Non-Alcoholic Fatty Liver Disease (NAFLD) is an imminent global epidemic due to the rapidly increasing rates of obesity and diabetes mellitus. As of this moment, NAFLD is the leading cause of chronic liver disorder in developed countries, with a concerningly higher incidence rate of 27% in Hong Kong.1-3 The alarmingly rising burden is due to the absence of much-needed accurate non-invasive assays to distinguish NAFLD to non-alcoholic steatohepatitis (NASH). Recently, three-dimensional (3D) liver models have resolved the geometrical and functional limitations of the current two-dimensional (2D) liver models, allowing for better 3D spatial resolution of the human liver tissues. Herein, the 3D liver models can quantify multi-parametric cellular and tissue signatures to define NAFLD progression, revealing new aspects of NAFLD progression.3
Alarmingly, the prevalence rates of NAFLD are on the rise, with a worldwide projected increase of 30%, without a sufficient treatment insight.1 NAFLD is characterized by an accumulation of fat, chiefly, triglycerides, and lipid droplets (LD) in the liver and insulin resistance independent of alcohol intake. As such, NAFLD encompasses a spectrum of liver diseases ranging from simple steatosis to NASH.4 Notably, patients with NASH are at risk of progressing to more severe stages, such as cirrhosis or hepatocellular carcinoma (HCC), inevitably leading to liver failure and transplantation. Further to this, a significant percentage of (~35-50%) HCC occurs in NASH before the symptoms, such as cirrhosis, appear.
For this reason, understanding the mechanism and early disease diagnosis is essential for the effective treatment of NAFLD. Presently, the gold standard for diagnosis and differentiation of the various stages of NAFLD and NASH consists of a biopsy and histological analysis of thin liver tissue slices (<10µm). However, because of the three-dimensional (3D) complexity of the liver tissue, 2D analyses lead to a poor low-resolution image of the liver tissue. Thus, designing an accurate non-invasive NAFLD diagnostic test requires incorporating both the complexity of human liver organ and the intricate mechanism of NAFLD.
Recently, a 3D geometrical and functional model of human liver tissue defining each stage of NAFLD progression was developed by a team of researchers at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden. In summation, the method involves applying multiphoton imaging, 3D digital reconstructions and computational simulations tools to resolve the spatial geometrical and functional challenges of the human liver tissues at different stages of NAFLD.4
Initial data indicated dysregulation in apical protein by demonstrating the redistribution of dipeptidyl peptidase IV (DPPIV) protein to the lateral membrane in pericentral hepatocytes in NASH, prompting further investigation into the bile canaliculi (BC). Interestingly, these findings revealed a sustained increase in BC radius in NASH throughout the CV-PV axis and a substantial reduction in the total length of the BC towards the pericentral zone.
Also, computational fluid dynamics (CFD) modeling enables the investigation of pressure and flow field for the biliary fluid dynamics at a temporal and spatial resolution, otherwise unachievable by the present clinical methodology, due to incompressible blood flows caused by comparatively larger capillaries. Significantly, the model can predict bile velocities in the periportal area in patients suffering from mild to serve NASH, depending on the BC geometry.
Besides, the geometrical models of liver tissue from human biopsies combined with computational simulations revealed new aspects of NAFLD pathology by identifying a set of cellular and tissue parameters connected with disease progression. In particular, novel discovery, such as changes in nuclear texture, might serve as a potential histological scoring system for the NAFLD progression.
Interestingly, the data revealed that the structure of 3D bile canaliculi network is profoundly different in the affected tissue, by using the personalized biliary fluid dynamic simulations in the areas of bile flow. Consequently, it leads to the discovery of critical structural changes with functional consequences, such as “micro-cholestasis”.
In conclusion, the emergence of new 3D Liver models has paved the way for newer methods of treating patients with NAFLD and NASH. With the discovery of first successful 3D-liver tissue histology model in determining the correlation between bile flow and NAFLD progression, there is growing optimism that a new wave of 3D liver models might eventually decipher the NAFLD blueprint and disease profile, facilitating better management techniques and efficacious NAFLD therapeutics to the market soon.