significant fibrosis Fibrosis stage F2 or F3 as defined histologically.11,12* is a strong predictor of liver-related mortality in NASH1,2
In NASH, impairment of hepatic thyroid hormone signaling is a factor that worsens hepatic lipotoxicity, driving fibrosis progression3-6
NASH with fibrosis is a complex, progressive liver disease driven by multiple factors such as genetics, environment, other conditions, and disease site dynamics.7,8
- In NASH, there can be disruption of hepatic thyroid hormone signaling mediated via thyroid hormone receptor-β (THR-β), which is found predominately in the liver3,5
- THR-β signaling disruption can cause mitochondrial dysfunction and impaired lipid metabolism, and is a factor that can worsen hepatic lipotoxicity that drives NASH and fibrosis progression.3-6
- As a result, hepatic stellate cells lay down scar tissue (fibrosis) in the liver, which can progress to cirrhosis, decompensated liver disease, and an increased risk of liver-related mortality1,2,4,5,9
For more information, please visit the FAQs below.
Once a patient develops significant fibrosis, Fibrosis stage F2 or F3 as defined histologically.11,12 the risk of liver-related mortality increases substantially1,2
~10x-17x higher risk of liver-related mortality vs F0
(95% confidence interval)
fibrosis F1Mild fibrosis F2 F3 F4Cirrhosis
- For some patients, time to development of severe liver disease may substantially accelerate with each stage of fibrosis progression starting at F210†‡
Once significant fibrosisFibrosis stage F2 or F3 as defined histologically.11,12 develops, it is important to monitor and manage patients with NASH11
- Due to the increased risks of morbidity and mortality, identification of patients with significant fibrosisFibrosis stage F2 or F3 as defined histologically.11,12 is important to target efforts at preventing disease progression2,12,13
- The absence of a validated approach to predict the speed of progression for any individual patient further underscores the need for active monitoring
What is the role of the thyroid hormone signaling pathway in the liver?
Thyroid hormone plays a central role in hepatic lipid metabolism and processing. The effects of thyroid hormone on hepatic lipid homeostasis are primarily exerted through thyroid receptor-β (THR-β), the predominant isoform expressed in the liver.3
- In a healthy liver, hepatic thyroid hormone signaling activates lipid metabolism and contributes to normal liver function3
- In NASH, studies have shown 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 species4,13-15
- Impairment of hepatic thyroid hormone signaling medicated through THR-β worsens hepatic lipotoxicity, driving progression of liver fibrosis in NASH3-6
What do current clinical guidelines recommend regarding the treatment goal or goals for NASH?
According to current clinical guidelines, the treatment goal in NASH is to resolve the underlying inflammation and steatohepatitis that drive disease progression, in addition to halting and reversing fibrosis. Evidence of fibrosis reversal or halting as well as NASH resolution are considered the best surrogate endpoints to likely predict clinical benefit and correlate to improved disease outcomes.12,16
Why is it important to actively manage NASH?
It’s important to manage NASH because the rates of fibrosis progression and hepatic decompensation vary significantly for each patient. Once a patient develops stage F2, the progression of fibrosis can accelerate unpredictably and the risk of liver-related mortality can increase substantially.5,10,17,18
*Fibrosis stage F2 or F3 as defined histologically.11,12
†Cirrhosis, liver failure, liver decompensation, or hepatocellular carcinoma.
‡The lower end of the 95% CI for the 10th percentile.
Noninvasive tests (NITs) can be used for
disease identification and staging.19-21
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