What are the causes of intrahepatic cholestatic jaundice?

Causes of Intrahepatic Cholestatic Jaundice

Intrahepatic cholestatic jaundice is caused by a wide range of conditions that can be broadly categorized into hepatocellular and cholangiocellular etiologies, with the most common causes being drug-induced liver injury, viral hepatitis, genetic disorders, and autoimmune conditions. 1

Hepatocellular Causes

Drug-Induced Cholestasis

• Medications: Numerous drugs can cause cholestatic liver injury through inhibition of hepatocellular transporter expression/function or idiosyncratic inflammatory reactions 1
• Common culprits include:
  • Antibiotics (amoxicillin-clavulanate, erythromycin)
  • Psychotropic drugs (chlorpromazine)
  • Anabolic steroids
  • Oral contraceptives
  • Herbal supplements
• Drug-induced cholestasis may progress to vanishing bile duct syndrome in rare cases 1

Infections

• Sepsis/endotoxemia-induced cholestasis
• Cholestatic variants of viral hepatitis (A, B, C, E)
• HIV-related cholangiopathy

Metabolic and Infiltrative Disorders

• Alcoholic or non-alcoholic steatohepatitis
• Total parenteral nutrition-induced cholestasis
• Malignant infiltration (lymphoma, metastatic cancer)
• Benign infiltration:
  • Amyloidosis
  • Sarcoidosis and other granulomatoses
  • Storage diseases

Vascular Disorders

• Budd-Chiari syndrome
• Veno-occlusive disease
• Congestive hepatopathy (heart failure)

Genetic Disorders

• Benign recurrent intrahepatic cholestasis (BRIC)
• Progressive familial intrahepatic cholestasis (PFIC) types 1-3 1
• ABCB4 deficiency
• Intrahepatic cholestasis of pregnancy
• Erythropoietic protoporphyria
• Citrin deficiency
• Alagille syndrome (JAG1, NOTCH2 mutations) 1

Cholangiocellular Causes

Autoimmune Disorders

• Primary biliary cholangitis (PBC) - both AMA-positive and AMA-negative variants
• Primary sclerosing cholangitis (PSC)
• IgG4-associated cholangitis
• Overlap syndromes (PBC or PSC with autoimmune hepatitis)

Structural Abnormalities

• Idiopathic adulthood ductopenia
• Ductal plate malformations:
  • Biliary hamartomas
  • Caroli syndrome
  • Congenital hepatic fibrosis

Other Causes

• Cystic fibrosis
• Drug-induced cholangiopathy
• Graft versus host disease
• Secondary sclerosing cholangitis:
  • Ischemic cholangiopathy
  • Cholangiolithiasis
  • Infectious cholangitis

Diagnostic Approach

1. Initial evaluation:

   • Differentiate intrahepatic from extrahepatic cholestasis using ultrasound 1
   • Assess pattern of liver enzyme elevation (ALP/GGT predominance)
   • Detailed medication history (including herbal supplements)

2. Further workup for intrahepatic cholestasis:

   • Serologic testing for autoimmune markers (AMA, ANA)
   • MRCP if bile duct abnormalities are suspected 1
   • Liver biopsy for unexplained intrahepatic cholestasis 1
   • Genetic testing for suspected hereditary disorders 1

Special Considerations

• Premature ductopenic variant of PBC: Characterized by marked bile duct loss without significant fibrosis, causing severe cholestasis 2
• Vanishing bile duct syndrome: Progressive loss of intrahepatic bile ducts that can occur in drug reactions, autoimmune conditions, or graft-versus-host disease 1
• Overlap syndromes: Features of both cholestatic liver disease and autoimmune hepatitis may coexist 3

Pitfalls to Avoid

• Don't assume all cholestasis with normal bile ducts is drug-induced; consider genetic and autoimmune etiologies
• Cholestasis may persist for months after drug discontinuation
• Some patients may have "silent" progressive cholestatic disease for years before developing jaundice 4
• Genetic disorders of cholestasis can present in adulthood, not just in childhood 1

Remember that early identification of the cause is crucial for appropriate management and prevention of progression to cirrhosis and liver failure.