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Extrahepatic manifestations of hepatitis C.

Abstract: Hepatitis C affects approximately 170 million people worldwide. Extrahepatic manifestations of chronic hepatitis C infection are clinically evident in nearly 40% of patients. Much research has been done over the last decade to better understand their incidence, clinical presentation, mechanism of disease, and the role of antiviral therapy in their treatment. Of the commonly reported manifestations, cryoglobulinemia, membranoproliferative glomerulonephritis, and porphyria cutanea tarda remain the best understood manifestations. More recently, the association of insulin resistance and diabetes mellitus with chronic hepatitis C has been demonstrated. This paper serves to review the growing body of literature detailing the extrahepatic manifestations of chronic hepatitis C.

Key Words: hepatitis C, extrahepatic manifestations, membranoproliferative glomerulonephritis, mixed cryoglobulinemia, porphyria cutanea tarda

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Hepatitis C virus (HCV), an RNA flavivirus, was first identified in 1989. Approximately 170 million people worldwide are infected. It has been estimated that 1.8% of the population in the United States has HCV antibodies. (1) Over the last decade, HCV has been implicated in the development of multiple extrahepatic manifestations. In large studies assessing the prevalence of extrahepatic manifestations, at least one clinical manifestation was found in 38% of patients (2) while up to 74% demonstrated at least one serologic manifestation. (3) Some associations, such as cryoglobulinemia, membranoproliferative glomerulonephritis (MPGN), and porphyria cutanea tarda (PCT), are well established. Other manifestations, although reported frequently, are considered probable or merely possible associations. The following paper will review the commonly reported extrahepatic manifestations of HCV (Table).

Hematologic and Immunologic Manifestions

There is a high prevalence of extrahepatic hematologic and immunologic abnormalities in patients with chronic HCV, (4) with cryoglobulinemia and autoantibodies being the most common, found in up to 50% and 70% of patients respectively. (4,5) In addition, an overall increase in extrahepatic malignancies has been demonstrated, (6) including an association with the development of B-cell non-Hodgkin lymphoma (NHL). (7)

Cryoglobulinemia

Mixed cryoglobulinemia (type II and type III), a systemic vasculitic disease, was first described by Meltzer and Franklin in 1964. (8) It is typically characterized by depositions of immune complexes in small and medium-sized blood vessels leading to lower extremity purpura, arthralgias, and Raynaud syndrome. In type II mixed cryoglobulinemia, precipitates contain polyclonal IgG and monoclonal IgM with anti-gammaglobulin (rheumatoid factor) activity. (9) Type III mixed cryoglobulinemia has both polyclonal IgG and polyclonal IgM. (9)

Ferri and colleagues initially demonstrated that 41 of 45 Italian patients with mixed cryoglobulinemia had anti-HCV antibodies. (10) Since then multiple studies confirmed what is now considered the strongest association of HCV and an extrahepatic manifestation. In 1993, Ferri and colleagues demonstrated that 96% of patients were positive for HCV antibodies (HCV Ab), and 91% were positive for HCV RNA. (11) Subsequently, Agnello (12) demonstrated both HCV Ab and HCV RNA are highly concentrated in type II cryoprecipitates, as opposed to type I cryoprecipitates in patients used as controls. In a large prospective study, Cacoub et al (13) discovered cryoglobulins in 54% of all patients with HCV, one-third with type II cryoglobulinemia and two-thirds with type III cryoglobulinemia. Up to 21% of patients in this study had clinical symptoms related to cryoglobulinemia. More recent studies found similar findings and noted that patients with mixed cryoglobulinemia were of older age while sex was not a risk factor. (14,15) In addition, HCV genotype 2a had a significantly higher prevalence in HCV positive patients with mixed cryoglobulinemia. (16)

The mechanism by which HCV may result in mixed cryoglobulinemia remains unclear. One hypothesis is that HCV Ab complexes may lead to clonal expansion of Blymphocytes within the liver, which have been shown to produce rheumatoid factor (RF) and recognize HCV epitopes. (7,9) Overproduction of RF resulting in immune complex formation is therefore possible.

Treatment of mixed cryoglobulinemia has been well studied. Conventional treatment had included steroids, cytotoxic agents, and plasmapheresis. In patients with HCV, interferon alpha (IFN-[alpha]) has been reported as efficacious for the treatment of mixed cryoglobulinemia. In a 1994 randomly controlled prospective study by Misiani et al 53 patients with HCV and type II cryoglobulinemia were studied. (17) Twenty seven patients received IFN-[alpha] for 23 weeks compared with 26 control patients. Sixty percent of patients who received IFN-[alpha] had undetectable levels of HCV RNA, and in all of these patients signs and symptoms of cryoglobulinemia disappeared with significant improvement in serum cryocrit levels and IgM RF. After treatment was discontinued, viremia and cryoglobulinemia recurred in all patients. Further studies supported these findings. In a 1997 study (18) there was a 65% response rate to IFN-[alpha], with disappearance of cryoglobulins. Recurrence occurred in two-thirds of patients after treatment was stopped. A similar effect has been seen with ribavirin therapy. (7) Ribavirin, however, also appears effective in the management of recurrent symptomatic cryoglobulinemia after liver transplantation. (7)

Lymphoproliferative disorders and non-Hodgkin lymphoma

In a study of 103 patients with HCV in Israel, (6) extrahepatic malignancies of any type were found in 14.6% of patients compared with controls (2.9%) and significantly higher than the general population. The strongest association, however, has been with B-cell NHL.

Over the last decade multiple studies have been done to clarify the relationship between HCV and B-cell NHL, demonstrating an overall prevalence of HCV in patients with B-cell NHL of 9 to 42%. (7) Studies have also demonstrated the presence of HCV RNA by PCR in peripheral lymphocytes, bone marrow, or lymphoma tissue. In 1995, Silvestri and colleagues evaluated 537 patients affected by lymphoproliferative disorders including Hodgkin lymphoma, multiple myeloma, acute lymphocytic leukemia, and NHL. All patients were tested for HCV Ab and HCV RNA. There was only an increase in HCV infectivity in patients with B-cell NHL with a relative risk of 3.24. (7)

It is now understood that HCV is both a hepatotropic and lymphotropic virus, replicating in not only hepatocytes but also in peripheral blood mononuclear cells. This has lead to a better understanding of the possible mechanism of both benign and malignant lymphoproliferative syndromes in HCV to include: portal tract lymphatic nodules, mucosal lymphoproliferative tissue, abnormal bone marrow B-cell proliferation, immunoplasmacytomas, and malignant B-cell NHL. It is now felt that HCV antigens bind to CD81, leading to B-cell specific multimolecular signaling. (19) This ultimately results in B-cell clonal expansion. A malignant transformation could then result from any number of gene rearrangements or mutations occurring during this clonal expansion. Franzin and colleagues (20) analyzed the clonal expansion of a B-cell population in HCV patients, demonstrating a high frequency of clonal Ig gene rearrangements. Crouzier then showed IgM RF somatic and affinity mutations. (21)

Lymphocytic sialadenitis

Lymphocytic sialadenitis, similar to Sjogren syndrome, is considered a common finding in HCV patients, found in 14 to 57% of patients in various studies. (22) It results from the infiltration of the salivary gland by lymphocytes, but unlike Sjogren syndrome, the lesion is pericapillary rather than periductal and never destroys the duct walls. Most patients demonstrate cryoglobulins but autoantibodies seen in Sjogren syndrome (SS-A, SS-B) are almost always absent. (19) In 1992, Haddad and collegues demonstrated lymphocytic sialadenitis in 57% of patients with HCV compared with less than 5% in controls. (23) Ten of 28 patients had xerostomia, but none had xerophthalmia.

Autoantibodies

Autoantibodies are frequently seen in patients with HCV. In one study of 321 patients with HCV, 70% had at least one autoantibody. (2) Of these, RF was found in 38 to 71% of patients, (2,4,5) antinuclear antibody in 10 to 41%, (2,3,4,5) antismooth muscle antibody in 9 to 22%, antithyroglobulin antibody in 7 to 14%, anti-LKM1 antibody in 5%, and anticardiolipin antibody in up to 44%. (24) The presence of autoantibodies appears to be a nonspecific event likely related to immune stimulation favoring synthesis by B-lymphocytes, and patients typically show no clinical symptoms.

One exception to this is in patients with thyroid abnormalities, where it has been hypothesized that such abnormalities may predispose the patient to thyroiditis when treated with IFN-[alpha]. (5) After IFN-[alpha] treatment, up to 12% of patients developed thyroid dysfunction. (19) Approximately 10% develop hypothyroidism. This is especially prevalent (39%) in those patients with high antithyroid peroxidase antibody titers at baseline. (22) After discontinuation of IFN-[alpha], 60% have reversal of dysfunction. (22)

Another exception is the increased prevalence of anti-endothelial cell antibody (AECA) in patients with HCV (41%) noted in one study. (25) These antibodies are found in various connective tissue diseases with a high prevalence of systemic vasculitis. It has, therefore, been suggested that sensitized T-cells to HCV-containing endothelial cells may initiate the vasculitic process. AECA may then be a marker for HCV induced vasculitis.

Thrombocytopenia

Thrombocytopenia is frequently observed in patients with HCV, often believed to be due to hypersplenism; however, thrombocytopenia has been observed in HCV without evidence of cirrhosis or splenomegaly. Even with cirrhosis and splenomegaly, HCV patients seem to develop lower platelet counts than patients with other causes of cirrhosis. Thrombocytopenia in patients with HCV shares many clinical features of idiopathic thrombocytopenic purpura (ITP) with large platelets on peripheral smear and normal to increased megakaryocytes on bone marrow biopsy. (26) In one Italian study, 36% of patients with ITP were HCV positive. (27) It was theorized that immune complexes of RF IgM and HCV-IgG Ab in type II cryoglobulinemia could bind to Fc receptors on platelets prompting their clearance. More recently, Kajihara and collegues demonstrated an increased frequency of anti-GPIIb-IIIa antibody producing B cells in patients with cirrhosis compared with healthy controls as well as the presence of anti-GPIIb-IIIa antibodies on the surface of circulating platelets in patients with cirrhosis. (28) This anti-GPIIb-IIIa autoantibody response is similar to that seen in ITP, suggesting that in those patients with cirrhosis, autoantibody platelet destruction contributes to thrombocytopenia.

In a small study aimed at treating HCV induced thrombocytopenia, IFN-[alpha] was given for 24 weeks. There was a significant increase in the platelet count in 63% of patients with a mean increase of 44 X [10.sup.9]/L. (26) Larger studies need to be conducted before treatment recommendations can be made.

Renal Manifestations

Chronic hepatitis C infection is a significant cause of membranoproliferative glomerulonephritis (MPGN). In 1993, Johnson and collegues reported 8 cases of MPGN in patients with HCV. (29) All patients had hypocomplementemia and proliferative glomerular lesions characterized by deposition of IgG, IgM, and C3 on capillary walls and subendothelial and mesangial immune deposits. Prior HCV infection is now recognized in up to 60% of patients with MPGN in Japan and up to 20% of patients with MPGN in the United States. (30)

Often renal involvement is clinically silent. The most common presentation is microscopic hematuria and proteinuria. Approximately 50% of patients present with mild to moderate renal insufficiency, 25% present with acute nephritic syndrome, and 25% with nephrotic syndrome. (30)

Most evidence supports deposition of immune complexes as the cause of glomerular injury. It is felt that once the complexes are deposited in the subendothelium and mesangium, there is activation of the complement system leading to cellular proliferation and mononuclear cell infiltration. This results in protease and oxidant release causing cellular injury and altered glomerular permeability. D'Amico et al (31) postulated that the abnormal proliferation of B-cell clones, similar to the lymphoproliferative manifestations of HCV, results in overproduction of monoclonal IgM, which then deposits in the glomerulus. (30)

Lab findings include elevated RF, low complement levels, and elevated C1q assay. Fifty percent have cryoglobulins at presentation. Renal biopsies show mesangial proliferation and sclerosis, increased cellularity, double contours of basement membrane, and tubular atrophy. Immunoflorescence shows depositions of IgM, IgG, and complement.

The best treatment for HCV MPGN is yet to be defined. Small studies show an improvement in proteinuria with variable effects on creatinine levels in those patients treated with IFN-[alpha]. (29,30) Treating HCV-associated MPGN with 3 million units of IFN-[alpha] three times a week for 6 to 12 months also reduces acute nephritic or nephrotic flare-ups of MPGN in 50 to 60% of patients. (32) However, the renal disease seems to relapse with discontinuation of IFN-[alpha].

While MPGN remains the most common renal disease associated with HCV, membranous nephropathy, fibrillary glomerulonephritis, rapid progressive glomerulonephritis, and IgA nephropathy have also been reported in patients with HCV. (33)

Dermatologic Manifestations

Porphyria cutanea tarda

Porphyria cutanea tarda (PCT) results from decreased activity of uroporphyrinogen decarboxylase. In type I, the sporadic form of the disease, the enzyme is 50% decreased in hepatocytes only, as opposed to type II, an autosomal dominant inherited disease, where the defect is present in other cell types including red blood cells. (22) A very strong association, ranging from 50 to 90% in multiple studies, between sporadic PCT and HCV infection has been demonstrated in patients from Japan, the European Mediterranean basin, and the United States. (34) The mechanism of action of HCV-induced PCT remains undetermined, but it produces the same clinical, laboratory, and histopathologic findings seen in other forms of sporadic PCT. (35) Some researchers have suggested that HCV decompartmentalizes iron leading to the formation of free radicals and the oxidation of uroporphyrinogens. Others speculate that a decrease in intracellular glutathione induced by HCV acts as a potential trigger. There are reports of response to IFN-[alpha] therapy in HCV patients with PCT, (22) however further studies need to be done to define the role of IFN-[alpha] in the treatment of PCT.

Leukocytoclastic vasculitis

First described to be associated with HCV (then called non-A non-B hepatitis) in 1981, cutaneous necrotizing vasculitis is characterized by destruction of dermal blood vessels with neutrophilic infiltration. Patients typically present with lower extremity palpable purpura. In a 1995 study, palpable purpura corresponding histologically to leukocytoclastic vasculitic (LCV) was the most frequent cutaneous involvement in patients with HCV. (36) These patients with palpable purpura had significantly higher serum cryocrit levels than patients without purpura. IFN-[alpha] has been associated with a resolution of purpuric lesions in some studies. (22)

Lichen planus

Lichen planus (LP) is a benign disease characterized by pruritic, violaceous and papulosquamous eruptions (37) involving the extremities, genitalia, or mucosal surfaces. Histologically there is a dense infiltration of lymphocytes in the upper dermis. (37) Studies demonstrate up to 26% of patients with oral LP have chronic liver disease, 33% of which have HCV. (22,38) LP is felt to be due to a T-cell mediated immunologic process, however the role of HCV remains unclear. Treatment with IFN-[alpha] has shown conflicting results in a few cases with either a complete resolution of LP or sudden worsening of pre-existing LP. (37)

Other skin diseases have been described in association with chronic hepatitis C virus, but are noted in only a few case reports and include urticaria, polyarteritis nodosa, erythema nodosum, and erythema multiforme. (39)

Neurologic Manifestations

The most common neuropathy associated with HCV is peripheral neuropathy, which is usually associated with cryoglobulinemia-induced vasculitis. (19) A study of 89 patients with HCV found electrophysiological evidence of polyneuropathy in 37% of patients. (40) In this study, polyneuropathy was more common in patients with cryoglobulinemia although it was unrelated to cryocrit levels or type of cryoglobulinemia. In fact, one third of patients without other symptoms related to cryoglobulinemia had polyneuropathy. Following this, in a small study of HCV patients with polyneuropathy, nerve biopsies of patients showed HCV RNA localized in epineural cells by PCR (41) to support the actual involvement of HCV in the development of polyneuropathy. To date the mechanism of the development of polyneuropathy is unclear, and there are no large controlled studies evaluating treatment.

Other possible neurologic manifestations of HCV that have been reported include paresthesias, (42) encephalopathy (43) and Guillain-Barre syndrome. (44)

Endocrine Manifestations

As opposed to the hypothyroidism described above which is seen as a consequence of treatment with interferon, chronic HCV may lead directly to insulin resistance independent of obesity. (45) Epidemiologic studies have demonstrated an association between HCV and diabetes mellitus. (46) More recently, Shintani and colleagues demonstrated that the hepatitis C viral core protein induces hepatic insulin resistance in transgenic mice. (47) Perhaps equally interesting, interferon therapy has been shown to improve insulin sensitivity in patients with chronic hepatitis C virus. (48)

Conclusion

Since its discovery in 1989, HCV has been associated with multiple extrahepatic manifestations. To date, mixed cryoglobulinemia, membranoproliferative glomerulonephritis and porphyrea cutanea tarda are the strongest associated manifestations. The exact mechanism by which HCV may induce each of the extrahepatic manifestations reported here is still uncertain. In small studies, IFN-[alpha] has shown benefit in some extrahepatic manifestations, although relapse rates are high after discontinuation of therapy. Further studies need to be conducted to determine the mechanism leading to these extrahepatic manifestations and to define the role of interferon in their treatment.

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46. Lonardo A, Adinolfi LE, Loria P, et al. Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 2004;122:1649-1657.

47. Shintani Y, Fujie H, Miyoshi H, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology 2004;126:840-848.

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Nicole A. Palekar, MD, and Stephen A. Harrison, MD

From the Department of Medicine, Gastroenterology and Hepatology Service, Brooke Army Medical Center, Fort Sam Houston, TX.

Reprint requests to Nicole A. Palekar, MD, Brooke Army Medical Center, Department of Medicine, Gastroenterology and Hepatology Service, 3851 Roger Brook Drive, Fort Sam Houston, TX. Email: nicole.palekar@cen.amedd.army.mil

The opinions or assertions contained herein are those of the authors and are not to be construed as official policy or as reflecting the views of the Department of the Army or the Department of Defense.

Accepted October 19, 2004.

RELATED ARTICLE: Key Points

* Extrahepatic manifestations are commonly seen in patients with hepatitis C.

* Mixed cryoglobulinemia, membranoproliferative glomerulonephritis and porphyria cutanea tarda appear to have the strongest association.

* Antiviral therapy with interferon 2a, interferon 2b, and ribaviron is effective in the treatment of some extrahepatic diseases but relapse rates are high if the virus is not eradicated.
Table. Extrahepatic Manifestations of Hepatitis C

Hematologic
 Mixed cryoglobulinemia
 B-cell non-Hodgkin Lymphoma
Autoimmune
 Lymphocytic sialadenitis
 Autoantibodies
 Idiopathic thrombocytopenic purpura
Renal
 Membranoproliferative glomerulonephritis
 Mebranous nephropathy
 Fibrillary glomerulonephritis
 Rapid progressive glomerulonephritis
 IgA nephropathy
Dermatologic
 Porphyria cutanea tarda
 Leukocytoclastic vasculitis
 Lichen planus
Neurologic
 Peripheral neuropathy
 Guillain-Barre syndrome
Endocrine
 Hypothyroidism
 Diabetes mellitus
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Title Annotation:symptoms
Author:Harrison, Stephen A.
Publication:Southern Medical Journal
Geographic Code:1USA
Date:Oct 1, 2005
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