Manifestations of Chronic Hepatitis C Virus Infection Beyond the Liver

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2010;8:1017–1029

STATE OF THE ART Manifestations of Chronic Hepatitis C Virus Infection Beyond the Liver IRA M. JACOBSON,* PATRICE CACOUB,‡ LUIGINO DAL MASO,§ STEPHEN A. HARRISON,储 and ZOBAIR M. YOUNOSSI¶ *Division of Gastroenterology and Hepatology, Center for the Study of Hepatitis C, Joan and Sanford I. Weill Medical College of Cornell University, New York, New York; ‡Department of Internal Medicine, Hôpital La Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France; §Epidemiology and Biostatistics Unit, Aviano Cancer Center, Aviano, Italy; 储Department of Gastroenterology, Brooke Army Medical Center, San Antonio, Texas; and ¶Center for Liver Disease, Inova Fairfax Hospital, Falls Church, Virginia

This article has an accompanying continuing medical education activity on page e126. Learning Objectives—At the end of this activity, the learner should be able to appreciate the extraintestinal manifestations of HCV infection, understand the link between HCV infection and mixed cryoglobulinemia, and learn the treatments for mixed cryoglobulinemia in HCV infection.

In addition to its effects in the liver, chronic hepatitis C virus (HCV) infection can have serious consequences for other organ systems. Extrahepatic manifestations include mixed cryoglobulinemia (MC) vasculitis, lymphoproliferative disorders, renal disease, insulin resistance, type 2 diabetes, sicca syndrome, rheumatoid arthritis–like polyarthritis, and autoantibody production; reductions in quality of life involve fatigue, depression, and cognitive impairment. MC vasculitis, certain types of lymphoma, insulin resistance, and cognitive function appear to respond to antiHCV therapy. However, treatments for HCV and other biopsychosocial factors can reduce quality of life and complicate management. HCV treatment has a high overall cost that increases when extrahepatic manifestations are considered. HCV appears to have a role in the pathogenesis of MC vasculitis, certain types of lymphoma, and insulin resistance. Clinicians who treat patients with HCV infections should be aware of potential extrahepatic manifestations and how these can impact and alter management of their patients. Keywords: Hepatitis C Virus; Burden of Disease; Extrahepatic Comorbidities; Health-Related Quality of Life; Epidemiology.

Summary Table ●

Hepatitis C virus (HCV) infection is associated with morbidity from a broad range of other clinical conditions.

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Extrahepatic manifestations of chronic HCV infection include vasculitis, lymphomas, and insulin resistance.

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Epidemiologic evidence also suggests a potential association of HCV with other disorders such as rheumatologic conditions.

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Chronic HCV infection is associated with reduced healthrelated quality of life, in which depression, cognitive impairment, and fatigue might be factors.

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Health care costs imposed by these conditions must be considered in addition to those normally associated with chronic HCV infection.

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Clinicians should appreciate the extrahepatic as well as the hepatic consequences of HCV infection and the potential of treatment strategies to reduce this overall impact.

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epatitis C virus (HCV) primarily infects hepatocytes, causing inflammation that later results in liver damage. End-stage liver disease caused by chronic HCV infection is the most common indication for liver transplantation in the United States,1 and HCV markers have been found in half of all hepatocellular carcinoma cases.2,3 As a consequence of these and other complications, HCV infection appears to be a cause of premature death, with mortality rates in HCV-infected individuals being up to 3 times higher than those in the general population.4,5 HCV infection might result in an 8- to 12-year reduction of overall life expectancy in infected individuals.6 This might be partly due to a greater prevalence of preexisting comorbidities (such as human immunodeficiency virus or hepatitis B) or other risk factors (eg, a history of alcohol use) in patients with HCV. However, findings from a number of studies7–11 show that effective clearance of the virus can reduce mortality, emphasizing a direct impact of HCV on risk of death. A wide series of manifestations involving other organ systems, including the central nervous system (CNS), endocrine system, lymphatic system, eyes, kidneys, blood vessels, skin, joints, and peripheral nerves, can occur in HCV infection. HCV also affects health-related quality of life (HRQOL), such as fatigue, pain, and reduced physical, emotional, and social functioning.12 Clinicians treating HCV need to be aware of the burden of the disease, including its extrahepatic manifestations, and how these might alter patient management.13,14 Recognition of extrahepatic symptoms of HCV infection could facilitate early Abbreviations used in this paper: BMI, body mass index; CNS, central nervous system; HCV, hepatitis C virus; HOMA-IR, homeostasis model assessment of insulin resistance; HRQOL, health-related quality of life; IL, interleukin; KDIGO, Kidney Disease Improving Global Outcomes; MC, mixed cryoglobulinemia; NHL, non-Hodgkin lymphoma; NSAID, nonsteroidal anti-inflammatory drug; RA, rheumatoid arthritis; RR, relative risk; SOCS, suppressor of cytokine signaling; SVR, sustained virologic response; TNF, tumor necrosis factor. © 2010 by the AGA Institute 1542-3565/$36.00 doi:10.1016/j.cgh.2010.08.026

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diagnosis and treatment. This review examines the available data on the extrahepatic manifestations associated with HCV infection and assesses their clinical and societal implications.

Evidence Acquisition This clinical review reflects the detailed discussions and opinions of the authors on key articles from the published literature reviewed at an advisory board meeting on the extrahepatic manifestations of HCV held in New York, NY in December 2007. Before the meeting, MEDLINE searches via the PubMed interface were designed and conducted by Paula Michelle del Rosario, a professional medical writer at Gardiner-Caldwell Communications (Macclesfield, UK). The searches encompassed mixed cryoglobulinemia (MC) vasculitis, lymphoproliferative disorders, glucose disorders, rheumatologic disease, and quality of life issues by using the search terms [hepatitis C] and either [cryoglobulinemia], or [lymphoma OR non-Hodgkin lymphoma (NHL)], or [metabolic syndrome X OR glucose metabolism disorders OR body weight], or [Quality of life OR sickness impact profile], or [costs and cost analysis OR economics OR cost-benefit analysis OR cost of illness OR health care costs OR direct service costs OR hospital costs OR employer health costs OR hepatitis C/economics]. Studies analyzing or projecting the overall economic costs related to HCV infection were included; those pertaining to the cost-effectiveness of individual treatment regimens were excluded. Articles not published in the English language and editorials, correspondence, letters, comments, and news articles were excluded. The authors received the search terms and results of the searches in advance of the meeting, and they selected relevant articles for discussion. The authors were responsible for several additions to content and topics covered. Throughout the development of the manuscript, the authors were personally responsible for a marked expansion in the scope of the article, including new references and concepts published since the original advisory board, making this essentially a new article. In addition, the manuscript was thoroughly updated with a repeated PubMed search by Gardiner-Caldwell Communications in September 2009 to capture articles published since the original search was conducted, and relevant publications were selected for inclusion by the authors.

Extrahepatic Manifestations of Hepatitis C Virus Infection A number of extrahepatic manifestations have been reported in patients infected with HCV, although the exact mechanisms underlying their development require further elucidation. The most prominent manifestations are MC vasculitis, lymphoproliferative malignancies, sicca syndrome, rheumatoid arthritis (RA)–like polyarthritis, autoantibody production, and glucose disorders (Table 1).15–136 These conditions might have a substantial impact on morbidity, patient management, and, in some instances, mortality.

Mixed Cryoglobulinemia Vasculitis MC vasculitis is the best-known manifestation of HCV infection; it has been reported at least subclinically in 19%–50% of patients with HCV infection.15 In one study, HCV was identified in 91% of patients with persistent MC.16 More than 85% of patients with MC do not have symptomatic disease,15 but

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even asymptomatic patients might develop cryoglobulinemiarelated symptoms in the future. Therefore, patients presenting with MC vasculitis should be screened for HCV infection. MC vasculitis is the result of virus-triggered immune-mediated mechanisms17 and is characterized by the deposition of circulating immunoglobulin G and immunoglobulin M immune complexes containing HCV particles in the vasculature. Infection or, more likely, chronic stimulation of lymphocytes is thought to induce the B-cell clonal expansion underlying the production of antibodies, including rheumatoid factor, that are incorporated into cryoglobulins (Figure 1). Tissue damage in MC vasculitis is probably T-cell induced.18,19 Manifestations of MC associated with HCV infection include vasculitis (prevalence, 4%– 40%), palpable purpura (18%–33%), fatigue (35%–54%), arthralgia-myalgia (35%– 54%), sicca syndrome (10%–25%), neuropathy (11%–30%), and renal complications such as membranoproliferative glomerulonephritis (27%).20 –25 Given the similarity of some of these symptoms with other disorders, including RA and primary Sjögren’s syndrome, careful evaluation is required to ensure correct diagnosis of MC vasculitis (Figure 2).26 Two prospective, randomized controlled trials have demonstrated significant improvement in cryoglobulinemia in patients experiencing virologic suppression on interferon-alfa therapy, suggesting a causal link between HCV and MC vasculitis.27,28 Moreover, MC vasculitis usually responds to clearance of HCV during combination therapy with peginterferon plus ribavirin, emphasizing the role of HCV infection in MC. This approach has been recommended for HCV-related MC vasculitis with mild to moderate disease. For patients with severe vasculitis, including glomerulonephritis with renal insufficiency or intestinal ischemia, control of disease with potent immunosuppressive regimens (for example, the anti-CD20 antibody rituximab), with or without plasmapheresis, is usually required before initiation of antiviral therapy.29 Further evidence for a link between HCV and MC vasculitis comes from a study of patients who relapsed after responding to a course of antiviral therapy. In these patients, vasculitis typically also relapsed with the return of viremia.30 In patients with persistent MC, relapse of MC vasculitis might also occur in a few patients with HCV infection, despite achieving a sustained virologic response (SVR). In patients with persistent MC vasculitis symptoms, a different underlying condition should be considered, especially B-cell lymphoma.31 There is no clear evidence that SVR rates are different in HCV-infected patients whether they have cryoglobulinemia or not. Recently, rituximab was reported to reduce signs of vasculitis, with a clinical response noted in 32 of 40 patients (80%) for skin involvement, 27 of 34 (79.4%) for arthralgia, 27 of 29 (93.1%) for neuropathy, and 15 of 18 (83.3%) for glomerulonephritis.32 In a second study, rituximab significantly improved clinical neuropathy disability score at 12 months in patients with MC vasculitis.33 In a further study of 11 HCV-infected patients with MC vasculitis, rituximab treatment led to improvements or amelioration of constitutional symptoms and the reversal of bone marrow abnormalities to normal.34 The novel approach of combining rituximab with peginterferon alfa-2b plus ribavirin was assessed in 16 patients with severe refractory HCV-related MC vasculitis. Peripheral neuropathy and nephropathy, which are among the most clinically challenging manifestations of this disorder, were present in 13 and 7 cases, respectively. Clinical improvement was seen in 15 patients, 10 of whom were complete responders.35 Complete re-

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Table 1. Summary of HCV-Related Extrahepatic Manifestations With Clinical Manifestations, Differential Diagnosis, and Treatment Options Extrahepatic manifestations

Clinical manifestations

Differential diagnosis

Treatment options

Presence of mixed cryoglobulins in serum, vasculitis, palpable purpura, fatigue, arthralgia-myalgia, sicca syndrome, neuropathy, renal complications (eg, membranoproliferative glomerulonephritis) Glomerulonephritis, proteinuria, microscopic hematuria, hypertension

“Essential” MC, RA, primary Sjögren’s syndrome, B-cell lymphoma

Mild–moderate: HCV clearance via peginterferon/RBV. Severe: potent immunosuppressive regimens ⫾ plasmapheresis before initiation of antiviral therapy. Novel: rituximab ⫾ peginterferon/RBV

Chronic kidney disease

Lymphoproliferative disorders19,41–61

Nodal or extranodal lymphoproliferative pathology, bone marrow substitution ⱖ30%, peripheral-blood cytopenia

Carcinoma, melanoma, Burkitt’s lymphoma, anaplastic large cell lymphoma, Hodgkin’s lymphoma

Sicca\Sjögren syndrome62–75

Oral or ocular dryness, histologic evidence of Sjögren-like sialadenitis; more rarely: Sjögren syndrome. Patients might exhibit xerostomia, an absence of classic systemic symptoms of primary Sjögren syndrome, and anti–Sjögren syndrome A/anti–Sjögren syndrome B antibody negativity Joint symptoms: small joints affected, resembling mild RA; rheumatoid factor identified in 50%–80% of cases; arthralgia; synovitis (rare); no erosive joint changes

Primary Sjögren’s syndrome, other ocular processes (eg, conjunctivitis, blepharitis), other autoimmune disease

Moderate proteinuria/slow progressive kidney failure: rituximab and then HCV clearance via peginterferon/RBV treatment. With renal insufficiency: rituximab and then lower dose peginterferon plus RBV (RBV not recommended if glomerular filtration rate ⬍50 mL/min per 1.73 m2 unless closely monitored). Nephrotic range proteinuria and/or rapidly progressive kidney function: rituximab, plasmapheresis, immunosuppression (corticosteroids/cytotoxic agents) Antiviral therapy, monotherapy against biological targets (rituximab) downstream of viral infection, or a combination, should be individually optimized on the basis of disease pathobiology, efficacy, and safety issues. HCV clearance via peginterferon/ RBV might be effective for some HCV-related lowgrade lymphomas. If chemotherapy is given, monitor for hepatotoxicity. No improvement of sicca syndrome associated with HCV treatment. Topical agents to increase moisture and decrease inflammation might reduce symptoms.

Production of mixed cryoglobulins; antibodies: antinuclear; anti–smooth muscle cell; antithyroglobulin; anticardiolipin Depressive symptomsa

Other autoimmune disease

MC vasculitis15–37

Renal complications36,38–40

RA-like polyarthritis70,71,76–86

Autoantibody production71,73,87–92

Depression93–99 Glucose disorders100–136

Insulin resistance, metabolic syndrome, type 2 diabetes

RA, MC syndrome

Major depressive disorder, fatigue Insulin resistance, metabolic syndrome, type 2 diabetes

Peginterferon/RBV might induce complete or partial response. NSAIDs, hydroxychloroquine, and lowdose corticosteroid (although HCV arthritis does not often respond to anti-inflammatory therapy). Severe: immunosuppression (eg, methotrexate) might be used with caution to avoid liver-related adverse events —

Antidepressant or anxiolytic treatment might be considered before initiating HCV therapy HCV clearance by using peginterferon/RBV can improve insulin resistance and reduce risk of glucose abnormalities. Efficacy of antiviral therapy might be diminished in insulin-resistant, HCVinfected patients. Lifestyle changes and insulinsensitizing agents might enhance SVR rates

aAlthough

some studies suggest that HCV might directly affect the CNS through alterations in serotoninergic and/or dopaminergic neurotransmission, it remains possible that depression might be related to the psychologic burden of chronic HCV infection or its treatment.

mission of peripheral neuropathy and nephropathy was achieved in 38% and 57% of cases, respectively. More recently, in the largest comparative study to date (n ⫽ 93), patients with HCV-related MC experienced a shorter time to clinical remission and higher rates of cryoglobulin clearance when treated with rituximab and peginterferon alfa-2a plus ribavirin, compared with those treated with peginterferon alfa and ribavirin alone.36 Antiviral therapy plus rituximab therefore appears to provide an effective therapeutic option in HCV MC vasculitis.29,37

Renal Manifestations Potentially life-threatening renal complications such as membranoproliferative glomerulonephritis have been reported in patients with HCV infection who have also developed MC. However, HCV is also associated with glomerulonephritis38 in the absence of MC. There is some evidence that renal insufficiency might be higher in HCV-infected patients than in the general population. In 1 recent cross-sectional study, HCV in-

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Figure 1. Possible mechanisms of mixed cryoglobulinemia vasculitis. HCV-mediated effects on lymphocytes may lead to antibody production and formation/deposition of immune complexes containing rheumatoid factor, resulting in tissue damage. IgG, immunoglobulin G.

fection was associated with 40% higher prevalence of renal insufficiency (defined by a serum creatinine concentration ⱖ1.5 mg) compared with people without HCV infection, after adjusting for age, gender, race, diabetes, and hypertension.39

As a result of the evidence on this subject, the Kidney Disease Improving Global Outcomes (KDIGO) group has specific guidelines relating to HCV and kidney disease. In these guidelines, KDIGO recommends that all patients with chronic kidney disease should be tested for HCV.38 Despite the lack of welldesigned trials, KDIGO also recommends that patients with acute flares of MC and membranoproliferative glomerulonephritis be treated with interferon-based antiviral therapy. However, patients should be carefully monitored for adverse events and changes in kidney function. In addition, ribavirin dosage should be closely monitored because of the risk of anemia and should be avoided altogether in patients with chronic kidney disease.40 There is some recent evidence that the addition of rituximab might be useful; HCV-related MC patients with kidney involvement showed greater renal response rates when treated with a combination of rituximab and peginterferon alfa-2a plus ribavirin compared with peginterferon alfa-2a and ribavirin alone.36

Lymphomas

Figure 2. Differential diagnosis between mixed cryoglobulinemia and other autoimmune-lymphoproliferative disorders in the setting of HCV infection. MC syndrome, primary SS, and RA show a clinicopathological overlap, including the possible association with HCV infection. Adapted with permission (Ferri C, Mascia MT. Cryoglobulinemic vasculitis. Curr Opin Rheumatol 2006;18:54 – 63). The following parameters may be usefully employed for a correct differential classification/diagnosis: primary SS shows typical histopathological pattern of salivary gland involvement and specific autoantibodies (anti-RoSSA/LaSSB), which are rarely found in MC patients; conversely, cutaneous leukocytoclastic vasculitis, visceral organ involvement (glomerulonephritis, hepatitis), low C4, and HCV infection are typically found in MC. Moreover, erosive symmetrical polyarthritis and serum anti-CCP characterize classical RA. Finally, B-NHL may complicate these diseases, more frequently MC and SS. The appearance of B-NHL can be detected by timely and careful clinicoserological monitoring and diagnosed by bone marrow/lymph node biopsies and total body CT scan. Anti-CCP, anti-cyclic citrullinated peptide antibodies; B-NHL, B-cell NHL; RF, rheumatoid factor; SS, Sjögren’s syndrome.

An association between lymphomas and HCV has been suggested by the relatively high prevalence of HCV seropositivity (15%) in patients with B-cell lymphoproliferative disorders, particularly B-cell NHL.41 Findings from epidemiologic research and meta-analyses indicate that patients positive for anti-HCV had a 2.5-fold increased risk of NHL versus controls.42 After adjusting for sex and age, the overall risk for lymphomas was more than doubled in HCV-positive individuals (relative risk [RR], 2.4) compared with HCV-negative individuals. This positive association with HCV was present regardless of primary site of presentation (nodal NHL [RR, 2.5] and extranodal NHL [RR, 3.7]). The increase in risk was even higher in HCV-infected patients with MC vasculitis (RR, 35).43,44 The association between HCV and cryoglobulinemia, NHL, and even Waldenstrom’s macroglobulinemia was given further strong support in a large analysis of the United States Veteran’s Administration database.45 Some evidence suggests that effective HCV treatment might be beneficial in the management of some subtypes of lym-

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phoma. In a small group of patients with splenic lymphoma featuring villous lymphocytes46 and in some low-grade lymphomas,47 therapy with interferon plus ribavirin achieved lymphoma regression. However, results of sufficiently large, controlled trials on the effect of HCV treatment in a broad spectrum of NHL are not yet available. The biological mechanism linking HCV infection with the development of lymphoma remains under debate (Figure 3).48 –50 However, it is likely that the mechanisms involved in MC and NHL pathogenesis share similar features. It is possible that the antigendriven, benign clonal B-cell lymphoproliferation of HCV MC might occasionally progress to overt, low-grade NHL on continued antigenic stimulation. Consistent with this, the lymphomas in HCV patients frequently express the same rheumatoid factor– encoding immunoglobulin genes as do the cells involved in cryoglobulinemia, strongly suggesting an antigen-dependent component common to both conditions.51–54 A fundamentally different mechanism probably underlies the development of aggressive, higher-grade HCV-related NHL in the absence of MC. HCV has been proposed to directly infect B cells, leading to their malignant transformation.55 In a study of 75 patients with chronic HCV infection, a multivariate analysis revealed that the presence of HCV RNA in B cells was an independent risk factor associated with at least 1 marker of lymphoproliferation.56 HCV has alternatively been postulated to exert its oncogenic potential by an indirect mechanism through HCV antigen stimulation of B cells via an increase in BLyS ligand-receptor activity57,58 or directly through growth stimulation of B cells to counter HCV-induced apoptosis.58,59 Persistent HCV stimulation might initiate growth dysregulation of infected cells as part of a multistep process, eventually giving rise to malignant lymphoproliferative disease.19,60 Worse survival outcomes have been reported for HCV-positive patients with diffuse large B-cell lymphoma compared with non–HCV-infected patients, and this has been attributed to the short-term hepatotoxicity of chemotherapy.61

Glucose Disorders Insulin resistance, metabolic syndrome, and type 2 diabetes occur frequently in patients with chronic HCV infection. Insulin resistance has been reported in 32%–70% of patients,100 –102 metabolic syndrome in 26%–51%,103,104 and the prevalence of type 2 diabetes was 14%–50% in patients with chronic HCV infection.105 Factors associated with the development of type 2 diabetes in chronic HCV infection include a high body mass index (BMI),106 as well as older age, male gender, black ethnicity, and family history of diabetes.105 In a multivariate analysis of a National Health and Nutrition Examination Survey database, positive HCV infection status was not associated with metabolic syndrome, but it was associated with high homeostasis model assessment of insulin resistance (HOMA-IR) levels (P ⫽ .02).107 In addition, a large 7-year prospective cohort study of Taiwanese patients found HCV infection to be an independent predictor of diabetes, especially for anti–HCV-positive persons who are younger or have a higher BMI.108 Recent meta-analyses based on retrospective studies suggested a significant relationship between HCV and new-onset type 2 diabetes after liver and renal transplantation.109,110 Three processes acting either independently or synergistically to promote insulin resistance have been proposed (Figure

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4).105 First, insulin resistance might result from the fibrosis and possible cirrhosis caused by HCV.111,112 Second, HCV has a direct effect on insulin sensitivity. Although the specific mechanisms are not fully elucidated, evidence suggests that alterations in specific proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣) might lead to impaired insulin signaling, in part, through activation of specific proteins such as suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3, which negatively regulate insulin signaling pathways.113–115 In addition, TNF-␣ has been implicated in the development of insulin resistance via down-regulation of insulin receptor substrate-1 and stimulation of lipolysis, leading to increased free fatty acids.116 –118 Third, obesity in patients with concomitant hepatitis C might play a role in the development of insulin signaling defects, leading to insulin resistance and subsequent coexistent steatosis, which might be found in ⬎50% of chronically infected patients.119 White adipose tissue from visceral adiposity produces a number of important adipocytokines, including adiponectin, leptin, resistin, visfatin, vaspin, and apelin, as well as TNF-␣, interleukin-6 (IL-6), and IL-8,120,121 which might contribute to the development or worsening of insulin resistance in patients with hepatitis C.122–124 Lower SVR rates after treatment with peginterferon plus ribavirin have been noted in insulin-resistant patients with HCV genotype 1, 2, or 3 infection.125,126 Small studies have also found that insulin resistance correlates with higher viral loads102,127 and that fasting insulin levels and higher HOMA-IR levels are associated with a poorer virologic response to therapy.128 These observations suggest that the efficacy of antiviral therapy is diminished in insulin-resistant, HCV-infected patients. Improving insulin sensitivity through weight loss,129 exercise, and the use of insulin-sensitizing agents, which are under clinical investigation in this setting, might potentially enhance SVR rates. One study showed that SVR achieved with interferon plus ribavirin treatment reduced the risk of developing impaired fasting glucose and type 2 diabetes in patients with chronic hepatitis C.130 The lead-in phase of the Hepatitis C Long-term Treatment against Cirrhosis (HALT-C) trial showed that insulin resistance could be improved with virologic response. Ninety-six nongenotype 3, HCVinfected patients underwent HOMA-IR testing. After 20 weeks of treatment with peginterferon plus ribavirin, patients who achieved a complete virologic response had a significantly greater reduction from baseline in mean HOMA-IR than those who achieved a partial response or no response (mean change in HOMA-IR from baseline, –2.68 vs – 0.72 vs 0.1, respectively; P ⫽ .017 for complete vs partial/null responders).131 Similarly, in a retrospective cohort study of 2842 HCV-infected Japanese patients treated with interferon or with interferon plus ribavirin,132 a multivariate analysis revealed that type 2 diabetes was more likely to develop after cessation of antiviral therapy if an SVR was not achieved. Two further studies also support the premise that HCV clearance induced by antiviral therapy can improve insulin resistance and reduce the risk of glucose abnormalities.133,134 However, a study of 202 HCV-infected patients found no difference in the incidence of glucose abnormalities between longterm responders and nonresponders to HCV treatment.135 These data require clarification in randomized controlled trials because they might influence decision-making about which HCV-infected patients to treat on the basis of considerations other than the severity of liver disease alone. Specifically, the

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Figure 3. Possible mechanisms of lymphoma development include growth stimulation via BLys ligand-receptor activity, progression from MC to lymphoma via an oncogenic event, and direct and indirect lymphocyte transformation. AID, activation-induced deaminase; BCR, B cell receptor; NOS, nitric oxide synthase.

presence of insulin resistance or risk factors for diabetes in an HCV-infected patient with histologically mild liver disease might play a role in leading a physician and patient to embark on a course of antiviral therapy rather than deferral of such therapy on the grounds that fibrosis is mild. Studies are underway to investigate whether improving insulin sensitivity results in better antiviral treatment outcomes in patients receiving pegylated interferon and ribavirin.101 One such study recently demonstrated improved rates of SVR in insulin-resistant female

patients, but not the overall cohort, treated with metformin concomitant with peginterferon and ribavirin.136

Sicca (and Gougerot–Sjögren) Syndromes An association between HCV infection and Gougerot– Sjögren syndrome (a chronic autoimmune disorder) has been suggested. For example, Haddad et al62 reported lymphocytic sialadenitis among 57% of HCV-infected patients versus 5% in controls. Analysis of further prospective studies has been made

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Figure 4. Possible mechanisms of insulin resistance include effects of HCV-induced fibrosis/cirrhosis, direct viral effects on insulin sensitivity via proinflammatory cytokines, and effects of obesity in the development of insulin signalling defects.

difficult by the different diagnostic scales (European, Copenhagen, Manthorpe, or Fox criteria) used to differentiate Gougerot-Sjögren syndrome from the similar but less severe sicca syndrome.63– 65 In cohorts of patients with definite primary Gougerot–Sjögren syndrome, HCV antibodies were found in only 4%–11% of patients,66 – 68 with one study reporting a prevalence of 19%.66 In prospective studies of HCV-infected patients, sicca syndrome is frequently reported at a prevalence ranging from 9%– 67%.68 –72 The large range might be related to differences between the diagnostic criteria applied.73 Histologic examination of salivary glands in HCV-infected patients usually shows changes different from those found in Gougerot–Sjögren syndrome, including pericapillary and non-pericanalary lymphocytic infiltration, and lack of damage of the glandular canals. Thus, although an ocular and/or mouth sicca syndrome is frequently found in

HCV-infected patients, a definite Gougerot–Sjögren syndrome is rare. There is no frank improvement of such sicca syndrome after HCV treatment, even after SVR is achieved.74 Further research is required to establish whether the observed link between HCV and sicca syndrome has a causal basis.75

Rheumatologic Disease Rheumatologic disorders such as polyarthralgia and arthritis are frequently observed in patients with HCV. However, symptoms of arthralgia and arthritis are also common in adults with other forms of liver disease, and some studies suggest that the prevalence of these conditions might be similar in patients with or without HCV.76 –78 Therefore, the relationship between rheumatologic disorders and HCV is somewhat difficult to determine.

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Polyarthralgia is the most common rheumatologic symptom in HCV-infected patients,71 with a prevalence of up to 23%.70,79 A causative association has not yet been identified, but several pathogenetic mechanisms might be involved.80 HCV arthritis could be part of the MC syndrome. It might also be linked to a direct invasion of synovial cells by the virus or a cytokine-induced disease.81,82 Two subsets of HCV arthritis have been identified, a polyarthritis involving small joints resembling mild RA and an intermittent mono-oligoarthritis associated with the presence of serum cryoglobulins.83 RA-like HCV arthritis is more common, and the presence of rheumatoid factor has been identified in 50%– 80% of cases.84 However, rheumatoid factor is often found in patients with HCV, whether in the presence or absence of joint symptoms, and its occurrence does not necessarily imply a diagnosis of actual RA. Patients with HCV arthritis might present with arthralgia or rarely synovitis. To distinguish between actual RA and HCV arthritis, clinicians should test for anticyclic citrullinated peptide antibodies, which are more frequent in RA than in HCV-infected patients with RA-like polyarthritis.85,86 Unlike RA, no erosive joint changes are noted in HCV arthritis, and the condition does not often respond to antiinflammatory therapy. The therapeutic approach for HCV arthritis includes the use of nonsteroidal anti-inflammatory drugs (NSAIDs), hydroxychloroquine, and low doses of corticosteroids.79,80 However, NSAIDs and corticosteroids are more effective in patients with HCV mono-oligoarthritis. In severe cases, immunosuppressive drugs (eg, methotrexate) might be used, but with caution to avoid developing liverrelated adverse events. Antiviral treatment with interferonalfa has also been shown to induce a complete or partial response in patients.83

Autoantibody Production The production of MC is the most frequent extrahepatic abnormality in HCV-infected patients. Other immunologic abnormalities are also frequently found including antinuclear (17%– 41%), anti–smooth muscle cell (9%– 40%), antithyroglobulin (8%–13%), and anticardiolipin (20%–27%) antibodies.71,73,87–91 In general, no clinical correlation has been found between such autoantibodies and hepatic or extrahepatic manifestations, although a higher prevalence of clinical hypothyroidism has been demonstrated by some studies.92 Considering the high prevalence of HCV infection, clinicians should be aware of the high frequency of these autoantibodies, which can lead to misdiagnosis of autoimmune diseases.

Other Hepatitis C Virus Symptoms and Their Impact on Health-Related Quality of Life There is a clear association between HCV and reduction in HRQOL; a growing literature indicates that HRQOL of HCV patients is diminished compared with population norms.137–139 Infection with HCV, along with its treatment, leads to an array of symptoms that compromise HRQOL and affects all aspects of function.140 HRQOL worsens with more advanced liver disease (cirrhosis). It can also worsen with interferon- and ribavirin-based therapy as a result of the significant side effects of these treatments,141 potentially leading to a reduction in adherence. Importantly, however, successful treatment through eradication of the virus correlates positively with improvements

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in HRQOL.74,139 Monitoring and attempting to improve the HRQOL of HCV-infected patients are therefore important. Depression. Depression has been documented in 28% of chronically HCV-infected patients by using the Structured Clinical Interview for DSM-IV Axis I Disorders: Clinician Version before HCV therapy.93 The presence of depressive symptoms is a consistent predictor of HRQOL during HCV therapy with peginterferon plus ribavirin.94 Depression might simply be related to the psychological burden of chronic HCV infection or its treatment, although some studies suggest that HCV might directly affect the CNS through alterations in serotoninergic and dopaminergic neurotransmission, with resultant depressive symptoms.95 This mechanism might explain other CNS symptoms seen in HCV infection, such as fatigue and cognitive impairment, although a causal link remains to be established.96,97 Before starting antiviral therapy for HCV, mental health should be thoroughly assessed, because patients with a history of major depressive disorder are at greater risk of developing depression during HCV treatment.98 In some cases, antidepressant or anxiolytic treatment might be considered before initiating HCV therapy.99 Cognitive impairment and fatigue. Cognitive impairment is well-described in chronic HCV infection and is a common symptom in persons with end-stage liver disease.142 Whether this impairment is directly attributable to the infection itself or results from one of the several commonly occurring comorbid conditions associated with this population remains contentious. In the HALT-C trial, 33% of 201 patients with advanced fibrosis who underwent neuropsychological testing had mild cognitive impairment (ie, standard score ⬍40 on at least 4 of 10 tests) on entering the trial.143 Although there was no evidence that this impairment was due to preexisting or comorbid conditions rather than to the infection itself, this could not be excluded. A small pilot study (n ⫽ 38) recently suggested that patients with chronic HCV who are free from comorbid factors do have higher levels of cognitive impairment than healthy controls.144 A prospective clinical trial (n ⫽ 34) has also shown that successful eradication of HCV leads to improved cognitive function.145 These data suggest a possible impact of HCV on cognitive impairment; however, further investigation is required to draw firm conclusions. The exact relationship between HCV and fatigue is difficult to determine88; nevertheless, fatigue is one of the most frequent and disabling complaints among patients with chronic HCV infection (prevalence range, 50%– 67%)140,146 and independently predicts poor HRQOL.147,148 Further implications of a reduced HRQOL. HCV infection has been associated with a decreased ability to function both at work and at home, with obvious cost implications. Poor HRQOL can also lead to difficulties with interpersonal relations, decreased feelings of self-value and utility, and depression. On the basis of the Short Form 36 Health Survey questionnaire, patients with chronic HCV infection consistently show deficits in several domains, particularly those involving their physical role, general health, and vitality, versus healthy controls.12,140,149

The Burden of HCV to Society Beyond the considerable impact on morbidity and potential mortality, HCV infection generates a major financial

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burden to society. The cost of treatment for managing HCV and sequelae can be substantial for many government health agencies or HCV-infected patients. The most recent estimate of the total cost of HCV-related illness in the United States (1997) was $5.46 billion.150 Of this, direct costs primarily related to use of medical resources comprised 33% ($1.80 billion), and indirect costs primarily related to loss of work benefits comprised 67% of total costs ($3.66 billion). The total value is comparable to that associated with 1998 data for the most costly gastrointestinal diseases: gastroesophageal reflux disease ($9.80 billion), gallbladder disease ($6.05 billion), colorectal cancer ($4.95 billion), and peptic ulcer disease ($3.26 billion).151 From 1994 through 2001, HCV-related hospitalizations, hospital days, total hospital charges, and hospital deaths increased at average annual rates of ⬃20%–30%.152 On the basis of these findings, the use of health care resources and the health care costs associated with HCV infection (involving only hepatic manifestations) are expected to increase over time. The projected annual direct medical care cost of HCV treatment from 2010 through 2019 is $6.5–$13.6 billion, with indirect costs expected to reach $75.5 billion.153 HCV infection thus represents a major economic and societal burden. The exact contribution of extrahepatic manifestations to the overall cost of HCV infection in terms of treatment costs and effects on productivity is presently unknown but could be substantial. The additional economic and societal impact related to the extrahepatic manifestations of the disease supports the need for early and effective HCV therapy. Characterizing the full economic cost of HCV might be 1 way of framing the magnitude of HCV infection.

Conclusions It is now clear that the deleterious effects of HCV are not confined to the liver alone. The involvement of several body systems other than the liver indicates that chronic HCV infection is a multiorgan disease. Epidemiologic data linking HCV infection with MC vasculitis, lymphoproliferative disorders, insulin resistance, type 2 diabetes, RA-like polyarthritis, poor HRQOL, and other manifestations continue to emerge. Widespread physician education programs might help health care providers recognize the less than obvious extrahepatic effects of HCV and to specifically motivate them to ask their patients about these effects. The management of diseases previously thought to be unrelated to HCV might need to be modified to allow coordination of care across multiple specialties. This proactive, integrated approach to HCV therapy should maximize the benefits of HCV therapy, even when liver disease is mild. Major steps to prevent new HCV infections have been taken in developed countries and should be extended worldwide.153 As part of secondary prevention, HCV-infected individuals should be counseled to minimize their risk of transmitting HCV and referred for medical evaluation and consideration of antiviral therapy. Given the expected introduction of novel therapies that are likely to improve rates of viral eradication,154 consideration of HCV infection as a systemic as well as hepatic disease should be incorporated into the formulation of treatment decisions in the future.

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Cornell University, 1305 York Avenue, New York, New York 10021. e-mail: [email protected]; fax: (212) 746-2127.

Reprint requests Address requests for reprints to: Ira M. Jacobson, MD, Division of Gastroenterology and Hepatology, Medical Director, Center for the Study of Hepatitis C, Joan and Sanford I. Weill Medical College of

Funding This review is based partially on publications identified by the authors during an advisory board meeting conducted by Vertex Pharmaceuticals Incorporated.

Acknowledgments We are grateful to Paula Michelle del Rosario, MD, and Magdy Fahmy, PhD, of Gardiner-Caldwell Communications, Macclesfield, UK (supported by Vertex Pharmaceuticals Incorporated) for designing and conducting the PubMed literature search. We also thank them for their professional medical writing assistance in developing the first draft of the manuscript, based on our recommendations of relevant published papers and our debate and discussion during the meeting, though this draft was substantially expanded and rewritten by the authors. We thank Gardiner-Caldwell communications for collating our contributions and for editing/styling support. We gratefully acknowledge Drs Lynn Dustin and Edgar Charles of Rockefeller University, New York, for their helpful comments on the sections covering cryoglobulinemia and lymphoma. Conflicts of interest The authors disclose the following: Ira M Jacobson: Vertex Pharmaceuticals Incorporated: consultant (including Advisory Board for manuscript), investigator; Merck: consultant, speaker, and investigator; Gilead Sciences: consultant, speaker, and investigator; Bristol-Myers Squibb: consultant and speaker; Genentech: consultant, speaker, and investigator; Boehringer Ingelheim: consultant and investigator; Pfizer: consultant and investigator; Human Genome Sciences: consultant and investigator; Zymogenetics: consultant and investigator; Anadys: consultant and investigator; Novartis: consultant, speaker, and investigator; Pharmasset: consultant and investigator; GlobeImmune: consultant and investigator; Abbott: consultant and investigator; Tibotec: consultant and investigator; Idenix: investigator; Achillion: consultant; GlaxoSmithKline: consultant. Patrice Cacoub: Vertex Pharmaceuticals Incorporated: consultant (Advisory Board for manuscript); ScheringPlough: consultant and research grants; Roche: consultant and research grants; Servier: consultant and research grants; Encysive: consultant and research grants; Gilead: consultant and research grants; AstraZeneca: consultant; Bristol-Myers Squibb: consultant; Sanofi Aventis: consultant. Luigino Dal Maso: Vertex Pharmaceuticals Incorporated: consultant (Advisory Board for manuscript). Stephen A Harrison: Advisory Boards for Three Rivers Pharmaceuticals, Vertex, and Amylin; Speaker’s bureau for Bristol-Myers Squibb and Salix; grant support from Genentech, Merck, and Pfizer. Zobair M Younossi: Vertex Pharmaceuticals Incorporated: consultant and Advisory Boards, investigator; GlobeImmune: consultant; Salix: Advisory Board; Sanofi-Aventis: consultant; Tibotec: advisory board.