Influence of NOD2 risk variants on hepatic encephalopathy and association with inflammation, bacterial translocation and immune activation

Liver International, vol. 43, pp. 1793–1802

Abstract

BACKGROUND: Nucleotide-binding oligomerization domain containing 2 (NOD2) risk variants lead to impaired mucosal barrier function, increased bacterial translocation (BT), and systemic inflammation. AIM: To evaluate the association between the presence of NOD2 risk variants, BT, inflammation, and hepatic encephalopathy (HE). PATIENTS AND METHODS: This prospective multicenter study included patients with cirrhosis and testing for NOD2 risk variants (p.R702W, p.G908R, c.3020insC, N289S, and c.-958T>C). Patients were evaluated for covert (C) and overt (O) HE. Markers of systemic inflammation (leukocytes, CRP, IL-6, LBP) and immune activation (soluble CD14) as well as bacterial endotoxin (hTRL4 activation) were determined in serum. RESULTS: Overall, 172 patients (70% men; median age 60 [IQR 54-66] years; MELD 12 [IQR 9-16]; 72% ascites) were included, of whom 53 (31%) carried a NOD2 risk variant. In this cohort, 11% presented with OHE and 27% and CHE. Presence and severity of HE and surrogates of inflammation, BT, and immune activation did not differ between patients with and without a NOD2 risk variant, also not after adjustment for MELD. HE was associated with increased ammonia and systemic inflammation, as indicated by elevated CRP (w/o HE: 7.2 [2.7-16.7]; with HE 12.6 [4.5-29.7] mg/dL; p < 0.001) and elevated soluble CD14 (w/o HE 2592 [2275-3033]; with HE 2755 [2410-3456] ng/mL; p = 0.025). CONCLUSIONS: The presence of NOD2 risk variants in patients with cirrhosis is not associated with HE and has no marked impact on inflammation, BT, or immune activation. In contrast, the presence of HE was linked to ammonia, the acute phase response, and myeloid cell activation.

Authors 11

1. Cristina Ripoll corresponding

   Jena University Hospital · Friedrich Schiller University Jena

   Affiliation as printed

   Internal Medicine IV Jena University Hospital, Friedrich Schiller University Jena Germany

   Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany

2. Robin Greinert

   Martin Luther University Halle-Wittenberg

   Affiliation as printed

   Internal Medicine I Martin Luther University Halle‐Wittenberg Halle Germany

   Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Germany

3. Philipp Alexander Reuken

   Jena University Hospital · Friedrich Schiller University Jena

   Affiliation as printed

   Internal Medicine IV Jena University Hospital, Friedrich Schiller University Jena Germany

   Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany

4. Matthias Reichert

   Universitätsklinikum des Saarlandes · Saarland University

   Affiliation as printed

   Department of Medicine II Saarland University Medical Center Homburg Germany

   Department of Medicine II, Saarland University Medical Center, Homburg, Germany

5. Susanne Nicole Weber

   Universitätsklinikum des Saarlandes · Saarland University

   Affiliation as printed

   Department of Medicine II Saarland University Medical Center Homburg Germany

   Department of Medicine II, Saarland University Medical Center, Homburg, Germany

6. Yvonne Hupfer

   Jena University Hospital · Friedrich Schiller University Jena

   Affiliation as printed

   Internal Medicine IV Jena University Hospital, Friedrich Schiller University Jena Germany

   Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany

7. Raphaela Staltner

   University of Vienna

   Affiliation as printed

   Department of Nutritional Sciences, Molecular Nutritional Science University of Vienna Vienna Austria

   Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria

8. Magdalena Meier Clinien

   Jena University Hospital · Friedrich Schiller University Jena

   Affiliation as printed

   Internal Medicine IV Jena University Hospital, Friedrich Schiller University Jena Germany

   Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany

9. Frank Lammert

   Medizinische Hochschule Hannover

   Affiliation as printed

   Hannover Medical School (MHH) Hannover Germany

   Hannover Medical School (MHH), Hannover, Germany

10. Tony Bruns Aachen Internal Medicine III

    RWTH Aachen University · Universitätsklinikum Aachen · Jena University Hospital · Friedrich Schiller University Jena

    Affiliation as printed

    Internal Medicine III University Hospital RWTH Aachen Aachen Germany

    Internal Medicine IV Jena University Hospital, Friedrich Schiller University Jena Germany

    Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany

    Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany

11. Alexander Zipprich

    Jena University Hospital · Friedrich Schiller University Jena

    Affiliation as printed

    Internal Medicine IV Jena University Hospital, Friedrich Schiller University Jena Germany

    Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany