NASH

NASH Definition and Prevalence:

NASH (non-alcoholic steatohepatitis) occurs when there is a build-up of excess fat in the liver that is accompanied by inflammation and fibrosis. Some amount of liver fat is normal, but a higher amount is termed nonalcoholic fatty liver disease (NAFLD). NASH is a progressive inflammatory disease occurring in fatty liver that leads to severe fibrosis (cirrhosis) and may require liver transplantation. NASH usually occurs in people with NAFLD who are obese and may have other health problems, such as type 2 diabetes and hyperlipidemia. NASH has been termed “the next big global epidemic”. About 30% of the global population has fatty liver, up to 30% of these patients will develop NASH, and up to 25% of patients with NASH will develop cirrhosis within 7 years from diagnosis.

 

NASH Biology:

Progression from NAFLD to NASH is thought to require “two hits”: the first being an accumulation of excess liver fat, and the second being the initiation of an inflammatory process. As a “first hit”, uric acid is known to increase liver uptake of triglycerides.
 
A number of factors have been proposed as the “second hit”. However, the physiologic production of uric acid itself generates “reactive oxygen species” (ROS) that are linked to tissue damage and inflammation in multiple diseases, including NASH, gout, atherosclerosis, and chronic kidney disease. ROS-induced lipid peroxidation triggers inflammation and generates cytokines that promote collagen formation that ultimately leads to liver fibrosis (cirrhosis).

 

Relationship of NASH to Uric Acid:

A subgroup of NASH patients (30% to 50%) have elevated serum uric acid (UA).  In such patients, serum UA has shown a “dose:effect correlation” with NASH: namely, higher UA levels are clearly linked to a higher risk of developing NASH from fatty liver, as well the severity and progression of NASH to cirrhosis.

With additional laboratory studies, this association – observed over the last 15 years – has suggested that UA may actually be causative in some NASH patients. Recent studies have also shown that drugs that block UA production and/or accelerate its excretion can inhibit both development and progression of NASH. These results have prompted calls for clinical trials of potent hypouricemic drugs in NASH.

Relburn plans to test its unique drugs in clinical trials of patients afflicted with NASH in the setting of hyperuricemia.

References

Lanaspa M, et al.:  Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver. J Biol Chem 48:40732-44, 2012.
http://www.jbc.org/content/287/48/40732.long

Sirota JC, et al.:  Elevated serum uric acid levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome in the United States.  Metabolism 62:392-99, 201.  doi:  
10.1016/j.metabol.2012.08.013

Choi Y-J, et al.:  Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes. Lab Invest 94;1114–25, 2014. 
http://www.nature.com/labinvest/journal/v94/n10/full/labinvest201498a.html?foxtrotcallback=true

Kushiyama A, et al.:  Role of uric acid metabolism-related inflammation in the pathogenesis of metabolic syndrome components such as atherosclerosis and nonalcoholic steatohepatitis.  Mediators Inflam 2016.   
https://dx.doi.org/10.1155%2F2016%2F8603164

Sun DQ, et al.:  Serum uric acid: a new therapeutic target for nonalcoholic steatohepatitis.  Expert Opin Ther Targets, 20:375-87, 2016.  https://www.ncbi.nlm.nih.gov/pubmed/26419119

Zhou Z, et al.:  Associations between serum uric acid and the remission of non-alcoholic fatty liver disease in Chinese males. PLos One 11/11/2016 
https://doi.org/10.1371/journal.pone.0166072