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ABSTRACT: Recovery from hepatitis B virus (HBV) infection is associated with the presence of antibodies against HBV surface (HBs) antigen and HBV core (HBc) antigen. However, anti-HBs antibodies are lost in many cases, and only anti-HBc antibodies persist. A higher frequency of the anti-HBc-alone pattern has been demonstrated for anti-hepatitis C virus (HCV)-positive patients. In this report, 1126 anti-HCV-positive/anti-HBc-positive patients were studied, and the role of HCV replication in influencing the presence or absence of anti-HBs antibodies was investigated. The anti-HBc-alone phenotype was significantly more frequent in HCV-viraemic than in HCV-recovered patients. This finding represents new information regarding the immunopathogenesis of chronic HCV infection and supports previous data indicating impaired humoral immune responses in HCV infection.
Clinical Microbiology and Infection 02/2004; 10(1):70-2. · 4.54 Impact Factor
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ABSTRACT: Interferon alpha (IFN-alpha) therapy for chronic hepatitis C may trigger induction of autoimmunity against several organs. Immune reactions against distinct adrenocortical protein antigens involved in adrenal autoimmune disease have not been reported to date. Therefore, we investigated the development of highly sensitive and specific adrenal autoantibodies in patients with chronic hepatitis C in response to IFN-alpha treatment. In addition, we studied induction of pancreatic islet and thyroid autoantibodies.
Sera of 75 patients (42 males, 33 females; mean age 47 (13) years) were analysed before, during, and after IFN-alpha therapy (9-18x10(6) IE/week; mean duration 8.3 (3.5) months). Autoantibodies (Abs) to adrenal 21-hydroxylase (21OH-Abs), and to islet glutamic acid decarboxylase (GAD65-Abs) and protein tyrosine phosphatase (IA2-Abs) were determined by a radiobinding assay using (35)S labelled protein generated by an in vitro translation system. Thyroid antibodies were measured by a commercially available ELISA.
Thirteen of 75 patients were initially positive for some of the autoantibodies. During or after IFN-alpha therapy, 3/62 initially negative patients (4.8%) developed 21OH-Abs. GAD65-Abs or IA2-Abs appeared in 5/62 and 1/62 patients, respectively (9.7% in total). In 12/62 patients (19.4%), thyroid specific antibodies appeared. In none of the 21OH-Ab positive subjects was adrenal dysfunction observed, and no patient with islet autoantibodies developed diabetes mellitus or impaired glucose tolerance.
IFN-alpha induces 21OH-Abs in some cases, while islet and thyroid specific autoantibodies are more frequently found. However, our results indicate for the first time that the adrenal cortex also has to be considered as a potential target of IFN-alpha related autoimmunity.
Gut 04/2001; 48(3):378-83. · 10.11 Impact Factor
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ABSTRACT: Cytochrome P450 2D6 (CYP2D6) has been documented as the major target antigen of liver kidney microsomal autoantibodies type-1 (anti-LKM-1) in both autoimmune hepatitis type-2 (AIH-2) and hepatitis C (HCV). In HCV/anti-LKM-1-positive patients, the choice between alpha-interferon (alpha-IFN) or immunosuppression may be difficult. This study was conducted to evaluate the course and outcome of alpha-IFN therapy in HCV/anti-LKM-1-positive and -negative patients and the alterations in these autoantibody titers by the indirect immunofluorescence and a novel radioligand assay. Epitope mapping was also performed to screen for a potential shift in anti-LKM-1 binding towards small linear epitopes, which are more often detected in AIH-2 patients.
Twenty-one patients with HCV infection received alpha-IFN. Seven patients were anti-LKM-1 positive (study group) and 14 patients were anti-LKM-1 negative (disease control group). Anti-CYP2D6 detection was based on immunoprecipitation of [35S]-methionine-labeled CYP2D6 recombinant protein (rCYP2D6) produced by in vitro transcription/translation.
Four out of seven (57%) patients in the study group and 5/14 (36%) in the disease control group initially responded, but subsequently relapsed. During follow-up, alanine aminotransferase significantly increased in the study group compared to the disease control group (p<0.01). A slight increase, followed by a plateau of autoantibody titers was recorded by the radioligand assay and by indirect immunofluorescence during therapy and follow-up in most cases. In one patient, however, gamma-globulins and anti-LKM-1 titers increased, reaching very high levels (1:40 960). alpha-IFN was interrupted and immunosuppression was started. HCV/anti-CYP2D6 positive sera recognized CYP2D6 expressed in E. coli and two truncated proteins (aa 250-494 and 321-494). Two out of seven sera, in addition reacted with a small linear epitope of aa 257-269 (one of which also reacted with a C-terminal domain of aa 350-494).
A rather mild deterioration in liver disease was observed in only 1/7 HCV/anti-LKM-1-positive patients during alpha-IFN treatment. This patient showed high anti-CYP2D6 titers before the initiation of therapy, a sharp increase in anti-LKM-1 titers during treatment, and reactivities to a small linear epitope and an infrequently recognized C-terminal domain of CYP2D6. After switching to immunosuppressive treatment, a complete and sustained response was recorded. Further prospective studies from many centers are needed to define whether these features have general, clinical significance or not.
Journal of Hepatology 03/1999; 30(3):366-75. · 9.26 Impact Factor
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ABSTRACT: Combination therapy of chronic hepatitis C with interferon alpha and ribavirin has been proven to be highly effective in naive and relapse patients with two to ten-fold increase of the response rate. However, combination therapy of primary non-responders to interferon alpha is discussed controversially. Therefore, to analyze the response rate to retreatment with a combination therapy with interferon alpha and ribavirin, we compared data of 555 patients described in 23 publications to the data of 16 non-responders treated in our center. The patients received interferon alpha (at least 3 MU tiw) and ribavirin in a dose of 1,000/1,200 mg per day. At the end of treatment 14% of our patients had normal ALT values and were HCV-RNA-negative compared to 34% of all patients described in the literature. In our patients the viral load decreased from 1,110 +/- 670 x 10(3) copies/ml prior to therapy to 300 +/- 480 x 10(3) copies/ml at the end of treatment (p = 0.002). After a follow-up period of six months quantitative RNA-levels rose again to 1,485 +/- 755 x 10(3) copies/ml. Whereas only 7.4% (24/325) of all patients described showed a response with normal ALT values and negative HCV-RNA at the end of follow-up, no sustained response was observed in our patients. In contrast to naive and relapse patients, the response rate of combination therapy in patients previously not responding to interferon alpha alone is only low. Thus, standard regime (IFN 3MU twi plus ribavirin for six months) as a regular therapy for non-responders is not recommended.
Zeitschrift für Gastroenterologie 10/1998; 36(9):819-27. · 0.90 Impact Factor
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ABSTRACT: Recently it was shown that perihepatic lymphadenopathy (PHL) correlates with histological activity in chronic hepatitis C. However, the question whether there is a correlation between the response to interferon alpha and PHL has not yet been raised.
We examined 103 patients who had been treated with interferon alpha for hepatitis C. Prior to treatment all patients had undergone high resolution ultrasonography. Thirty-six patients had follow up ultrasound scans during the course of the treatment. According to size and number of lymph nodes we introduced a grading of the PHL and determined grade I as minimal, grade II as medium and grade III as extensive PHL.
Classification of PHL prior to treatment revealed 40 patients with PHL I, 30 with grade II and 33 with grade III. Hepatic inflammatory activity according to the Ishak score was increased in patients with PHL III (9.1+/-2.4) compared to PHL II (6.7+/-2.9) and PHL I (7.3+/-3.1) (p=0.01). In patients with PHL grade I prior to treatment 45% were initial responder, patients with grade II or III showed response rates of 40% and 33%, respectively. During therapy we found an increase of PHL in one out of 13 primary responder vs. 10 out of 23 non-responder (p=0.03).
In conclusion, monitoring of PHL by abdominal ultrasonography is a simple, non-invasive and cheap additional marker of response to interferon alpha.
Hepato-gastroenterology 45(22):1062-8. · 0.66 Impact Factor
