What is cholestatic liver disease?

Cholestatic Liver Disease

Cholestatic liver disease is characterized by impaired bile flow that leads to accumulation of bile acids in the liver, resulting in progressive hepatobiliary damage that can advance to fibrosis, biliary cirrhosis, and end-stage liver disease if left untreated. 1

Definition and Classification

• Cholestasis is clinically defined by increased serum bilirubin and elevated alkaline phosphatase levels due to impairment of bile flow 1
• Anatomically categorized as:
  • Intrahepatic cholestasis: Occurs within the liver due to various hepatobiliary disorders 1
  • Extrahepatic cholestasis: Primarily due to obstructive lesions of bile ducts outside the liver 1

Pathophysiological Mechanisms

• Hepatocellular cholestasis: Impaired bile formation at the hepatocyte level due to:

  • Sepsis or endotoxemia 1
  • Viral hepatitis (cholestatic variant) 1
  • Alcoholic or non-alcoholic steatohepatitis 1
  • Drug-induced or parenteral nutrition-induced mechanisms 1
  • Genetic disorders (e.g., BRIC, PFIC, ABCB4 deficiency) 1

• Cholangiocellular cholestasis: Impairment at the bile duct level due to:

  • Primary biliary cirrhosis (PBC) 1
  • Primary sclerosing cholangitis (PSC) 1
  • Overlap syndromes of PBC and PSC with autoimmune hepatitis 1
  • IgG4-associated cholangitis 1
  • Drug-induced cholangiopathy 1

Drug-Induced Cholestatic Liver Disease

Drug-induced cholestasis represents approximately 30% of all drug-induced liver injury (DILI) cases and has a prevalence between 1 in 10,000 and 1 in 100,000 patients, though this is likely underreported 1, 2.

Mechanisms

• Two major mechanisms of drug-induced cholestasis:
  • Inhibition of hepatocellular transporter expression/function affecting bile secretion 1, 2
  • Idiosyncratic inflammatory or hypersensitive reactions at the bile ductular/cholangiocellular level 1, 2
• Rarely, drugs can induce vanishing bile duct syndrome (VBDS) that may progress to biliary cirrhosis 1

Risk Factors

• Age, gender, medication dosage, and co-administered medications can increase susceptibility 1, 2
• Genetic variations in hepatobiliary transporters and biotransformation enzymes may determine individual susceptibility 1

Diagnosis

• Based on temporal relationship between drug intake and onset of cholestasis 1, 2
• Laboratory criteria: Elevated alkaline phosphatase (AP) >2 ULN or ALT/AP ratio <2 1, 2
• Requires exclusion of other causes through careful history and diagnostic workup 1
• Liver biopsy is usually not required unless the course is severe, progressive, or prolonged 1
• Abdominal ultrasound is indicated to exclude other liver diseases 1

Treatment

• The only effective treatment for drug-induced cholestasis is withdrawal of the suspected drug 1, 2
• Early detection of abnormal liver tests and prompt drug withdrawal are crucial to avoid serious liver injury 1, 2
• Ursodeoxycholic acid (UDCA) may beneficially affect cholestasis in approximately two-thirds of cases, though evidence is limited 1, 2
• Corticosteroids may potentially benefit hypersensitivity-induced cholestasis, but controlled trials are lacking 1
• Prognosis is generally good after drug withdrawal, with drug-induced cholestatic injury having a better prognosis than hepatocellular injury 1, 2

Genetic Cholestatic Disorders

Progressive Familial Intrahepatic Cholestasis (PFIC)

• Group of three inherited cholestatic diseases that may start early after birth or at young age 1
• Caused by mutations in canalicular transporter genes of the ATP-binding cassette (ABC) transporters 1
• Types include:
  • PFIC type 1 (Byler disease): Mutations in ATP8B1 gene encoding a phospholipid flippase 1
  • PFIC type 2 (Byler syndrome): Mutations in ABCB11 gene encoding the canalicular bile salt export pump 1
  • PFIC type 3: Mutations in ABCB4 gene encoding the canalicular phospholipid transporter 1
• No medical therapy of proven long-term benefit exists for PFIC 1

Cystic Fibrosis-Associated Liver Disease (CFALD)

• Affects approximately one-third of patients with cystic fibrosis during long-term follow-up 1
• UDCA (20-30 mg/kg/d) improves serum liver tests and histological parameters but no therapy of proven long-term benefit exists 1
• Liver transplantation is the treatment of choice in end-stage CFALD 1

Emerging Treatments for Cholestatic Liver Diseases

• For PBC: Ursodeoxycholic acid is the first-line treatment, with obeticholic acid, budesonide, and fibrates showing potential 3, 4
• For PSC: No officially approved drugs, though ursodeoxycholic acid may have clinical benefits 3, 4
• New therapeutic directions include:
  • Fibroblast growth factor 19 3
  • Farnesoid X receptor agonists 3, 4
  • Peroxisome Proliferator-Activated Receptor Agonists (PPARs) 4
  • Ileal Bile Acid Transporter (IBAT) inhibitors for pruritus related to PBC 4

Clinical Approach to Cholestatic Liver Disease

• Careful patient history and physical examination are essential in the diagnostic process 1
• Abdominal ultrasonography is usually the first step to exclude dilated intra- and extrahepatic ducts and mass lesions 1
• Further workup may include:
  • Magnetic resonance cholangiopancreatography (MRCP) to explore the biliary tree 1
  • Endoscopic ultrasound (EUS) for detection of biliary tract obstruction 1
• Genetic testing may be considered in cases suggesting hereditary disorders 1

Pitfalls and Caveats

• Drug-induced cholestasis can be misdiagnosed due to lack of specific diagnostic tests 1
• Rechallenge to confirm drug-induced cholestasis is potentially harmful and not indicated in clinical practice 1
• Prolonged cholestasis can occur after drug withdrawal, with chlorpromazine being a prototype drug causing cholestasis longer than 6 months 1
• Some patients may develop permanent liver damage despite drug withdrawal 1
• Liver biopsy may be necessary if the course is severe, progressive, or prolonged to exclude other causes of cholestasis 1