VIRAL IMMUNOLOGY

Volume 30, Number 9, 2017 Review

ª Mary Ann Liebert, Inc.
Pp. 1–9
DOI: 10.1089/vim.2017.0009

Hepatitis C Virus-Associated Extrahepatic Manifestations

in Lung and Heart and Antiviral Therapy-Related
Cardiopulmonary Toxicity
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Syeda Zainab Ilyas,1,* Rabia Tabassum,1,* Haroon Hamed,2 Shafiq Ur Rehman,1 and Ishtiaq Qadri2

Abstract

Besides liver cirrhosis and hepatocellular carcinoma, chronic hepatitis C virus (HCV) infection is associated
with many extrahepatic manifestations (EHMs). HCV exhibits lymphotropism that is responsible for various
EHM. An important characteristic of HCV is escape from the immune system, which enables it to produce
chronic infections and autoimmune disorders along with accumulation of circulating immune complexes. These
EHMs have large spectrum, because they affect many organs such as heart, lungs, kidney, brain, thyroid, and skin.
HCV-related cardiac and pulmonary manifestations include myocarditis, cardiomyopathies, cardiovascular dis-
eases (i.e., Stroke, ischemic heart disease), chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis,
asthma, and interstitial lung diseases. This review discusses etiology and pathogenesis of HCV-associated cardiac
and pulmonary manifestations and how different genes, immune system, indirectly linked factors (mixed cryo-
globulinemia), liver cirrhosis, and antiviral treatment are involved in HCV-related heart and lung diseases,
however, their exact mechanism is not clear.

Keywords: chronic hepatitis C virus, extrahepatic manifestations, cardiac and pulmonary manifestations,
pathogenesis, mixed cryoglobulinemia, antiviral treatment

Introduction The HCV infects about 3% of world population, while 17–

37% HCV-infected people also suffer with HCV-related heart

H epatitis C virus (HCV) infection is a chronic blood-

borne disease that mainly affects the liver, but due to
lymphotropic nature of this virus, it also leads to many ex-
trahepatic manifestations (EHMs) (7). Several studies found
EHMs of the disease in 70–74% of HCV patients (24). One
of the major attributes of HCV is its ability to escape from
activity of host immune system leading to chronic infec-
tion. During chronic infections, accumulation of circulat-
ing immune complexes (CIC) and activation of autoimmune
responses lead to extra hepatic manifestations (26). In addi-
tion to this, certain EHMs are also associated with advanced
liver disease. HCV being both hepatotropic and lymphotropic
virus, acts as a stimulator of the immune system (23).
Therefore, beside the ordinary cardiovascular risk factors
(hypertension, obesity, diabetes, physical inactivity, smok-
ing, and high cholesterol), it acts as an indirect risk factor for
various cardiopulmonary diseases (10). Although the cases
of HCV-related cardiac diseases are present all around the
globe, they are highly prevalent in Asia, Africa, and under-
developed countries (41).
diseases (51). The most common cardiac manifestations are
cardiomyopathies, myocarditis, atherosclerosis, cardiovascu-
lar disorders (stroke and ischemic heart disease), coronary
artery disease (CAD), and peripheral artery disease (PAD)
(28). Along with heart diseases, HCV-associated pulmonary
complications are also reported. HCV-related lung patholo-
gies could be the primary outcome of the infection, however,
there are certain other pathologies such as pulmonary vas-
culature and damage of pulmonary parenchyma attributed to
mixed cryoglobulinemia (MC), interferon therapy liver cir-
rhosis (60), hepatopulmonary syndrome, and portopulmonary
hypertension (3). The primary or direct outcomes of the HCV
infection on lung pathologies include the chronic obstructive
pulmonary disease (COPD), idiopathic pulmonary fibrosis
(IPF), asthma, and interstitial lung diseases (60).
In this study, we will discuss the etiology and pathogenesis
of HCV-associated cardiac and pulmonary manifestations
and how different genes, immune system, indirectly linked
factors (diabetes and cryoglobulinemia), and antiviral treat-
ment contribute to the HCV-related cardiopulmonary diseases.

1
Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan.
2
Department of Biological Sciences, King Abdul Aziz University, Jeddah, Kingdom of Saudi Arabia.
*These two authors contributed equally to this work.
 2 ILYAS ET AL.
HCV-Related Cardiomyopathies and Myocarditis
Cardiomyopathies can be defined as a group of hetero-
geneous diseases of myocardium. It includes idiopathic di-
lated, hypertrophic or restrictive disease cardiomyopathies,
arrhythmogenic right ventricular cardiomyopathy, and in-
flammation of the myocardium or myocarditis (66). One
of the major reasons of myocarditis is cardiotropic viruses
(66) such as enteroviruses, coxsackievirus B, adenovirus,
and parvovirus (52). Recently, a high prevalence of HCV
infection has been noted in patients with hypertrophic car-
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diomyopathy, dilated cardiomyopathy (DCM), and myo-
carditis (49). Among all of the HCV-associated cardiac
disorders, DCM is a relatively common disorder, which may
lead to severe heart failure. Besides this, HCV infection causes
induction of proliferative stimuli that lead to the formation of
myocytes responsible for cardiomyopathy and hypertrophic
cardiomyopathy (HCM). HCM refers to a heart defect char-
acterized by increased thickness of the wall of the myocardium,
mostly left ventricle, causing functional impairment of the heart.
It is possible that both direct viral cytotoxic and indirect
immune-mediated mechanisms of myocardial tissue damage
are crucial in the pathogenesis of viral-induced cardiac
disease (40). Previously, immunological mechanisms were
described for chronic liver disease-mediated myocarditis
and cardiomyopathies. Patients having chronic HCV-
mediated myocarditis had normal serum levels of hepatic
transaminases, until the final stages of heart failure (51). In
case of congestive hepatopathy, the main driver of this
condition is activation of cytotoxic T cell response in liver
tissue. When protein products of HCV stimulate the toll-like
receptors, CD4+ cell-mediated T helper-1 (Th1) response is
induced, which results in release of interleukin-12 (IL-12),
interferon (IFN)-a and -b from monocytes, macrophages,
and neutrophils. Highly activated CD4+ cells produce IFN-c,
which stimulates the macrophages to produce proin-
flammatory cytokines. IL-1 and tumor necrosis factor alpha
FIG. 1. Postulated behavior of the HCV-mediated immune activation, resulting development of myocarditis, which
ultimately leads to cardiomyopathies. DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HCV, hepatitis
C virus; IFN-a, interferon alpha; IL-12, interleukin-12; Th1, T helper-1; TNF-a, tumor necrosis factor alpha.
(TNF-a) are the two major cytokines produced by macro-
phages, responsible for recruiting inflammatory cells and
factors toward the myocardium (71). This mechanism
suggests that chronic HCV can act as a risk factor for the
development of myocarditis and subsequently to cardio-
myopathies (Fig. 1).
Many studies have shown a stronger association between
increased expressions of TNF-a and depressed myocardial
function with its increasing concentrations in plasma and
myocardium of patients. The TNF-a binds to two different
receptors (TNF-a receptor 1 [TNFRI] and TNF-a receptor 2
[TNFRII]) present on the surface of cardiomyocytes, and
cause negative inotropic effects. In cardiac myocytes, con-
traction and relaxation depend on cyclic release and re-
moval of calcium ions from the sarcoplasmic reticulum (84).
Extracellular calcium ions enter the cell via L-type Ca+2
channels during membrane depolarization and help in the
release of calcium ions from the sarcoplasmic reticulum.
The SR Ca+2/Mg+2-ATPase (SERCA) present in the sarco-
plasmic reticulum of myocytes is involved in the calcium
uptake during muscular movement and higher concentra-
tions of TNF-a restrict L-type Ca+2 channels and affect the
systolic phase by inhibiting high concentration of calcium
ions (87). It also affects the relaxation phase by inhibiting
SERCA (16).
Another mechanism by which TNF-a affects the myo-
cardium is by stimulating the production of nitric oxide
(NO), which acts as an endogenous inhibitor and has a
negative inotropic effect on the myocardium. In the pres-
ence of proinflammatory cytokine (TNF-a), the concentra-
tion of inducible nitric oxide synthase (iNOS), (calcium
independent, a nonexpressive isoform of NO synthase) is
increased. Expression of iNOS in the myocardium causes
the decrease in the contractile function of the heart and
isolated cardiomyocytes (71).
Autoimmunity is another important mechanism of HCV-
linked myocarditis and DCM. The presence of some human
 HCV-ASSOCIATED EXTRAHEPATIC MANIFESTATIONS
leukocyte antigen (HLA) and non-HLA haplotypes ge-
netically predispose some HCV patients toward HCV-
associated cardiomyopathies (71). All human HLA class II
loci (HLA-DP, HLA DQ. HLA-DR) show polymorphism,
which affects the epitope’s affinity to bind with different
peptides involved in the pathogenesis of some autoimmune
diseases (11). In HCV-related cardiomyopathies, certain
genes have been found to play their roles. The gene for
human major histocompatibility complex (MHC) is located
on the short arm of chromosome 6 and encodes for several
protein products involved in immune function, including
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complement, TNF-a, and HLA complex. Any polymor-
phism in this gene is proposed as determinant for the sus-
ceptibility to various diseases.
MHC class II genes may play their roles, in conferring
susceptibility to HCV infection, and may influence the de-
velopment of different phenotypes of cardiomyopathy (62).
Recently, several studies have reported that dilated and hy-
pertrophic cardiomyopathies are associated with certain al-
leles of the HLA system. For example, the HLA-DPB1*0901
and HLA-DRB1*1201 have been reported to be more preva-
lent in chronic HCV-infected patients who develop DCM, and
HLA DRB1*0901 and DQB1*0303 haplotypes are more
prevalent in chronic HCV-infected patients with hypertrophic
cardiomyopathy (50). Another study described that HCV-
linked DCM was due to alleles of non-HLA genes rather than
with those of the HLA genes. Specifically, a group of in-
vestigators mapped the gene factor, responsible for HCV-
related DCM at non-HLA gene locus spanning from the
NF-kappa-B inhibitor-like protein 1 (NFKBIL1) to the MHC
class I chain-related protein A (MICA) gene loci within the
MHC class III-class I boundary region (78).
Cardiovascular Diseases
Chronic hepatitis C (CHC) is a major independent risk
factor for the development of cardiovascular diseases
(CVDs), including atherosclerosis, cardiovascular disorders
(stroke and ischemic heart disease), CAD, and PAD (15).
According to the World Health Organization, stroke and
ischemic heart disease are the two major causes of death
worldwide. People suffering from chronic HCV have in-
creased risk of CAD, PAD, and cerebrovascular disease
(28). CHC also develops the major risk factors for other
metabolic diseases such as insulin resistance (IR), diabetes
mellitus (DM), atherosclerosis, and hypertension (39).
It has been assumed that HCV promotes atherogenesis
and causes CVDs by stimulating different biological
mechanisms. These mechanisms involve liver steatosis, fi-
brosis, diabetes, IR, HCV colonization and proliferation
within arterial walls, excessive and imbalance production of
cytokines, oxidative stress, endotoxemia, and hyperhomo-
cysteinemia (89). Among the various CVDs, HCV mainly
promotes the atherosclerosis. Recent studies indicated that
HCV is associated with carotid atherosclerosis and carotid
intima-media thickness independent of other risk factors of
CVDs (35). In a cross-sectional study, association between
HCV and carotid artery plaques was indicated by the pres-
ence of anti-HCV antibodies and HCV core protein in the
serum of HCV-affected patients (36). HCV infection is as-
sociated with coronary artery plaques and high levels of
HCV-mediated plaque calcification.
3
HCV infection increases the risk of developing PAD.
PAD responsible for the development of calcium and fat
plaques in the arteries, which upon increase in size lead to
atherosclerosis (32). Some data from a Taiwanese study
indicated that HCV-infected patients are at higher risk of
developing PAD compared with noninfected patients. The
incidence of PAD development in HCV-infected patients
occurs in the first and third years of disease (12). HCV
chronic infection and related inflammation may be associ-
ated with several unfavorable pathologic conditions, in-
cluding atherosclerosis (6). Chronic HCV infection causes
liver fibrosis, which induces metabolic changes that are in-
volved in the production of atherosclerosis (39). In HCV-
infected patients, atherosclerosis is the main cause of strokes
and heart attacks. It has been reported in different studies
that HCV infection is an independent risk factor for strokes,
cerebrovascular diseases, and ischemic heart diseases. HCV-
infected patients showed a marked association between in-
flammatory markers and atherosclerosis (12).
The liver is a major inflammatory regulator; it regulates both
local and systemic inflammation by the production of mole-
cules having inflammatory-inducing properties. When HCV
infects liver, inflammatory cascade begins. Proinflammatory
and inflammatory cytokines, including IL 1-b, TNF-a, and -b,
are produced, which cause local inflammation and fibrosis
(90). Steatosis is another factor that has contributed in the
mechanism of EHM of HCV via the production of inflam-
matory markers such as IL-6 and TNF-a. These molecules play
roles in the inhibition of insulin signaling pathway, and adi-
ponectin levels subsequently results in the progression of
steatosis and IR (43). In some HCV patients, a high level of
inflammatory markers due to steatosis is a major cause of CAD
(9). The other mechanism that causes inflammation due to
HCV is oxidative stress. Imbalance between antioxidants and
reactive oxygen species is linked with local and systemic in-
flammation. Other factors that are involved in oxidative stress
damage include necrosis, tissue regeneration, apoptosis, is-
chemia, and fibrinogenesis (89) (Fig. 2).
Idiopathic Pulmonary Fibrosis
IPF is a chronic disease of the lungs that includes low-
grade inflammation of alveoli, leading to the derangement of
lung interstitium. IPF usually develops in cases of chronic
HCV infection (19). It is characterized by the accumulation
of extracellular matrix, impaired gas exchange, and worsen-
ing dyspnea (58,88). Various pathologic features of IPF in-
clude epithelial cell injury, diffuse alveolar damage, variable
inflammation, lung damage and fibrosis, and temporal and
spatial heterogeneity in lung areas (27,58). The precise cause
for the IPF is unknown (67), however, HCV is said to be a
triggering agent for inflammation in the lung interstitium that
leads to lung fibrosis (23,64). The relationship between HCV
infection and IPF was confirmed by a retrospective study,
which reports 11% of patients with HCV-induced cirrhosis,
who also showed obstructive airway disease (4).
There are many factors that contribute to the chronic lung
diseases such as persistent antigens, viral infection, lung
injury, and immune cell activation (47). HCV-related IPF is
said to be an outcome of occult infection, in which virus (an
inflammatory agent) disrupts the normal healing process of
the lung, resulting in lung fibrosis (70). In case of IPF, both
 4 ILYAS ET AL.
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FIG. 2. Factors related to HCV that causes chronic inflammation, which plays a role in hepatic and systemic manifes-
tations. HCC, hepatocellular carcinoma.
lytic and latent viruses have found to play their roles in
causing lung fibrosis. In case of IPF, HCV RNA is also
detectable in bronchoalveolar lavage (BAL) fluid, and in
lung biopsies of patients, indicating the direct involvement
of the virus in IPF (8), however, the presence of HCV-RNA
at lower quantity is indicative of virus airway transmission;
as no difference was found between the T cell and B cell
populations among the cases and controls (34). Certain other
immune cells, such as neutrophil, eosinophil, macrophages,
mast cells, and fibroblast cause some nonspecific inflam-
matory reactions (47), ultimately resulting in lung fibrosis.
In HCV patients, immune complexes found to have no role
in causing the IPF, because fluorescence microscopy of the
lung biopsies has not revealed any immune complex.
There was a high prevalence of anti-HCV antibodies
against the C100-3 antigen (a polypeptide containing 363
amino acids) of HCV in the sera of IPF patients (82). In HCV-
related IPF, virus-induced immune-mediated fibroblast acti-
vation is thought to have a key role in pathogenesis (17), as
these fibroblast cells are activated after the viral infection.
With these activated fibroblasts, epithelial cells, mast cells,
monocytes, and macrophages have found to release higher
levels of IL-10, IL-13, and IL-4 (47). IL-4 and IL-13 act as
proinflammatory mediators and either directly or indirectly
affect the fibroblast activation (85). In this type 2 cytokine
environment, an increase in the levels of IL-4 and IL-13 results
in the production of increased extracellular matrix proteins and
fibroproliferation. Excessive deposition of the extracellular
matrix proteins in the lungs causes pulmonary fibrosis (85).
IPF can also be an outcome of autoantibodies produced in
response to the HCV infection as there is a relationship
between the Jo-1 autoantibody and IPF (83).
From the published data, various evidences have
been provided for viral etiology of IPF. The conditions of
IPF+HCV patients were improved when treated with anti-
virals, valacyclovir and ganciclovir (58,88). In addition to
this, IPF+HCV patients have higher mean age suggestive of
the immunosenescence, particularly in case of viral infec-
tions (25,59), along with different spatial or temporal mor-
phology of the lung indicative of reminiscent infection
(27,58). Besides this, a large population of activated lym-
phocytes is observed in the BAL fluids of IPF patients with
enhanced expression of the host defense genes (58,59,86).
Chronic Obstructive Pulmonary Disease
COPD is characterized by a chronic inflammation of the
lung parenchyma tissue with varying degree of airway ob-
struction (60). COPD can be a result of spontaneous pul-
monary reactions, or sometimes it develops in response to
certain medical treatment. In 1990, COPD was considered
as the sixth most common cause of death that is estimated to
be the third most common cause of death in 2020 (79).
COPD is characterized by the fixed airflow restriction and
forced expiratory volume (FEV) as these factors can be used
as prognostic markers for the disease (79). Various viral
infections aggravate the previously caused COPD and
asthma (58). HCV can either initiate or increase the severity
of the disease, as HCV+COPD have reduced values for
pulmonary function tests, including FEV1 and carbon
monoxide diffusion capacity of the lungs (DLCO) values,
compared with the HCV-COPD patients (79).
HCV exacerbates the COPD directly by causing chronic
inflammation due to latent viral infection and indirectly by
triggering the HCV-specific T-Lymphocytic response. Be-
sides this, HCV infection reduces the lung functions in pa-
tients suffering from COPD. In patients with COPD, the
disease conditions mainly worsened due to the chronic HCV
 HCV-ASSOCIATED EXTRAHEPATIC MANIFESTATIONS
conditions. In a study, various anthropological factors such
as mean age, sex, exposure to environmental pollutants, risk
factors for acquisition of HCV, and smoking habits were
assessed to find their associations with HCV. A significant
difference has been found only in the mean age of the two
groups, as patients with HCV and COPD have higher mean
ages compared with those with HCV and no COPD (77),
thereby suggesting an association between chronic HCV,
with longer duration to COPD. In patients with HCV and
increased mean ages, there is a long period of immune ac-
tivation and inflammation due to chronic viral infection that
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aggravates the COPD. Because of long-term viral replica-
tion in the body, the expression of CD8+ T lymphocytes is
upregulated. This upregulation activates a cascade of in-
flammatory pathways resulting in the release of inflamma-
tory mediators, which causes the airway obstruction in
COPD (60). In addition, in HCV patients, increased level of
IL-8 causes the inflammatory response in the body as well as
suppresses the action of IFN-c (79).
Mixed Cryoglobulinemia
Cryoglobulinemia is a blood disorder, characterized by
the presence of special blood immunoglobulins called
cryoglobulins. The MC is a systemic vasculitis with various
clinical symptoms (23). Cryoglobulins are common in the
blood of HCV patients, as MC is found to be the most
common and severe EHM of HCV infection (70). The as-
sociation of MC with HCV has been defined on the basis of
its higher prevalence and pathogenesis in HCV patients (93).
Cryoglobulins starts to precipitate or deposit in the vessels
when blood is chilled (below 37C), thus restricting the blood
flow in vessels resulting in vasculitis (24,94). Longer duration
of HCV infection and clonal B cell expansion in hepatocytes
is among the many factors that cause MC (68,75). Along with
many other complications of MC, pulmonary hemorrhage
and cardiovascular disorders are found to be common in HCV
patients (65). Among the patients of HCV, percentage of MC-
affected patients is 19–50% (26), however, its prevalence
varies with the geographical heterogeneity. In HCV patients
the organs that are mostly affected by MC include the lungs,
joints, nerves, and kidneys (70).
In HCV patients, MC is the result of antigen-driven
lymphoproliferative process of B cells. HCV is known to
reside on the peripheral lymphocytes circulating in the body
where it replicates and increases its number. HCV has
ability to bind with the CD81 ligand present on the B-
Lymphocyte through E2 protein. E2 protein present on viral
envelope mimics the human IgS (26), thus, it activates
complement cascade, resulting in the formation of immune
complexes upon its binding to CD81 (33). Furthermore, this
binding triggers expression of a special set of genes en-
coding the variable region (VH, VK) of immunoglobulins
and of those involved in production of IgM-RF with cross-
reactive WA-idiotype (69,94). In type 2 MC, gene expres-
sion results in the production of polyclonal antibodies (IgG)
followed by production of monoclonal antibodies (IgG,
IgM, and IgA) after the emergence of a single-type domi-
nant B cell. While in case of type 3 MC, only polyclonal
(IgG, IgM) antibodies are produced (26). In addition, the
presence of cryoglobulins mainly complexed with HCV
5
RNA (70) in patients of HCV+MC further indicates the
involvement of HCV in causing MC.
Cardiovascular manifestations of MC include ischemic
heart disease with coronary vasculitis, valvular heart disease
with mitral valvular damage, pericarditis, acute myocardial
infarction, congestive heart failure, and dilative and hyper-
trophic cardiomyopathies (5). Pulmonary alterations that are
mostly resulted from MC are mild in nature, while some-
times they lead to the severe outcomes such as diffuse al-
veolar damage and organizing pneumonia. In HCV patients,
various cytokines, inflammatory cells, and immune com-
plexes act as major contributors of heart diseases, however,
in the serum of MC+HCV patients, there is a direct in-
volvement of viral antigens (bind with immunoglobulins)
and various immune complexes that ultimately deposit in
lung interstitium (23).
In patients with HCV and MC, various B cell subsets and
autoantibodies are observed, which cause lung fibrosis. CIC
comprises IgG, IgM, IgA, C3, and C4 and were detected in
HCV patients with heart diseases in different proportions. For
example, patients with valvular disease present high levels of
C3, however, the levels of IgM are higher in patients with
myocarditis (14). Cytokine zTNF4 (a member of the tumor
necrosis factor family) was found at higher levels in patients
with MC-linked HCV. CXCL10-mRNA is overexpressed in
hepatocytes in HCV patients and plays a role in the patho-
genesis of disease through recruitment of inflammatory cells
(T cells) to the site of inflammation. Presence of high levels of
CXCL10 in serum results in histological severity and globular
inflammation. In HCV+MC patients, certain genetic muta-
tions also play their roles in overexpansion of the B cell
community. Among these mutations, there includes translo-
cation of the bcl2 gene. This mutation results in the over-
expression of antiapoptotic bcl2 gene, resulting in increased
survival of B cell populations (76,94).
Cardiopulmonary Diseases Related
to Liver Cirrhosis
HCV is one of the major causes of liver cirrhosis in the
world. Chronic liver inflammation is responsible for liver
cirrhosis that leads to severe liver diseases such as liver
cancer and liver failure. Cardiac and liver diseases are
mutually interrelated (63). The major cardiac manifestations
that arise due to liver cirrhosis are cirrhotic cardiomyopathy
(CCM), pericardial effusion, systolic and diastolic dys-
function, and noncirrhotic high-output heart failure that
occurs due to hepatic arteriovenous shunts. The exact defi-
nition of CCM was reported in 2005 by experts in annual
meeting of the World Gastroenterology Organization (57).
The main clinical features of CCM are cardiac dysfunction
(systolic and diastolic), hyperdynamic circulation, and ab-
normal electrophysiological findings (73).
In patients suffering from chronic liver diseases, cardiac
dysfunction is the main heart problem that depends on many
factors. These factors include defects in the cardiac b-
adrenergic receptor system, plasma membrane fluidity,
abnormalities in the membrane calcium channels, and
pathological effects of many humoral factors such as NO,
cytokines, carbon monoxide, and endocannabinoids (56).
HCV-related CCM shows three major pathophysiologic
abnormalities, which include cardiac electrophysiological
 6 ILYAS ET AL.
abnormalities, structural and functional ventricular abnor-
malities, and abnormal ventricular response to stress (44).
Other cardiac manifestations related to cirrhosis are en-
docarditis, arrhythmias, and tachycardia (45). Arrhythmias
are associated with hepatic pulmonary syndrome. In liver
cirrhosis, different markers such as natriuretic peptides, cy-
tokeratin 18, TNF, and microRNAs are produced in high
number. These biomarkers are used to access cardiac diseases
due to chronic liver diseases (61). Despite many pulmonary
diseases that are attributable to the lymphoproliferative nature
of HCV, certain pulmonary alterations can be the direct
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outcome of advanced liver diseases such as liver cirrhosis in
HCV patients. Among these outcomes, there include hepa-
topulmonary syndrome and portopulmonary hypertension
(29).
Hepatopulmonary syndrome is characterized by altering
gas function in the lungs and shunting of blood from right to
left side because of the intrapulmonary vascular dilatations.
Any level of liver damage, including liver cirrhosis and
portal hypertension, contributes to disease. Among the HCV
patients, it is more prevalent among those who are suffering
from the advanced liver diseases (20,29). Until now, endo-
thelial cell injury in the lungs has been said to be a main
reason for the intrapulmonary vascular dilatations. In HCV
patients, endothelial cell injury occurs due to increased
levels of bile acid and cytokines (TNF-a). Bile acids are
produced due to liver cirrhosis, while cytokines mainly re-
sult from HCV-induced immune activation (29,30). TNF-a
is known to perform the proinflammatory function that
further promotes the leukocyte–endothelium interaction or
sometimes activates the arachidonic acid pathway (70). The
second outcome of advanced liver diseases is porto-
pulmonary hypertension. It is characterized by the altered
pressure in the pulmonary arteries and veins. About 5% of
the patients suffered from cirrhosis also develop porto-
pulmonary hypertension (29).
HCV Antiviral Therapy and Cardiopulmonary
Complications
Before 2011, the approved therapies for treating the chronic
HCV infection include IFN, PEGylated IFN-a alone, or in
combination with ribavirin (RBV) (42). IFN and RBV com-
bination is in use for treating the HCV infection, however,
PEGylated IFN a-2b is approved for the treatment of chronic
HCV as a monotherapy. Antiviral-related lung pathologies are
mostly rare, but are potentially fatal with an incidence of 0.4%
to <1% (13). The spectrum of these pathologies includes di-
verse outcomes such as interstitial pneumonitis, bronchiolitis
obliterans organizing pneumonia (BOOP) (secondary orga-
nizing pneumonia), pulmonary sarcoidosis, pleural effusion,
and exacerbation of asthma (13). Interstitial pneumonia (IP)
and sarcoidosis are among the well-documented complica-
tions of the IFN therapy of HCV patients (3). The incidence
rate of IP is estimated to be 0.01–0.3% (37).
The exact mechanism for the toxicity of lungs by IFN-a is
not well understood, however, IFN-a causes the inhibition
of suppressor T cells and enhances the expression of cyto-
toxic T cells (55). In addition, it increases the release of
fibrinogenic cytokines, thus causing the lung injury. In the
presence of higher level of type 2 cytokines (IL-13 and IL-
4), the extracellular matrix proteins produced by activat-
ing myofibroblast cells start to deposit in the lung tissues,
thereby causing the lung tissue fibrosis (85). Pulmonary
sarcoidosis is another IFN-a-related complication resulted
from the stimulation of Th1 response and macrophages, along
with the induction of autoantibodies due to IFN therapy (2).
The mechanism is known to cause pulmonary sarcoidosis,
granuloma formation in lung tissues, and macrophage acti-
vation due to dysregulated IFN-c.
To date, only few cases of IFN-related sarcoidosis have
been reported in patients of myelogenous leukemia, multiple
myeloma, and HCV (1,2,54). IFN treatment is also re-
sponsible for causing pulmonary arterial hypertension
(PAH) in HCV patients (72). Cardiovascular complica-
tions due to PEG-IFN-a include congestive heart failure,
myocardial infarction, life-threatening arrhythmias, ische-
mic heart disease, CAD, pericarditis, and DCM (38). These
cardiac complications occur only after prolong treatment of
IFN-a therapy. Anemia is a common outcome of Peg-IFN/
RBV treatment in many HCV patients, however, some pa-
tients who have CAD cannot tolerate anemia (18). Besides
this, DCM was completely resolved when Peg IFN-a and
RBV therapy was stopped (92).
In the United States, the triple therapy, including the
RBV, PEGylated IFN, and protease inhibitors (boceprevir
and telaprevir), has been adopted in 2011 (80). The direct
acting antivirals (DAAs) reduced the duration of therapy up
to 24–28 weeks in *50% of patients, while responsible for
the improvement in sustained virological response (SVR)
rate in naive and experienced patients. These benefits could
be achieved only when DAAs are used in combination with
peg-IFN/RBV (91), but the treatment is not effective in case
of patients suffering with cirrhosis. In last 3 years, DAAs
revolutionized the treatment of HCV by using multiple
classes of DAAs in IFN-free regimens (46).
Until now a large number of antivirals have been ap-
proved by the European Medicine Agency (EMA) and the
Food and Drug Administration (FDA) starting with boce-
previr and telaprevir in 2011 for the treatment of HCV ge-
notype 1, followed by the approval of four new protease/
polymerase inhibitors: sofosbuvir, simeprevir, daclatasvir,
and ledipasvir, and a NS3/4A protease inhibitor asunaprevir
in 2014 (74). A new combination of ombitasvir/paritaprevir
was also approved as a treatment option for HCV in the year
2015. Recently in 2016, another combination of grazoprevir/
elbasvir has been recommended by EMA. These antivirals
are associated with higher SVR rate (90–100%) as it has
been proven from various pivotal studies (53). Use of
multiple classes of the DAAs has been proven to be effec-
tive in cirrhosis patients because short and tolerated regi-
mens increased the SVR rate up to 95% (22). This treatment
has limited EHMs, but mostly it affects the kidneys.
Although the efficacy of DAAs therapy is higher, it has
some severe side effects such as lymphopenia, hemolytic
anemia, and decomposition of cirrhosis (80). These side
effects also favor the lung infections by bacterial pathogens
such as mycobacterium abscessus (80). Pneumonia is an-
other outcome of cirrhotic HCV patients who were given
DAA therapy. DAAs are responsible for the cardiovascular
manifestation in those HCV patients suffering with DM
(48). The most common side effects of the DAAs include
fatigue, headache, nausea, and insomnia. Percentage of
HCV patients suffering with anemia is lower when treated
 HCV-ASSOCIATED EXTRAHEPATIC MANIFESTATIONS
with simeprevir/sofosbuvir compared with the RBV, how-
ever, two serious complications, including renal failure and
aspiration pneumonia, were considered for treatment-related
patients’ death. Besides, this simeprevir and sofosbuvir were
also associated with pulmonary manifestations, including mild
diffuse emphysema, PAH, and interstitial pneumonitis (31,81).
Among various DAAs, ombitasvir/paritaprevir/ritonavir and
dasabuvir were found to have serious pulmonary and cardiac
complications, including acute respiratory failure, sinus
tachycardia, ventricular extrasystoles, and acute transient
stroke (21).
Downloaded by Gothenburg University Library from online.liebertpub.com at 09/28/17. For personal use only.
Conclusion
Although HCV causes the liver cirrhosis and hepatocel-
lular carcinoma, chronic HCV infection is involved in many
EHMs that affect every organ specially heart and lungs via a
variety of mechanisms. The crucial cardiopulmonary dis-
eases related to HCV include myocarditis, cardiomyopa-
thies, CVDs, strokes, COPD, IPF, asthma, and interstitial lung
diseases. Mostly cardiopulmonary manifestations of HCV are
immune-mediated and some occurred due to chronic inflam-
mation. Cryoglobulinemia, liver cirrhosis, and HCV antiviral
therapy are the most significant source of HCV-related lung
and heart diseases in those persons suffering with advanced
liver diseases. The classic anti-HCV therapy (IFN-RBV) is also
linked with many adverse effects, however, with the discovery
of new directly acting anti-HCV compounds the IFN-RBV-
mediated side effects will be decreased with the more efficient
viral control.
Acknowledgment
IQ received funding from KACST large grant #162-34.
Author Disclosure Statement
No competing financial interests exist.
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Address correspondence to:
Dr. Ishtiaq Qadri
Department of Biological Sciences
King Abdul Aziz University
Jeddah 110809
Kingdom of Saudi Arabia
E-mail: ishtiaq80262@yahoo.com