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Hanover, Germany

Bechmann L.P.,University of Duisburg - Essen | Gieseler R.K.,University of Duisburg - Essen | Gieseler R.K.,Rodos BioTarget | Sowa J.-P.,University of Duisburg - Essen | And 8 more authors.
Liver International | Year: 2010

Background & aims: Hepatocyte apoptosis is a key event in non-alcoholic steatohepatitis (NASH). We studied the effect of obesity on free fatty acid (FFA) levels, fatty acid transport proteins (FATPs) and on extrinsic and intrinsic activation of apoptosis in the liver. Methods: Liver biopsies were harvested from 52 morbidly obese patients [body mass index (BMI): 53.82±1.41; age: 45±10.50; 15 males/37 females] undergoing bariatric surgery, and were scored for NASH, evaluated for fibrosis, and investigated for intrahepatic expression of FATPs, death receptors and cytosolic apoptosis-related molecules. Findings were correlated with serum FFA levels and the degrees of intrahepatic (terminal dUTP nick end labelling) and systemic (M30) apoptosis. Results: In patients' liver sections, FATPs as well as select parameters of extrinsic and intrinsic apoptosis were found to be upregulated (CD36/FAT: × 11.56; FATP-5: × 1.33; CD95/Fas: × 3.18; NOXA: × 2.79). These findings correlated with significantly elevated serum FFAs (control: 14.72±2.32 mg/dl vs. patients: 23.03±1.24 mg/dl) and M30 levels (control: 83.12±7.46 U/L vs. patients: 212.61±22.16 U/L). We found correlations between FATPs and apoptosis mediators as well as with histological criteria of NASH and fibrosis. Conclusions: Increased FFA and FATPs are associated with extrinsically and intrinsically induced apoptosis, liver damage and fibrosis in obese patients. Thus, FATPs may offer an interesting new approach to understand and potentially intervene NASH pathogenesis. © 2010 John Wiley & Sons A/S.

Bechmann L.P.,University of Duisburg - Essen | Jochum C.,University of Duisburg - Essen | Kocabayoglu P.,University of Duisburg - Essen | Sowa J.-P.,University of Duisburg - Essen | And 8 more authors.
Journal of Hepatology | Year: 2010

Background & Aims: Predicting the probability of patients with acute liver failure (ALF) to recover spontaneously is of major clinical importance. As apoptotic and necrotic cell death are crucial in the pathogenesis of ALF, we determined whether selected cell-death markers predict outcome of patients with ALF and/or discriminate between etiologies. Methods: In a prospective study (11/2006-06/2009), 68 ALF patients were recruited consecutively. Data were collected over four weeks or until discharge, death or LTx, including CK18/M65 and M30 ELISA and glutathione S-transferase, subtype α. Data at date of admission and at the date of peak levels of M65 were individually analyzed and correlated with the patients' prognosis and etiology. Results: The predictive sensitivity of total serum M65 for lethal outcome was comparable to the Model for End-Stage Liver Disease (MELD) score at time of admission and at its peak value. In contrast, serum bilirubin levels had no prognostic value, neither at admission nor at later time points. In order to accurately predict the clinical prognosis of ALF patients, we tested a modified MELD score where CK18 M65 substituted bilirubin. This CK18/M65-based MELD score significantly better predicted the prognosis of ALF patients compared with the current MELD score or KCC. A combination of tested parameters contributed to improved discrimination of ALF etiologies by applying cell death and established laboratory parameters. Conclusions: The CK18 M65-based MELD score has superior sensitivity and specifically predicts survival of ALF patients. Further prospective clinical studies could validate its potential role to predict requirement of LTx in ALF patients. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Saner F.H.,University of Duisburg - Essen | Gieseler R.K.,University of Duisburg - Essen | Gieseler R.K.,Rodos BioTarget | Akz H.,Cukorova University | And 3 more authors.
Digestion | Year: 2013

Liver transplantation in cirrhotic patients is accompanied by severe bleeding. Indeed, the first 100 recipients of liver allografts transplanted by Thomas E. Starzl died mainly by uncontrolled bleeding. Since then, much progress has been made as to the understanding of the pathophysiology and the treatment of hemostatic disorders in cirrhotic patients. The aim of this review is to provide a state-of-the-art overview on recent developments and treatment options for hemostatic disorder in cirrhotic patients. Patients with end-stage-liver disease (ESLD) do not suffer only from procoagulant deficiency; there is also a lack of natural anticoagulants (i.e. proteins C and S) and profibrinolytics. Conventional laboratory methods such as the determination of the international normalized ratio or the activated partial thromboplastin time cannot predict bleeding complications in these patients. Progressive diagnostic techniques reveal that cirrhotic patients have the same capacity to produce thrombin like healthy volunteers. Moreover, cirrhotic patients - and particularly those with primary biliary cirrhosis or primary sclerosing cholangitis - are at a higher risk for developing thrombosis as compared with healthy controls. Hemostatic alterations are common in cirrhotic patients; they involve both the pro- and the anticoagulant pathways. However, this is a very delicate balance, which may be shifted to either of these pathways by different treatments thereby causing bleeding or thrombosis, respectively. Copyright © 2013 S. Karger AG, Basel.

Dechene A.,University of Duisburg - Essen | Sowa J.-P.,University of Duisburg - Essen | Gieseler R.K.,University of Duisburg - Essen | Gieseler R.K.,Rodos BioTarget | And 13 more authors.
Hepatology | Year: 2010

Acute liver failure (ALF) is associated with massive short-term cell death, whereas chronic liver injury is accompanied by continuous cell death. Hepatic stellate cells (HSCs) contribute to tissue repair and liver fibrosis in chronic liver injury, although their role in ALF remains unexplained. Twenty-nine patients (median age = 43 years, 17 females and 12 males) with ALF according to the Acute Liver Failure Study Group criteria were included. Upon the diagnosis of ALF and after 7 days, we determined liver stiffness (LS) with Fibro-Scan, standard laboratory parameters, and serum levels of matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-9, tissue inhibitor of metalloproteinases 1 (TIMP-1), TIMP-2, hyaluronic acid, and markers of overall cell death (M65) and apoptosis (M30). Stellate cell activation and progenitor response were analyzed immunohistochemically in biopsy samples of 12 patients with α-smooth muscle actin (α-SMA), keratin-17, and keratin-19 staining, respectively. Cell death markers (M30 level = 2243 ± 559.6 U/L, M65 level = 3732 ± 839.9 U/L) and fibrosis markers (TIMP-1 level = 629.9 ± 69.4 U/mL, MMP-2 level = 264 ± 32.5 U/mL, hyaluronic acid level = 438.5 ± 69.3 μg/mL) were significantly increased in patients versus healthy controls. This was paralleled by collagen deposition, elevated α-SMA expression, and higher LS (25.6 ± 3.0 kPa). ALF was associated with ductular progenitor proliferation. Conclusion: Our results demonstrate HSC activation and a progenitor response in ALF. Positive correlations between LS, the degree of liver cell damage, and the intensity of HSC activation suggest that fibrosis is a response to ALF in an attempt to repair damaged tissue. Copyright © 2010 by the American Association for the Study of Liver Diseases.

Beilfuss A.,University of Duisburg - Essen | Sowa J.-P.,University of Duisburg - Essen | Sydor S.,University of Duisburg - Essen | Beste M.,University of Duisburg - Essen | And 10 more authors.
Gut | Year: 2014

Objective Non-alcoholic fatty liver disease (NAFLD) is closely linked to obesity and constitutes part of the metabolic syndrome, which have been associated with low serum vitamin D (VD). Due to known crosstalk between VD and transforming growth factor (TGF)-β signalling, VD has been proposed as an antifibrotic treatment. Design We evaluated the association between VD, the vitamin D receptor (VDR) and liver fibrosis in primary human hepatic stellate cells (phHSC) and 106 morbidly obese patients with NAFLD. Results Treating phHSC with VD ameliorated TGF-β- induced fibrogenesis via both VDR-dependent and VDRindependent mechanisms. Reduction of fibrogenic response was abolished in cells homozygous for GG at the A1012G single nucleotide polymorphisms within the VDR gene. Compared with healthy livers, NAFLD livers expressed higher levels of VDR mRNA and VDR fragments. VDR mRNA was lower in patients homozygous for GG at A1012G and expression of profibrogenic genes was higher in patients carrying the G allele. Conclusions VD may be an antifibrotic treatment option early in the onset of fibrosis in specific genotypes for VDR. Known polymorphisms of the VDR may influence the response to VD treatment.

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