Hepatitis: Beuers U

Kremer AE, Rust C, Eichhorn P, Beuers U, Holdenrieder S. · AMC Liver Center, S1-164, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands. · Expert Rev Mol Diagn. · Pubmed #19298138 No free full text.

Abstract: Primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis are the three major immune-mediated liver diseases. The etiologies of primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis are largely unknown, but seem to be influenced by genetic and environmental factors. Autoantibodies can be found in nearly all patients with primary sclerosing cholangitis and autoimmune hepatitis, and in the vast majority of patients with primary sclerosing cholangitis. In addition, autoimmune hepatitis is associated with high concentrations of serum globulins. Enhanced liver cell death by apoptosis has been described in all of these liver diseases, although the precise mechanisms remain unclear. In general, apoptosis can be initiated via an extrinsic pathway that is triggered by engagement of death receptors on the cell surface, or via an intrinsic pathway that is induced by mitochondrial injury and is influenced by members of the Bcl-2 family. In both pathways, effector caspases are finally activated that cleave and degrade cell structures, resulting in the release of apoptotic products into the circulation. New diagnostic tests can detect these apoptotic markers and programmed cell death ligands such as Fas and Fas-ligands, nucleosomes, caspases, cytokeratin fragments, macrophage migration inhibitory factor, soluble intracellular adhesion molecule, natural killer cells group 2D and programmed death ligands. Several of these markers have been found to be altered in tissue and/or blood of immune-mediated liver diseases, some also in nonimmune-mediated liver diseases. Beyond their potential usefulness as additional diagnostic markers, they may be valuable for the estimation of disease severity and therapy monitoring. This review summarizes current knowledge on apoptotic mechanisms, death receptor ligands and circulating apoptotic markers in immune-mediated liver diseases.

Rust C, Beuers U. · Department of Gastroenterology and Hepatology, University of Amsterdam, Amsterdam NL-1100 DE, The Netherlands. · World J Gastroenterol. · Pubmed #18528934 links to  free full text

Abstract: The three major immune disorders of the liver are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Variant forms of these diseases are generally called overlap syndromes, although there has been no standardised definition. Patients with overlap syndromes present with both hepatitic and cholestatic serum liver tests and have histological features of AIH and PBC or PSC. The AIH-PBC overlap syndrome is the most common form, affecting almost 10% of adults with AIH or PBC. Single cases of AIH and autoimmune cholangitis (AMA-negative PBC) overlap syndrome have also been reported. The AIH-PSC overlap syndrome is predominantly found in children, adolescents and young adults with AIH or PSC. Interestingly, transitions from one autoimmune to another have also been reported in a minority of patients, especially transitions from PBC to AIH-PBC overlap syndrome. Overlap syndromes show a progressive course towards liver cirrhosis and liver failure without treatment. Therapy for overlap syndromes is empiric, since controlled trials are not available in these rare disorders. Anticholestatic therapy with ursodeoxycholic acid is usually combined with immunosuppressive therapy with corticosteroids and/or azathioprine in both AIH-PBC and AIH-PSC overlap syndromes. In end-stage disease, liver transplantation is the treatment of choice.

Beuers U, Rust C. · Department of Medicine II-Grosshadern, Ludwig Maximilians-University of Munich, Germany. · Semin Liver Dis. · Pubmed #16143946 No free full text.

Abstract: In hepatology, the term overlap syndrome describes variant forms of the major hepatobiliary autoimmune diseases, autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Patients with overlap syndromes present with both hepatitic and cholestatic biochemical and histological features of AIH, PBC, and/or PSC, and usually show a progressive course toward liver cirrhosis and liver failure without adequate treatment. AIH-PBC overlap syndromes have been reported in almost 10% of adults with AIH or PBC, whereas AIH-PSC overlap syndromes were found in 6 to 8% of children, adolescents, and young adults with AIH or PSC. A minority of patients may also show transition from stable PBC to AIH, AIH to PBC, or AIH to PSC, as documented by single case reports and small case series. Single cases of AIH and autoimmune cholangitis (antimitochondrial antibody-negative PBC) overlap have also been reported. Empiric medical treatment of AIH-PBC and AIH-PSC overlap syndromes includes anticholestatic therapy with ursodeoxycholic acid and immunosuppressive therapy with corticosteroids and azathioprine. In end-stage disease, liver transplantation is the treatment of choice.

Beuers U. · Department of Medicine II-Grosshadern, Ludwig Maximilians-University of Munich, Marchioninistrasse 15, 81377 Munich, Germany. · J Hepatol. · Pubmed #15777577 No free full text.

This publication has no abstract.

Wiegand J, Schüler A, Kanzler S, Lohse A, Beuers U, Kreisel W, Spengler U, Koletzko S, Jansen PL, Hochhaus G, Möllmann HW, Pröls M, Manns MP. · Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. · Liver Int. · Pubmed #16162148 No free full text.

Abstract: BACKGROUND: Autoimmune hepatitis (AIH) is a chronic liver disease that is effectively treated with immunosuppressive therapy. Predniso(lo)ne, often in combination with azathioprine, is the basic therapeutic option to induce remission. However, this regimen can cause numerous side effects. The aim of the present study was to evaluate budesonide as a treatment option in the induction of remission in patients with previously untreated AIH. METHODS: Between October 1998 and August 1999, 12 patients were treated with 3 mg budesonide thrice daily for 3 months in this open one-arm multicenter phase IIa study. Primary end point was induction of remission indicated by a drop of aspartate aminotransferase and alanine aminotransferase levels below two times the upper limit of normal. RESULTS: Seven of the 12 patients (58%) reached complete remission, three patients (25%) had a partial response. Thus, 10/12 individuals (83.3%) responded to therapy. Therapy was tolerated well in 10/12 cases (83.3%). CONCLUSIONS: Budesonide monotherapy was effective in the induction of remission and well tolerated in treatment naïve patients with AIH. It should be further evaluated in prospective controlled trials and should be compared to predniso(lo)ne both in monotherapy and in combination with azathioprine.

Poupon RE, Bonnand AM, Queneau PE, Trépo C, Zarski JPí, Vetter D, Raabe JJ, Thieffin G, Larrey D, Grangé JD, Capron JP, Serfaty L, Chrétien Y, St Marc Girardin MF, Mathiex-Fortunet H, Zafrani ES, Guéchot J, Beuers U, Paumgartner G, Poupon R. · INSERM, Unit 370, Faculté de Médecine Necker, Paris France. · Scand J Gastroenterol. · Pubmed #10912666 No free full text.

Abstract: BACKGROUND: Ursodeoxycholic acid (UDCA) could potentiate the effect of interferon (IFN) in patients with chronic hepatitis C resistant to IFN. We compared the efficacy of IFN with that of a combination of IFN and UDCA. METHODS: Patients were randomized to receive UDCA (13-15 mg/kg/day) (n = 47) or placebo (n = 44) plus interferon (3 MU three times weekly) for 6 months and were then followed up for 6 additional months. RESULTS: At entry 30% of patients had cirrhosis, and 70% had HCV genotype 1. Five and four patients withdrew from the combination and the monotherapy groups, respectively. At 6 months alanine aminotransferase (ALAT) and gamma-glutamyl transferase (GGT) activities were significantly lower (P < 0.001) in the combination group than in the monotherapy group; the differences were no longer significant at 1 year. At 6 months ALAT activities normalized in 10 and 8 patients in the combination and the monotherapy groups, respectively (P = 0.67). In 10 of them (5 in each group) HCV RNA levels became undetectable. At 1 year four versus one patient had a sustained normalization of ALAT, and in one patient the HCV RNA became negative. There was no difference in the histologic progression. In this setting, in contrast to chronic cholestasis, UDCA administration induced an increase in total serum bile acids and did not change primary bile acids. CONCLUSIONS: An IFN plus UDCA combination is more effective than IFN alone in terms of ALAT but not in terms of the virologic response. These results favor the hypothesis that UDCA has an effect on the biochemical indices of cellular injury independent of a change in primary bile acids.

Von Hahn T, Halangk J, Witt H, Neumann K, Müller T, Puhl G, Neuhaus P, Nickel R, Beuers U, Wiedenmann B, Berg T. · Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Germany. · Scand J Gastroenterol. · Pubmed #18415752 No free full text.

Abstract: OBJECTIVE: The lipopolysaccharide (LPS)-triggered release of inflammatory cytokines from Kupffer cells is mediated via the CD14/TLR4 receptor complex. This inflammatory pathway can be influenced by alterations in genes encoding for LPS receptor components. Thus, a -260 C>T transition in the CD14 promoter is thought to result in enhanced CD14 expression thereby increasing the LPS responsiveness in chronic liver diseases, whereas a D299G exchange in the TLR4 gene has the opposite effect. Our objective was to analyze these two variations. MATERIAL AND METHODS: The study comprised 1712 patients with chronic liver diseases of different etiologies and 385 healthy controls. Genotyping was carried out by melting curve analysis with fluorescence resonance energy transfer (FRET) probes in the LightCycler. RESULTS: Genotype frequencies of CD14 -260C>T and TLR4 D299G did not significantly differ between patients and controls (CD14 TT 21.6% versus 21.8%; TLR4 DG or GG 9.7% versus 10.4%). We found no significant correlation of these alterations with disease course either in the groups of patients with alcoholic liver disease or hepatitis C virus (HCV) infection or among patients requiring liver transplantation. A significantly higher frequency of the CD14 -260TT genotype was observed (36.6% versus 21.8% in healthy controls, p=0.036) only in a small subgroup of patients (n=41) with mild cryptogenic chronic liver disease. CONCLUSIONS: Variants within these LPS receptor genes were equally distributed among patients with chronic liver diseases of different etiologies and obviously do not confer an increased risk for the severity of these chronic liver processes.

Holdenrieder S, Eichhorn P, Beuers U, Samtleben W, Stieber P, Nagel D, Peterfi A, Steinle A, Salih HR. · Institute of Clinical Chemistry, University Hospital of Munich, 81377 Munich, Germany. · Anticancer Res. · Pubmed #17649819 No free full text.

Abstract: BACKGROUND: Proteolytic shedding of the immunostimulatory NKG2D ligands MICA and MICB from cancer cells constitutes a novel immune escape strategy that diminishes antitumor reactivity by NKG2D-bearing cytotoxic lymphocytes. In consequence, serum levels of soluble MICA and MICB are frequently found to be elevated in cancer disease. PATIENTS AND METHODS: As the diagnostic potential depends strongly on the organ-specific benign diseases and is affected by diseases involved in marker metabolism, both markers were analyzed by ELISA in sera of 141 patients with hepatic autoimmune diseases (34 autoimmune hepatitis, 35 primary sclerosing cholangitis, 72 primary biliary cirrhosis), 18 patients with acute bacterial infections, 21 patients with renal insufficiency, 13 patients with cholestasis and 62 healthy individuals. RESULTS: Similarly to healthy controls (median sMICA < 30 pg/mL; sMICB < 30 pg/mL), low levels of both markers were generally found in sera of patients with hepatic autoimmune diseases. In contrast, significantly elevated concentrations of sMICA and sMICB were observed in sera of patients with acute infections (median sMICA 890 pg/mL; sMICB 111 pg/mL), in those with renal insufficiency (sMICA 195 pg/mL; sMICB 50 pg/mL), and in those with cholestasis (sMICA 1058 pg/mL; sMICB 146 pg/mL). CONCLUSION: While hepatic autoimmune diseases have no general impact on the amount of circulating sMICA and sMICB, acute bacterial infections, renal insufficiency and cholestasis can lead to notably elevated serum levels of the NKG2D ligands.

Schramm C, Herkel J, Beuers U, Kanzler S, Galle PR, Lohse AW. · Department of Medicine I, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. · Am J Gastroenterol. · Pubmed #16464221 No free full text.

Abstract: 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.

Terjung B, Bogsch F, Klein R, Söhne J, Reichel C, Wasmuth JC, Beuers U, Sauerbruch T, Spengler U. · Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany. · Eur J Med Res. · Pubmed #15546809 No free full text.

Abstract: INTRODUCTION: Antineutrophil cytoplasmic antibodies (atypical p-ANCA) are detected at high prevalence in sera from patients with autoimmune hepatitis (AIH), but their diagnostic relevance for AIH has not been systematically evaluated so far. METHODS: Here, we studied sera from 357 patients with autoimmune (autoimmune hepatitis n=175, primary sclerosing cholangitis (PSC) n=35, primary biliary cirrhosis n=45), non-autoimmune chronic liver disease (alcoholic liver cirrhosis n=62; chronic hepatitis C virus infection (HCV) n=21) or healthy controls (n=19) for the presence of various non-organ specific autoantibodies. Atypical p-ANCA, antinuclear antibodies (ANA), antibodies against smooth muscles (SMA), antibodies against liver/kidney microsomes (anti-Lkm1) and antimitochondrial antibodies (AMA) were detected by indirect immunofluorescence microscopy, antibodies against the M2 antigen (anti-M2), antibodies against soluble liver antigen (anti-SLA/LP) and anti-Lkm1 by using enzyme linked immunosorbent assays. To define the diagnostic precision of the autoantibodies, results of autoantibody testing were analyzed by receiver operating characteristics (ROC) and forward conditional logistic regression analysis. RESULTS: Atypical p-ANCA were detected at high prevalence in sera from patients with AIH (81%) and PSC (94%). ROC- and logistic regression analysis revealed atypical p-ANCA and SMA, but not ANA as significant diagnostic seromarkers for AIH (atypical p-ANCA: AUC 0.754+/-0.026, odds ratio [OR] 3.4; SMA: 0.652+/-0.028, OR 4.1). Atypical p-ANCA also emerged as the only diagnostically relevant seromarker for PSC (AUC 0.690+/-0.04, OR 3.4). None of the tested antibodies yielded a significant diagnostic accuracy for patients with alcoholic liver cirrhosis, HCV or healthy controls. CONCLUSIONS: Atypical p-ANCA along with SMA represent a seromarker with high diagnostic accuracy for AIH and should be explicitly considered in a revised version of the diagnostic score for AIH.

Kenngott S, Lohse P, Beuers U. · Medizinische Klinik II-Grosshadern, Klinikum der Universität München. · MMW Fortschr Med. · Pubmed #14610864 No free full text.

Abstract: Intrahepatic cholestasis of pregnancy is a hepatopathy that occurs in the second or third trimester and accounts for 20% of cases of jaundice occurring in pregnancy. Both genetic and hormonal factors appear to play important roles in its development. The leading symptom is pruritus, and jaundice is common. Transaminases, serum bile acids and bilirubin are typically elevated, while gamma-GT is usually normal. For the differential diagnosis, in particular viral hepatitis, cholelithiasis, gestosis and acute fatty liver of pregnancy must be excluded. While the prognosis of intrahepatic cholestasis of pregnancy for the mother is good, the associated increased tendency for a premature birth represents a potential risk for the child. Early treatment with ursodeoxycholic acid appears to have a positive influence on both the mother's symptoms and the course of the pregnancy. Should the symptoms persist after delivery, consideration must be given to a chronic hepatopathy.

Schwarze C, Terjung B, Lilienweiss P, Beuers U, Herzog V, Sauerbruch T, Spengler U. · Department of Internal Medicine I, University of Bonn, Germany. · Clin Exp Immunol. · Pubmed #12869036 links to  free full text

Abstract: Antineutrophil cytoplasmic antibodies (ANCA) of IgG class have been described at high prevalence in autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). Data on IgA class ANCA in these diseases are limited. The aim of this study was to determine the prevalence and fluorescence patterns of IgA class ANCA in AIH and PSC and to examine a relationship between the presence of IgA ANCA and clinical characteristics in these patients. Sera from 35 patients with PSC (21 with concomitant inflammatory bowel disease), 40 patients with AIH and 10 healthy controls were studied. ANCA were detected on ethanol-fixed neutrophils using an indirect immunofluorescence technique. ANCA of the IgA class were found in 20% of sera from patients with PSC and in 50% of AIH sera. The majority of AIH patients with IgA class ANCA showed a 'classical' perinuclear staining pattern, whereas the 'classical' and 'atypical' perinuclear fluorescence patterns were distributed equally in PSC. In sera containing IgG and IgA class ANCA simultaneously, IgG class ANCA showed an 'atypical' pANCA fluorescence pattern whereas IgA class ANCA produced a 'classical' perinuclear staining. The presence of IgA class ANCA was not associated with disease-specific clinical characteristics. IgA class ANCA are more frequently detected in sera of patients with AIH than PSC. The diversity of fluorescence patterns points to different target antigens of IgA class ANCA with distinct subcellular localizations.

Pihusch R, Rank A, Göhring P, Pihusch M, Hiller E, Beuers U. · Medizinische Klinik III, Klinikum der Ludwig-Maximilians-Universität - Grosshadern, 81377 München, Germany. · J Hepatol. · Pubmed #12399218 No free full text.

Abstract: BACKGROUND/AIMS: As compared to other chronic liver diseases, cholestatic disorders are associated with a better outcome of variceal bleeding and less blood loss at transplantation, suggesting the presence of a hypercoagulable state. We have assessed plasmatic coagulation and platelet function in patients with cholestatic and non-cholestatic liver disease. METHODS: Thirty-seven patients with chronic cholestatic liver disease (primary biliary cirrhosis (PBC)/primary sclerosing cholangitis (PSC)), 53 patients with chronic hepatitis C (HCV) or alcoholic cirrhosis (C2), and 62 healthy controls were studied. RESULTS: Thrombelastography revealed a hypercoagulable state in non-cirrhotic patients with PBC/PSC, but not in those with HCV (ma-value: 6.54[6.25-6.92, 95%CI] vs. 5.39[5.11-5.58], P < 0.05) possibly due to higher fibrinogen levels in PBC/PSC patients (369[329-418]mg/dl vs. 263[250-275]mg/dl, P < 0.05). PFA-100 closure time was prolonged in HCV/C2 patients with advanced cirrhosis, but not in cirrhotic patients with PBC/PSC (Child B; epinephrine stimulation: 192[161-229]s vs. 132[105-158]s, P < 0.05). Flow cytometric studies of platelet receptors and granules revealed a higher surface expression of CD42b (112[105-119]% vs. 100[95-104]%, P < 0.05) and LIBS-1 (261[184-348]% vs. 121[92-145]%, P < 0.05) in patients with PBC/PSC than in those with HCV/C2. CONCLUSIONS: These results indicate that platelet function differs between patients with cholestatic and non-cholestatic liver disease and is stable or even hyperactive in patients with PBC and PSC.

Berghaus TM, Beuers U. · Medizinische Klinik II, Klinikum Grosshadern der Ludwig-Maximilians-Universität München. · MMW Fortschr Med. · Pubmed #11481912 No free full text.

Abstract: Alcoholic and non-alcoholic steatohepatitis (NASH) are often histopathologically indistinguishable. Apart from the clinical and laboratory findings, the patient's history is of key importance for differentiating between alcoholic steatohepatitis with its poor prognosis, and NASH, with its usually bland course. While the latter rarely requires specific treatment, the former, in particular in its severe form, is a therapeutic challenge. In addition to suitable dietary measures, patients with a Maddrey Score > 32, may need corticosteroids. In patients with mild to moderate steatohepatitis, the daily alcohol consumption appears to be decisive for the prognosis. In severe forms of this condition, in contrast, mortality is high, and patients surviving the acute phase often develop cirrhosis, irrespective of their further drinking habits.

Oswald M, Kullak-Ublick GA, Paumgartner G, Beuers U. · Department of Medicine II, Klinikum Grosshadern, University of Munich, 81377 Munich, Germany. · Liver. · Pubmed #11454187 No free full text.

Abstract: BACKGROUND/AIMS: In chronic cholestatic liver diseases, biliary excretion of organic anions from blood into bile is impaired. The aim of this study was to identify the underlying mechanism. METHODS: Expression of the basolateral organic anion transporting polypeptide OATP-C (SLC21A6) and the canalicular multidrug resistance protein 2 (MRP2) was studied in patients with primary sclerosing cholangitis (PSC) (n=4), a chronic cholestatic liver disease, and in non-cholestatic controls (n=4) (two with chronic hepatitis C, one with idiopathic liver cirrhosis and one with fatty liver). Total RNA was isolated from liver tissue, reverse transcribed and subjected to polymerase chain reaction (PCR) amplification using primers specific for OATP-C, MRP2 and beta-actin. PCR products were quantified densitometrically. RESULTS: When normalized for beta-actin expression, the level of OATP-C mRNA in liver tissue of patients with PSC was 49% of controls (OATP-C/beta-actin 1.60+/-0.25 vs. 3.24+/-0.69; p<0.05) and the level of MRP2 mRNA was 27% of controls (MRP2/beta-actin 0.70+/-0.36 vs. 2.54+/-0.56; p<0.01). CONCLUSIONS: Both OATP-C and MRP2 are decreased as measured by mRNA level in PSC. Downregulation of OATP-C might be the consequence of impaired canalicular secretion of organic anions and could serve to reduce the organic anion load of cholestatic hepatocytes.