Kinetics of anti-hepatitis C virus response during acute hepatitis in an immunosuppressed HCV chronically infected patient.

A hepatitis C virus (HCV) chronically infected patient developed an episode of acute hepatitis during the course of immunosuppressive therapy given for a lymphoproliferative disease. It was noted that anti-HCV antibody response, seen to be relatively stable during the follow-up, lowered dramatically in coincidence with the hepatocytolytic peak. A diagnostic liver biopsy taken at the time of the acute phase of hepatitis demonstrated a typical feature of lobular hepatitis with widespread lymphocytic infiltrates, the predominant type of which expressed CD8 immunophenotype. Cytotoxic and immunosuppressive drugs may interfere with hepatitis virus infections. However, at variance from hepatitis B virus infection in which acute liver decompensation develops after withdrawal of chemotherapy in our HCV chronically infected patient it appeared during the course of the treatment, suggesting a different hepatocytolytic mechanism. Although the actual frequency of the phenomenon is presently unknown, this observation seems to indicate that immunosuppressive and cytotoxic agents should be used with caution in HCV chronic infection in which cell-mediated immune response seems to play a major role in the production of the liver damage.     

Polyarteritis nodosa and cryoglobulinemic glomerulonephritis related to chronic hepatitis C

CASE REPORT: A 53-year-old man with hepatitis C virus (HCV) infection underwent cholecystectomy for presumed cholecystitis. Gallstones were not present, and histological examination demonstrated medium-sized arteritis, consistent with polyarteritis nodosa (PAN). The patient later developed rapidly progressive glomerulonephritis. Kidney biopsy demonstrated cryoglobulinemic glomerulonephritis. Because of the severity of the patient's vasculitic manifestations, treatment included pulse methylprednisolone followed by oral prednisone and monthly intravenous cyclophosphamide for 6 months. During treatment, microhematuria resolved, proteinuria decreased, and serum creatinine concentration stabilized. The patient subsequently underwent treatment for HCV with interferon resulting in a marked decrease in HCV RNA. The patient has had no relapse of his vasculitis, his renal function is stable, and viral load remains low after completing 36 weeks of interferon. CONCLUSION: Life-threatening vasculitis related to HCV was successfully treated with immunosuppressive therapy. After obtaining clinical remission, antiviral therapy was instituted, resulting in a dramatic decrease in HCV RNA.     

Late-Onset Immune Thrombocytopenic Purpura After Withdrawal of Interferon Treatment for Chronic Hepatitis C Infection: A Case Report

Immune thrombocytopenic purpura (ITP) is a life-threatening complication following pegylated interferon alpha (PEG-IFN) plus ribavirin treatment, the standard treatment for hepatitis C virus (HCV) infection. We reported a rare case with late-onset ITP after withdrawal of PEG-IFN treatment.A 53-year-old male with hepatitis C developed massive gum bleeding and a severe, reversible, immune thrombocytopenia 2 weeks after cessation of PEG-IFN treatment for HCV due to anemia and depression. The platelet count decreased to 4000 cells/μL. The HCV viral load was undetectable at the end of PEG-IFN treatment and during follow-up for 5 months. Other potential autoimmune disorders were ruled out. Late-onset ITP associated with PEG-IFN treatment was diagnosed.The patient was treated successfully with steroid and azathioprine. Platelet count gradually increased to 117 × 10³ cells/μL on the 18th day after admission.ITP is a rare complication in patients with hepatitis C or in patients who received PEG-IFN treatment. The particular case supported that it may occur even after withdrawal of PEG-IFN treatment. Physicians should be aware of this late-onset complication.     

Acquired amegakaryocytic thrombocytopenia previously diagnosed as idiopathic thrombocytopenic purpura in a patient with hepatitis C virus infection

We report the first case of a patient with hepatitis C virus(HCV) infection and idiopathic thrombocytopenic purpura(ITP), who later developed acquired amegakaryocytic thrombocytopenia(AAMT), with autoantibodies to the thrombopoietin(TPO) receptor(c-Mpl). A 64-year-old woman, with chronic hepatitis C, developed severe thrombocytopenia and was diagnosed with ITP. She died of liver failure. Autopsy revealed cirrhosis and liver carcinoma. In the bone marrow, a marked reduction in the number of megakaryocytes was observed, while other cell lineages were preserved. Therefore, she was diagnosed with AAMT. Additionally, autoantibodies to c-Mpl were detected in her serum. Autoantibodies to c-Mpl are one of the causes of AAMT, acting through inhibition of TPO function, megakaryocytic maturation, and platelet formation. HCV infection induces several autoantibodies. HCV infection might also induce autoantibodies to c-Mpl, resulting in the development of AAMT. This mechanism may be one of the causes of thrombocytopenia in patients with HCV infection.     

Transient loss of T-cell reactivity in a patient with hepatitis C virus reinfection

BACKGROUND/AIMS: Self-limited acute hepatitis C virus (HCV) infection with spontaneous recovery is only rarely observed in clinical practice. All existing studies correlate strong cellular immune responses to the recovery from HCV infection. CASE REPORT: Here, we present a 49-year-old haemophiliac, who had successfully recovered from an acute hepatitis, which was classified retrospectively as HCV infection based on his antibody profiles. This patient was reinfected with HCV 18 years later from an exogenous source, and successfully recovered from this reinfection within 2 months. After his first hepatitis the patient displayed strong cellular responses against recombinant HCV proteins. During reinfection, T-cell proliferation was markedly reduced, while HCV antibody titres increased. However, E2 antibodies were consistently not detectable. T-cell proliferation returned to the pre-reinfection level only several months after loss of viraemia. DISCUSSION: Our observations resulted in the unexpected finding that our patient cleared HCV reinfection despite an apparent loss of his pre-existing T-cell reactivity in the peripheral blood.     

Immune thrombocytopenic purpura in patients with chronic hepatitis C virus infection

OBJECTIVE: Hepatitis C virus (HCV) infection has been associated with the production of autoantibodies and the development of several autoimmune disorders. Immune thrombocytopenic purpura (ITP) is an immune-mediated syndrome of unknown etiology characterized by the presence of autoantibodies against platelet membrane proteins. METHODS: Retrospective chart review. RESULTS: Seven patients with chronic HCV infection (five with cirrhosis and two with chronic active hepatitis) developed thrombocytopenia, out of proportion to their liver disease, and were diagnosed with ITP based on the presence of anti-platelet antibodies and their response to treatment. The number of patients with ITP which occurred in a population of 3440 HCV patients seen over this time interval is much greater than would be expected by chance (p < 0.00001). Six patients required treatment and four required hospitalization. Four of the six responded to corticosteroids alone. Both of the patients who failed to respond to corticosteroids responded to cyclophosphamide. No mortality occurred from complications of thrombocytopenia. CONCLUSIONS: ITP occurs more commonly in patients with chronic HCV infection than would be expected by chance. This should be considered in patients with liver disease and unexplained thrombocytopenia, as well as in patients with newly diagnosed ITP. Evaluation of antiplatelet antibodies, using an antigen-specific assay, was useful in supporting this diagnosis. Therapy with either corticosteroids or cyclophosphamide was successful in the six patients who required treatment.     

Resolution of diabetes in type 2 diabetic patient treated with IFN-alpha and ribavirin for hepatitis C

We report on a patient whose type 2 diabetes mellitus resolved during IFN-alpha therapy for hepatitis C virus (HCV). A 40-year-old man was diagnosed with type II diabetes in year 2000. His body mass index (BMI) was 30.8 kg/m and glycosylated haemoglobin (HbA1c) was 10.7%. He was treated with metformin. Later, his glycaemic control deteriorated despite additional dietary and lifestyle advice and the addition of glibenclamide. He was started on subcutaneous insulin in 2002 with the continuation of metformin. In 2003 he was diagnosed with chronic hepatitis caused by HCV. In September 2003 he was started on IFN-alpha and ribavirin. After 24 weeks of treatment his HCV polymerase chain reaction remained positive and treatment was stopped as per guidelines. At the commencement of antiviral therapy, HbA1c was 7.7%. In April 2004 his BMI of 29.38 kg/m had reduced and he then stopped insulin therapy because of repeated hypoglycaemia. After stopping insulin his HbA1c was 4.7%. Fasting plasma glucose of 6.2 mmol/l and anti-glutamic acid decarboxylase antibodies were negative. Urea and creatinine levels were normal. Most of the earlier literature describes diabetes developing in the course of IFN-alpha therapy for a variety of diseases. More recent research has described a relationship between hepatitis C infection and the development of diabetes and insulin resistance. Responders to IFN-alpha treatment manifest an improvement in insulin sensitivity compared with non-responders after the completion of IFN-alpha therapy. Our case shows the resolution of pre-existing diabetes in a patient with chronic HCV infection, which did not respond to IFN-alpha therapy. Whether this occurred as a direct result of IFN-alpha on insulin sensitivity or indirectly as a result of weight loss because the therapy for HCV precipitated additional lifestyle changes in the patient is as yet unclear.     

Immune Thrombocytopenic Purpura Complicated by Hepatitis C Virus-related Membranoproliferative Glomerulonephritis after Rituximab Therapy

We herein report the case of a 54-year-old Japanese man with hepatitis C virus (HCV)-related membranoproliferative glomerulonephritis (MPGN), which developed at the time of relapse of immune thrombocytopenic purpura (ITP) after rituximab therapy. Antiviral therapy for HCV led to the improvement of both MPGN and ITP. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and the relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for treating ITP itself.     

Hepatitis C-autoimmune hepatitis overlap syndrome: five new cases

PURPOSE: The hepatitis C-Autoimmune hepatitis overlap syndrome is an uncommon condition whose management can be difficult in both diagnosis and treatment. PATIENTS AND METHODS: Five cases of hepatitis C and autoimmune hepatitis overlap syndrome, brought by a retrospective study, are reported. Hepatitis C was proven by a positive HCV viral load and the autoimmune hepatitis was proven by characteristic immunological and/or histological features. RESULTS: All patients were female, the mean age at diagnosis was 54.2 years (+/-6.6), only one patient had a history of autoimmune disease (autoimmune thyroiditis). Four patients had significant autoantibodies levels (over 1/320) and 4 had a high serum gammaglobulin level (over 1.5 times the upper normal limit). Liver biopsy showed characteristic features of autoimmune hepatitis in all cases and characteristic features of chronic HCV infection in 3 cases. Corticosteroid and/or immunosuppressive treatment was given as a first line therapy in 4 cases while an antiviral treatment has been tried in 4 cases with a good viral response in 2 of them. Corticosteroid and/or immunosuppressive treatment enhanced HCV viral load in all cases, however a histological improvement was observed in every case in which a control biopsy has been performed (3 cases). CONCLUSION: This study highlights the deciding contribution of the initial histological findings in the diagnosis of such a HCV/autoimmune hepatitis overlap syndrome; it also demonstrates that histological outcome is not necessarily compromised by corticosteroid and/or immunosuppressive treatment.     

IFN-alpha-induced psoriatic arthritis and HCV-related liver cirrhosis. Therapeutic options and patient's opinion

Hepatitis C virus (HCV) infection in the setting of Psoriatic Arthritis is an additional variable to be considered in the therapeutic approach to the disease because of the complications of an immunosuppressive treatment in the course of a chronic infection and the possible hepatotoxicity of many drugs conventionally used to treat psoriatic arthritis. The case reported explores the therapeutic options in a patient with IFN-alpha-induced psoriatic arthritis, characterised by severe arthritis and psoriasis but also the concomitant presence of HCV chronic hepatitis, in light of the patient's concerns.     

Rituximab for the treatment of glomerulonephritis in hepatitis C associated cryoglobulinaemia

Mixed-type cryoglobulins are strongly associated with hepatitis C virus (HCV) infection and may lead to vasculitis with renal involvement. The treatment of this condition is antiviral therapy for HCV, but this may be ineffective or not tolerated because of side effects. Alternative strategies such as immunosuppressive drugs and plasmapheresis are of limited use, especially in patients after liver transplantation (LTx). We describe an LTx patient with cryoglobulinaemia-associated glomerulonephritis, who was treated successfully with the B cell depleting monoclonal antibody rituximab.     

Management of psoriasis patients with hepatitis B or hepatitis C virus infection

The systemic therapies available for the management of Psoriasis(PsO) patients who cannot be treated with more conservative options, such as topical agents and/or phototherapy, with the exception of acitretin, can worsen or reactivate a chronic infection. Therefore, before administering immunosuppressive therapies with either conventional disease-modifying drugs(c DMARDs) or biological ones(b DMARDs) it is mandatory to screen patients for some infections, including hepatitis B virus(HBV) and hepatitis C virus(HCV). In particular, the patients eligible to receive an immunosuppressive drug must be screened for the following markers: antibody to hepatitis B core, antibody to hepatitis B surface antigen(anti-HBs Ag), HBs Ag, and antibody to HCV(anti-HCV). In case HBV or HCV infection is diagnosed, a close collaboration with a consultant hepatologist is needed before and during an immunosuppressive therapy. Concerning therapy with immunosuppressive drugs in PsO patients with HBV or HCV infection, data exist mainly for cyclosporine a(Cy A) or b DMARDs(etanercept, adalimumab, infliximab, ustekinumab). The natural history of HBV and HCV infection differs significantly as well as the effect of immunosuppression on the aforementioned infectious diseases. As a rule, in the case of active HBV infection, systemic immunosuppressive antipsoriatic therapies must be deferred until the infection is controlled with an adequate antiviral treatment. Inactive carriers need to receive antiviral prophylaxis 2-4 wk before starting immunosuppressive therapy, to be continued after 6-12 mo from its suspension. Due to the risk of HBV reactivation, these patients should be monitored monthly for the first 3 mo and then every 3 mo for HBV DNA load together with transaminases levels. Concerning the patients who are occult HBV carriers, the risk of HBV reactivation is very low. Therefore, these patients generally do not need antiviral prophylaxis and the sera HBs Ag and transaminases dosing can be monitored every 3 mo. Concerning PsO patients with chronic HCV infection their management with immunosuppressive drugs is less problematic as compared to those infected by HBV.In fact, HCV reactivation is an extremely rare event after administration of drugs such as CyA or tumor necrosis factor-α inhibitors. As a rule, these patients can be monitored measuring HCV RNA load, and ALT, aspartate transaminase, gamma-glutamyl-transferase, bilirubin, alkaline phosphatase, albumin and platelet every 3-6 mo. The present article provides an updated overview based on more recently reported data on monitoring and managing PsO patients who need systemic antipsoriatic treatment and have HBV or HCV infection as comorbidity.     

Recurrent hepatitis C after liver transplantation: clinical and therapeutical issues

Hepatitis C virus (HCV) reinfection after liver transplantation is almost constant, assessed by the persistence of HCV RNA in 90% of cases. Acute hepatitis appeared in 75% of patients at a median of 4 months' post-transplantation. The 5-year actuarial rate of acute and chronic hepatitis on the graft is 75% and 60%, respectively. The rate of HCV cirrhosis on the graft is variable from 8 to 25% at 5 years. After transplantation, HCV viraemia is dramatically increased and correlates with the occurrence of acute hepatitis on the graft. Intrahepatic levels of HCV are high at the time of acute hepatitis, and decrease with constitution of chronic graft hepatitis lesions, implying an immunological response to the viral infection. A relationship between genotype 1b and the prevalence of HCV hepatitis on the graft has been suggested in European but not American series. The influence of the age of the recipient, quasispecies, viral compartmentalization, immunosuppressive treatment, and of HLA matching is being evaluated. The 5-year patient survival is around 65-80%. However, the occurrence of cirrhosis with a risk of graft failure may decrease the 10 and 15-year patient survival. Attempts to give prophylactic post-transplant antiviral treatment are under evaluation. Antiviral treatment of post-transplant graft lesions with combination therapy interferon–ribavirin gave promising results but indications and duration of treatment should be evaluated.
In conclusion, HCV reinfection is frequent, but medium-term survival is good. However, the long-term graft and patient survival remains unknown, and efficient prevention and treatment of HCV graft is mandatory.     

Resolution of chronic hepatitis C following parasitosis

An inefficient cellular immune response likely leads to chronic hepatitis C virus （HCV） infection. Resolution of chronic HCV infection in the absence of treatment is a rare occurrence. We report the case of a 39-year old white male with a 17-year history of chronic HCV infection, who eradicated HCV following a serious illness due to co-infection with Babesia （babesiosis）, Borriela Borgdorferi （Lyme disease） and Ehrlichia （human granulocytic ehrlichiosis）. We hypothesize that the cellular immune response mounted by this patient in response to his infection with all three agents but in particular Babesia was sufficient to eradicate HCV.     

Hepatitis C virus infection prevalence and liver dysfunction in a cohort of B-cell non-Hodgkin's lymphoma patients treated with immunochemotherapy

Several studies have reported a higher prevalence of hepatitis C virus (HCV) infection in patients with B-cell non-Hodgkin's lymphoma (NHL) than in the general population. Treatment for NHL includes the use of chemotherapeutic agents such as cytotoxic drugs, corticosteroids, and rituximab, which can be immunosuppressive and hepatotoxic. While reactivation of hepatitis B virus (HBV) when undergoing immunosuppressive therapy for haematological malignancies is a well-documented complication, data on HCV reactivation or liver function impairment after chemotherapy for NHL are controversial. From January 2006 to December 2009, 207 consecutive NHL patients treated with chemotherapy without rituximab (CHOP) or with rituximab (R-CHOP) were observed; screening for HCV infection and baseline liver function tests were performed in all patients. The prevalence of HCV infection was 9.2%. This prevalence is higher than that observed in the general population in Italy (3%). Among the HCV-infected subjects, the incidence of hepatitis flares was 26.3% vs 2.1% among the HCV-uninfected individuals. Although less frequent and less severe than in HBV-infected subjects, liver dysfunction can occur as a consequence of rituximab-containing regimens in HCV-infected patients with NHL. In the cases considered in this study, no patient treated with chemotherapy without rituximab developed hepatitis flares. The frequency and the severity of this complication vary in different reports. Therefore, we recommend the assessment of liver function and the screening of all patients with NHL for HCV infection before starting chemotherapy; we also recommend monitoring of liver function tests and HCV-RNA serum levels during treatment.     

Anti-Hepatitis C Virus Serology in Immune Thrombocytopenia: A Retrospective Analysis in 101 Patients

Hepatitis C virus (HCV), an RNA virus, is known to be the major cause of post-transfusion non-A, non-B hepatitis. HCV can induce several expressions of autoimmunity, including both serological abnormalities and clinical disorders. The relationship between the HCV infection and anti-platelet autoimmunity has been occasionally described, but is still far from well-defined. We retrospectively analysed 101 serum specimens, collected between 1988 and 1994, from patients with immune thrombocytopenia (ITP) for the presence of anti-HCV antibodies. Eighty-seven patients were classified as having idiopathic, and 14 secondary ITP (4 systemic lupus erythematosus, 9 non-Hodgkin's lymphoma and 1 Evan's syndrome).

Anti-HCV antibodies were determined by second generation tests (ELISA + RIBA). A specimen was considered positive for HCV antibodies in the presence of ELISA reactivity (sample optical density/cut-off > 1.00) accompanied by RIBA reactivity to at least one HCV specific antigen. 20 sera (20%) were positive, with a prevalence higher in secondary than in idiopathic ITP (43% vs. 16%, p < 0.05). No differences were found between anti-HCV positive and negative patients regarding gender, platelet count, platelet associated immunoglobulins, hepatitis B virus serology and liver enzyme profile. On the contrary, mean age was higher in the HCV positive vs HCV negative ones (58±18SD vs. 44±20yrs, p < 0.01), in keeping with the increasing prevalence of HCV infection with ageing. HCV positive patients, showed a poor response to treatment (platelet count lower than 50,000/μl after conventional medical therapy for immune thrombocytopenia) compared to anti-HCV negative ones, (50% versus 7.3%, p < 0.001). When we excluded patients who were exposed to risk factors for HCV infection after ITP diagnosis and before the serum collection, the prevalence of anti-HCV antibodies was not very different (17.6%) from that found in the series as a whole (19.8%). Our results seem to indicate that HCV infection may play a role in triggering several cases ITP, and moreover might constitute a negative prognostic factor for therapy response.     

Recurrence of HCV infection in a sustained responder after chemotherapy for non-Hodgkin's lymphoma: successful retreatment

It is known that sustained virological response (SVR) in patients with chronic hepatitis C is associated with sustained elimination of hepatitis C virus (HCV) and that late relapse after SVR in HCV patients is doubtful. A 47-year-old man with chronic hepatitis C genotype 3, achieved SVR after combination treatment with pegylated interferon and ribavirine for 6 months. Sixteen months later non-Hodgkin's lymphoma was diagnosed. After successful completion of chemotherapy for non-Hodgkin's lymphoma, he presented with HCV infection recurrence of the same genotype. Retreatment with the same schedule resulted in normalization of aminotransferases and disappearance of HCVRNA from the serum. This case suggests that recurrence of HCV infection in a sustained responder may be probable after immunosuppressive therapy. Prevention is currently impossible but retreatment may be successful.     

Chronic graft-versus-host disease complicated by acute hepatitis B

We observed a 45-year-old man with acute hepatitis B while receiving treatment of chronic graft-versus-host disease (GVHD) of the liver. When he developed a sudden elevation of serum aminotransferases 17 months after bone marrow transplantation, he was under immunosuppressive therapy consisting of cyclosporin A against chronic GVHD of the liver. Serologic tests for hepatitis B virus (HBV) showed no reactivation but de novo acute infection. The serum levels of aminotransferases after elevation of biliary tract enzymes increased mildly. However, icterus was not observed in his sequential course. A liver biopsy specimen revealed mild acute liver injury accompanied by slight degeneration of bile ducts. It is presumed that owing to immunosuppressive therapy, his liver dysfunction was relatively mild, and the hepatitis became quiescent without becoming serious. On the other hand, the serum of the patient remained hepatitis B surface antigen positive for more than 1 year after the onset of the hepatitis, which suggested chronicity of HBV infection.     

De novo hepatitis B virus infection in hepatocellular carcinoma following eradication of hepatitis C virus by interferon therapy

Epidemiological studies have revealed that hepatocellular carcinoma (HCC) is still observed in hepatitis C virus (HCV)‐positive patients with a sustained response to interferon (IFN) treatment, although a substantial decrease in the incidence of hepatocellular carcinoma (HCC) has been achieved in those patients. Why HCC develops in patients who have a complete clearance of HCV remains unclear. Here, we provided evidence of latent hepatitis B virus (HBV) infection in an initially HCV‐positive chronic hepatitis patient who developed HCC after the complete eradication of HCV by IFN therapy. Although he was initially negative for anti‐hepatitis B surface antigen (HBsAg) or circulating HBV DNA but positive for anti‐hepatitis B core antigen (anti‐HBc) in his sera, he developed HBsAg and HBV DNA during the course of the management of a series of cancers. HBV DNA was detectable in the liver tissues before HBV reactivation and the viral sequences derived from his anti‐HBc‐positive liver showed 100% homology to that from the serum after HBsAg appearance. These findings indicates that HCV‐positive individuals who are positive for anti‐HBc in the absence of HBsAg could have latent HBV infection in their liver tissues and intrahepatic HBV infection may play a pivotal role in the development of HCC after the IFN‐mediated eradication of HCV.     

Successful treatment of myelodysplastic syndrome and chronic hepatitis C using combined peginterferon‐α‐2b and ribavirin therapy

We report a patient with myelodysplastic syndrome (MDS) and hepatitis C virus (HCV) infection who was successfully treated with a combination of peginterferon and ribavirin therapy. A 65‐year‐old man was referred to our hospital for treatment of chronic hepatitis C and close examination of pancytopenia. MDS of “refractory cytopenia with multilineage dysplasia” was diagnosed on the basis of bone marrow findings. Although the patient was not a good candidate for interferon (IFN) therapy because of his pancytopenia, we decided to proceed with IFN therapy for the following reasons: his elevated transaminases could not be controlled; he had a high possibility of recovery from chronic hepatitis C in consideration of his HCV genotype 2a and relatively low RNA titer; and his pancytopenia was expected to worsen in the future. After combination peginterferon/ribavirin therapy, the patient achieved sustained viral response, and the bone marrow findings showed neutrophils with normal granulation and megakaryocytes with normal morphological features. Additionally, the normal 46, XY karyotype converted from 45, X0 which was found before IFN therapy. This suggested that the patient's MDS was completely resolved.