EXTRAHEPATIC MANIFESTATIONS ASSOCIATED WITH HCV INFECTION

BACKGROUND

Hepatitis C virus (HCV) is one of the most common hepatotropic viruses and is recognized worldwide as a major healthcare problem. Various extrahepatic manifestations have been identified in patients with chronic HCV infection, including essential mixed cryoglobulinemia (EMC) type 2 or 3, porphyria cutanea tarda (PCT), membranoproliferative glomerulonephritis, sicca syndrome, thyroiditis, and a wide spectrum of autoantibodies. The presence of HCV as a triggering factor in several of these manifestations has been debated; only some have definite associations. The exact frequency of extrahepatic manifestations is not known; for some, the frequency seems to be very high. The precise mechanism that predisposes persons with HCV to extrahepatic manifestations has not been accurately established. Autoimmune phenomena elicited by the virus or interaction between the host and the virus may be causative factors. In addition to being found in hepatocytes, HCV is found in lymphocytes, peripheral and bone marrow monocytes, polymorphonuclear leukocytes, and various other tissues. The therapeutic armamentarium is limited and mainly targets the virus itself. Immunosuppressants, cytotoxic agents, and plasmapheresis have been used to treat these manifestations when the mainstay regimes fail. Unfortunately, the efficacy of various regimens is not optimal; many regimens cause severe adverse reactions.

EXTRAHEPATIC MANIFESTATIONS

Nonspecific autoantibodies
A wide variety of low-titer autoantibodies might be present with HCV infection. The clinical significance of this finding, however, has been questioned. Autoantibodies detected include rheumatoid factor (the most commonly detected autoantibody), antinuclear and smooth muscle antibodies, antibodies to liver-kidney microsome type 1 (anti-LKM-1), and antibodies to GOR.

Essential mixed cryoglobulinemia
The association between HCV and EMC type 2 or 3 has been studied extensively. The prevalence of HCV with EMC type 2 or 3 has been estimated as relatively high (35-90%), though only 10% of patients with this complication develop clinically apparent symptomatology. Female patients with cirrhosis are more likely to develop this complication. Genotype 2 may predispose patients to the development of lesions due to immune complexes of antibodies and viral elements that precipitate in the walls of the small- and medium-sized vessels, producing lesions compatible with leukocytoclastic vasculitis.

Glomerulonephritis
Cryoglobulinemic glomerulonephritis: Renal involvement occurs in approximately 50% of patients with EMC. The prognosis is not favorable. The most common presenting symptomatology is nephrotic syndrome with microscopic hematuria, proteinuria, and mild renal insufficiency.
Non-cryoglobulinemic glomerulonephritis: The presence of nephrotic syndrome or non-nephrotic proteinuria and renal insufficiency in the absence of symptoms or detection of cryoglobulinemia raises the suspicion of non-cryoglobulinemic glomerulonephritis (NCGN). The renal biopsy specimen in these cases is remarkable for membranoproliferative or acute proliferative glomerulonephritis.
Membranous glomerulonephritis: Membranous glomerulonephritis (MG) is relatively uncommon, and the potential pathogenesis involves deposition of immune complexes with HCV proteins.
Other glomerulopathies: Other glomerulopathies have also occurred, including IgA nephropathy, postinfectious glomerulonephritis, focal and segmental glomerulosclerosis, fibrillary glomerulonephritis, and immunotactoid glomerulopathy.

Cutaneous manifestations
Cutaneous vasculitis: The most common findings are palpable purpura and petechiae on the lower extremities.
Lichen planus: Approximately 5% of patients with HCV exhibit signs of lichen planus (LP). On the other hand, 38% of patients with LP test positive for antibodies against HCV. Signs of LP may include angular, violaceous, scaling papules on the flexor areas of the limbs; white reticular lesions on the mucous membranes and the genitalia; and oral findings.
Acquired porphyria cutanea tarda: The prevalence of acquired PCT is higher in southern Europe than in northern Europe. The presentation of this complication consists of bullae (sun exposure predisposes to the formation of the lesions), vesicles, skin fragility, hyperpigmentation, and hirsutism.
Additional cutaneous lesions: Polyarteritis nodosa, erythema nodosum, erythema multiforme, urticaria, Adamantiades-Behçet syndrome, and vitiligo may also be associated with chronic HCV infection.

Lymphoproliferative disorders, non-Hodgkin B cell lymphoma
Published prevalence rates are conflicting and range from 9–32% in Italy and Japan. In comparison, the prevalence rates are 0-3.1% in people without HCV. In these trials, whether HCV infection preceded the onset of lymphoma is not clear. Thus, long-term observational studies are needed in order to determine the real impact of HCV on induction of non-Hodgkin B cell lymphoma (NHL).

Endocrine disorders
In an estimated 20-30% of patients with HCV, autoantibodies against the thyroid gland (thyroglobulin, thyroid microsomal, and thyroid peroxidase antibodies) are detected. Occasionally, the titer of these autoantibodies is increased during treatment. A possible link between these autoantibody levels and the etiopathogenesis of autoimmune thyroiditis (primarily hypothyroidism) that has been observed during treatment remains unclear.

An association between type 2 diabetes and HCV has also been reported, and genotype 2a has been found in a higher number of cases. This observation must be further investigated.

Neuropathy
Peripheral neuropathy can be identified in patients with features of cryoglobulinemia-induced vasculitis. Symptoms include paresthesias, painful dysesthesias, and moderate motor weakness of the lower extremities with subsequent progression of the manifestations to sensory asymmetric axonal polyneuropathy or a multifocal neuropathy. Central nervous system involvement with transient dysarthria and hemiplegia is unusual, and confusional states are rare.

Sialadenitis
Keratoconjunctivitis sicca (dry eye) with features of Sjögren syndrome (SS) has been noted in 11% of patients with HCV infection. This finding has been reported in a number of studies, but a definite association remains to be established.

Miscellaneous conditions
A distant correlation, if any, may exist among patients with idiopathic pulmonary fibrosis, dilated cardiomyopathy, Mooren corneal ulcer, thrombocytopenia, SS, and aplastic anemia.

PATHOGENESIS

HCV has been recovered from various cells other than hepatocytes, such as lymphocytes. This finding leads to the hypothesis for a tropism and proliferation in multiple sites. The relation of this finding to the presentation of the extrahepatic manifestations is still under investigation.

Perhaps the best studied model is EMC. In particular, the stimulation of B cells by HCV results in an expansion of the peripheral CD5+ cells and clonal expansion. At a later stage, the production of immunoglobulins (IgM) occurs; most of the molecules display the WA cross-idiotype. Cryoglobulins (immunoglobulins that turn into a gel at cool temperatures) consist of a complex of HCV RNA and viral antigens bound to IgG antibodies that, in turn, are bound to IgM with anti-IgG properties. These complexes tend to precipitate in the walls of the small- and medium-sized vessels with subsequent activation of the complement cascade, producing leukocytoclastic vasculitis.

A strong relationship between EMC and NHL has been postulated. The HCV lymphotropism might be responsible for the evolution of EMC to malignant lymphoma, extranodal marginal cell lymphoma, or lymphoplasmacytoid immunocytoma. Recently, a different mechanism has been proposed. According to this hit-and-run hypothesis, in vitro infection of B cell lines by HCV induces DNA polymerases zeta and iota and activates cytidine deaminase, resulting in increased mutation frequencies in immunoglobulin heavy chains, p53, Bcl-6, and beta-catenin genes, leading to HCV-associated neoplasia.

Three distinct types of nephropathy have been described. Although the pathophysiology is related to EMC, NCGN and MG have also been identified.

In patients with HCV-type 2 cryoglobulinemia and palpable purpura, HCV has been found in keratinocytes and glandular epithelial cells in the inflammatory lesions but not in normal skin.

HCV has been isolated from epithelial cells of the salivary glands of patients with HCV and sialadenitis or HCV and SS, although a causative relationship has been questioned. HCV-specific CD4+ and CD8+ lymphocytes are detectable in LP lesions but not in the blood. Therefore, HCV may be either a primary or a contributing factor in cases of HCV and LP or HCV and SS.

TREATMENT

Antiviral treatment with interferon alfa alone or in combination with ribavirin appears to improve the clinical features of the aforementioned complications. Unfortunately, most patients experience relapse after ceasing antiviral therapy. Patients with HCV glomerulopathies may benefit from ribavirin alone, but underlying renal insufficiency may predispose such patients to profound anemia. Plasmapheresis has also been implemented with encouraging results for patients with EMC-related complications. In patients with PCT, the antiviral regimen should be administered with phlebotomy.

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