INN-217 (NASH)


Nonalcoholic Steatohepatitis

Nonalcoholic steatohepatitis (NASH) is a smaller subset of liver disease stemming from the most common liver disease in the world, fatty liver disease, which affects about a quarter of the adults in the United States. Nonalcoholic steatohepatitis, identified by increased liver enzyme tests in the absence of other causes of liver injury, is definitively diagnosed via a biopsy finding of fat accumulation (steatosis) in the liver as well as microscopic findings of cellular injury to the cells in the organ. This form of fatty liver disease could lead to fibrosis of the liver over time and could lead to liver-related death, involving cirrhosis and cancer.


There are strong correlations to NASH with overweight and/or obese individuals, patients prone to dyslipidemia profiles, and patients known to have type 2 diabetes mellitus. The disease is strongly associated with a condition known as metabolic syndrome, which is a disorder of the body’s energy metabolism and is often accompanied by visceral fat deposition in adults.


The burden of illness on the healthcare system in the United States alone is beginning to approach unmanageable numbers already. It is estimated that the current costs associated with NASH and its associated sequelae will top $100 billion in annual direct medical expenditure.


The actual pathogenesis of the progression from fatty liver disease to steatohepatitis to the fibrotic pathways of the liver and cancer are being studied by many research groups in hopes of developing effective interventions to stem the disease which is estimated to reach epidemic proportions over the next decade. Areas of interest for researchers include, mitigating exposure of hepatocytes to inflammation via various mediators, various cytokines, and gut derived products and toxins which may enter the systemic circulation via a “leaky” and disrupted epithelial tight junction network.


A growing body of evidence suggests the progression of fatty liver disease to NASH is multifactorial, with bacterial translocation thorough the intestinal wall and small intestinal bacterial overgrowth being a contributing factor. Understanding the mechanisms behind intestinal hyperpermeability in patients with confirmed fatty liver and NASH is critical to intervening in this at-risk population and to develop treatments to stem progression. There is no cure or approved medicines for fatty liver disease or NASH.

Mechanism

Intestinal tight junctions control the passage of large molecules such as intact proteins, particles and cells through the paracellular space. This passive transport is known as intestinal paracellular permeability, and while it accounts for only 10% of total protein uptake it serves as the major portal for intact protein and antigen delivery into the body. Protein entry is in close proximity to the submucosal lymphocytes, which comprise 80% of immunoglobulin producing cells in the human body.


Increased intestinal paracellular permeability leads to antigen presentation for processing and antibody response. Tight junctions in other organs have a similar function: the regulation of paracellular transport. In the capillary endothelia of the blood brain barrier, tight junctions are the anatomical barrier interfacing blood and CNS.


Tight junction dysfunction has been implicated in a host of disease states, including a variety of autoimmune diseases. Ischemia - reperfusion injury also appears to be associated with tight junction dysfunction, while many cytokines, bacterial toxins, infections, and drugs have also been implicated in tight junction injury or destruction.