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Biomedical subjects

G Gerken

Publications and source records attributed to G Gerken.

At least 163 records · Page 9Linked to original sources
PubMed1995

Liver cirrhosis associated with heterozygous alpha-1-antitrypsin deficiency type Pi MS and autoimmune features.

Patients with homozygous protease inhibitor (Pi) type ZZ or a few rare M-like types may develop liver cirrhosis due to intracellular storage of alpha-antitrypsin (AAT), whereas some patients with heterozygous Pi MZ or SZ normally present with transient abnormal liver function tests in childhood. We report a 42-year-old obese patient who developed liver cirrhosis in association with heterozygous Pi MS (AAT) deficiency. Immunohistological and electron microscope examination showed storage of AAT in the hepatocytes. Interestingly, autoimmune features in this patient suggest that abnormal immune responses may contribute to the pathology of chronic liver disease.

Adult↗
PubMed1995

Parenchymal and nonparenchymal liver cells and their interaction in the local immune response.

Nonparenchymal liver cells (Kupffer cells, sinusoidal endothelial cells, Ito-cells and liver-associated lymphocytes) interact with hepatocytes and with each other by soluble mediators and direct cell-cell contact. The acute phase response is a nonspecific reaction of the organism to trauma, injury or infection and its main constituents the acute phase proteins are produced by hepatocytes. The profile of acute phase protein production is influenced by the local presence of cytokines with IL-6 as the principal regulator. Nonparenchymal cells (Kupffer cells, sinusoidal endothelial cells and Ito-cells) are a source of IL-6 and therefore participate in the generation of acute phase response. The release of IL-10 by Kupffer cells with consecutive down-regulation of IL-6 production may be a mechanism by which resolution of acute phase response is achieved. Still, the mechanisms underlying chronic inflammation remain unclear. Concerning the antigen-specific immune response nonparenchymal liver cells have a number of important functions. They can act as antigen-presenting cells (Kupffer cells) or mediate effector functions (liver associated lymphocytes). Local interaction of nonparenchymal cells with hepatocytes can be mediated by cytokines and/or adhesion molecule expression which again may lead to mutual influence of immunological functions, e.g. TNF-alpha release by Kupffer cells may enhance MHC-II expression on hepatocytes and consequently augment antigen-presenting capacity leading to an improved antigen-specific immune response. Leukocytes are attracted and home to the liver by mechanisms poorly defined because the initial contact between leukocytes and macrovascular endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute-Phase Reaction↗
PubMed1995

Interferon-alpha retreatment in chronic hepatitis C.

For chronic hepatitis C virus (HCV) infection, interferon-alpha (IFN-alpha) treatment has recently been established. However, the complete responding rate is not higher than 20-25%. The aim of our study was to assess IFN-alpha retreatment in chronic hepatitis C. In summary, during a second cycle of IFN-alpha, 60% of the patients responded to the retreatment. Indeed, a sustained complete response, together with long-lasting normal alanine aminotransferase values and negative serum HCV-RNA, was observed in about 40% of the retreated patients. Future prospective and controlled trials must define the optimal retreatment strategy, as well as the response-predicting factors including HCV genotypes and quantitative HCV-RNA levels.

Adult↗
PubMed1995

The role of autoimmunity in hepatitis C infection.

Viral infections are considered a possible trigger of autoimmune diseases. In autoimmune liver diseases the hepatotropic viruses, especially hepatitis C virus (HCV), have received particular attention as possible etiological agents. The present study was undertaken to investigate the relation between hepatitis virus infections and autoimmune liver diseases. We found a very low incidence of HCV infection in patients with autoimmune liver diseases. Only 5% (n = 7) of patients with AIH types I and III had antibodies against HCV antigens, but only two of these seven were HCV-RNA positive. Similar results were obtained in patients with PBC and PSC. Furthermore, the coexistence of LKM autoantibodies with chronic HC is a rare event and less common than low-titer ANA and SMA in viral liver diseases. In conclusion, a link between hepatitis viruses B or C and AI-liver diseases is very unlikely. Autoantibodies in viral liver diseases appear to be an expression of a generalized immune activation by cytokines, as observed during interferon treatment in viral liver diseases.

Autoantibodies↗
PubMed1995

Focal lymphocytic aggregates in chronic hepatitis C: occurrence, immunohistochemical characterization, and relation to markers of autoimmunity.

Intrahepatic lymphocytic aggregates are observed in chronic hepatitis C as well as in autoimmune chronic hepatitis. Autoantibodies and autoimmune manifestations may occur in hepatitis C. It has been suggested that the lymphocytic aggregates play a role in the liver injury of chronic hepatitis C by an immune-mediated mechanism. We studied the occurrence of intrahepatic lymphocytic aggregates and of autoantibodies in a consecutive series of 128 patients with chronic hepatitis C. For the phenotypic characterization of the lymphocytic aggregates cryostat sections and microwaved paraffin embedded sections were immunostained with monoclonal antibodies directed against T cell subsets, B cells, killer/natural killer cells, follicular dendritic cells, and macrophages. Autoantibodies were tested by immunofluorescence (antinuclear, anti-smooth muscle, antimitochondrial) and by enzyme-linked immunosorbent assay (anti-soluble liver antigen, anti-liver/kidney microsome, anti-human receptor for asialoglycoprotein). Focal lymphocytic aggregates in portal tracts were observed in 76 of 128 (59%) patients. The cellular composition of the aggregates was constant: a core of B cells mixed with many T helper/inducer lymphocytes, and an outer ring was prominently formed by T suppressor/cytotoxic lymphocytes. A germinal center was rarely identifiable. The presence of lymphocytic aggregates was inversely correlated with the degree of fibrosis. Lymphocytic aggregates appeared more frequently in chronic persistent and chronic active hepatitis in comparison with cirrhosis and in the presence of bile duct damage. No correlation was found between lymphocytic aggregates and autoantibodies or other markers of autoimmunity. The lymphocytic aggregates are frequent in chronic hepatitis C. Their cellular composition is similar to that of primary lymphoid follicles in lymph nodes. Their presence does not seem to be correlated with features of autoimmunity.

Adult↗
PubMed1995

Hepatitis B virus superinfection in a patient with chronic hepatitis C receiving alpha-interferon treatment.

We report on a patient with chronic hepatitis C who developed acute hepatitis B during interferon alpha treatment. However, our patient promptly eliminated HBsAg and had a sustained complete response to interferon, even 6 months after the end of treatment. Acute hepatitis B superinfection in patients with chronic hepatitis C is a rarely observed event. The natural course of these patients is unknown. In our case it may be speculated that alpha-interferon treatment contributed to the prompt elimination of HBsAg from the serum.

Acute Disease↗
PubMed1995

[Re-treatment with interferon-alpha in chronic hepatitis B and C virus infection].

The efficacy of interferon-alpha retreatment was assessed in patients with chronic hepatitis B or C, not responding to a first cycle of interferon or reactivating thereafter. 27 patients with chronic hepatitis B and 25 patients with chronic hepatitis C were investigated. After an interval of at least 6 months these patients received an interferon-alpha retreatment in a higher dosage schedule and with a different interferon-alpha subtype. In patients with chronic hepatitis B a loss of serum HBV-DNA was observed in 59% patients after interferon-alpha retreatment. HBeAg seroconversion occurred in 8 of these patients. In chronic hepatitis C 32% of the patients responded completely to the second cycle of interferon-alpha treatment with a normalization of ALT associated with a loss of serum HCV-RNA. A partial response with a marked reduction of ALT was seen in 4 patients. In chronic hepatitis B and C a complete or partial response to the retreatment was closely associated with the response status after the first cycle. Thus, interferon retreatment seems to be effective in patients with chronic hepatitis B or C, especially in the subgroup of patients exhibiting a partial or complete response after the first interferon treatment.

Adult↗
PubMed1995

Analysis of the precore DNA sequence and detection of precore antigen in liver specimens from patients with anti-hepatitis B e-positive chronic hepatitis.

A number of naturally occurring hepatitis B virus (HBV) mutants unable to synthesize the hepatitis B e antigen (HBeAg) have been identified in patients characterized by HBV DNA and anti-HBe in their serum. Because the analysis of the HBV-associated DNA and antigens in the liver tissue is still not complete, we investigated the precore sequence of HBV DNA and its encoded proteins in the liver tissue of 32 patients positive for HBV DNA and anti-HBe in their serum. Three different groups of patients were identified. Group I (n = 14) was characterized by viral DNA sequences with a G-A transition in the distal precore gene region, thus creating a termination codon (TAG). Liver tissue from this group was negative for HBeAg but positive for hepatitis B core antigen (HBcAg) and a peptide containing the last 10 aminoacids of the precore and the first four aminoacids of the c region. Group II (n = 6) showed variable mutations in base sequences further upstream and negative for HBeAg and the precore peptide. Group III (n = 12) contained wild-type HBV DNA sequences in the tissue and positivity for precore- and core-encoded proteins. We conclude from our study that the group of patients with HBV DNA and anti-HBe in the serum is rather heterogeneous, including HBV DNA mutations in the precore region as well as infection with the wild-type virus being negative for HBeAg in the serum. The precore peptide is produced and expressed in the tissue even when the formation of a stop codon at base 1896 prevents the complete translation of the entire HBe protein.

Base Sequence↗
PubMed1995

Relation between autoimmune liver diseases and viral hepatitis: clinical and serological characteristics in 859 patients.

An etiopathological link between hepatitis virus infection and autoimmune liver disease, in particular autoimmune hepatitis has been suggested. In some patients features of both viral and autoimmune disease are present. We have studied 352 patients with autoimmune liver disease and 507 patients with viral hepatitis for diagnostic characteristics as well as for evidence of an etiological connection. 38 of the 201 patients with hepatitis C (19%) and 42 of the 306 patients with hepatitis B (14%) had significant titres of autoantibodies (ANA, SMA or LKM). SLA autoantibodies were found exclusively in patients with autoimmune liver disease. LKM auto-antibody was found in only one of the 201 HCV patients. Evidence of past or present hepatitis B virus and past hepatitis A virus infection was most common in the hepatitis C virus patients and least common in autoimmune hepatitis. 28 of the 352 patients with autoimmune liver diseases tested positive in the second generation anti-HCV ELISA, but only five patients (two with autoimmune hepatitis, one with primary sclerosing cholangitis and two with primary biliary cirrhosis) were positive in confirmatory anti-HCV assays, and only in these could HCV-RNA be isolated. Autoimmune hepatitis patients had significantly higher transaminase, GLDH and IgG levels. HLA-B8, HLA-DR3 and HLA-DR4 were significantly more common in autoimmune hepatitis. Distinction between autoimmune liver disease and viral hepatitis C could be made reliably on clinical and laboratory grounds. Our data show that a link between hepatitis A, B, or C virus infection and autoimmune liver diseases is highly unlikely.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Significance of IgG and IgM HCV antibody secretion in vitro in patients with chronic hepatitis C: correlation with disease activity and response to interferon-alpha.

Hepatitis C virus antibodies are found in the serum of most patients with chronic hepatitis C. However, the significance of the humoral response is still uncertain. In this study, in vitro IgG and IgM anti-hepatitis C virus secretion by peripheral blood mononuclear cells of patients with chronic hepatitis C was analyzed. Peripheral-blood mononuclear cells from 21 of 36 patients (58.3%) secreted IgG anti-hepatitis C virus in vitro, as demonstrated with anti-hepatitis C virus-specific enzyme immunoassays and recombinant immunoblot assays. Ten of the 36 patients (27.8%) showed both IgG and IgM anti-hepatitis C virus core in vitro. In 9 of these 10 patients, IgM anti-hepatitis C virus was also detected in serum. Patients with in vitro IgM or IgG anti-hepatitis C virus secretion had higher ALT levels in serum than did patients without such secretion in vitro (99.5 +/- 22.1 and 85.6 +/- 34.4 vs. 38.1 +/- 37.4 U/L; p < 0.0001, p < 0.001). Furthermore, with a histology activity score it was demonstrated that patients with in vitro IgM or IgG HCV antibodies (or both) had more severe chronic active hepatitis than did patients without in vitro hepatitis C virus antibody secretion (p < 0.01). To analyze the therapy outcome, we included in this study 18 patients who had received interferon-alpha previously. Seven of eight in vitro hepatitis C virus antibody-positive patients were nonresponders, whereas the in vitro hepatitis C virus antibody-negative patients were mostly complete therapy responders (8 of 10).(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1994

Mutation specific PCR and direct solid phase sequencing assay for the detection of hepatitis B virus pre-C/C mutants in anti-HBe-positive, chronic hepatitis B.

Sequence analysis of the HBV DNA from patients with anti-HBe+, chronic hepatitis B revealed that the lack of HBeAg is mostly due to a single G-->A transition at nucleotide position 1896, resulting in a translational stop codon. A point mutation-specific polymerase chain reaction (msPCR) for the detection of this genetic variant was established. Two serologically defined groups of patients with symptomatic chronic hepatitis B (HBeAg+ n = 14, anti-HBe+ n = 11) were included in this study. Viral DNA from 43 sera (26 eAg+/17 anti-HBe+) was amplified twice, using two different sets of PCR primers. Each set contained the same -strand primer, but the +strand primers differed at their 3'-end, thus being complementary only to the wild-type or to the mutant DNA. Unspecific amplification was ruled out by choosing high annealing temperatures (66 degrees C) and cloned HBV-DNA as specificity controls. Furthermore, the results were compared to our findings obtained with direct solid-phase sequencing of the amplified viral DNA. Using msPCR, we found the mutation in four of 26 of the eAg+ sera and in 17 of 17 of our anti-HBe+ samples. Mixed virus populations were identified in 13 of 21 cases. Compared to the sequencing results, msPCR is more sensitive and less time consuming for the detection of the stop codon and thus is suitable as a rapid and specific screening method.

Base Sequence↗
PubMed1994

Mixed cryoglobulinemia type II in chronic hepatitis B associated with HBe-minus HBV mutant: cellular immune reactions and response to interferon treatment.

The case of a young female patient with chronic active hepatitis B, vasculitic purpura, edema, and circulating immune complexes due to mixed cryoglobulinemia is described. Serum transaminases were elevated. Serological assays showed hepatitis B surface antigen (HBsAg), antibody to hepatitis B e antigen (anti-HBe), and antibody to hepatitis B core antigen (anti-HBc) antibodies but no antibody to hepatitis C virus (anti-HCV) or antibody to hepatitis delta virus (anti-HDV) antibodies. Using hepatitis B virus-polymerase chain reaction (HBV-PCR) and direct sequencing a precore/core (preC/C) mutant unable to synthesize HBeAg was detected in serum. HBV antigens were demonstrated in the circulating immune complexes. Following 1 month of treatment with interferon-alpha 2b3 miu three times weekly, alanine aminotransferases returned to normal levels while cryoglobulins and immune complexes disappeared from serum. In addition, 2 months after the onset of treatment serum HBV-DNA was no longer detectable by PCR. Prior to treatment the analysis of cellular immune reactions of peripheral blood mononuclear cells showed a major proliferative response to HBcAg, preS1Ag and HBxAg and a minor response to HBeAg and HBsAg. One month after conclusion of treatment a decline in T-cell reactivity against all HBV antigens was observed. During clinical response to the therapy, however, a strong proliferative response of T cells to HBcAg and HBeAg was demonstrated. In conclusion, immune complex disease may complicate chronic hepatitis B in patients expressing HBe-minus HBV mutants. Treatment with interferon-alpha was found to be effective in mixed cryoglobulinemia even in the presence of HBe-minus HBV mutants.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Sustained elimination of hepatitis B virus from serum induced in a patient with chronic hepatitis B and advanced human immunodeficiency virus infection.

A 48-year-old male patient was admitted with acquired immunodeficiency syndrome (stage III, Centers for Disease Control 1993) and viremic hepatitis B. Blood CD4 count was 15/microliters. Discontinuation of prednisolone, previously prescribed by the patient's family practitioner because of elevated liver enzymes, resulted in severe hepatitis (alanine aminotransferase > 300U/l). Administration of interferon-alpha (9 x 10(6) U s.c. 3 x weekly) was initiated. Serum markers of viral replication disappeared, and aminotransferase levels returned to normal within a few weeks. The patient's serum was found negative for HBsAg after 3 months. Immunohistochemical analysis of liver biopsies before and during interferon therapy showed disappearance of all hepatitis B virus antigens and a marked reduction in inflammatory activity. Hepatitis B virus seroconversion remained stable until the patient died from the syndrome 2 years later. This case shows that in spite of severe HIV-associated immune deficiency with CD4 counts constantly below 100/microliters, interferon-alpha can lead to sustained serological and histological improvement of viremic hepatitis B. Previous administration and discontinuation of cortisone may have helped to reach this effect.

AIDS-Related Opportunistic Infections↗
PubMed1994

In vitro secretion of anti-GOR protein and anti-hepatitis C virus antibodies in patients with chronic hepatitis C.

BACKGROUND/AIMS: Anti-GOR antibodies may reflect hepatitis C virus (HCV)--related autoimmunity or cross-reactivity with HCV core antigen. This study aimed to evaluate the clinical significance of anti-GOR antibodies. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 35 patients with HCV and 48 controls and cultured for 8 days. The in vitro antibody secretion by PBMC was determined using specific enzyme-linked immunosorbent assays and recombinant immunoblot assay. RESULTS: In 22 of 35 patients with HCV (62.9%), PBMCs secreted anti-c22-3 or anti-c33c antibodies. However, in 3 of 48 controls (6.2%), PBMCs secreted anti-c33c antibodies alone. A significant in vitro anti-GOR response was found in 13 of 35 patients (37.1%) with HCV in relation to 4 of 48 controls (8.3%). In 12 of these patients (92.3%), anti-GOR were found in vitro and in serum. Two patients with HCV produced in vitro anti-GOR but not anti-c22-3 antibodies. Regarding disease activity, in vitro anti-GOR-positive patients with HCV had significantly higher alanine aminotransferase levels (108.8 +/- 17.8 U/L vs. 64.5 +/- 7.6 U/L; P < 0.01) and more frequent signs of chronic active hepatitis (10 of 13 [76.9%] vs. 10 of 22 [45.5%]) than patients with HCV without in vitro anti-GOR response. CONCLUSIONS: The humoral anti-GOR response in vitro is closely related to HCV infection and disease activity. Anti-GOR and anti-HCV core antibodies are regulated independently. It is likely that anti-GOR may reflect an HCV-associated autoimmune phenomenon.

Adult↗
PubMed1994

Complete congenital heart block in autoimmune hepatitis (SLA-positive).

Complete congenital heart block is a serious complication of neonatal lupus erythematosus which most often occurs in children of mothers suffering from connective tissue disease. We report the occurrence of complete congenital heart block associated with autoimmune hepatitis (SLA-positive). A 32-year-old woman was treated for more than 10 years for autoimmune hepatitis (SLA-/ANA-positive) and remained in clinical remission under immunosuppressive therapy. She showed an MHC-haplotype typical for autoimmune hepatitis (A1, B8, DR3). After a normal first pregnancy, an emergency caesarean section was performed in the 32nd week of her second pregnancy because of fetal bradycardia. The child died a few hours after delivery of complete congenital AV-block. Retrospective analysis of the maternal serum showed the emergence of SS-A/Ro-antibodies prior to the second pregnancy. The maternal serum antibodies were reactive with the 52 kD SS-A/Ro-antigen, as demonstrated by immunoblot employing recombinant SSA/Ro-antigen. The occurrence of complete congenital heart block has been shown to be associated with the presence of SS-A/Ro antibodies as well as the MHC-haplotype DR3. With respect to this genetic linkage, pregnant patients with autoimmune hepatitis and the MHC-haplotype DR3 should be examined for the presence of SS-A/Ro-antibodies. They should be closely followed during pregnancy to enable early detection of the development of congenital heart block, as prevention by plasmapheresis plus dexamethasone may be possible at an early stage.

Adult↗
PubMed1994

The treatment effect of alpha interferon in chronic hepatitis B is independent of pre-treatment variables. Results based on individual patient data from 10 clinical controlled trials. European Concerted Action on Viral Hepatitis (Eurohep).

Alpha interferon induces HBeAg seroconversion in about one third of treated patients and has become an established treatment of chronic hepatitis B. A number of smaller studies have suggested that response to treatment is more likely to occur in patients with higher levels of transaminases, with recent (adult) onset, a history of acute hepatitis, low levels of HBV DNA and in heterosexual males. The aim of this European co-operative study was to estimate the effect of alpha interferon more accurately and to evaluate the influence of host pre-treatment variables on the effect of interferon. Individual data were collected from 751 patients from 10 controlled clinical trials on alpha interferon (lymphoblastoid or recombinant) treatment for chronic hepatitis B. Alpha interferon was administered to 496 patients, while 255 were untreated controls. Individual patient data were analysed by survival analysis (log rank test and Cox regression analysis), stratified by trial, with the disappearance of HBeAg as the major endpoint. The results showed that the HBeAg disappearance rate with or without interferon treatment was higher in patients with high aminotransferase levels, with a history of acute hepatitis and in male heterosexual patients disregarding HIV status. If HIV-positive patients were excluded, the effect of sexual orientation was not significant. Therapy with alpha interferon increased the a priori HBeAg disappearance rate by a factor of 1.76; the relative treatment effect of alpha interferon was independent of the tested pretreatment host variables, but dependent on the total (intended) interferon dose (low dose < or = 200 MU/m2 increased HBeAg disappearance by a factor 1.37; medium/high dose > or = 200 MU/m2 increased HBeAg disappearance by a factor 2.05). In conclusion, this meta-analysis suggests that the effect of alpha interferon is less than previously assumed and independent of pretreatment host variables tested. It confirms the higher therapeutic benefit of a total dose exceeding 200 MU/m2 and of selection of patients based on disease activity and immune reactivity. Although all patient seem to have the same relative benefit, the absolute benefit of alpha interferon treatment seems to be greatest in patients with high transaminase levels and with a history of acute hepatitis.

Adult↗