Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes
Klinik für Innere Medizin II - Gastroenterologie und Endokrinologie
Leitung: Univ.-Prof. Dr. Frank Lammert
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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.