Extrahepatic Manifestations of Hepatitis C Virus

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Key points

  • Hepatitis C virus (HCV) infection is associated with injury of organs other than the liver, which is thought to contribute to increased rates of morbidity and all-cause mortality.

  • Extrahepatic manifestations (EHMs) of HCV infection are variegate because they include mixed cryoglobulinemia (MC), lymphomas, membranous glomerulonephritis, porphyria cutanea tarda (PCT), lichen planus, thyroiditis, sicca syndrome, polyarthritis, diabetes mellitus (DM), cardiovascular diseases, and neurocognitive

Mixed cryoglobulinemia

MC is an autoimmune, lymphoproliferative disorder characterized by circulating immune complexes named cryoglobulins (CGs) that reversibly precipitate at low temperatures.7 MC is the dominant and most thoroughly documented EHM of HCV infection, which in some patients results in systemic vasculitis after the deposition of CGs in small- and medium-sized blood vessels. The relationship between HCV and CGs is substantiated by the exceedingly high rates (up to 90%) of patients with CGs who have

Treatment of mixed cryoglobulinemia syndrome

Antiviral therapy with interferon is the mainstay for the long-term control of MCS because HCV RNA suppression leads to interruption of lymphocyte stimulation by HCV and results in an improvement or disappearance of most clinical and laboratory manifestations of virus-related MCS (Table 1). While cumulatively the achievement of a sustained virological response (SVR) to interferon-based therapy has resulted in the recovery from signs and symptoms of MCS in up to 90% of patients, access to

Lymphoproliferative disorders

The well-documented, strong association between HCV and B-cell NHL follows a geographic gradient whereby the incidence rates are higher in northern countries than in the southern ones.51, 52, 53, 54, 55, 56, 57, 58 A most convincing pathogenetic link between HCV and lymphoma was the finding of lower cumulative incidence rates of lymphoma in patients in whom HCV was successfully eradicated following interferon therapy based on a large population study in Japan.8 In this study, a lymphoma

Treatment of lymphoproliferative disorders

Remission of a low-grade NHL after HCV eradication is well documented.67, 68, 69, 70, 71, 72, 73, 74, 75, 76 In the late 1990s, regression of a splenic lymphoma with villous lymphocytes (SLVL) was documented in HCV-seropositive patients who responded to interferon-based therapy,68 whereas the oncologic benefits provided by a virological response to interferon were documented in patients with other indolent lymphoma subtypes, such as mucosa-associated lymphoid tissue lymphomas, SMZLs, and

Porphyria cutanea tarda

PCT is caused by the inhibition of hepatic uroporphyrinogen decarboxylase activity resulting in overproduction of uroporphyrinogen in blood and urine. Clinical features of PCT include photosensitivity, skin fragility, bruising, vesicles and bullae that may become hemorrhagic, hypopigmentation or hyperpigmentation, alopecia, hirsutism, and skin thickening. The prevalence of HCV infection in patients with PCT is high, that is, about 50%, and likely accounts for hepatic iron overload in

Lichen planus

Lichen planus is a recurrent pruritic eruption characterized by flat-topped scarlet papules that can develop on any skin site of arms, trunk, genital, nails and scalp, and mucosal membranes.86 The prevalence of serum HCV in patients with oral lichen planus is around 27%, and HCV RNA has been detected in oral mucous membranes of the affected patients.87, 88 Unfortunately, remission of lichen planus following antiviral therapy is not the rule.89, 90

Thyroid disorders

Hypothyroidism is the most common thyroid disorder encountered in patients chronically infected by HCV. In this population, up to 13% have clinical hypothyroidism and up to 25% have circulating thyroid antibodies.91, 92, 93 These antibodies can help in identifying patients with HCV infection who are at an increased risk of thyroid dysfunction following interferon therapy.94

Arthralgias and arthritis

Arthralgias and/or arthritis affect the vast majority of patients with MC and may manifest as bilateral joint pain and symmetric, nondeforming inflammation, mainly of knees and hands, and more rarely elbows and ankles. Characteristically, HCV-related arthritis does not lead to joint destruction and may be present in less than 10% of all MC-free HCV-infected patients.95 In patients with clinical signs and symptoms or rheumatologic involvement, attention should be paid to define whether

Sicca syndrome and Sjögren syndrome

Chronic lymphocytic sialoadenitis similar to the salivary and ocular disorders seen in the idiopathic Sjögren syndrome may approximately affect 50% of patients with HCV infection. Sjögren syndrome is defined by the presence of xerostomia, xerophthalmia, anti-Sjögren's syndrome A (SSA) or anti-Sjögren's syndrome B (SSB) antibodies, and typical salivary gland histology; yet less than 5% of these patients are infected by HCV.96 In the transgenic mice, expression of envelope proteins of HCV is

Diabetes mellitus and vascular disorders

DM arises from a complex interaction between HCV and the low inflammation status generated by insulin resistance. DM is more commonly diagnosed in patients with chronic hepatitis C than in the general population and is particularly strongly associated with advanced liver fibrosis or cirrhosis.98, 99 The association of DM and HCV is also suggested by the remarkable reduction of DM risk seen in patients with HCV infection responding to interferon-based therapy, and, even more convincingly, by the

Neurocognitive impairment

The reversal of the typical symptoms of neurocognitive impairment such as depression, fatigue, and reduced quality of life on achieving HCV clearance with the potent and well-tolerated DAA regimens has conclusively validated the association between HCV and several CNS dysfunctions.113 Approximately one-third of patients with advanced HCV infection have symptoms related to neurocognitive impairment,114 which may be a direct consequence of HCV affecting the CNS through serotonergic and

Summary

The pathogenicity of HCV is not limited to the liver, owing to the fact that the virus may cause significant morbidity related to EHM that in some patients overrides that related to the liver in terms of clinical severity. The pathogenic role of HCV in EHM is clearly explained by the declining rates of all-cause mortality that have been documented in patients with chronic HCV infection who successfully responded to interferon therapy. Although this may have several practical implications on the

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    Conflict of Interest: M. Viganò: speaking and teaching: Roche, Gilead Sciences, BMS; Massimo Colombo: grant and research support: Merck, Roche, BMS, Gilead Sciences; advisory committees: Merck, Roche, Novartis, Bayer, BMS, Gilead Sciences, Tibotec, Vertex, Janssen Cilag, Achillion, Lundbeck, Abbott, Boehringer Ingelheim,Wasserman; speaking and teaching: Tibotec, Roche, Novarti-s, Bayer, BMS, Gilead Sciences, Vertex, Glaxo, Janssen Cilag, Merck, Abbott.

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