significant fibrosis Fibrosis stage F2 or F3 as defined histologically.3,4* is a strong predictor of liver-related mortality in NASH1,2

Lipotoxicity in the liver is a key driver of fibrosis5-9

  • NASH is a form of hepatitis (liver inflammation) where the major inciting factor is lipotoxic fat accumulation in hepatocytes (liver cells). NASH is defined by the presence of:10-15
    Hepatic steatosis.
    Hepatocellular damage.
    Lobular inflammation.
  • Lipotoxic fat within hepatocytes drives an ongoing inflammatory state characterized by hepatocellular injury/death and increased numbers and activity of a variety of inflammatory cells, including hepatic stellate cells10-13
    • In the presence of lipotoxicity, hepatic thyroid function mediated through thyroid hormone receptor-β (THR-β) is disrupted, impacting lipid metabolism and fatty acid oxidation in the liver16,17
    • In NASH, normal thyroid hormone conversion (prohormone T4 to active hormone T3) shifts to conversion of T4 to inactive reverse T3 (rT3) in the liver. This produces a localized dysfunction in hepatic thyroid hormone activity, resulting in the impairment of mitochondrial activity and lipid management, including the generation of proinflammatory lipid species18,19
    • Hepatic thyroid dysfunction has no effect on the hormone's activity elsewhere in the body (systemic activity and the central thyroid axis are unaffected)18
  • As a result of persistent lipotoxicity and inflammation, hepatic stellate cells lay down scar tissue in the liver (fibrosis)10,11,20
    • Increasing fibrosis can lead to cirrhosis, decompensated liver disease (ascites, esophageal varices, encephalopathy) and liver-related mortality1,2,21,22

Once a patient develops significant fibrosis, Fibrosis stage F2 or F3 as defined histologically.3,4 the risk of liver-related mortality increases substantially1,2

  • For some patients, time to development of severe liver disease may substantially accelerate with each stage of fibrosis progression starting at F221§†

Once significant fibrosisFibrosis stage F2 or F3 as defined histologically.3,4 develops, it is important to actively manage patients with NASH23

  • Due to the increased risks of morbidity and mortality, identification of patients with significant fibrosisFibrosis stage F2 or F3 as defined histologically.3,4 is important to target efforts at preventing disease progression2,3,24
  • The absence of a validated approach to predict the speed of progression for any individual patient further underscores the need for active monitoring

§Cirrhosis, liver failure, liver decompensation, or hepatocellular carcinoma.
The lower end of the 95% CI for the 10th percentile.
*Fibrosis stage F2 or F3 as defined histologically.
T3=triiodothyronine; T4=thyroxine.

Noninvasive tests (NITs) are changing what’s possible with diagnosis and staging25-27