What is cholestasis?

What is Cholestasis?

Cholestasis is an impairment of bile formation and/or bile flow that results in the accumulation of bile constituents in the liver and blood, clinically presenting with fatigue, pruritus, and in severe cases, jaundice. 1

Pathophysiological Definition

Cholestasis occurs when bile cannot flow properly from the liver to the intestine, leading to retention of bile acids, bilirubin, and other compounds normally excreted in bile. 1, 2 This impairment can occur at multiple levels:

• Hepatocellular level: Functional defects in bile secretion by liver cells 1
• Canalicular level: Problems with bile transport at the smallest bile channels 1
• Bile duct level: Obstruction or damage to intrahepatic or extrahepatic bile ducts 1, 2

Clinical Presentation

The clinical manifestations depend on severity and chronicity:

• Early/asymptomatic stage: Often discovered incidentally on routine laboratory testing 1
• Symptomatic stage: Fatigue and pruritus (itching) are the predominant symptoms 1
• Advanced stage: Overt jaundice (yellowing of skin and eyes) develops 1

Biochemical Markers

The diagnostic hallmark is elevation of serum alkaline phosphatase (AP) and gamma-glutamyltransferase (GGT), followed by conjugated (direct) hyperbilirubinemia in more advanced stages. 1, 3

Key laboratory findings include:

• Early markers: Elevated serum AP and GGT are the first biochemical indicators 3
• Later markers: Conjugated bilirubin rises as disease progresses 1, 3
• Diagnostic thresholds: AP levels >1.5 times upper limit of normal (ULN) and GGT >3 times ULN warrant diagnostic workup 1

Important caveat: Isolated GGT elevation has little specificity for cholestasis and may result from alcohol or drug-induced enzyme induction. 1 Similarly, isolated AP elevation can occur in bone disease, rapid bone growth in children, or pregnancy. 1

Anatomical Classification

Cholestasis is categorized into two main types:

Intrahepatic Cholestasis

• Results from hepatocellular functional defects or obstruction of intrahepatic bile ducts 1
• Caused by diverse hepatobiliary diseases with overlapping presentations 1
• Examples include primary biliary cirrhosis, primary sclerosing cholangitis, drug-induced cholestasis, and genetic disorders 1

Extrahepatic Cholestasis

• Largely due to obstructive lesions of bile ducts outside the liver 1
• Requires imaging (ultrasound as first-line) to identify mechanical obstruction 1, 4

Chronic vs. Acute Cholestasis

By convention, cholestasis is considered chronic if it persists for more than 6 months. 1 Most chronic cholestatic diseases are purely intrahepatic. 1

Special Populations

Neonatal Cholestasis

• Defined as jaundice due to conjugated bilirubin lasting longer than 2-3 weeks after birth 1, 5
• Incidence of 1 in 2,500 live births 1, 5
• Represents a medical emergency requiring immediate attention to prevent permanent liver and organ damage 5
• Genetic and/or metabolic causes account for 25-30% of affected patients 1, 5

Consequences of Cholestasis

The lack of bile flow into the intestine produces serious complications:

• Malabsorption and malnutrition: Impaired fat and fat-soluble vitamin absorption 2, 4
• Skeletal changes: Due to vitamin D deficiency and calcium malabsorption 2
• Progressive liver damage: Accumulation of toxic bile constituents leads to hepatocyte injury 2
• Biliary cirrhosis: End-stage consequence of chronic cholestasis 2, 4
• Pruritus: Often severe and debilitating, significantly impacting quality of life 1, 6

Common Pitfalls

Never assume isolated GGT elevation indicates cholestasis without confirming AP elevation and excluding alcohol/drug effects. 1 Additionally, certain rare genetic disorders (PFIC types 1 and 2, bile acid synthesis defects) can present with cholestasis despite normal or only mildly elevated AP levels, requiring high clinical suspicion and genetic testing. 3