Computational simulation of liver fibrosis dynamics.

Liver fibrosis is a result of homeostasis breakdown caused by repetitive injury. The accumulation of collagens disrupts liver structure and function, which causes serious consequences such as cirrhosis. Various mathematical simulation models have been developed to understand these complex processes. We employed the agent-based modelling (ABM) approach and implemented inflammatory processes in central venous regions. Collagens were individually modelled and visualised depending on their origin: myofibroblast and portal fibroblast. Our simulation showed that the administration of toxic compounds induced accumulation of myofibroblast-derived collagens in central venous regions and portal fibroblast-derived collagens in portal areas. Subsequently, these collagens were bridged between central-central areas and spread all over areas. We confirmed the consistent dynamic behaviour of collagen formulation in our simulation and from histological sections obtained via in vivo experiments. Sensitivity analyses identified dead hepatocytes caused by inflammation and the ratio of residential liver cells functioned as a cornerstone for the initiation and progression of liver fibrosis. The validated mathematical model demonstrated here shows virtual experiments that are complementary to biological experiments, which contribute to understanding a new mechanism of liver fibrosis.

Plasma vitamin K concentrations depend on CYP4F2 polymorphism and influence on anticoagulation in Japanese patients with warfarin therapy.

INTRODUCTION: Warfarin is characterized by a large inter-individual variability in dosage requirement. This study aimed to analyze the contribution of the CYP4F2 genetic polymorphism and plasma vitamin K concentration on the warfarin pharmacodynamics in patients and to clarify the plasma vitamin K concentration affecting warfarin sensitivity index in rats. MATERIALS AND METHODS: Genetic analyses of selected genes were performed and plasma concentrations of warfarin, vitamin K1 (VK1) and menaquinone-4 (MK-4) were measured in 217 Japanese patients. We also assessed the association of plasma VK1 and MK-4 concentrations with the warfarin sensitivity index (INR/Cp) in rats. RESULTS: Patients with the CYP4F2 (rs2108622) TT genotype had significantly higher plasma VK1 and MK-4 concentrations than those with CC and CT genotypes. The multiple linear regression model including VKORC1, CYP4F2, and CYP2C9 genetic variants, age, and weight could explain 42% of the variability in warfarin dosage. The contribution of CYP4F2 polymorphism was estimated to be 2.2%. In contrast, plasma VK1 and MK-4 concentrations were not significantly associated with warfarin dosage in patients. Nevertheless, we were able to demonstrate that the warfarin sensitivity index was attenuated and negatively correlated with plasma VK1 concentration by the oral administration of VK1 in rats, as it resulted in a higher VK1 concentration than that in patients. CONCLUSIONS: The plasma VK1 and MK-4 concentrations are significantly influenced by CYP4F2 genetic polymorphism but not associated with warfarin therapy at the observed concentration in Japanese patients. The CYP4F2 polymorphism is poorly associated with inter-individual variability of warfarin dosage requirement.

Effect of VKORC1-1639 G>A polymorphism, body weight, age, and serum albumin alterations on warfarin response in Japanese patients.

INTRODUCTION: To establish individualized warfarin therapy, we investigated the contribution of genetic variations of vitamin K epoxide reductase complex subunit 1 gene (VKORC1) -1639 G>A and Cytochrome P450 2C9 gene (CYP2C9) and clinical factors on warfarin sensitivity in Japanese patients. MATERIALS AND METHODS: Genetic analyses of VKORC1 -1639 G>A and CYP2C9 2, 3, and 4 were performed in 259 Japanese patients and 341 healthy subjects. We selected 259 patients who have been prescribed warfarin with a 1.5-3.0 range of prothrombin time normalized as an international normalized ratio for at least 3 months and investigated factors that contribute to individual variability in warfarin dose. Furthermore, multivariate analysis was performed to investigate a warfarin dosing algorithm. RESULTS AND CONCLUSIONS: There were great inter-individual differences in warfarin maintenance dose in 259 patients, ranging from a minimum dose of 0.75 mg/day to a maximal dose of 8.00 mg/day. VKORC1 -1639 G>A polymorphism, body weight, age, and serum albumin were found to affect the inter-individual variability. The dosing algorithm of warfarin maintenance dose was investigated by multivariate linear regression. The regression equation was able to account for 33.2% (R(2)(Adj)=0.332) of the overall variability in warfarin dose.