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Chapter 9

Extrahepatic Manifestations of Hepatitis C Virus

Infection

Lucija Virović Jukić and Dominik Kralj

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70728

Provisional chapter

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

and reproduction in any medium, provided the original work is properly cited.

DOI: 10.5772/intechopen.70728

Extrahepatic Manifestations of Hepatitis C Virus

Infection

Lucija Virović Jukić and Dominik Kralj

Additional information is available at the end of the chapter

Abstract

Chronic hepatitis C virus (HCV) infection causes progressive liver brosis, cirrhosis, liver

failure, and hepatocellular carcinoma. Additional to liver damage, HCV infection causes

a variety of systemic disorders, some of which sometimes bear more severe morbidity

than the liver disease itself. These extrahepatic manifestations represent a wide spectrum

of disorders, ranging from the presence of a variety of clinically insignicant autoan-

tibodies to diseases aecting a variety of organ systems. Mixed cryoglobulinemia is a

common manifestation, and associated vasculitis can aect many organs (kidney, skin,

and joints). The skin can also be aected by porphyria cutanea tarda and lichen planus.

Other common extrahepatic manifestations include autoimmune disorders, lymphopro-

liferative disorders, and a number of neurological and neuropsychiatric disorders such

as fatigue, depression, or cognitive impairment. Insulin resistance, diabetes mellitus,

accelerated atherosclerosis, and increased cardiovascular disease morbidity and mortal-

ity have also been associated with chronic HCV infection. The existence and severity of

extrahepatic manifestations do not correlate with the severity of liver disease, and the

mainstay of treatment is HCV eradication. Patients with systemic manifestations of HCV

infection should be prioritized for treatment, especially in the era of new interferon-free

therapies with fewer side eects.

Keywords: chronic hepatitis C infection, extrahepatic manifestations, interferon therapy,

direct-acting antiviral agents

1. Introduction

Hepatitis C virus (HCV) is a single-stranded RNA virus, a member of the Flaviviridae fam-

ily. As a primarily hepatotropic virus, the main target of infection is hepatocytes, resulting in

chronic inammation in about 80% of cases of infection. It is well known that chronic hepatitis

© 2017 The Author(s). Licensee InTech. Distributed under the terms of the Creative Commons Attribution-

NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution

and reproduction for non-commercial purposes, provided the original is properly cited.

C leads to cirrhosis, the terminal stage of liver disease, and hepatocellular carcinoma. It is,

however, less known that chronic HCV infection leads to a series of systemic disorders and

diseases that can often leave greater health consequences than the liver disease alone. These

disorders are commonly called extrahepatic manifestations of chronic hepatitis C and encom-

pass a wide spectrum of conditions, from a clinically insignicant presence of dierent auto-

antibodies to vasculitis, skin disease, kidney damage, lymphoproliferative disorders, diabetes,

various neurological and neuropsychiatric changes, and even increased cardiovascular mor-

bidity and mortality [1]. Extrahepatic manifestations in any form may appear in up to 74% of

patients with chronic HCV infection and may long precede manifest hepatic disease presenting

with various nonspecic health impairments including malaise, fatigue, nausea, weight loss,

and musculoskeletal pain [2]. Specic extrahepatic manifestations of chronic hepatitis C can

be divided according to the aected organ or organ system, pathological mechanism, or the

strength of available evidence connecting them to chronic hepatitis C infection. Some of the

extrahepatic manifestations according to organ system and proposed pathological mechanism

are shown in Tables 1 and 2. The fact that the severity of these disorders does not necessarily

correlate with the severity of hepatic disease is of great clinical signicance because even in

cases of mildly active chronic hepatitis, a considerable disruption of overall health and quality

Hematopoietic Essential mixed cryoglobulinemia

Monoclonal gammopathy

B-cell non-Hodgkin lymphoma

Skin Leukocytoclastic vasculitis

Porphyria cutanea tarda

Lichen planus

Kidneys Membranoproliferative glomerulonephritis

Membranous nephropathy

Renal impairment

Immunological Autoimmune antibodies: rheumatoid factor, antinuclear, antithyroid,

anticardiolipin, anti-smooth muscle antibodies

Thyroid Thyroiditis

Hypothyroidism

Hyperthyroidism

Endocrine and exocrine glands Type 2 diabetes mellitus

Sicca syndrome

Musculoskeletal Arthralgia/myalgia

Neurological and neuropsychiatric

disorders

Fatigue

Depression

Impaired cognitive function

Sensory or sensorimotor polyneuropathy

Mononeuritis multiplex

Cardiovascular Accelerated atherosclerosis

Increased rate of cardiovascular and neurovascular incident and peripheral

artery disease

Increased mortality from cardiovascular and neurovascular incidents

Table 1. The most common extrahepatic manifestations of chronic hepatitis C according to organ system involvement.

Update on Hepatitis C112

of life can occur. On the other hand, numerous studies have shown that treatment of chronic

HCV infection accomplishes the resolution of extrahepatic disease or greatly increases func-

tion of the aected organ and lowers accompanying morbidity and mortality risks. Because of

this reason, it is accepted and highlighted in current European guidelines, as well as Croatian

recommendations for treatment of chronic hepatitis C infection, that patients with extrahepatic

manifestations should be prioritized for treatment, regardless of the activity/severity of their

liver disease alone [3, 4].

2. Essential mixed cryoglobulinemia

Essential mixed cryoglobulinemia or type II cryoglobulinemia is classied into the group of

lymphoproliferative disorders in which clonal B lymphocyte expansion leads to immunoglob-

ulin production—polyclonal immunoglobulin (Ig) G class and monoclonal IgM as rheumatoid

factor (RF)—leading to development of immune complexes that precipitate in the cold and are

therefore called cryoglobulins. As a consequence of the precipitation of cryoglobulin com-

plexes in small- and middle-sized blood vessels, the occurring complement activation leads to

endothelial damage and cryoglobulinemic vasculitis [5]. The syndrome can aect blood ves-

sels in dierent organs and manifest on the skin, large joints, peripheral nerves, or kidneys.

Cryoglobulins are present in about 50% of patients with chronic hepatitis C infection, but do

not always cause clinically manifest cryoglobulinemic vasculitis. On the other hand, over 90%

of patients with essential mixed cryoglobulinemia have chronic hepatitis C infection. The skin

is commonly aected in cryoglobulinemic syndrome manifesting as palpable purpura as a

consequence of leukocytoclastic vasculitis [6]. Joint involvement manifests with arthralgias;

perineural vasculitis is a cause of distal sensory or sensorimotor polyneuropathy, while kid-

ney involvement most often leads to membranoproliferative glomerulonephritis with renal

function impairment. Diagnosis is based on cryoglobulin presence, elevated RF, and immu-

nouorescence of complement xing IgM in aected tissues. It is important to note that many

studies have shown clinical manifestations of essential mixed cryoglobulinemia to withdraw

Autoimmune mechanism Proliferative eect Inammatory/metabolic Other

mechanism

Autoantibodies Essential mixed

cryoglobulinemia

Insulin resistance and diabetes

mellitus

Porphyria

cutanea tarda

Thyroiditis Monoclonal gammopathy Fatigue/malaise

Hepatitis Non-Hodgkin lymphoma Depression

Sicca syndrome Cognitive function damage

Arthralgia/myalgia Cardiovascular disease (coronary

disease, stroke)

Table 2. Proposed pathogenetic mechanism through which chronic HCV infection leads to extrahepatic manifestations.

Extrahepatic Manifestations of Hepatitis C Virus Infection

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113

after successful HCV infection treatment and that the presence of mixed cryoglobulinemia is

associated with a reduced virological response rate [7]. Withdrawal of essential mixed cryo-

globulinemia, with low recurrence levels, has been established earlier with interferon therapy,

and recently some smaller scale studies showed a very good eect of combined direct-acting

antiviral therapy (so-called "interferon-free" therapy) in cryoglobulin clearance, renal func -

tion improvement, and proteinuria reduction [8, 9]. The success rates seem to be lower than

those observed in large registration studies, but the fact the treatment is new and that sample

sizes were relatively small should be taken into account. It is important to highlight that, in

some patients, interferon therapy can lead to the worsening of clinical manifestations and that

in everyday practice optimal antiviral therapy with direct-acting antiviral drugs represents

the standard of care for patients with clinically mild to moderate cryoglobulinemic vasculitis.

In severe cases additional therapy modalities such as rituximab, corticosteroids, and plasma-

pheresis may be used before starting antiviral therapy. For refractory forms of cryoglobuline-

mia, cyclophosphamide and other immunosuppressants are sometimes used.

3. B-cell lymphoma and monoclonal gammopathies

Hepatitis C virus is primarily hepatotropic, but it has also been shown to be lymphotropic,

and a connection between chronic HCV infection and B-cell non-Hodgkin lymphoma (NHL)

has been established [10, 11]. It is assumed that chronic B lymphocyte stimulation by the HCV

antigen leads to monoclonal B-cell expansion present in mixed cryoglobulinemia. This seems

to predispose to NHL occurrence, with studies showing increased risk relative to the general

population [12]. In a retrospective study comparing untreated HCV-infected patients to those

treated with interferon, it has been shown that the rates of malignant lymphoma occurrence

(diuse large cell lymphoma and follicular lymphoma) were signicantly higher in untreated

patients, as well as in those who did not achieve sustained virologic response (SVR), com-

pared to those who were cured [13]. The importance of chronic HCV infection in lymphoma

development was additionally conrmed with reports of successful NHL remission after

HCV eradication. Results with new interferon-free therapies are so far only available as case

reports but point to lymphoma withdrawal after hepatitis C eradication. It can be expected

that the wide use of new therapies will show results in larger cohorts of patients.

There are studies suggesting HCV to be a risk factor for monoclonal gammopathies, but

the results are inconsistent, and a routine screening of patients with chronic hepatitis C for

monoclonal gammopathies is not recommended. In patients with HCV infection, polyclonal

or oligoclonal hypergammaglobulinemia (mostly IgG) is present. The gamma globulin level

often correlates with disease severity on liver biopsy, and its decrease after successful HCV

treatment has been noted.

4. Kidney impairment

Chronic hepatitis C infection is connected with glomerular disease which is most probably

a consequence of immune complex deposition in glomerular capillaries. The most common

Update on Hepatitis C114

form of kidney disease is membranoproliferative glomerulonephritis, typically connected

with essential mixed cryoglobulinemia, while membranous nephropathy is less common [14,

15]. Other non-cryoglobulin-based renal diseases described in HCV-infected patients include

IgA nephropathy, postinfectious glomerulonephritis, as well as focal and segmental glomeru-

losclerosis. Patients most often present with proteinuria and microhematuria with dierent

degrees of renal impairment and with renal biopsy showing glomerular immune complex

deposition. Acute nephrotic or nephritic syndrome with new onset of arterial hypertension is

also possible. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines thus rec-

ommend screening for renal impairment at the time of HCV infection diagnosis and then once

a year by determining serum creatinine and performing urinalysis. All patients with chronic

kidney disease should also be tested for HCV infection [16]. The existence of renal impair-

ment, especially membranoproliferative glomerulonephritis, is an indication for HCV infec-

tion treatment. Until now the standard of treatment was combined interferon and ribavirin

(with necessary precaution and kidney function-adjusted dosage), while rituximab, corticoste-

roids, or immunosuppressants are added in patients with severe cryoglobulinemic vasculitis.

Data about the ecacy of new interferon-free therapies in this indication is only available from

studies involving a relatively small number of patients, but it can be expected that it could sig-

nicantly change the clinical presentation and improve treatment of this group of patients [8].

5. Skin manifestations

Porphyria cutanea tarda (PCT) is a disease caused by the reduced activity of the hepatic uro-

porphyrinogen decarboxylase (UROD) which leads to accumulation of uroporphyrinogen in

the blood and urine and is the most common porphyria. PCT can be inherited (autosomal dom-

inant) or acquired (sporadic), and exactly this form was connected with HCV infection in many

studies. Meta-analysis that included 50 studies and a total of 2167 patients with PCT showed

that the prevalence of HCV infection was around 50%, while the frequency of PCT in patients

with chronic HCV infection is about 1–5% [17]. The exact mechanism by which HCV can cause

or induce PTC is not known, but it is presumed to be mediated through changes in iron metab-

olism. Namely, increased iron saturation, estrogens, and alcohol consumption can provoke or

induce PCT. Skin changes develop as a consequence of photosensitivity and skin friability and,

upon sun exposure and/or minor trauma, manifest as erythema and bullae which may turn

hemorrhagic [18, 19]. In later stages hyperpigmentation, hypopigmentation, hirsutism, and

sclerodermic changes can appear. In the liver, a spectrum of histological changes can be found,

including steatosis, mild to severe inammation, brosis, and cirrhosis. Diagnosis of PCT is

made on the basis of clinical suspicion and is conrmed by measuring increased levels of por-

phyrin in urine and, if available, direct measurement of the UROD enzyme activity. Treatment

consists of avoiding precipitating factors (sun, alcohol, estrogens) and, if necessary, lowering

iron overload (venipuncture) as well as treating HCV infection in aected patients. In general,

treatment of chronic HCV infection leads to the normalization of UROD enzymatic activity,

levels of liver aminotransferase and urine porphyrin, as well as disappearance of skin changes.

Lichen planus is a chronic inammatory disease of the skin and mucosa which can aect

hair and nails and is characterized by pruritic papulae. These most often appear on the skin

Extrahepatic Manifestations of Hepatitis C Virus Infection

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115

of extremities, face, scalp, nails, and mucosa of the gastrointestinal and genitourinary tract.

Lichen planus occurs in various chronic liver diseases, and anti-HCV antibodies can be found

in 10–40% of patients with lichen planus [20]. It is assumed that the occurrence of lichen pla-

nus is immunologically mediated, but the exact mechanism is unknown. It is also considered

a premalignant condition and is known to progress to squamous cell carcinoma. The treat-

ment of HCV infection with interferon therapy did not result in regression of lichen planus in

most studies; on the contrary, there are reports of appearance or exacerbation of lichen pla-

nus during interferon therapy. A recent case series involving seven patients with oral lichen

planus treated with interferon-free protocols showed an improvement of symptoms without

adverse events [21].

Leukocytoclastic vasculitis is associated with essential mixed cryoglobulinemia and is a

consequence of blood vessel involvement. It is clinically characterized by palpable pruritic

changes and petechiae which usually aect lower extremities and is treated as other manifes-

tations of essential cryoglobulinemia.

Necrolytic acral erythema, a condition characterized by painful, pruritic, and erythematous

skin lesions of extremities is reported to be strongly associated with chronic HCV infection.

Zinc supplementation has been associated with improvement of the condition.

Some data supports a possible connection of chronic HCV infection with chronic pruritus,

while sporadic reports also suggest an association of HCV infection with psoriasis, chronic

urticaria, pyoderma gangrenosum, erythema nodosum, and erythema multiforme.

6. Ocular manifestations

Mooren's corneal ulcer represents a rare painful peripheral corneal ulceration, usually with-

out accompanying scleritis. Some studies have made a connection between this rare form of

corneal ulcer and chronic HCV infection, but the pathogenetic mechanism is not known [22].

Chronic HCV infection has been linked to other diseases of the eye such as sicca syndrome,

keratitis, increased intraocular pressure, and episcleritis, while some disorders such as retinal

bleeding, vision impairment, as well as rare cases of retinal artery or vein obstruction have

been described as possible complications of interferon therapy.

7. Thyroid disorders

Thyroid disorders are relatively frequent in patients with chronic hepatitis C, especially in

women. Antithyroid antibodies are, according to various reports, present in 5–17% (averaging

at 10%) of patients with HCV infection, while thyroid diseases (mostly hypothyroidism) occur

less often, in 2–13% of patients [23]. Thyroid function disorders appear even more often during

interferon therapy, probably as a consequence of autoimmune activity precipitated by immu-

nomodulatory therapy, but can persist even after treatment completion. There is some evi -

dence of a possible HCV infection of thyroid tissue causing a local inammatory response that

might trigger the autoimmune process. In any case, determining thyroid hormones as well as

Update on Hepatitis C116

anti-thyroglobulin and antithyroid peroxidase antibodies is necessary in all HCV-infected

patients, especially before and periodically during interferon therapy. Substitution therapy

with thyroid hormones is used in hypothyroidism treatment. In cases of mild hyperthyroid-

ism, symptomatic therapy is used, while thyrostatic therapy is reserved for more severe cases.

Interferon therapy should be stopped in cases of severe hyperthyroidism caused by the treat-

ment. It will be interesting to see how the eradication of HCV infection with new drug combina-

tions without interferon aects thyroid function disorders in patients with chronic hepatitis C.

8. Sicca syndrome

The sicca syndrome develops in most patients with Sjögren's syndrome. Lymphocytic sial-

adenitis resembling Sjögren's syndrome has been described in patients with chronic HCV

infection who complain of mouth or eye dryness in 20–30% of cases [15]. There are, however,

histological (milder, mostly pericapillary lymphocytic inltration without ductal destruction

in HCV infection as opposed to periductal inltration with destruction of excretory ducts in

classic Sjögren's syndrome) and clinical dierences (less pronounced symptoms, later onset,

increased levels of serum cryoglobulin and RF, lower complement levels, positive antinu-

clear, and negative Ro/La antibodies). Therefore, it seems that HCV does not cause Sjögren's

syndrome but rather symptoms that imitate it [14]. Treatment of chronic HCV infection leads

to symptom resolution in patients with the sicca syndrome.

9. Other autoimmune manifestations

Various autoantibodies are frequently found in patients with chronic HCV infection.

Rheumatoid factor (around 60%) is most often present followed by antinuclear antibod-

ies (ANA, around 40%), antithyroid (35%), anticardiolipin (15%), and anti-smooth muscle

antibodies (ASMA, around 7%), respectively. These antibodies appear in about one-half of

patients with chronic HCV infection (40–65% according to dierent studies) but are com-

monly present in low titer and, for the most part, do not seem to aect the clinical course

of the disease [1]. Antibodies to liver and kidney microsomes (anti-LKM-1) and actin are an

exception and can be of clinical signicance in some HCV-infected patients. These antibodies

are usually characteristic for autoimmune hepatitis, and it has been noticed that, although

patients with hepatitis C and anti-LKM-1 antibodies mostly benet from interferon therapy,

in some cases an increase in liver function tests can be observed. Some of these patients

respond well to standard therapy for autoimmune hepatitis which consists of azathioprine

and corticosteroids. Determining the primary cause of hepatitis in patients with overlapping

HCV infection and autoantibodies can be very challenging, even though it has been shown

that anti-LKM-1 antibodies in these patients are directed against dierent epitopes of cyto-

chrome P450 2D6 compared to patients with autoimmune hepatitis [24]. Even though there

are no recommendations for routinely determining the presence of these antibodies, if they

are known to be present, greater caution during interferon therapy is recommended. The role

of direct-acting antiviral drugs in these patients is yet to be determined.

Extrahepatic Manifestations of Hepatitis C Virus Infection

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117

Numerous studies have shown a connection between HCV infection and immune thrombo-

cytopenic purpura (ITP) and/or hemolytic anemia, whether as a consequence of the infection

itself or of interferon therapy. According to the results of one of the largest studies, it seems

that chronic HCV infection is associated with a higher frequency of ITP in both treated and

untreated patients, while increased risk of autoimmune hemolytic anemia was only present

in patients treated with interferon therapy.

10. Musculoskeletal system

Arthralgia is common and reported by 40–80% of patients with chronic hepatitis C [1]. The

joints are usually symmetrically aected, mostly knees and hands. The aicted joints are

painful, without deformities. True arthritis is rare, presenting as rheumatoid like arthritis in

two-thirds and oligoarthritis in one-third of patients. Rheumatoid factor is present in 70–80%

of patients with mixed essential cryoglobulinemia, but its presence does not correlate with

joint aection [15]. Likewise, cyclic citrulline antibodies characteristic for rheumatoid arthritis

are usually not present. Myalgia is also a common complaint. According to epidemiological

studies, chronic HCV infection is associated with reduced bone mineral density and increased

risk of fractures. The mechanism is probably linked to chronic inammation and liver disease.

Hepatitis C-associated osteosclerosis, mostly reported in patients with a history of intrave-

nous drug abuse, is an uncommon disorder characterized by an increase in bone mass during

adulthood. The increased bone turnover in periosteal, endosteal, and trabecular bone leads

to the thickening of the skeleton and may respond to bisphosphonate or calcitonin therapy.

11. Neurological manifestations

Neurological manifestations of HCV infection can vary from central nervous system (CNS)

involvement to peripheral neuropathy including sensorimotor neuropathy and mononeuritis

multiplex. Evidence of CNS involvement includes the demonstration of HCV RNA in brain

tissue and cerebrospinal uid suggesting active replication and as well as a possible associa-

tion of HCV infection and small vessel cerebrovascular disease [25–27]. The most common

form of nerve involvement is distal sensory or sensorimotor polyneuropathy, which clinically

presents with painful, asymmetric paresthesia, while multiple mononeuropathy occurs rarely

[15 ]. These changes are a consequence of vasculitis, sometimes associated with cryoglobuline-

mia, involving vasa nervorum.

In a recently published study, chronic HCV infection has been linked to Parkinson's disease [28].

12. Neuropsychiatric disorders

Neurocognitive damages can manifest with a wide array of neuropsychiatric conditions, such

as tiredness, depression, and lack of concentration and working memory, of which patients

Update on Hepatitis C118

with chronic HCV infection often complain. These disorders are often seen and intertwined

with other associated additions, such as chronic liver disease, cirrhosis, the use of drugs,

and others. Some studies have managed to show that these neurocognitive damages are a

consequence of the HCV infection itself, regardless of comorbidities [29]. Functional imag-

ing methods have shown metabolic changes in brains of chronic hepatitis C patients, with

improvement of cognitive function and brain metabolism observed after treating the HCV

infection [30]. Some of these disorders such as depression and fatigue are important because

they can exacerbate under interferon therapy. This is why it is important to perform mental

status evaluation at the beginning and during this therapy, so as to be able to timely act with

suitable psychiatric support, antidepressants, and anxiolytics. Fatigue, depression, and cogni-

tive damage signicantly impair functional ability (at work and at home) and impact the qual-

ity of life of patients with chronic HCV infection, while the eradication of the virus positively

correlates with an improvement in quality of life.

13. Metabolic manifestations: diabetes mellitus and insulin resistance

Disturbed glucose metabolism, onset of insulin resistance (IR), and type 2 diabetes mellitus

(T2DM) are often associated with chronic HCV infection. A meta-analysis of 34 studies con-

rmed a positive correlation between HCV infection and risk of T2DM, which is 1.7 times

greater than the general population and notably increased compared to chronic hepatitis

B patients [31]. It appears that the risk of T2DM in patients with chronic HCV infection is

increased in patients with risk factors such as older age, obesity, advanced liver brosis, and

a family history of diabetes [32]. Likewise, results of multiple studies have shown that suc-

cessful eradication of HCV infection decreases IR and that the risk of T2DM is decreased in

patients who achieved SVR [33]. Multiple studies have conrmed an association between the

HCV infection and IR development that can be present without manifest T2DM. Experimental

studies have shown that HCV causes signicant changes in the lipid and glucose metabolism

and that it leads to IR in the liver and peripheral tissue through direct (immediate inuence of

HCV proteins on intracellular insulin signal pathways) and indirect (the inuence of TNF-α

and other cytokines on the development of peripheral IR) mechanisms. Insulin resistance

causes a series of changes in lipid and lipoprotein metabolism and leads to the development

of liver steatosis [34]. Clinical implications of HCV-induced IR, besides T2DM development,

include a worse response to interferon therapy, accelerated brosis and development of cir-

rhosis, increased risk of hepatocellular carcinoma, as well as increased cardiovascular mor-

bidity and mortality [35].

14. Cardiovascular disease

Chronic HCV infection has been associated with accelerated atherosclerosis [36]. Risk of early

carotid artery atherosclerosis (determined by intima-media thickness measurement) was

four times greater in HCV patients than noninfected patients [14, 37]. In several cohorts of

HCV-positive patients, increased cardiovascular mortality (1.5–25 times) as well as a higher

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119

incidence of cerebrovascular and acute coronary syndromes was noted [38]. Besides coronary

and cerebrovascular disease, an increased rate of peripheral arterial disease in patients with

a chronic HCV infection has been described. Rates of acute coronary syndrome and ischemic

stroke were signicantly reduced in patients treated with peginterferon and ribavirin com-

pared to untreated patients [39]. Although this association was found in studies originating

from Far East countries, Western European and American studies, as well as a recent meta-

analysis, have not established a clear correlation of HCV infection and increased cardiovas-

cular and cerebrovascular risk [40, 41]. Likewise, the pathogenetic mechanism through which

HCV leads to accelerated atherosclerosis has not been fully elucidated. There is evidence of

HCV RNA presence in carotid plaques and endothelial cells in the brain, and it is possible

that local infection leads to tissue damage, but atherosclerosis is more probably a conse-

quence of the aforementioned IR, metabolism disturbance, and proinammatory cytokine

action. Many unsolved questions leave space for further research, and the arrival of new

therapies opens new possibilities in treating patients with an expected decrease in cardiovas-

cular morbidity and mortality.

15. Other HCV infection-associated diseases

Pulmonary brosis is a disease characterized by interstitial inammation with focal broblast

proliferation and collagen deposits leading to brosis, which clinically commonly manifests

as dyspnea on exertion and nonproductive cough. The disease pathogenesis is unknown, and

several studies have found a connection between pulmonary brosis and chronic HCV infec-

tion. A higher prevalence of pulmonary brosis was seen in HCV-infected patients than con-

trol groups, and vice versa, a group of patients with diagnosed idiopathic pulmonary brosis

had an increased anti-HCV positivity rate (25%) [38].

Myasthenia gravis was associated with HCV infection in case reports only, and a clear link

has not been established. Cases of this disease developing during interferon treatment have

been described, but it is assumed that these cases were in fact exacerbations of subclinical

disease precipitated by immunomodulatory therapy.

16. Conclusion

Chronic hepatitis C infection (HCV) is a systemic disease which, besides the liver as its pri-

mary target, aects a number of other organs and organ systems. So far more than 30 dier-

ent conditions have been associated with chronic HCV infection. In general, the appearance

of extrahepatic manifestations of HCV infection is unpredictable, that is, independent of the

stage of the liver disease. A clear association with chronic hepatitis C has been established for

many of these conditions, while, for some diseases, good-quality evidence linking them to

HCV infection is still missing.

Considering the appearance of new direct-acting antiviral therapies that oer an excellent

prospect for cure of infected patients, although at a relatively high expense, the practice in

Update on Hepatitis C120

Croatia, as well as in many economically limited countries, is to set treatment priorities, so as

to sooner treat the patients that need it most. Taking this into regard, patients with established

extrahepatic manifestations of HCV infection have priority in receiving treatment, regardless

of the stage of their liver disease, as stated in the latest guidelines.

For example, patients with essential mixed cryoglobulinemia and its skin (leukocytoclastic

vasculitis), kidney (membranoproliferative glomerulonephritis or membranous nephropathy,

renal failure), or nerve (neuropathy) manifestations, as well as patients with non-Hodgkin

lymphoma, porphyria cutanea tarda, and some other more rare autoimmune disease mani-

festations, will benet from treatment not only by eradicating HCV but also in treating the

extrahepatic manifestation and its sometimes very debilitating symptoms.

It can be expected, and recent studies show promising results, that new therapies with-

out interferon which greatly improve therapeutic success with fewer adverse eects

will prove especially benecial in patients with immunologically mediated extrahepatic

manifestations.

Author details

Lucija Virović Jukić1* and Dominik Kralj2

*Address all correspondence to: lucija.jukic@gmail.com

1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Sestre

milosrdnice University Hospital Center, University of Zagreb School of Medicine, Zagreb,

Croatia

2 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Sestre

milosrdnice University Hospital Center, Zagreb, Croatia

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Update on Hepatitis C124

... However, the strength of accessible evidence linking them to CHC varies. 3 The clinical presentation of patients with CHC range from subclinical cases to very serious immunological diseases. Indeed, sometimes, autoimmune manifestations linked to HCV infection lead to the diagnosis of HCV infection. ...

Hepatitis C virus (HCV) has been shown to affect many tissues other than liver. However, of the many extrahepatic manifestations (EMs) that have been associated with HCV, including cryoglobulinemia, lymphoma, insulin resistance, type 2 diabetes and neurological disorders, only a few have been shown to be directly related to HCV infection of extrahepatic tissues. HCV-triggered immune-mediated mechanisms account for most of the EMs. It is estimated that up to 74% of patients with chronic hepatitis C can develop at least one EM. All HCV patients with EMs should be considered for antiviral therapy, although not all will resolve with sustained virological response.

• L. S. Babinets
• Olena R Shaihen
• Halyna Ol Homyn
• Iryna Halabitska

Objective: Introduction: In this publication we analyzed the specific aspects of clinical course in case of combination of chronic pancreatitis and concomitant viral hepatitis C. The aim: Discover the clinical course of chronic pancreatitis with concomitant viral hepatitis C . Patients and methods: Materials and methods: 57 patients with chronic pancreatitis and concomitant viral hepatitis c were examined. Diagnosis of chronic pancreatitis and viral hepatitis c was verified based on disease history, clinical symptoms and the results of clinical-instrumental tests. Clinical and biochemical investigations in people with chronic pancreatitis were done in exacerbation and unstable remission phases and for people with viral hepatitis C - in stable remission phase. Results: Results: In patients, who have chronic pancreatitis with concomitant hepatitis C, pain, dyspeptic syndromes and defecation disturbances take the major place in clinical course of the disease. These symptoms were more severe than in the control group (possible difference in numbers in the group of patents with isolate viral hepatitis C (p<0,05). Conclusion: Conclusions: According to the studies data-the negative influence of concomitant viral hepatitis C in clinical course of chronic pancreatitis was identified.

• Tomasz Laskus
• Marek Radkowski
• Agnieszka Bednarska
• Jorge Rakela

Hepatitis C virus (HCV) sequences were detected in cerebrospinal fluid (CSF) in 8 of 13 HCV-positive patients. In four patients harboring different virus strains in serum and peripheral blood mononuclear cells (PBMC), CSF-derived virus was similar to that found in PBMC, which suggests that PBMC could carry HCV into the brain.

• Yumiko Nagao
• Kanae Kimura
• Yuji Kawahigashi
• Michio Sata

Objectives: Oral lichen planus (OLP) is one of the extrahepatic manifestations of hepatitis C virus (HCV) infection. Presently developed interferon (IFN)-free direct-acting antivirals (DAAs) used to treat HCV infection have low side effect profiles and high efficacy. However, there are no studies examining the relationship between OLP and IFN-free DAAs. The aim of this study was to evaluate the disease course in patients with HCV-associated OLP, who received treatment with IFN-free DAAs. Methods: Seven patients with HCV-related OLP (including one with cutaneous LP), who received IFN-free treatment with daclatasvir (DCV)/asunaprevir (ASV) at our hospital in Japan from October, 2014 to February, 2015 were enrolled in the study. The subjects included four males and three females (average age, 73.9 years). We compared the symptoms of OLP in the patients before and at 24 weeks after the end of DAA therapy. Results: No worsening of symptoms was observed during treatment with the DAAs. The symptoms of OLP had subsided in all seven patients. Lesions of OLP and cutaneous LP disappeared in four, and improved in three of the seven patients after sustained virological response 24. No systemic clinical adverse events were observed in all patients. Conclusions: Herein, we have reported the outcomes of HCV-associated OLP in patients who received successful treatment with IFN-free DAAs, using the DCV/ASV combination therapy.

• Lydia Tang
• Lauren Marcell
• Shyam Kottilil

Chronic hepatitis C (HCV) is a common infection affecting 185 million people worldwide. The most common manifestation of chronic HCV is progressive liver fibrosis, cirrhosis, liver failure and hepatocellular carcinoma. However, several systemic manifestations of HCV have been recognized and reported in the literature. The purpose of this review is to assimilate published literature based on evidence to categorize these extrahepatic manifestations with the likelihood of a causal association with HCV. Exciting recent developments have resulted in simple all oral interferon-free highly effective therapy for HCV. However, this treatment is also expensive and less accessible to most affected individuals as treatment recommendations are based on stage of liver fibrosis. Expanding the scope of HCV therapy to those with extrahepatic manifestations beyond what is currently recommended will significantly reduce the morbidity and mortality in this aging population.

Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide. Liver steatosis is a common finding in many hepatic and extrahepatic disorders, the most common being metabolic syndrome (MS). Over time, it has been shown that the frequent coexistence of these two conditions is not coincidental, since many epidemiological, clinical, and experimental studies have indicated HCV to be strongly associated with liver steatosis and numerous metabolic derangements. Here, we present an overview of publications that provide clinical evidence of the metabolic effects of HCV and summarize the available data on the pathogenetic mechanisms of this association. It has been shown that HCV infection can induce insulin resistance (IR) in the liver and peripheral tissues through multiple mechanisms. Substantial research has suggested that HCV interferes with insulin signaling both directly and indirectly, inducing the production of several proinflammatory cytokines. HCV replication, assembly, and release from hepatocytes require close interactions with lipid droplets and host lipoproteins. This modulation of lipid metabolism in host cells can induce hepatic steatosis, which is more pronounced in patients with HCV genotype 3. The risk of steatosis depends on several viral factors (including genotype, viral load, and gene mutations) and host features (visceral obesity, type 2 diabetes mellitus, genetic predisposition, medication use, and alcohol consumption). HCV-related IR and steatosis have been shown to have a remarkable clinical impact on the prognosis of HCV infection and quality of life, due to their association with resistance to antiviral therapy, progression of hepatic fibrosis, and development of hepatocellular carcinoma. Finally, HCV-induced IR, oxidative stress, and changes in lipid and iron metabolism lead to glucose intolerance, arterial hypertension, hyperuricemia, and atherosclerosis, resulting in increased cardiovascular mortality.

Chronic hepatitis C (CHC) is associated with multiple extrahepatic manifestations that may impact infected patients. The mechanisms through which these develop include those which are immunological, in which the chronic persistence of virus leads to the circulation of immune complexes (mixed cryoglobulinemia) and other autoimmune phenomena, and those which are virological and related to the extrahepatic tropism of the virus to other tissues. It is estimated that 40-74 % of patients with CHC may develop at least one extrahepatic manifestation during the course of the disease. Extrahepatic syndromes may represent the first signal of hepatitis C infection in some patients. CHC is associated with a four-fold increased risk of insulin resistance and type 2 diabetes mellitus; with cardiovascular disease in 17-37 % of patients; and with increased risk for cerebrovascular deaths, with a biological gradient of cerebrovascular mortality correlating with an increasing serum viral load. CHC is also associated with lymphoproliferative disorders, particularly non-Hodgkin B-cell lymphoma. The kidney is involved in 35-60 % of patients with CHC-associated mixed cryoglobulinemia. The prevalent type of glomerulonephritis associated with mixed cryoglobulinemia is membranoproliferative glomerulonephritis. In 30 % of cases, renal involvement begins with a nephritis syndrome and acute renal failure, while in 55 % there is only mild hematuria, microalbuminuria, proteinuria and renal insufficiency. CHC is also associated with cognitive impairment, especially in memory and concentration. Thus, extrahepatic CHC manifestations involve multiple organ systems outside the liver linked to a variety of comorbidities which may lead to significantly increased mortality from non-liver-related events.

Hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC) vasculitis commonly regresses upon virus eradication, but conventional therapy with pegylated interferon and ribavirin yields approximately 40% sustained virologic responses (SVR). We prospectively evaluated the efficacy and safety of sofosbuvir-based direct-acting antiviral therapy, individually tailored according to the latest guidelines, in a cohort of 44 consecutive patients with HCV-associated MC. In two patients MC had evolved into an indolent lymphoma with monoclonal B-cell lymphocytosis. All patients had negative HCV viremia at week 12 (SVR12) and at week 24 (SVR24) posttreatment, at which time all had a clinical response of vasculitis. The mean (±standard deviation) Birmingham Vasculitis Activity Score decreased from 5.41 (±3.53) at baseline to 2.35 (±2.25) (P < 0.001) at week 4 on treatment to 1.39 (±1.48) (P < 0.001) at SVR12 and to 1.27 (±1.68) (P < 0.001) at SVR24. The mean cryocrit value fell from 7.2 (±15.4)% at baseline to 2.9 (±7.4)% (P < 0.01) at SVR12 and to 1.8 (±5.1)% (P < 0.001) at SVR24. Intriguingly, in the 2 patients with MC and lymphoma there was a partial clinical response of vasculitis and ∼50% decrease of cryocrit, although none experienced a significant decrease of monoclonal B-cell lymphocytosis. Adverse events occurred in 59% of patients and were generally mild, with the exception of 1 patient with ribavirin-related anemia requiring blood transfusion. Conclusion: Interferon-free, guideline-tailored therapy with direct-acting antivirals is highly effective and safe for HCV-associated MC patients; the overall 100% rate of clinical response of vasculitis, on an intention-to-treat basis, opens the perspective for curing the large majority of these so far difficult-to-treat patients. (Hepatology 2016;64:1473-1482).

• Fanny Domont
• Patrice Cacoub

Background: Among the large scope of extrahepatic manifestations related to hepatitis C virus (HCV) infection, many studies recently evaluated the frequency and characteristics of cardiovascular involvement. Objective: To assess the current published data on HCV infection and cardiovascular diseases. Methods: Published studies on cardiovascular disease, i.e. cerebrovascular accident and ischemic heart disease in subjects with HCV infection were analyzed from literature databases. Results: Subjects with HCV chronic infection have an increased prevalence of carotid atherosclerosis and increased intima-media thickness compared to healthy controls or those with hepatitis B or nonalcoholic steatohepatitis. Active chronic HCV infection appears as an independent risk factor for ischemic cerebrovascular accidents. Active chronic HCV infection is associated with increased risk of ischemic heart disease. In some studies, successful interferon-based therapy showed a beneficial impact on the cardiovascular risk. Conclusion: The risk of major cardiovascular events is higher in patients with HCV infection compared to controls, independent of the severity of the liver disease or the common cardiovascular risk factors. The beneficial impact of interferon-based therapy needs to be confirmed with new direct antiviral interferon-free agents in prospective studies with extended follow-up. This article is protected by copyright. All rights reserved.

Objective: To determine whether hepatitis C virus (HCV) infection is a risk factor for developing Parkinson disease (PD). Methods: This nationwide population-based cohort study was based on data obtained from a dataset of the Taiwan National Health Insurance Research Database for the period 2000 to 2010. A total of 49,967 patients with viral hepatitis were included for analysis. Furthermore, 199,868 people without viral hepatitis were included for comparisons. Patients with viral hepatitis were further grouped into 3 cohorts: hepatitis B virus (HBV) infection, HCV infection, and HBV-HCV coinfection. In each cohort, we calculated the incidence of developing PD. A Cox proportional hazards model was applied to estimate the risk of developing PD in terms of hazard ratios (HRs) and 95% confidence intervals (CIs). Results: The crude HRs for developing PD was 0.66 (95% CI = 0.55-0.80) for HBV infection, 2.50 (95% CI = 2.07-3.02) for HCV infection, and 1.28 (95% CI = 0.88-1.85) for HBV-HCV coinfection. The association between HCV and PD remained statistically significant after adjustments for age, sex, and comorbidities (adjusted HR = 1.29, 95% CI = 1.06-1.56). Conclusions: We conducted a large nationwide population-based study and found that patients with HCV exhibit a significantly increased risk of developing PD.

• Simone Garcovich

The association of chronic hepatitis C virus (HCV) infection with a wide spectrum of cutaneous manifestations has been widely reported in the literature, with varying strength of epidemiological association. Skin diseases which are certainly related with chronic HCV infection due to a strong epidemiological and pathogenetic association are mixed cryoglobulinemia, lichen planus and porphyria cutanea tarda. Chronic pruritus and necrolytic acral erythema are conditions that may share a possible association with HCV infection, while several immune-mediated inflammatory skin conditions, such as psoriasis, chronic urticaria and vitiligo, have been only anecdotally reported in the setting of chronic HCV infection. Traditional interferon-based treatment regimens for HCV infection are associated with substantial toxicity and a high-risk of immune-related adverse events, while the advent of new direct-acting antivirals with sustained virological response and improved tolerability will open the door for all-oral, interferon-free regimens. In the new era of these direct acting antivirals there will be hopefully a renewed interest in extra-hepatic manifestations of HCV infection. The aim of the present paper is to review the main cutaneous HCV-related disorders - mixed cryoglobulinemia, lichen planus, porphyria cutanea tarda and chronic pruritus - and to discuss the potential impact of new antiviral treatments on the course of these extra-hepatic manifestations of chronic HCV infection.

Source: https://www.researchgate.net/publication/320265740_Extrahepatic_Manifestations_of_Hepatitis_C_Virus_Infection

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