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  • Extrahepatic Manifestationsof Hepatitis C Virus Infection

    Anna Linda Zignego, MD, PhDa,*,Antonio Crax`, MDb

    aCenter for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department

    of Internal Medicine, University of Florence, Viale GB Morgagni 85, 50134 Firenze, ItalybGastroenterologia and Epatologia, Di.Bi.M.I.S., University of Palermo, Piazza Marina,

    3490133 Palermo, Italy

    Hepatitis C virus (HCV) is at the same time a hepatotropic and a lympho-tropic virus and may cause hepatic and extrahepatic diseases. Extrahepaticmanifestations linked to HCV range from disorders for which a signicantassociation with viral infection is supported by epidemiologic data and bybiological plausibility, to anecdotal observations without clear proof of cau-sality. B cell lymphoproliferative disorders (ie, mixed cryoglobulinemia andnon-Hodgkins lymphoma) are the extrahepatic conditions most closelylinked to HCV, having been investigated extensively, and represent a modelfor both pathogenetic and clinicotherapeutic deductions. An associationbetween HCV infection and other morbid conditions, including dermato-logic, nephrological, neurologic, endocrinologic, cardiocirculatory, andlung disorders also has been suggested. Overlap syndromes characterizedby the presence in one patient of manifestations belonging to various path-ologic conditionsdtypically of autoimmune/lymphoproliferative naturedwould suggest that chronic HCV infection is a distinct systemic diseasewith a varying spectrum of clinical manifestations. Interferon-based antivi-ral therapy is considered, when feasible, the mainstay of treatment for mostHCV-linked extrahepatic diseases. Although its ecacy in curtailing a non-hepatic manifestation after obtaining viral clearance often is seen as a conr-mation of the key pathogenetic role played by HCV, clinical symptoms andviral persistence also may be disjointed, the former persisting even beyonda sustained viral response to therapy. Because of this fact and the intrinsic

    Clin Liver Dis 12 (2008) 611636potential inecacy of interferon, which in some cases may even exacerbate

    * Corresponding author.

    E-mail address: a.zignego@dmi.unifi.it (A.L. Zignego).

    1089-3261/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.cld.2008.03.012 liver.theclinics.com

  • substantial epidemiologic data and groups C and D associations still require

    immunoglobulin composition. In type I, they are composed of a pure mono-clonal component and usually associated with an indolent B-cell lymphoma,

    and in types II and III mixed CGs, they are composed of a mixture of poly-clonal IgG and monoclonal IgM or polyclonal IgG and polyclonal IgM, re-conrmation and/or a more detailed characterization as opposed to obser-vations that are of similar pathologic nature but of dierent etiology, or id-iopathic in nature, or only anecdotal (see Box 1).

    Hepatitis C virus-related lymphoproliferative disorders

    Mixed cryoglobulinemia

    Mixed cryoglobulinemia (MC) is a systemic vasculitis caused by deposi-tion of circulating immune complexes in the small vessels and characterizedby multiple organ involvement, mainly skin, peripheral nerves, kidney, andsalivary glands, and less frequently associated with widespread vasculitisand malignant lymphoma [36]. The strong association between HCV andMC has been conrmed repeatedly by serologic and molecular investiga-tions [4,6,7]. Generally speaking, cryoglobulinemias are conditions charac-terized by the presence of serum immunoglobulins that become insolublebelow 37C and can dissolve by warming serum (cryoglobulins, CGs). Ac-cording to Brouet and colleagues [8], CGs are classied on the basis of theirextrahepatic conditions, an individualized tailoring of therapy is needed inthese patients.

    Classication of extrahepatic manifestations of hepatitis C virus

    Extrahepatic manifestations of HCV infection (EHMs-HCV) range fromdisorders for which a signicant association with HCV infection is sup-ported clearly by multiple lines of evidence to anecdotal observations with-out clear proof of causality [1,2]. A tentative classication of EHMs-HCV issuggested in Box 1. According to such classication, extrahepatic manifesta-tions of HCV infection are distinguished, taking into account the robustnessof available scientic data. It is thus likely that the nosography of someEHMs-HCV may change over time.

    Group A includes EHMs-HCV characterized by a strong associationproven by both epidemiologic and pathogenetic evidence. This category in-cludes B-cell lymphoproliferative disorders (LPDs). Group B includes disor-ders for which a signicant association with HCV infection is supported by

    612 ZIGNEGO & CRAXI`spectively. In MC, the IgM represents an autoantibody bearing rheumatoidfactor (RF) activity. In type II MC (MC II), the IgM RF molecules mostfrequently display the WA cross-reactive idiotype [9]. MC II accounts for50% to 60%, and type III (MC III) for the remaining 40% to 50% of MC.

  • Box 1. Classification of extrahepatic manifestations of hepatitisC virus infection

    Association defined on the basis of high prevalenceand pathogenesisMixed cryoglobulinemia (complete or incomplete clinical

    syndrome)B-cell non-Hodgkins lymphoma

    Association defined on the basis of higher prevalencesthan in controlsMonoclonal gammopathiesPorphyria cutanea tardaLichen planusDiabetes mellitus

    Associations to be confirmed/characterizedAutoimmune thyroiditisThyroid cancerSicca syndromeAlveolitislung fibrosisNoncryoglobulinemic nephropathiesErectile dysfunctionsCarotid AtherosclerosisPsychopathological disorders

    Anecdotal observationsPsoriasisPeripheral/central neuropathiesChronic polyarthritisRheumatoid arthritisPolyarthritis nodosaBechets syndromeMyositis/dermatomyositisFibromyalgiaChronic urticariaChronic pruritusKaposis pseudosarcomaVitiligoCardiomyopathiesMooren corneal ulcerNecrolytic acral erythema


  • The prevalence of chronic HCV infection in patients who have CGs intheir serum ranges from 19% to more than 50% according to various stud-ies [10,11]. CGs, however, are generally present at low levels, and symptomsare generally absent or mild in chronically HCV-infected patients, whereasclinically overt MC syndrome (MCS) would be evident in 10% to 30% ofMC subjects [1012].

    Serum mixed CGs, high RF values, and reduced C4 values are the mostfrequent laboratory data. The most common symptoms of MCS are weak-ness, arthralgias, and purpura (Meltzer and Franklin triad). Raynauds phe-nomenondmicrocirculatory changes of the small vessels of the hands andfeet, identied as color changes in response to colddperipheral neuropathy,sicca syndrome, renal involvement, lung disorders, fever, and cytopeniasalso may be observed [3]. In a recent study involving 231 Italian MC pa-tients, peripheral neuropathy was observed in most cases, representing themost frequent clinical feature after the triad, followed by sicca syndrome,Raynaud phenomenon, and renal involvement [13].

    MC-related peripheral neuropathy typically includes mixed neuropathies,which are more often sensitive and axonal. They can manifest themselves assymmetric distal neuropathies, multiple mononeuritis, or mononeuropa-thies. Involvement of the central nervous system is unusual and generallypresents as transient dysarthria and hemiplegia. Pathologic ndings showaxonal damage with epineural vasculitic inltrates and endoneuralmicroangiopathy.

    A sicca syndrome (xerostomia and xerophthalmia) caused by involve-ment of salivary and lacrimal glands is recognized in a large proportionof MC patients [1418]. This syndrome close resembles primary Sjogrenssyndrome; however it typically lacks antinuclear autoantibodies and antiepi-thelial neutrophil-activating peptide (ENA, SSA/Ro, SSB/La) [13]. Thepathogenetic role of HCV infection in sicca syndrome and the characteris-tics distinguishing classic Sjogrens syndrome from those associated withHCV remain at issue [19]. It has been proposed that HCV infection is a crite-rion to exclude diagnosis of primary Sjogrens syndrome, especially if mixedcryoglobulins and hypocomplementemia are present, and anti-SSA/Roantibodies are absent [20].

    Signicant renal involvement is present in up to one third of patientswho have MC, being observed in about 20% of patients upon clinical pre-sentation of MC and in 35% to 60% of patients over long-term follow-up[13,21]. The most common features at diagnosis are one or more subclin-ical features of renal involvement including microscopic hematuria, pro-teinuria below the nephrotic range (!3 g/24 h), and with normal oronly fairly reduced renal function (creatinine !1.5 mg%). Arterial hyper-

    614 ZIGNEGO & CRAXI`tension is observed in up to 80% of cases [22]. In about 20% of patients,proteinuria is in the nephrotic range, and in them a nephrotic syndromemay represent the principal manifestation of MC. About 20% to 30%of cases present with an acute nephritic syndrome as their rst renal

  • manifestation [4,23]. Presence of a signicant renal involvement is amongthe worst prognostic indices in patients who have MC, even when itscourse is variable [13,23]. In a study of 231 patients who had MC, glomer-ulonephritis with subsequent renal failure was the main complication(33%), leading to death during long-term follow-up [13]. The typical his-tologic pattern of renal damage observed in patients who have MC type Iis membranoproliferative glomerulonephritis (MPGN) [13]. The presenceof capillary thrombi, made up of precipitated cryoglobulins and depositsof IgM in capillary loops typically dierentiates the cryoglobulinemicform from idiopathic MPGN. In a minority of cases (generally type IIIMC), dierent pathologic ndings have been described (ie, focal and me-sangioprolifer