Immunological and clinical follow up of hepatitis C virus associated cryoglobulinaemic vasculitis

OBJECTIVE: To study immunological markers and compare these markers with standard measures for the clinical and immunological follow up of vasculitis activity in hepatitis C virus (HCV) associated cryoglobulinaemic vasculitis (CV). METHODS: Serial serum samples from eight patients with newly diagnosed HCV associated CV were followed during interferon alpha treatment induced remission of the CV. Vasculitis activity and disease extent were evaluated with the Birmingham vasculitis activity score (BVAS) and disease extent index (DEI). Cryoglobulinaemia, complement levels (C3c, C4, and CH50), rheumatoid factor (RF), autoantibodies such as antinuclear antibodies, soluble interleukin 2 receptor (sIL2r), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble CD30 (sCD30) were determined. RESULTS: All patients achieved either complete or partial remission of their CV during interferon alpha treatment. There was a significant reduction in vasculitis activity and disease extent (BVAS, DEI), cryoglobulinaemia, RF, sIL2r, sICAM-1, and sCD30. Complement C3c levels increased significantly during this period. Erythrocyte sedimentation rate and levels of complement C4 and CH50 did not change significantly. Both clinical measures (BVAS and DEI) correlated significantly only with C3c and sCD30. CONCLUSIONS: Although this study was of only a small group of patients, it shows that BVAS and DEI as clinical measures and C3c and sCD30 as immunological markers may be useful in the follow up of disease activity of HCV associated CV. The data indicate that activity of the humoral (cryoglobulinaemia, RF, autoantibodies) and cellular (sIL2r, sICAM-1, sCD30) immune response and endothelial damage (sICAM-1) are found in HCV associated CV.     

Antiplatelet antibodies contribute to thrombocytopenia associated with chronic hepatitis C virus infection

Abstract

Thrombocytopenia is one of the most frequent hematological manifestations of hepatitis Cvirus (HCV) infection; which typically worsens with progression of the liver disease and can become a major clinical complication. Several mechanisms have been postulated to explain thrombocytopenia in HCV hepatic patients, including immune mechanisms. The aim of the present work is to investigate the role of immune mechanisms as a causative agent of thrombocytopenia in HCV hepatic patients. The study included 50 hepatic patients with HCV infection (30 with thrombocytopenia and 20 with normal platelets counts). Platelets associated glycoprotein specific antibodies were evaluated by flow cytometry and confirmed by quantitative monoclonal immobilization of platelet antibodies (MAIPA). The frequency of platelet associated immunoglobulin (PAIg) in thrombocytopenic HCV positive hepatic patients by FCM was 86·7, 83·3, 46·7 and 33·3% for total PAIg, PAIgG, PAIgM and PAIgA respectively. MAIPA found platelet specific antibodies in 26/30 (86·7%) of patients. The most likely target antigen for platelets antibodies were glycoprotein (GP) IIb/IIIa (30%), followed by GP IIIa (20·5), GP IIb (13·3%), GPIb (13·3%), then GPIa (10%). The platelets count was inversely correlated to the levels of platelets GP specific antibodies (r=?0·42, p=0·024), and significantly parallel to spleen size (p=0·024). Platelet associated glycoprotein specific antibodies represent a common mechanism inducing thrombocytopenia in patients with chronic HCV infections.     

Hyperlipasemia associated with hepatitis C virus

Extrahepatic manifestations of chronic hepatitis C virus (HCV) infection have been well described. However, hyperlipasemia and/or pancreatitis have not been reported. Following the observation that several HCV patients had elevated lipase levels, this retrospective study was conducted to assess the association between hyperlipasemia and/or pancreatitis with hepatitis C infection. Of 204 subjects who underwent evaluation for hepatitis C, 103 had lipase levels determined at baseline. The control group consisted of 41 nonHCV subjects with a variety of gastrointestinal diseases including 18 with nonalcoholic liver disease. Twenty-five percent of HCV patients had elevated lipase at baseline as compared to 10% of controls (P = 0.04; OR = 3.1; 95% CI: 1.02–9.60). Mean lipase levels were 253 ± 72 units/liter (normal range 114–286 units/liter and 210 ± 42 units/liter for the HCV and control groups, respectively (P = 0.002). No significant difference in amylase was found between the groups. There was a significant association between ALT (>1.5 times the upper limit of normal) and lipase (P = 0.02; OR = 3.0; 95% CI: 1.1–7.5). Among 30 patients who received interferon-based therapy ± ribavirin, 11 had elevated lipase at baseline. Six of these patients responded to therapy and demonstrated normalization of lipase levels. In contrast, allnonresponders with baseline hyperlipasemia continued to have high lipase levels (P = 0.17; OR = 4.0; 95% CI: 0.6–28.4). Furthermore, only 3 of 8 (37.5%) patients with normal lipase responded to treatment as compared to 6 of 10 (60%) of hyperlipasemic patients (P = 0.36; OR = 2.5; 95% CI: 0.4–16.9). In conclusion, hyperlipasemia and/or subclinical pancreatitis may represent extrahepatic manifestations of HCV infection and should not preclude treatment.     

Renal manifestations associated with hepatitis C virus

Among the several types of chronic glomerulonephritis (GN) described in association with hepatitis C virus (HCV) infection, cryoglobulinemic glomerulonephritis is by far the most frequent. It is usually associated with type II cryoglobulinemia with IgM k rheumatoid factor. It is a membranoproliferative GN, which shows some distinctive histologic features (intraglomerular monocyte infiltration, intraluminal thrombi due to massive precipitation of cryoglobulins, renal vasculitis), has a chronic course with acute recurrent episodes that can be controlled by corticosteroids more than by antiviral therapy (interferon alpha). More controversial is the association with type I non-cryoglobulinemic membranoproliferative GN, which has been found in some series from the USA and Japan but not in others. The demonstration of HCV antibodies and/or HCV-RNA in other types of chronic glomerulonephritis is usually reported in a small minority of cases suggesting the possibility of a coincidental finding more than an etiologic factor.     

Cryoglobulinaemia vasculitis in patients coinfected with HIV and hepatitis C virus

OBJECTIVE: To describe mixed cryoglobulinaemia (MC) vasculitis in patients coinfected with hepatitis C virus (HCV) and HIV. DESIGN: Retrospective multicentre study through the GERMIVIC Database of 4005 HIV/HCV-coinfected patients. METHODS: The characteristics and outcome of 11 HIV/HCV-coinfected patients with MC vasculitis were analysed and compared with those of 118 HCV-infected patients with MC vasculitis. RESULTS: The mean age was 46 years (SD, 14), with 82% male. The median initial CD4 cell count was 367 cells/microl (range, 252-846). After a mean follow-up of 44.4 months, two deaths (18%) were noted. Clinical manifestations of MC included polyneuropathy in seven (64%), purpura in four (36%), arthralgia in four (36%), and kidney involvement in three (27%). Six patients received combination treatment with interferon-alfa and ribavirin, three of whom had sustained HCV virological response and were complete clinical responders. Four patients received corticosteroids and two showed a partial clinical response. Regardless of the HIV virological response, antiretroviral therapy did not improve MC vasculitis. Compared with patients with HCV monoinfection, coinfected patients were younger (P < 0.001), more frequently male (P = 0.03), more frequently intravenous drug users (P < 0.001), had higher HCV viraemia (P = 0.004), higher liver necroinflammation (P = 0.03), higher gammaglobulinaemia (P < 0.001) and lower cryoglobulin level (P = 0.03). The clinical manifestations of MC vasculitis did not differ significantly between the two groups. CONCLUSION: There was a beneficial effect of anti-HCV therapy for HIV/HCV-coinfected patients with MC vasculitis.     

Isolated central nervous system vasculitis associated with hepatitis C infection.

Since its identification in 1989, hepatitis C has been implicated in the pathogenesis of an increasing number of diseases previously believed to be primary or idiopathic. We report 2 rarely seen cases of isolated central nervous system (CNS) vasculitis in patients with hepatitis C infection. Patient 1. A 43-year-old man with 4 day right temporal headache developed a left hemiparesis. Weakness was his only physical finding. Computed tomography (CT) scan demonstrated a large right frontotemporal hemorrhage, and angiography revealed focal dilatations and irregularities of multiple branches of the right middle and anterior cerebral arteries. Cerebral decompression was performed and leptomeningeal biopsies showed granulomatous angiitis. Laboratory results were normal except for elevated liver biochemical tests. Later testing for hepatitis C was positive. His neurological symptoms improved with corticosteroids and cyclophosphamide. Patient 2. A 39 yr old male developed 3 days of left sided weakness, slurred speech and difficulty swallowing fluids. Physical findings were limited to his weakness. Magnetic resonance imaging demonstrated a right superior pontine subacute infarct with a small left internal capsule lacunar infarct. Angiography revealed multiple areas of focal narrowing with no areas of abrupt vessel cut off. Cerebral spinal fluid showed 71 PMN, 29 RBC, normal glucose, elevated protein (64 mg/dl), no oligoclonal bands, and low myelin basic protein. Other laboratory analyses were normal including liver biochemical tests. However, hepatitis C serology was positive and mixed cryoglobulins were detected. CNS vasculitis was diagnosed and nearly full recovery was achieved with corticosteroids, cyclophosphamide and warfarin.     

Relapsing polychondritis associated with hepatitis C virus infection

This article is aimed to review of relapsing polychondritis (RP) and its association to hepatitis C virus (HCV) infection. A case of RP associated with HCV infection in a 59-year-old male is reported. The English medical literature was reviewed for RP and its association with HCV infection. RP is a rare autoimmune and multisystem disorder of unknown etiology in which the cartilaginous and related tissues are the primary targets of inflammation. HCV infection is a more common systemic illness with known hepatic and extra-hepatic manifestations. Although RP is associated with other diseases in about 35% of cases, only one case of RP, HCV, and mixed cryoglobulinemia has been reported. We report a case of RP associated with HCV infection. Treatment with pegylated interferon and ribavirin resulted in sustained virologic response and remission of treatment-resistant RP with azathioprine. We report a case of RP and associated HCV infection. Although treatment of HCV infection resulted in remission of RP, it is unknown if there is a causal relationship between HCV infection and RP.     

Cutaneous disorders associated with hepatitis C virus infection

Since the discovery of hepatitis C virus (HCV) in 1989, many cutaneous disorders have been observed in patients suffering from chronic HCV infection. The relationship between HCV infection and cryoglobulinemia or porphyria cutanea tarda (PCT) is now clearly established, but the link between HCV and other dermatoses is still controversial. This review of the main dermatologic disorders, directly or indirectly related to HCV infection, lead to conclude that HCV markers have to be investigated systematically in case of cryoglobulinemia, PCT or pruritus. In other dermatologic disorders, HCV serology will be necessary only in case of risk factors for HCV infection, or presence of abnormal liver function tests.     

丙型肝炎病毒相关的肾脏疾病

丙型肝炎病毒（hepatitis C virus，HCV）是一种常见的血源性传播的病毒，50％～80％的急性丙型肝炎可进展为慢性丙型肝炎、肝硬化甚至肝癌。许多研究发现，HCV感染除有肝脏表现外，还有许多肝外表现，如冷球蛋白血症、干燥综合征、淋巴细胞增生性疾病及肾小球肾炎等。膜增殖性肾小球肾炎是HCV相关的肾脏疾病中最常见的一种。笔者对HCV相关的肾脏疾病的发病机制、临床表现、治疗和预后的研究进展进行综述，以提示临床医师注意慢性丙型肝炎患者出现的肾功能异常，为HCV相关的。肾脏疾病的诊治提供依据。     

Neutralizing antibodies in hepatitis C virus infection

Hepatitis C virus (HCV) is a major cause of hepatitis world-wide. The majority of infected individuals develop chronic hepatitis which can then progress to liver cirrhosis and hepatocellular carcinoma. Spontaneous viral clearance occurs in about 20%-30% of acutely infected individuals and results in resolution of infection without sequaelae. Both viral and host factors appear to play an important role for resolution of acute infection. A large body of evidence suggests that a strong, multispecific and long-lasting cellular immune response appears to be important for control of viral infection in acute hepatitis C. Due too the lack of convenient neutralization assays, the impact of neutralizing responses for control of viral infection had been less defined. In recent years, the development of robust tissue culture model systems for HCV entry and infection has finally allowed study of antibody-mediated neutralization and to gain further insights into viral targets of host neutralizing responses. In addition, detailed analysis of antibody-mediated neutralization in individual patients as well as cohorts with well defined viral isolates has enabled the study of neutralizing responses in the course of HCV infection and characterization of the impact of neutralizing antibodies for control of viral infection. This review will summarize recent progress in the understanding of the molecular mechanisms of antibody-mediated neutralization and its impact for HCV pathogenesis.