Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes
Klinik für Innere Medizin II - Gastroenterologie und Endokrinologie
Kommissarischer Leiter der Klinik: Prof. Dr. med. Marcin Krawczyk
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Bundesministerium für Bildung und Forschung - BMBF

DFG/BMBF-Programm für Klinische Studien: Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver cirrhosis and ascites (INCA trial)

Patients with liver cirrhosis suffer an excess mortality of up to 60% within 12 months and in particular, ascites indicates poor prognosis. The development of better care and chronic disease management for patients with cirrhosis is hampered by lack of awareness and prestige in our health care systems. Infectious complications such as spontaneous bacterial peritonitis (SBP) increase the likelihood of death on the waiting list. Although secondary antibiotic prophylaxis after SBP has been established and low ascitic protein levels represents a potential risk factor, no definite primary prophylactic strategy exists. Recently we demonstrated that patients with advanced cirrhosis who carry variants of the NOD2 gene known to impair the intestinal mucosa barrier are at increased risk for both SBP and death (Hepatology 2010;51:1327-33). We now design a randomised, double-blind, placebo-controlled trial to assess the impact of antibiotic prevention with norfloxacin in cirrhotic patients with this genetic risk profile. Based on our previous study, we screen 1,380 patients with ascites in 11 German centres to randomise 186 patients who carry NOD2 risk variants with stratification for ascitic protein. The aim is to compare survival over 12 months with and without primary antibiotic prevention. We monitor bacteria in ascites and stool, with potential future analysis of the microbiome and its modulation in cirrhosis. Confirmation of a beneficial effect of this genotype-based prevention strategy is likely to change care for patients with cirrhosis in the immediate future and may reduce health care burden or even mortality.


BMBF-Forschungsnetz Liver Systems Medicine (LISYM): Pillar III - Regeneration und Repair in Acute-on-Chronic Liver Failure (ACLF)

The most common cause of death in patients with chronic liver disease is organ failure induced by acute challenges, in particular inflammation, drugs or surgery. The incidence of this life-threatening acute-on-chronic liver failure (ACLF) is increasing and early detection and cure are urgent clinical needs. LiSyM Pillar III “Regeneration and Repair in ACLF” applies a systems medicine approach to identify the critical mechanisms of ACLF and to foster liver regeneration and repair. Pillar III combines time resolved analysis of responses to acute injury in chronically diseased livers (human and mouse) from the cellular to the organ scale. In iterative cycles, dynamic pathway, multi-scale tissue and pharmacokinetic models are developed based on quantitative measurements in preclinical models and culture systems and linked to establish increasingly integrative models. Specific aims are to establish mechanistically understood biomarkers for the stratification of high-risk patients regarding their need for transplantation and to develop strategies for therapies facilitating liver regeneration. Pillar III facilitates clinical decision-making for better survival of patients with ACLF.


BMBF-Forschungsnetz zur Früherkennung und Prävention von Leberkrebs (LiSyM-Krebs): Mechanism-based Multiscale Model to Dissect the Tipping Point from Liver Cirrhosis to Hepatocellular Carcinoma (C-TIP-HCC)

A beneficial prognosis for HCC patients is limited by the fact that that curative treatment options
depend crucially on early detection. However, currently available procedures are not sufficiently
sensitive. A robust and reliable method for identifying patients in very early stages of tumor
development would represent a major advancement in the care of these patients. This would
significantly increase the time window for curative treatment options, but also open up new avenues for novel therapeutic interventions. We envision a non-invasive toolkit that identifies patients with end-stage liver disease (cirrhosis of the liver) who are at highest risk to develop HCC. We propose a Systems Medicine approach to identify (non-invasive) measurable tissue and cellular parameters in patients with cirrhosis, the common risk factor for HCC development, that are critical for crossing the Tipping point (TIP) from cirrhosis to HCC. Thereby, the TIP is defined as the stage of cirrhosis, where minor microenvironmental and cellular changes turn the tissue response into malignant transformation and cancer cell development. These tissue and cellular parameters comprise structural changes in the cirrhotic liver architecture, including cellular fate changes (hepatic stellate cells (HSC), macrophages and hepatocytes), qualitative and quantitative alterations of the matrisome, alterations in the TGFβ pathway, as well as longitudinal clinical data from very large national and European patient cohorts (contributions started in LiSyM). Imaging-, omics- and dynamic signaling data will be used to advance the existing mathematical models at the tissue, cellular and molecular scales (developed in LiSyM) to define the patient-specific TIP in the cirrhotic regeneration nodule.


BMBF-Forschungsnetz zur Früherkennung und Prävention von Leberkrebs (LiSyM-Krebs): A Systems Medicine Approach to Early Detection and Prevention of Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease (SMART-NAFLD)
Liver cancer with its predominant form hepatocellular carcinoma (HCC) is expected to rise dramatically over the next decade due to the obesity pandemic that results in an alarming increase in non-alcoholic fatty liver disease (NAFLD). Today already 25% of the global population is affected. NAFLD can progress to non-alcoholic steatohepatitis (NASH), liver fibrosis/cirrhosis and HCC, which is still one of the deadliest cancers worldwide. A particular challenge is that for yet unknown reasons, NAFLD-related HCC not only occurs in the context of advanced liver fibrosis/cirrhosis but a third of NAFLD-related HCC arises in non-cirrhotic liver tissue and the tumor is often only detected at a late, incurable state1. Strikingly, male patients are at higher risk of developing HCC and the reasons for this gender disparity are unknown. Therefore, strategies for early identification of NAFLD patients at high risk of developing HCC are urgently needed. Further, it is essential to assess the regenerative potential of the liver to guide decisions for curative resection of early lesions and reduce cancer mortality.
To address this urgent clinical need, SMART-NAFLD pursues an integrative systems medicine approach that builds on major achievements in LiSyM, such as development of dynamic pathway
models of growth factor and pro-inflammatory signal transduction in hepatocytes, as well as tissue models of liver steatosis and cutting-edge technologies, such as pattern recognition by neuronal networks and quantitative proteomics. Novel aspects are the development of a coarse-grained modeling approach tailored to essential metabolic reactions to interconnect metabolic networks with dynamic pathway models of signal transduction.

Our interdisciplinary team consisting of clinicians, clinician scientists, cell biologists, systems biologists, as well as theoreticians from the fields of physics and bioinformatics proposes that altered glucose and lipid metabolism in hepatocytes from NAFLD patients lowers the threshold for proliferation. Together with increased levels of proinflammatory cytokines, this metabolic state promotes the direct transition across the tipping point from NAFLD towards HCC formation
without cirrhosis (Fig.1). Other patients progress to fibrosis and cirrhosis, and the accompanying cycles of cell death and regeneration promote the development of HCC. Therefore, for early detection of HCC it is essential to uncover tumor promoting alterations in metabolism and growth factor and pro-inflammatory signaling. To dissect these complex interrelations, an integrative mathematical model of metabolism and signal transduction will be developed that quantitatively
represents the metabolic state and the extent of cellular responses in hepatocytes from i) healthy, ii) steatotic, iii) NASH, iv) HCC without cirrhosis and v) HCC with cirrhosis and integrated in a tissue model describing the structural changes during disease progression. Global proteome and metabolome profiling will be employed to identify alarm signatures for HCC in longitudinal blood samples and link these to mechanistic alterations in the tissue.
The key objectives addressed will be:
1. Identify tumor-promoting alterations in metabolism and signal transduction in NAFLD/NASH.
2. Define similarities and differences of HCC in NAFLD/NASH arising in the absence or presence of cirrhosis.
3. Establish a link between alterations in cellular responses to structural changes in tissue and define indicators of the dynamics of NAFLD/NASH progression towards HCC in the blood.

4. Elucidate gender specific differences in the molecular, structural and dynamic characteristics of these processes in NAFLD/NASH.
Using this strategy, we expect to develop a classifier for the early identification of NAFLD patients at high risk of progression to HCC. Through the development of this mechanism-based multiscale model it will become possible to predict the proximity to the tipping point for individual HCC patients and to guide therapeutic decisions for curative resection of early lesions.