From the Guidelines
Cholestatic liver injury, also known as cholestatic hepatitis, is primarily caused by medications, biliary obstruction, primary biliary cholangitis, and primary sclerosing cholangitis, as supported by the most recent evidence from 2020 1.
Causes of Cholestatic Liver Injury
The causes of cholestatic liver injury can be categorized into several key areas:
- Medications: Such as antibiotics, statins, and anabolic steroids, which can induce cholestasis as a side effect, as noted in the 2009 guidelines 1.
- Biliary obstruction: This can be due to gallstones, tumors, or other mechanical blockages that impede bile flow.
- Primary biliary cholangitis (PBC): An autoimmune disease that leads to the progressive destruction of the bile ducts within the liver.
- Primary sclerosing cholangitis (PSC): A chronic liver disease characterized by inflammation and scarring of the bile ducts, which can lead to cholestasis.
Management and Treatment
The management of cholestatic liver injury involves removing the underlying cause, particularly discontinuing offending medications, and may include the use of ursodeoxycholic acid (UDCA) to improve bile flow and reduce inflammation, as recommended in the 2020 consensus guidelines 1. Additional supportive care measures may include:
- Cholestyramine to relieve pruritus by binding bile acids.
- Fat-soluble vitamin supplementation (vitamins A, D, E, K) due to malabsorption.
- Nutritional support with medium-chain triglycerides that do not require bile for absorption. Regular liver function monitoring is essential, with follow-up every 2-4 weeks initially, to assess the progression of the disease and the effectiveness of the treatment.
Pathophysiology
The pathophysiology of cholestatic liver injury involves either mechanical obstruction of the bile ducts or functional impairment of bile formation at the hepatocyte level, leading to hepatocellular damage from accumulated toxic bile acids, as discussed in the context of PBC and PSC 1.
Clinical Considerations
It is crucial to differentiate between cholestatic liver injury and other liver diseases, such as autoimmune hepatitis, and to monitor for signs of hepatic decompensation, especially in patients with advanced liver disease, as emphasized in the 2020 guidelines 1. The use of Hy's Law and the assessment of liver biochemistries, including alkaline phosphatase, aminotransferases, and bilirubin levels, are important in the diagnosis and management of cholestatic liver injury.
From the FDA Drug Label
Lithocholic acid causes cholestatic liver injury and can cause death from liver failure in certain species unable to form sulfate conjugates. Lithocholic acid is formed by 7-dehydroxylation of the dihydroxy bile acids (ursodiol and chenodiol) in the gut lumen. Although liver injury has not been associated with ursodiol therapy, a reduced capacity to sulfate may exist in some individuals, but such a deficiency has not yet been clearly demonstrated. Lithocholic acid, a naturally occurring bile acid, is known to be a liver-toxic metabolite.
The causes of cholestatic liver injury (cholestatic hepatitis) include:
- Lithocholic acid: a naturally occurring bile acid that is a liver-toxic metabolite
- Reduced capacity to sulfate: may exist in some individuals, which can lead to lithocholate-induced liver damage 2, 2 Key points:
- Lithocholic acid is formed by 7-dehydroxylation of dihydroxy bile acids in the gut lumen
- A reduced capacity to sulfate may predispose individuals to lithocholate-induced liver damage
From the Research
Causes of Cholestatic Liver Injury
The causes of cholestatic liver injury, also known as cholestatic hepatitis, can be attributed to various factors, including:
- Obstruction of the biliary tracts, which can lead to the accumulation of bile acids in the liver 3
- Damage to bile ducts, resulting in the build-up of bile acids and inflammatory processes that cause injury to cholangiocytes and hepatocytes 4
- Drug-induced liver injury (DILI), which can present as bland cholestasis, cholestatic hepatitis, secondary sclerosis cholangitis, and vanishing bile duct syndrome 5
- Autoimmune mechanisms, which have been postulated and partially elucidated in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) 6
- Congenital or inherited conditions, particularly in infants and children 7
Risk Factors
Certain risk factors have been identified for cholestatic DILI, including:
- Older age
- Genetic determinants
- Certain medications, such as amoxicillin-clavulanate and cephalosporin 5
Pathogenesis
The pathogenesis of cholestatic liver disease is still unclear, although autoimmune mechanisms have been postulated and partially elucidated 6. The accumulation of bile acids in the liver is thought to be a major driver of liver injury during cholestasis, which can lead to eventual liver fibrosis and cirrhosis 3.