Prediction of postoperative liver regeneration from clinical information using a data-led mathematical model

Although the capacity of the liver to recover its size after resection has enabled extensive liver resection, post-hepatectomy liver failure remains one of the most lethal complications of liver resection. Therefore, it is clinically important to discover reliable predictive factors after resection. In this study, we established a novel mathematical framework which described post-hepatectomy liver regeneration in each patient by incorporating quantitative clinical data. Using the model fitting to the liver volumes in series of computed tomography of 123 patients, we estimated liver regeneration rates. From the estimation, we found patients were divided into two groups: i) patients restored the liver to its original size (Group 1, n?=?99); and ii) patients experienced a significant reduction in size (Group 2, n?=?24). From discriminant analysis in 103 patients with full clinical variables, the prognosis of patients in terms of liver recovery was successfully predicted in 85–90% of patients. We further validated the accuracy of our model prediction using a validation cohort (prediction?=?84–87%, n?=?39). Our interdisciplinary approach provides qualitative and quantitative insights into the dynamics of liver regeneration. A key strength is to provide better prediction in patients who had been judged as acceptable for resection by current pragmatic criteria

A novel comparative pattern analysis approach identifies chronic alcohol mediated dysregulation of transcriptomic dynamics during liver regeneration.

BACKGROUND: Liver regeneration is inhibited by chronic ethanol consumption and this impaired repair response may contribute to the risk for alcoholic liver disease. We developed and applied a novel data analysis approach to assess the effect of chronic ethanol intake in the mechanisms responsible for liver regeneration. We performed a time series transcriptomic profiling study of the regeneration response after 2/3(rd) partial hepatectomy (PHx) in ethanol-fed and isocaloric control rats. RESULTS: We developed a novel data analysis approach focusing on comparative pattern counts (COMPACT) to exhaustively identify the dominant and subtle differential expression patterns. Approximately 6500 genes were differentially regulated in Ethanol or Control groups within 24 h after PHx. Adaptation to chronic ethanol intake significantly altered the immediate early gene expression patterns and nearly completely abrogated the cell cycle induction in hepatocytes post PHx. The patterns highlighted by COMPACT analysis contained several non-parenchymal cell specific markers indicating their aberrant transcriptional response as a novel mechanism through which chronic ethanol intake deregulates the integrated liver tissue response. CONCLUSIONS: Our novel comparative pattern analysis revealed new insights into ethanol-mediated molecular changes in non-parenchymal liver cells as a possible contribution to the defective liver regeneration phenotype. The results revealed for the first time an ethanol-induced shift of hepatic stellate cells from a pro-regenerative phenotype to that of an anti-regenerative state after PHx. Our results can form the basis for novel interventions targeting the non-parenchymal cells in normalizing the dysfunctional repair response process in alcoholic liver disease. Our approach is illustrated online at http://compact.jefferson.edu

Longitudinal Ultrasound Imaging and Network Modeling in Rats Reveal Sex-Dependent Suppression of Liver Regeneration After Resection in Alcoholic Liver Disease

Liver resection is an important surgical technique in the treatment of cancers and transplantation. We used ultrasound imaging to study the dynamics of liver regeneration following two-thirds partial hepatectomy (PHx) in male and female rats fed via Lieber-deCarli liquid diet protocol of ethanol or isocaloric control or chow for 5–7 weeks. Ethanol-fed male rats did not recover liver volume to the pre-surgery levels over the course of 2 weeks after surgery. By contrast, ethanol-fed female rats as well as controls of both sexes showed normal volume recovery. Contrary to expectations, transient increases in both portal and hepatic artery blood flow rates were seen in most animals, with ethanol-fed males showing higher peak portal flow than any other experimental group. A computational model of liver regeneration was used to evaluate the contribution of physiological stimuli and estimate the animal-specific parameter intervals. The results implicate lower metabolic load, over a wide range of cell death sensitivity, in matching the model simulations to experimental data of ethanol-fed male rats. However, in the ethanol-fed female rats and controls of both sexes, metabolic load was higher and in combination with cell death sensitivity matched the observed volume recovery dynamics. We conclude that adaptation to chronic ethanol intake has a sex-dependent impact on liver volume recovery following liver resection, likely mediated by differences in the physiological stimuli or cell death responses that govern the regeneration process. Immunohistochemical analysis of pre- and post-resection liver tissue validated the results of computational modeling by associating lack of sensitivity to cell death with lower rates of cell death in ethanol-fed male rats. Our results illustrate the potential for non-invasive ultrasound imaging to assess liver volume recovery towards supporting development of clinically relevant computational models of liver regeneration

Additional file 2: of Systems analysis of non-parenchymal cell modulation of liver repair across multiple regeneration modes

Matlab code executing the model used in this study. (M 10 kb

Additional file 21: Figure S17. of Systems analysis of non-parenchymal cell modulation of liver repair across multiple regeneration modes

Simulations using hepaotyce-specific parameter alterations compared to disease regeneration profiles. Model fits to disease regeneration profiles reveals altered hepatocyte response to non-parenchymal cell signaling is sufficient to explain disease-induced inhibition of regeneration in (A) Non-alcoholic steatohepatitis (MSE = 1.96x10−2), (B) Alcoholic steatohepatitis (MSE = 1.89x10−2), and (C) Chirrhosis (MSE = 5.14x10−2), but not in (D) Diabetes (MSE = 1.19). In all cases, the previous set of parameters (Additional file 15: Table S2) gave lower MSE than the hepatocyte-specific parameter alterations (Additional file 20: Table S3). MSE = Mean Squared Error between experimental and simulated data. (TIFF 1791 kb

Additional file 18: Figure S15. of Systems analysis of non-parenchymal cell modulation of liver repair across multiple regeneration modes

Regeneration profiles for healthy livers and those with toxin-induced cirrhosis. (A) Fibrosis causes a delay in the initiation of regeneration (note change in time scale) but ultimately little change in overall mass recovery. Mass recovery is due mainly to hepatocyte replication rather than cell growth. (B) This profile is driven by a sustained inflammatory response, a lack of growth factor bioavailability, and impaired matrix deposition following wounding. (MSE = 2.50x10−3) (TIFF 302 kb

Additional file 14: Figure S12. of Systems analysis of non-parenchymal cell modulation of liver repair across multiple regeneration modes

Relationships between fitted parameters and body mass across species. (A) Metabolic demand shows a negative exponential relationship with body mass following the equation: Metabolic Demand = 47.315 ∗ Mass − 0.1825 (R2 = 0.95). (B) Cell growth rate for humans was estimated as the average growth for mouse and rat because there is little difference in cultured hepatocyte growth rates between species. (TIFF 66 kb