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Biomedical subjects

Ansgar W Lohse

Publications and source records attributed to Ansgar W Lohse.

At least 19 recordsLinked to original sources
PubMed2007

Prospective randomized comparison of minilaparoscopy and percutaneous liver biopsy: diagnosis of cirrhosis and complications.

BACKGROUND AND AIMS: Liver cirrhosis represents an advanced stage of hepatic fibrosis characterized by distortion of organ architecture and formation of regenerative nodules. Retrospective series reported percutaneous liver biopsy to miss cirrhosis in about 30%. The aim of this study was to prospectively compare diagnostic sensitivity regarding the detection of cirrhosis and the complication rates of percutaneous versus minilaparoscopic liver biopsy in chronic liver disease. METHODS: Eight hundred fifty-seven patients were randomized to percutaneous (415) or to minilaparoscopic liver biopsy (442). Macroscopic liver evaluation was documented as normal, fibrosis, or cirrhosis. Liver specimens were assessed blindly according to the modified Ishak score. RESULTS: Demographic and clinical data of procedure groups were comparable. Histologic grading alone diagnosed cirrhosis in 22.3% (n=85) of liver specimens obtained by percutaneous route compared with 26.0% (n=98) obtained by minilaparoscopy (P=0.270). By combining macroscopy and histology, minilaparoscopic staging diagnosed a significantly higher rate of liver cirrhoses with 33.8% (n=127) compared with percutaneous route with 22.3% (n=85) (P=0.001). Analysis of minilaparoscopic data revealed that 33 of the 128 cirrhoses were diagnosed by inspection only, suggesting a 26% underestimation of cirrhosis by histology alone. Severe complications occurred in 1.0% (n=4) of percutaneous and in 0.2% (n=1) of minilaparoscopic procedures (P=0.025). CONCLUSIONS: Minilaparoscopic evaluation based upon the combined macroscopic and histologic assessment is more sensitive with regards to the detection of cirrhosis and has a comparable safety profile.

Adult↗
PubMed2006

Genetic association of autoimmune hepatitis and human leucocyte antigen in German patients.

AIM: To report on our large German collective and updated data of 142 patients with autoimmune hepatitis (AIH) type 1. METHODS: Key investigations performed were liver biopsy, serum autoantibodies as well as serum markers such as IgG and elevated transaminases. Antinuclear antigen (ANA) and smooth muscle antigen (SMA) autoantibodies characterized type 1 AIH. Type 3 (AIH) was solely characterized by the occurrence of soluble liver antigen/liver-pancreas antigen (SLA/LP) autoantibodies either with or without ANA or SMA autoantibodies. RESULTS: Most prevalent HLAs were A2 (68 patients, 48%), B8 (63 patients, 44%), C7 (90 patients, 63%), DR3 (49 patients, 38%), DR4 (49 patients, 38%) and DQ2 (42 patients, 30%). Compared to the Italian and North American patients, we found fewer patients with a DQ2 subtype. Furthermore, the B8-DR3-DQ2 human leucocyte antigen (HLA) was also less prominent compared to the North American patients. However, prevalences of B8, DR3, DR4, DR7, DR11 and DR13 were comparable to the Italian and North American patients. Furthermore, we report on an additional subgroup of patients with SLA/LP positive AIH. Generally, in this subgroup of patients the same HLA subtypes were favoured as the AIH type 1. CONCLUSION: Although HLA subtypes were comparable between these three collectives, the German patients were distinct from the Italian and North American patients with respect to DQ2 and from the North American patients with respect to B8-DR3-DQ2 HLA. A clinical correlation, e.g. difference in severity or treatability of AIH type 1, has yet to be determined.

Autoantigens↗
PubMed2006

Five cases of de novo inflammatory bowel disease after orthotopic liver transplantation.

Immunosuppression is currently the treatment of choice for severe inflammatory bowel disease (IBD). Thus, it was anticipated that the course of preexisting IBD should improve after orthotopic liver transplantation (OLT). Despite sufficient allograft immunosuppressive therapy, however, exacerbation of IBD or the development of de novo IBD after OLT were described in some cases, primarily in patients transplanted for end-stage primary sclerosing cholangitis (PSC). In addition, the development of de novo IBD in patients undergoing OLT for indications other than PSC was described. Evaluating our collective of 314 liver transplanted patients we found five patients transplanted for various indications other than PSC (autoimmune hepatitis [AIH], acute-on-chronic hepatitis B, Wilson's disease, and cryptogenic cirrhosis) who developed de novo IBD after OLT despite sufficient immunosuppressive therapy with tacrolimus or cyclosporine. PSC was widely excluded in these patients by clinical and histological examinations and there was no sign of an enteric infection. It was remarkable that all patients were suspected to have an autoimmune background. Four of our patients were women and almost all patients showed histologically typical signs of an ulcerative colitis (UC). To prevent allograft rejection, three of five patients were treated with cyclosporine and the other two with tacrolimus. After diagnosis, treatment with aminosalicylates and corticosteroids led to complete clinical and histological remission. However, relapses occurred frequently after termination of specific therapy. In combination with previous reports, our cases indicate an immune dysregulation leading to the development of de novo IBD after OLT under immunosuppressive therapy. Reviewing the literature, it should be considered that apart from the autoimmune background, immunosuppressive therapy may itself play a major role in the development of de novo IBD. From the clinical point of view, it is of critical importance to detect this phenomenon, since diarrhea is an important cause of morbidity and mortality in transplanted patients and therapy for this disorder completely differs from the treatment for other causes of diarrhea. Aminosalicylates and courses of corticosteroids offer an effective treatment.

Adolescent↗
PubMed2006

Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice.

BACKGROUND/AIMS: In hepatic fibrogenesis, stellate cells are activated leading to production and deposition of extracellular matrix. To clarify the role of PDGF-B in liver fibrogenesis, we overexpressed PDGF-B in the liver of transgenic mice. METHODS: Transgenic mice for the conditional overexpression of PDGF-B in the liver under control of an albumin promoter were generated utilising the Cre/loxP system. Constitutive PDGF-B expression was achieved after breeding with mice expressing Cre-recombinase under actin promoter control. Tamoxifen inducible expression was achieved after breeding with mice expressing Cre under transthyretin receptor promoter control. Levels of fibrosis were assessed and the expression of regulators of matrix remodelling was measured. RESULTS: PDGF-B expression caused hepatic stellate cell and myofibroblast activation marked by alpha-smooth muscle actin and PDGFR-beta expression. Liver fibrosis was verified macroscopically, histologically and by collagen I mRNA quantification in 4-6 week-old animals. MMP-2, MMP-9 and TIMP-1 were upregulated whereas TGF-beta expression was unchanged. CONCLUSIONS: We identified PDGF-B as a proliferative and profibrogenic stimulus and potential inducer of stellate cell transdifferentiation in vivo. PDGF-B overexpression causes liver fibrosis without significantly upregulating TGF-beta1, suggesting a TGF-beta-independent mechanism. The established model provides a tool for testing anti-PDGF-B therapeutic strategies in liver fibrosis in vivo.

Animals↗
PubMed2006

Characterization of human gene encoding SLA/LP autoantigen and its conserved homologs in mouse, fish, fly, and worm.

AIM: To approach the elusive function of the SLA/LP molecule, we have characterized genomic organization and conservation of the major antigenic and functional properties of the SLA/LP molecule in various species. METHODS: By means of computational biology, we have characterized the complete SLA/LP gene, mRNA and deduced protein sequences in man, mouse, zebrafish, fly, and worm. RESULTS: The human SLA/LP gene sequence of approximately 39 kb, which maps to chromosome 4p15.2, is organized in 11 exons, of which 10 or 11 are translated, depending on the splice variant. Homologous molecules were identified in several biological model organisms. The various homologous protein sequences showed a high degree of similarity or homology, notably at those residues that are of functional importance. The only domain of the human protein sequence that lacks significant homology with homologous sequences is the major antigenic epitope recognized by autoantibodies from autoimmune hepatitis (AIH) patients. CONCLUSION: The SLA/LP molecule and its functionally relevant residues have been highly conserved throughout the evolution, suggesting an indispensable function of the molecule. The finding that the only non-conserved domain is the dominant antigenic epitope of the human SLA/LP sequence, suggests that SLA/LP autoimmunity is autoantigen-driven rather than being driven by molecular mimicry.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Pregnancy in autoimmune hepatitis: outcome and risk factors.

OBJECTIVE: Autoimmune hepatitis (AIH) may influence pregnancy outcome and pregnancy may affect AIH. We aimed at analyzing the disease course in pregnant AIH patients and at identifying disease-related risk factors for adverse pregnancy outcome. PATIENTS AND METHODS: AIH patients with at least one pregnancy were identified at four liver units. The patients' records and the data obtained by detailed questionnaires were analyzed retrospectively. Forty-two pregnancies of 22 AIH patients were included. RESULTS: The rate of adverse pregnancy outcome was 26%; a medical explanation could be elucidated in only 4 of 11 pregnancies with adverse outcome. Of note, the 7 unexplained adverse pregnancy outcomes were highly associated with the presence of antibodies to SLA/LP (odds ratio 51; p < 0.003) and Ro/SSA (odds ratio 27; p < 0.02). Of 35 live births, 30 children developed normally over a mean observation period of nearly 5 yr. Eleven of these had been exposed to azathioprine in utero. The rate of serious maternal complications was 9% and a high rate (52%) of postpartum flares was noted. CONCLUSIONS: The presence of autoantibodies may be a risk factor for adverse pregnancy outcome in AIH patients. Close monitoring of both mother and fetus seems advisable due to a significant rate of maternal and fetal complications.

Adolescent↗
PubMed2006

Response to transarterial chemoembolization as a biological selection criterion for liver transplantation in hepatocellular carcinoma.

Criteria to select patients with hepatocellular carcinoma (HCC) for liver transplantation (LT) are based on tumor size and number of nodules rather than on tumor biology. The present study was undertaken to assess the role of transarterial chemoembolization (TACE) in selecting patients with tumors suitable for LT. Ninety-six consecutive patients with HCC were treated by repeatedly performed TACE, 62 of them exceeding the Milan criteria. Patients meeting the Milan criteria were immediately listed, and patients beyond the listing criteria were listed upon downstaging of the tumor following successful TACE. Fifty patients were finally transplanted. Of these 50 patients, 34 exceeded the Milan criteria. In these 96 patients, overall 5-year survival was 51.9%. However, it was 80.9% for patients undergoing LT and 0% for patients without transplantation (P < 0.0001). Tumor recurrence was primarily influenced by the control of the disease through continued TACE during the waiting time. Freedom from recurrence after 5 years was 94.5% in patients (n = 39) with progress-free TACE during the waiting time. Tumor recurrence was significantly higher in patients (n = 11) who after initial response to TACE progressed again before LT (freedom from recurrence 35.4%; P = 0.0017). Progress-free course of TACE during the waiting time (P = 0.006; risk ratio, 8.95), and a limited number of tumor nodules as assessed in the surgical specimen (P = 0.025; risk ratio, 0.116) proved to be significant predictors for freedom from recurrence in the multivariate analysis. Milan criteria were without impact on recurrence. Our data suggest that sustained response to TACE is a better selection criterion for LT than the initial assessment of tumor size or number.

Carcinoma, Hepatocellular↗
PubMed2006

Evaluation of F-actin ELISA for the diagnosis of autoimmune hepatitis.

OBJECTIVE: Antibodies to F-actin have been proposed to increase specificity in the diagnosis of autoimmune hepatitis (AIH). We compared the diagnostic value of a new F-actin enzyme-linked immunosorbent assay (ELISA) with the current gold standard of detection of smooth muscle antibodies by indirect immunofluorescence (SMA-IFT). METHODS: Archived sera of 47 patients with SMA positive AIH were tested with the F-actin ELISA and SMA-IFT. Prospectively collected sera of 123 patients with various liver diseases, 35 of whom had AIH, were analyzed by both assays. Different cutoff limits were considered for the F-actin ELISA (increments between 20 and 60 ELISA units) and SMA-IFT (titers of 1:40, 1:80, and 1:160). RESULTS: The F-actin ELISA had a sensitivity of 100% to detect all of 47 SMA positive AIH sera and the value of the ELISA units correlated with that of SMA titers (p < 0.0001). In prospective analysis, F-actin ELISA showed a superior sensitivity (74% vs 34%) and a similar specificity (98% vs 99%) and positive predictive value (88% vs 92%), compared with SMA-IFT. Combining both assays improved neither sensitivity nor specificity. CONCLUSIONS: The new F-actin ELISA seems to be a useful diagnostic tool with similar specificity and superior sensitivity for the diagnosis of AIH, compared with standard SMA-IFT. Due to its simplicity and operator independency, the F-actin ELISA may become a preferred screening technique for detection of autoantibodies in patients with suspected AIH.

Actins↗
PubMed2005

MORT1/FADD is involved in liver regeneration.

AIM: To explore the role of the adaptor molecule in liver regeneration after partial hepatectomy (PH). METHODS: We used transgenic mice expressing an N-terminal truncated form of MORT1/FADD under the control of the albumin promoter. As previously shown, this transgenic protein abrogated CD95- and CD120a-mediated apoptosis in the liver. Cyclin A expression was detected using Western blotting. ELISA and RT-PCR were used to detect IL-6 and IL-6 mRNA, respectively. DNA synthesis in liver tissue was measured by BrdU staining. RESULTS: Resection of 70% of the liver was followed by a reduced early regenerative response in the transgenic group at 36 h. Accordingly, 36 h after hepatectomy, cyclin A expression was only detectable in wild-type animals. Consequently, the onset of liver mass restoration was retarded as measured by MRI volumetry and mortality was significantly higher in the transgenic group. CONCLUSION: Our data demonstrate for the first time an involvement of the death receptor molecule MORT1/FADD in liver regeneration, beyond its well described role as part of the intracellular death signaling pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Hepatic over-expression of TGF-beta1 promotes LPS-induced inflammatory cytokine secretion by liver cells and endotoxemic shock.

Transforming growth factor-beta (TGF-beta) is an important suppressor of inflammation. However, TGF-beta has also been found to promote secretion of inflammatory cytokines, and transgenic mice, which constitutively express TGF-beta in liver, have been found to be more susceptible to endotoxemia. To approach this apparent paradox, we investigated the role of hepatic TGF-beta1 in endotoxemia by utilising inducible TGF-beta1-transgenic mice that express TGF-beta1 under control of the C-reactive protein promoter. In contrast to non-transgenic littermates, administration of lipopolysaccharide (LPS) induced strongly increased expression of TGF-beta and acute phase proteins in the TGF-beta1-transgenic mice. Hepatic TGF-beta1-expression in the transgenic mice started an inflammatory cytokine cascade, marked by increased and prolonged secretion of TNF-alpha and IL-6 by hepatocytes. The inflammatory response of the TGF-beta1-transgenic mice to LPS was associated with high rates of mortality due to endotoxemic shock, marked by systemic hypotension and hypothermia. Endotoxemic shock was primarily mediated by TNF-alpha and IL-6, since inhibitory antibody to TNF-alpha or, more effectively, to IL-6 could reduce mortality in these mice. In conclusion, while TGF-beta-signalling to immune cells may suppress inflammatory effector function, TGF-beta-signalling to liver cells seems to promote LPS-stimulated secretion of inflammatory cytokines and to predispose for lethal endotoxemic shock.

Acute-Phase Reaction↗
PubMed2005

Treatment challenges and investigational opportunities in autoimmune hepatitis.

New drugs and advances in molecular biology afford opportunities to upgrade the treatment of autoimmune hepatitis. The aims of this study were to define treatment problems, identify possible solutions, and stimulate investigations to improve patient care. A clinical subcommittee of the International Autoimmune Hepatitis Group reviewed current management difficulties and proposed corrective actions. The assessment of new front-line and salvage therapies for adults and children were given top priority. Cyclosporine and mycophenolate mofetil were endorsed as drugs worthy of rigorous study in severe disease, and budesonide was endorsed for study as front-line therapy in mild disease. Diagnostic criteria and treatment regimens for children required codification, and pharmacokinetic studies were encouraged to develop optimal dosing schedules based on therapeutic ranges. Collaborative efforts were proposed to help understand racial, geographical, and genetic factors affecting outcome and to establish definitions and therapies for variant syndromes and graft dysfunction after transplantation. The development of experimental animal models was deemed essential for the study of site-specific molecular interventions, and gene therapy was endorsed as a means of bolstering reparative processes. In conclusion, evolving pharmacological and technical advances promise to improve the treatment of autoimmune hepatitis, and investigations of these advances are timely, feasible, and necessary.

Gastroenterology↗
PubMed2005

Murine liver antigen presenting cells control suppressor activity of CD4+CD25+ regulatory T cells.

CD4(+)CD25(+) regulatory T cells (Treg) are important mediators of peripheral immune tolerance; however, whether Treg participate also in hepatic immune tolerance is not clear. Therefore, we tested the potential of Treg to suppress stimulation of CD4(+) T cells by liver sinusoidal endothelial cells (LSEC), Kupffer cells (KC), or hepatocytes. In the absence of Treg, all 3 types of liver cells could stimulate CD4(+) T cell proliferation; in the presence of Treg, however, CD4(+) T cell proliferation was suppressed. Interaction with KC even stimulated the expansion of the Treg population; LSEC or hepatocytes, in contrast, could not induce proliferation of Treg. Because liver inflammation can be induced by infection, we tested the potential of liver cells to modify Treg suppressor activity in the presence of microbial signals. In the presence of immune-stimulatory CpG-oligonucleotides, LSEC, KC, and hepatocytes could indeed overcome Treg-mediated suppression; in the presence of lipopolysaccharide (LPS), however, only KC and hepatocytes, but not LSEC, could overcome Treg suppressor activity. Hepatocytes from mice with deficient toll-like receptor-4 signaling failed to abrogate Treg suppression in response to LPS, indicating that overcoming Treg suppressor activity was indeed a response of the liver cell and not of the Treg. In conclusion, Treg can suppress CD4(+) T cell stimulation by liver cells. However, in response to microbial signals, the liver cells can overcome the suppressive activity of Treg. Thus, liver cells may facilitate the transition from hepatic immune tolerance to hepatic inflammation by controlling Treg suppressor activity.

Animals↗
PubMed2005

Overlap syndromes of cholestatic liver diseases and auto-immune hepatitis.

Approximately 18% of patients with auto-immune liver disease present with features characteristic of a second auto-immune liver disease. These cases have been termed "overlap syndromes."The pathogenesis of overlap syndromes is poorly understood, and few data are available regarding the clinical characteristics and outcome of this disease. Therefore, a consensus on the definition of overlap syndromes has not been reached. A common genetic background between auto-immune hepatitis (AIH) and its overlap with primary biliary cirrhosis(PBC) or primary sclerosing cholangitis (PSC) might confer susceptibility to a more inflammatory phenotype, probably requiring combined immunosuppressive treatment. This article focuses on the prevalence, diagnosis, and treatment of the overlap syndrome of AIH and PBC or PSC.

Autoantibodies↗
PubMed2005

Characterization of OEBT, a LIM protein.

LIM Proteins have been demonstrated to play key roles in pattern formation during embryonic development, cell lineage determination, and cancer differentiation. These proteins are characterized by their conserved LIM domain, which functions as a specific protein-binding site. Recently, two new members of the LIM protein family, PRICKLE1 and PRICKLE2, were characterized in silico and demonstrated to be human orthologues of the Drosophila prickle proteins. We report on an additional member of this protein family, overexpressed breast tumor protein (OEBT). The corresponding gene was mapped to human chromosome 6p22.31. Orthologues in mouse and rat with 72 and 54% identities on a protein level were identified and the corresponding genes were mapped to mouse chromosome 17 and rat chromosome 9. The protein displays two LIM domains, as well as a PET domain, and was predicted to be localized in the nucleus. Expression of human OEBT was analyzed in silico, and the corresponding RNA was annotated to be highly expressed in a broad range of tissues. ESTs from several malignant tissue differentiations point towards a possible role of OEBT in cancer differentiation.

Adaptor Proteins, Signal Transducing↗
PubMed2005

In silico characterization of LZTS3, a potential tumor suppressor.

Members of the leucine zipper tumor suppressor (LZTS) protein family are thought to play roles in cell growth modulation. The two currently known members were identified by analyzing genomic and chromosomal alterations reported to be either involved or deleted in various types of cancer, suggesting a causative relationship. By means of computational biology, we have now identified a novel member of the LZTS protein family named LZTS3. The corresponding gene was localized to chromosome 20p13 and consisted of three exons. The novel LZTS3 protein demonstrated a high similarity to LAPSER1/LZTS2 and FEZ1/LZTS1, two members of the LZTS family. The conserved FEZ1 domain contains a leucine zipper motif similar to the cAMP-responsive activating transcription factor 5. As FEZ1 inhibits cancer cell growth through the regulation of mitosis and its alteration resulted in abnormal cell growth, the LZTS3 protein was expected to have similar functions during cancer differentiation. Furthermore, the protein was conserved in vertebrates, as orthologs could be identified in mouse, rat, and zebrafish. The intracellular localization of the LZTS3 protein was predicted to be nuclear by means of Reinhardt's neural network and the k-nearest neighbor algorithm. An RT-PCR-based expression profile available from the human unidentified gene-encoded (HUGE) database demonstrated the highest expression in the brain and kidney, accompanied by lower expression in multiple other tissues.

Amino Acid Sequence↗
PubMed2004

Control of organ transplant-associated graft-versus-host disease by activated host lymphocyte infusions.

BACKGROUND: Prolonged persistence of donor-derived T cells after organ transplantation has been proposed to improve long-term allograft survival. However, surviving transplant-derived T cells are also able to mediate devastating graft-versus-host disease (GvHD). Currently, GvHD after organ transplantation is usually refractory to conventional therapy and the disease outcome fatal. METHODS: Graft-reactive host T cells were generated ex vivo from a patient suffering from a severe and refractory liver-transplant-associated GvHD. To control GvHD, activated alloreactive host T cells were repetitively retransferred into the patient (activated host lymphocyte infusion [aHLI]). RESULTS: Adoptive transfer of ex vivo activated alloreactive host T cells (aHLI) led to the control and complete resolution of severe GvHD without inducing allograft rejection. CONCLUSIONS: aHLI opens a novel therapeutic window to control solid-organ transplant-associated GvHD while preserving allograft integrity.

Adoptive Transfer↗
PubMed2004

TGFbeta regulates the CD4+CD25+ T-cell pool and the expression of Foxp3 in vivo.

Factors influencing the development of CD4+CD25+ T-cells in vivo are poorly understood. In order to investigate the contribution of TGFbeta1 to the development and function of CD4+CD25+ T-cells, we generated a gain of function mutation resulting in the overexpression of an active form of TGFbeta1 in T-cells under control of the human CD2 promoter. In peripheral lymphoid organs and in the thymus, the frequency of CD4+CD25+ T-cells was increased in transgenic mice. This appeared to be due to an autocrine effect of TGFbeta on T-cells, since concomitant impairment of TGFbeta-signaling in double transgenic mice resulted in a phenotype similar to wild type. In contrast, in single transgenic mice with impaired TGFbeta-signaling in T-cells, CD4+CD25+ T-cell numbers were reduced in peripheral lymphoid organs but not in the thymus. In addition, TGFbeta was found to regulate the expression of Foxp3 in vivo, a transcription factor essential for the generation and function of regulatory T-cells. In CD4+CD25+ T-cells, TGFbeta1 increased the expression of Foxp3, whereas a decreased expression was seen in CD4+CD25+ T-cells with impaired TGFbeta-signaling. TGFbeta1 induced the expression of IL-10 in transgenic T-cells, but the increased in vitro suppressive capacity observed in transgenic CD4+CD25+ T-cells was due to the secretion of TGFbeta and not IL-10. Therefore, our study provides in vivo evidence for a role of TGFbeta in the homeostasis of CD4+CD25+ T-cells.

Animals↗