Welcome to LEAD, the Liver Excellence Academy on Demand, brought to you by Mirum.

As the hepatology field rapidly evolves, we are excited to share our learnings regarding the many parallels among different cholestatic liver diseases:

First: The symptomatic similarities and associated burdens, 

Second: The impact on bile acids, 

And third: The importance of uncovering the unspoken signals 

Cholestatic liver disease results in the intrahepatic and extrahepatic accumulation of bile acids, with subsequent spillover into the systemic circulation, driving disease progression and a symptom burden that could profoundly affect patient quality of life.

For adults, cholestatic liver disease could mean enduring the burdens of:

Cholestatic pruritus,

Cholestatic fatigue,

Sleepless nights,

Discomfort,

Poor nutrient absorption,

And jaundice

The spectrum of symptoms can range in severity, with some symptoms being easier to detect than others. 

Many adults often minimize or normalize their symptoms.

Cholestatic pruritus, even when mild or intermittent, could severely impact every aspect of a patient's life, including sleep, as it intensifies at night and worsens with heat.

Cholestatic fatigue is another debilitating symptom that often presents, regardless of the severity of cholestasis.

Timely recognition is critical, as these signs and symptoms could profoundly disrupt patients’ lives:

Embarrassment from cholestatic pruritus, 

Anxiety around the disease,

Depression and social isolation—which can be due to both cholestatic pruritus and fatigue,

Missing out on work and school,

And even uncertainty about their futures.

Although the cause of cholestatic pruritus remains unknown, it may be related to bile acid spillover and other bile components entering the bloodstream.

Cholestasis is characterized by elevated serum bile acid levels, though levels may fluctuate.

Intrahepatic bile acid accumulation could lead to

• Oxidative stress
• Mitochondrial injury
• Cell membrane disruption
• And hepatocyte cell death

Stressed hepatocytes release inflammatory cytokines, attracting neutrophils and other immune cells, and triggering an ongoing inflammatory response.

Persistent inflammation may also explain the profound fatigue in patients with cholestatic liver disease.

ALP, GGT, ALT, and AST levels change in response to hepatocellular liver injury across different cholestatic diseases, and are therefore important to monitor.

Additionally, when the liver loses half of its capacity to excrete bile, conjugated bilirubin levels rise. Persistently elevated bilirubin levels signal a worse clinical prognosis.

Persistent cholestasis and chronic inflammation set off fibrogenesis that can progress to cirrhosis.

If extensive scarring leads to liver failure, the only remaining option becomes liver transplant.

Inflammation also poses an increased risk of life-threatening cholangiocarcinoma or hepatocellular carcinoma.

Many patients live with unexplained cholestasis and burdensome symptoms without clear answers. 

As understanding evolves, new opportunities are emerging to better recognize, diagnose, and support them.

Digging deeper to search for the signals of cholestatic liver disease and talking to patients about their lived experiences could help address the full spectrum of symptoms. 

Without an accurate diagnosis or appropriate treatment, patients may continue to suffer in silence and experience a diminished quality of life. 

Every discussion creates an opportunity for earlier diagnosis and appropriate treatment to help address symptoms and potentially prevent further decline.