F Polzien

Universitätsmedizin Göttingen, Göttingen, Lower Saxony, Germany

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Publications (7)43.07 Total impact

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    ABSTRACT: Mixed cryoglobulinemia is frequently associated with chronic hepatitis C virus infection. We aimed to clarify the mechanism, kinetics and participating proteins in cryoprecipitate formation, which are still being debated. Eighteen patients with cryoglobulinemia were studied. Isolated serum cryoprecipitates and purified cryoglobulin IgM and IgG fractions were analyzed in vitro by turbidimetry for temperature-dependent complex formation. Immunoglobulin reactivity, i.e. in cryoprecipitates and in cryoglobulin-free sera, was studied using immunoblot and enzyme immunoassays. HCV RNA was detected by reverse transcriptase/polymerase chain reaction. By turbidimetry, purified cryo-IgM precipitated (in the absence of HCV RNA) with cryo-IgG as well as with non-cryoglobulin IgG and with IgG Fc or F(ab')2 fragments. In contrast, purified cryo-IgG did not precipitate with non-cryoglobulin IgM. Anti-HCV IgG reactivity was found in cryoglobulin-free sera, in cryoprecipitates and in purified cryoglobulin IgG fractions. The respective titers were similar. Purified cryo-IgM did not react to HCV-encoded proteins. Binding of cryo-IgM to heterologous IgG was inhibited by intact IgG (up to a mean of about 52%) as well as by IgG Fc (33%) and F(ab')2 fragments (17%). Binding of cryo-IgM to IgG was enhanced at low temperature (4 degrees C vs. 37 degrees C), particularly for type III cryoglobulin IgM. In hepatitis C virus-associated cryoglobulinemia the in vitro precipitate formation depended on cryo-IgM, while IgG appeared to act as an unspecific antigenic partner. Hepatitis C viral particles were probably not required. Cryo-IgM binding occurred primarily to intact IgG. Anti-HCV reactivity of either cryo-IgM or cryo-IgG was not necessary for precipitate formation. Regarding the pathogenesis, a direct hepatitis C virus protein-dependent stimulation of B-cells producing cryo-IgM seems to be unlikely.
    Journal of Hepatology 01/1998; 28(1):17-26. · 9.86 Impact Factor
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    ABSTRACT: Chronic hepatitis C virus infection is frequently associated with mixed cryoglobulinemia. The efficacy of interferon-alpha treatment in the presence of cryoglobulinemia, particularly the rate of sustained responders, has not yet been well defined. Fifty-nine consecutive patients with chronic HCV infection were studied prospectively with regard to the presence of cryoglobulinemia and their biochemical and virological response to interferon-alpha2a therapy. Cryoglobulins were detected in sera of 23 patients. For this latter group of patients, significant differences were found compared to the 36 patients without cryoglobulinemia, i.e. the prevalence of female sex was higher, the duration of liver disease was longer and distinctive laboratory abnormalities, e.g. higher rheumatoid factor activity, were noted as well as a higher prevalence of cirrhosis. The distribution of HCV genotypes and serum HCV RNA titers was similar in the two groups. Interferon-alpha treatment regimens were not different regarding mean cumulative dose and mean duration of therapy. The response to therapy was almost identical, i.e. 35% of patients with cryoglobulinemia showed a sustained response compared to 22% of patients without cryoglobulinemia. The percentages of patients showing a relapse or breakthrough were similar in both groups. Pre-treatment viremia levels were higher in non-responders compared to sustained responders. Non-responders appeared to be more frequent among patients infected with genotypes 1a and 1b, especially among male patients without cryoglobulinemia. The presence of cryoglobulinemia per se in chronic HCV-infected patients does not adversely affect the outcome of interferon-alpha therapy, including the rate of sustained response.
    Journal of Hepatology 08/1997; 27(1):63-71. · 9.86 Impact Factor
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    ABSTRACT: Background/Aims: Chronic hepatitis C virus infection is frequently associated with mixed cryoglobulinemia. The efficacy of interferon-α treatment in the presence of cryoglobulinemia, particularly the rate of sustained responders, has not yet been well defined.Methods: Fifty-nine consecutive patients with chronic HCV infection were studied prospectively with regard to the presence of cryoglobulinemia and their biochemical and virological response to interferon-α2a therapy.Results: Cryoglobulins were detected in sera of 23 patients. For this latter group of patients, significant differences were found compared to the 36 patients without cryoglobulinemia, i.e. the prevalence of female sex was higher, the duration of liver disease was longer and distinctive laboratory abnormalities, e.g. higher rheumatoid factor activity, were noted as well as a higher prevalence of cirrhosis. The distribution of HCV genotypes and serum HCV RNA titers was similar in the two groups. Interferon-α treatment regimens were not different regarding mean cumulative dose and mean duration of therapy. The response to therapy was almost identical, i.e. 35% of patients with cryoglobulinemia showed a sustained response compared to 22% of patients without cryoglobulinemia. The percentages of patients showing a relapse or breakthrough were similar in both groups. Pre-treatment viremia levels were higher in non-responders compared to sustained responders. Non-responders appeared to be more frequent among patients infected with genotypes 1a and 1b, especially among male patients without cryoglobulinemia.Conclusions: The presence of cryoglobulinemia per se in chronic HCV-infected patients does not adversely affect the outcome of interferon-α therapy, including the rate of sustained response.
    Journal of Hepatology - J HEPATOL. 01/1997; 27(1):63-71.
  • F Polzien, G Ramadori
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    ABSTRACT: Increase of serum levels of the soluble intercellular adhesion molecules in patients with the cholestatic liver diseases primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are known and have been thought to indicate activation of the immune system and the grade of the inflammatory process. In hepatitis and cholestatic diseases, expression of adhesion molecules was found on the surface of bile duct epithelia and hepatocytes. Serum levels of sICAM-1 in patients with intrahepatic cholestasis in PBC (n = 42) and extrahepatic cholestasis (n = 18) due to choledocholithiasis were investigated. sICAM-1 levels and "classical" cholestasis parameters as alkaline phosphatase (ALP), gamma-glutamyl-transpeptidase (gamma-GTP) and bilirubin levels were compared. Furthermore, sICAM-1 concentrations and "classical" cholestasis parameters were analysed before and after therapy with ursodeoxycholic acid (UDCA). In addition, sICAM-1 was detected in serum and bile fluid of four patients with cholestasis due to choledocholithiasis. Soluble ICAM-1 levels in sera and, if accessible, in bile fluids were determined using a commercially available ELISA system. Statistics were done by Wilcoxon's signed rank exact test and Spearman's rank correlation test. Sensitivity and specificity of cholestasis parameters and sICAM-1 concentrations was analysed by receiver operating characteristic (ROC) curves. Increased sICAM-1 serum concentrations in a similar range were found in patients with PBC (range 251-2620 micrograms/l; median 966 micrograms/l) as well as in patients with extrahepatic cholestasis (257-2961 micrograms/l; median 760 micrograms/l) compared to healthy controls (n = 12; 220-500 micrograms/l; median 318 micrograms/l). sICAM-1 levels correlated significantly to histological stage I to IV (p < 0.001), ALP (range 107-1877 U/l; median 545 U/l; r = 0.496, p = 0.0008), bilirubin (range 0.3-26 mg/dl; median 0.8 mg/dl; r = 0.52; p < 0.0004) and gamma-GTP levels (range 43-705 U/l; median 221 U/l; r = 0.36; p = 0.02) in PBC patients. In PBC patients a histological stage III or IV (n = 21) could be predicted with high sensitivity (95%) and specificity (85%) if sICAM-1 levels were above 840 micrograms/l. After treatment of PBC patients with UDCA, sICAM-1 levels decreased significantly with decline of other "classical" cholestasis parameters. Increased sICAM-1 levels (range 257-2961, median 745 micrograms/l) in extrahepatic cholestasis correlated also significantly with serum concentrations of bilirubin (r = 0.8; p < 0.01; range 0.3-19.7, median 1.6 mg/dl), gamma-GTP (r = 0.55; p = 0.03; range 33-1401, median 179 U/l) and ALP (r = 0.61; p = 0.1; range 110-1378, median 562 U/l). sICAM-1 was detectable in bile fluid (264-919 micrograms/l) of four patients with extrahepatic cholestasis and nose-biliary catheterisation. sICAM-1 concentrations were found to discriminate between histological stage I/II and stage III/IV of PBC with higher sensitivity and specificity than "classical" cholestasis parameters. Increased serum concentrations for sICAM-1 in intra- and in extrahepatic cholestasis and detection of sICAM-1 in the bile may indicate that sICAM-1 is eliminated through the bile. In other words, not only increased synthesis but also decreased elimination may be responsible for increased sICAM-1 serum levels in patients with cholestatic liver diseases.
    Journal of Hepatology 12/1996; 25(6):877-86. · 9.86 Impact Factor
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    ABSTRACT: Liver/kidney microsomal antibodies have been noted in liver disease of different etiology, e.g. in autoimmune hepatitis, chronic hepatitis C and D virus infection and in drug-induced liver disease. Unlike these, acute hepatitis of unknown etiology associated with high-titer liver/kidney microsomal-1 antibodies (cytochrome P450 2D6) is reported in identical twin brothers. Patients were studied using clinical, biochemical, serological and immunological methods, as well as liver biopsy. The acute icteric episodes were followed by spontaneous remission with complete normalization of liver function tests and liver histology. During the acute phase, serum titer for liver/kidney microsomal-1 antibodies (detected by indirect immunofluorescence, ELISA and Western blot analysis) was exceedingly high and decreased gradually thereafter. Hepatitis C and D virus infection were excluded by repeated serological testing; exposure to drugs or chemicals was not evident. Concomitant autoimmune disease was not detectable. HLA typing for class 1 and 2 antigens was positive for the HLA haplotype DQ2, but negative for HLA B4, B8, DR3 and DR4. The present observations might suggest a hitherto unreported form of acute hepatitis of unknown etiology, distinct from other liver diseases in which liver/kidney microsomal antibodies have been described so far.
    Journal of Hepatology 01/1996; 23(6):734-9. · 9.86 Impact Factor
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    ABSTRACT: Chronic hepatitis C virus infection can be associated with mixed cryoglobulinemia and systemic vasculitis. The pathogenesis remains poorly understood. 55 consecutive patients with chronic HCI infection (anti-HCV- and serum HCV RNA-positive) were studies prospectively. Cryoglobulinemia was detected in 28 patients (51%) with a mean cryocrit level of 2.2%. Clinical symptoms of vasculitis were encountered in six patients. Compared to those HCV-infected patients without cryoglobulinemia the following distinctive features were observed in the presence of cryoglobulinemia: increased age (p<0.02), female preponderance (p<0.002), longer-lasting HCV infection (mean of 10.7 vs. 4.7 yrs), higher prevalence of cirrhosis (42.8 vs. 0%), increased serum concentration of IgM and increased rheumatoid factor activity, decreased concentration of serum C4 (each p<0.05). The response to interferon treatment was similar in patients with and without cryoglobulinemia. When cryoprecipitates were analyzed by immunofixation, type II cryoglobulinemia was present in 1/3 and type III in 2/3 of patients. By SDS-PAGE four different proteins were demonstrable in cryoprecipitates each identified by immunoblotting as IgG and IgM heavy or light chains respectively. Cryoprecipitate IgGs were shown to react with HCV structural as well a non-structural proteins in a recombinant immunoblotting assay (RIBA). In contrast, cryoprecipitate IgMs reacted only to the HCV core protein c22-3. HCV RNA was detected in cryoprecipitates without a significant enrichment when compared to the corresponding serum or supernatant HCV RNA content. Given the monoclonality of some cryoprecipitate IgM and their reactivity to HCV core, a cross-reactivity to IgG was postulated. In fact, when performing a computer-assisted search for sequence homology, a motif within the core protein (EGLGWAGWL, conserved in HCV genotypes) was identified homologous to a sequence of IgG heavy chains. Thus, temperature-dependent affinity changes of IgM anti-HCV core (nonapeptide) and ensuing complex formation with IgG via binding to the homologous IgG sequence could be a mechanism of cryoprecipitate formation.
    Zeitschrift für Gastroenterologie 12/1995; 33(11):643-50. · 1.41 Impact Factor
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    ABSTRACT: The objective of this study was to investigate the effect of gender on monoethylglycinexylidide (MEGX) formation in normal subjects and cadaveric liver donors. The study included 92 male and female healthy volunteers < 45 years of age and 98 age- and sex-matched liver donors from a previous study, whose livers were used for transplantation. Women < 45 years not taking contraceptives showed significantly lower MEGX concentrations 30 min after lidocaine administration than men [median (16-84th percentile)]: 59 micrograms/L (41-70 micrograms/L) versus 81 micrograms/L (58-98 micrograms/L)]. The lowest MEGX 30 min values were observed in women taking contraceptives: 39 micrograms/L (25-48 micrograms/L). Intraindividual variability of serial MEGX tests was moderate (median: 17.8%, n = 8) when measured in female subjects taking no contraceptives and males. Cadaveric liver donors showed significantly higher MEGX 15 and 30 min values compared with normal subjects (p < or = 0.0001). There was no statistically significant difference between MEGX values obtained in male and female cadaveric donors. The urinary excretion of MEGX was similar in male and female normal subjects. Our results suggest that sex-related differences in MEGX formation as well as the influence of contraceptives have to be taken into account when test results from living related liver donors and patients with less advanced chronic liver disease are evaluated. In cadaveric liver donors, however, sex-related differences do not affect MEGX formation.
    Therapeutic Drug Monitoring 06/1994; 16(3):225-31. · 2.23 Impact Factor

Publication Stats

94 Citations
197 Views
43.07 Total Impact Points

Institutions

  • 1996–1998
    • Universitätsmedizin Göttingen
      • • Division of Legal Medicine
      • • Center for Internal Medicine
      Göttingen, Lower Saxony, Germany
  • 1996–1997
    • Georg-August-Universität Göttingen
      Göttingen, Lower Saxony, Germany