The epidemic increase of non-alcoholic fatty liver diseases (NAFLD) requires a deeper understanding of the regulatory circuits controlling the response of liver metabolism to nutritional challenges, medical drugs, and genetic enzyme variants. As in vivo studies of human liver metabolism are encumbered with serious ethical and technical issues, we developed a comprehensive biochemistry-based kinetic model of the central liver metabolism including the regulation of enzyme activities by their reactants, allosteric effectors, and hormone-dependent phosphorylation. The utility of the model for basic research and applications in medicine and pharmacology is illustrated by simulating diurnal variations of the metabolic state of the liver at various perturbations caused by nutritional challenges (alcohol), drugs (valproate), and inherited enzyme disorders (galactosemia). Using proteomics data to scale maximal enzyme activities, the model is used to highlight differences in the metabolic functions of normal hepatocytes and malignant liver cells (adenoma and hepatocellular carcinoma).

The maximal liver function capacity (LiMAx) test, a novel C-methacetin breath test, has proven clinical validity in determining hepatic metabolic capacity. In contrast to priorC-methacetin breath test protocols, the LiMAx test is performed by intravenous body-weight-adjusted substrate administration. Furthermore, the DOB kinetics (delta over baseline of the time-dependent exhaled CO/CO ratio) are measured online at the bedside with a high time resolution in order to determine the maximum DOB. The aim of this study was to analyze the recorded DOB kinetics in a large population for further refinement of the test protocol. Two new methods of kinetic analysis are proposed in this article: the time dependency of the DOB kinetics and the time interval until half of the DOB maximum. A total of 10 100 LiMAx tests on 8483 patients performed during routine clinics at eight centers were available. The kinetic analysis revealed a specific pattern of DOB kinetics depending upon LiMAx result. In addition, potential co-factors for DOB kinetics, such as weight, height, gender and age, were analyzed, yielding a potential influence of gender and smoking behavior. Both the specific patterns and the proposed kinetic analysis have the potential to further improve the sensitivity and specificity of the test and its clinical applicability by shortening its duration.

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