NASH is a common and serious chronic liver disease that resembles alcoholic liver disease, but occurs in people who drink little or no alcohol. In NASH patients, fat accumulation in the liver, known as nonalcoholic fatty liver disease (NAFLD) or steatosis, and other factors such as high LDL cholesterol and insulin resistance induce chronic inflammation in the liver and may lead to progressive scarring of tissue, known as fibrosis, and cirrhosis, followed eventually by liver failure and death.
Typically a silent disease with few or no symptoms, NASH is the fastest growing cause of liver transplantation in the United States and is a leading cause of hepatocellular carcinoma, the most common form of liver cancer. NASH patients have a ten-fold greater risk of liver-related mortality compared with the general population.
Based on an epidemiological study published in 2011, it is estimated that more than 10 percent of adults in the United States have NASH, representing over 30 million people. Although the prevalence of NASH is lower in children, it has also become a serious disease burden in the pediatric population. Other common co-existing conditions such as obesity and type 2 diabetes are important risk factors for NASH. From 1980 to 2010, the rate of obesity in the United States alone has more than doubled in adults and more than tripled in children 6 to 11 years of age and 12 to 19 years of age and has been projected to increase by an additional 33 percent over the next two decades. Globally, the rate of obesity has also nearly doubled since 1980 and is expected to double again by 2030 if not addressed.
IBAT inhibition has also been shown in the clinic to decrease LDL cholesterol and increase GLP1 secretion (which is linked to decreased insulin resistance) and, preclinically, to decrease pro-inflammatory markers (such as tumor necrosis factor alpha, or Tnf-α), and profibrotic markers (such as collagen, type 1, alpha 1 and 2) in the liver, as well as NAFLD (nonalcoholic fatty liver disease) Activity Score. High cholesterol, insulin resistance, increased liver inflammation and fibrosis are all key hallmarks of NASH, making IBAT inhibition, and bile acid modulation generally, a promising approach for treating NASH.