by which there may be a relationship between hepatocellular iron and
chronic hepatitis C-mediated liver disease. In this proposed model, the HCV may
also contribute to the pathogenesis of PCT as iron mediates the reaction that
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produces an inhibitor of URO-D, reported to contribute to the pathogenesis of
PCT [141].
The prevalence of chronic hepatitis C antibodies in patients with renal disease
was 7.9% in contrast to blood donors and pregnant women in whom the prevalence
was 1.03% and 0.98%, respectively. Chronic hepatitis C infection has been reported
in association with membranoproliferative glomerulonephritis, membranous
nephropathy, focal segmental sclerosis, brillary glomerulonephritis, immunotac-
toid nephropathy, IgA nephropathy, tubulointerstitial nephritis, and thrombotic
microangiopathy, usually associated with cryoglobulinemia [146]. The most com-
mon renal disease in patients with chronic hepatitis C associated with mixed cryo-
globulinemia is type I membranoproliferative glomerulonephritis exhibiting
proteinuria and microscopic hematuria, which may be complicated by impaired
renal function [131, 147, 148]. Population-based studies have reported an associa-
tion between proteinuria and hepatitis C virus infection, interpreted to suggest that
the association may be more common than what has been recognized [146].
Histologically, the renal lesion of hepatitis C associated nephropathy includes a
cellular inltrate comprised of monocytes, eosinophils, and intraluminal thrombi.
Subendothelial deposits of IgG, IgM, and complement components are prevalent,
and vasculitis of small renal arteries has been reported [146, 149]. It has been sug-
gested that high binding of immunoglobulin M kappa rheumatoid factor from type
II cryoglobulins to cellular bronectin in the glomerular mesangium contributes to
the pathogenesis of glomerulopathies associated with type II cryoglobulinemia and
chronic hepatitis C [150].
Xerostomia and xerophthalmia, symptoms typically comprising the sicca syn-
drome, have been reported as extrahepatic manifestations of chronic hepatitis C
[151–155]. The prevalence of chronic hepatitis C was stated as 19% in patients with
sicca syndrome in one study [152], and sicca syndrome was present in 62% of
patients with chronic hepatitis C studied prospectively [155]. Antibodies identied
with primary Sjogren’s syndrome, anti-SS-A/SS-B, were documented as signi-
cantly more prevalent in patients with sicca syndrome without chronic hepatitis C
than those with the syndrome without chronic hepatitis C [152, 153, 155] differen-
tiating primary from secondary Sjogren’s syndrome. Evidence of glandular dys-
function in chronic hepatitis C has been documented [153]. An inammatory
inltrate characterized by activated lymphocytes similar to that found in patients
with primary Sjorgren’s syndrome has been described in patients with chronic hepa-
titis C [156]. The pathogenesis of sicca syndrome with regard to hepatitis C viral
infection is not known. In this context, HCV RNA has been detected in saliva and in
salivary gland extracts in patients with Sjogren’s syndrome and chronic hepatitis C,
which has suggested that the virus may localize itself in the salivary glands and trig-
ger an inammatory response resulting in sialoadenitis and sicca symptoms [157];
however, viral particles have not been consistently detected in the affected
glands [153].
Lichen planus is histologically characterized by interface dermatitis that mani-
fests itself as purple polygonal pruritic papulosquamous lesions that can affect the
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skin, scalp, nails, and mucous membranes, of unknown etiology, for which an
immune-mediated pathogenesis is hypothesized [158]. Lichen planus has been doc-
umented in association with chronic hepatitis C [159]. In a cross-sectional study, the
prevalence was 5 percent [160]. Two meta-analyses have reported a signicantly
higher risk for patients with lichen planus to have chronic hepatitis C and patients
with chronic hepatitis C to develop lichen planus than those of control groups
[161, 162].
The association between adrenal tumors and chronic hepatitis C has been
reported [163, 164]. In a series of three patients, two of the tumors were functional,
as evidenced by hypokalemia and hypertension. The likely mode of acquiring hepa-
titis C in the patients preceded the manifestation of hyperaldosteronism by many
years; thus, it was inferred that the hepatitis C infection was the rst event. The
association was conrmed in a retrospective review of patients with adrenal tumors
over 10years, 2001 to 2010 [164]. Of 23 patients with adrenal tumors, 15 (65.2%)
had hepatitis C antibody, and 11 (47.8%) had hepatitis C RNA in serum, consistent
with chronic hepatitis C, signicantly different from the ndings in the control
group in which only one of 23 (4.3%) patients had hepatitis C antibody in the serum
[164]. The mechanism by which chronic hepatitis C may lead to the formation of
adrenal tumors may include replication of the hepatitis C virus in the adrenal gland
[165], by the systemic effects of IGF, reported as high in patients with chronic viral
hepatitis including hepatitis C [166], and by insulin, increased in patients with met-
abolic syndrome, which has been reported in association with chronic hepatitis
C.Both insulin and IGF increased the growth of bovine adrenal fasciculate cells in
culture [167]. As chronic hepatitis C and hypertension are prevalent conditions,
HCV infection should be excluded in patients with hypertension, even if not neces-
sarily difcult to control, as hyperaldosteronism is more prevalent than previously
considered [168], and thus, the exclusion of chronic hepatitis C in patients with
adrenal tumors seems warranted.
Diagnosis
The laboratory ndings of hepatitis C virus infection have been described above.
The diagnosis of acute HCV infection is made in the presence of hepatitis accompa-
nied by hepatitis C viral RNA in serum, which disappears over the 16weeks that
follow the infection in the patients who clear it, or that remains consistently detected
when the infection becomes chronic [88, 169]. Hepatitis C antibody, which can be
found from 4 to 15weeks from infection, remains detected in patients who have
been infected, regardless of RNA clearance. The presence of hepatitis C antibody is
suggestive of chronic hepatitis C in 80% of the patients. The serum liver prole is
usually abnormal with increase serum activity of liver associated transaminases, but
periods of normal activity occur.
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