What Cholestasis Means
Cholestasis is an impairment of bile formation and/or bile flow that results from either hepatocellular functional defects or obstruction of the biliary tract. 1
Definition and Pathophysiology
Cholestasis represents a disruption in the normal production or movement of bile from the liver to the intestine. This can occur at multiple levels:
- Intrahepatic cholestasis: Results from hepatocellular functional defects or obstructive lesions of the intrahepatic biliary tract distal from bile canaliculi 1
- Extrahepatic cholestasis: Caused by mechanical obstruction of the bile ducts outside the liver 1
The condition may also involve mixed mechanisms in certain diseases such as lymphoma 1.
Clinical Presentation
The clinical manifestations range from asymptomatic biochemical abnormalities to overt symptoms including:
- Fatigue - often the earliest symptom
- Pruritus (itching) - a hallmark symptom
- Jaundice - the most overt manifestation, though it may be absent in chronic cases 1
Important Clinical Caveat
Many adults with chronic cholestatic liver disease are entirely asymptomatic, particularly in early stages. Jaundice may be absent even in established disease 1.
Biochemical Markers
Early detection relies on laboratory abnormalities in often asymptomatic patients:
- Elevated alkaline phosphatase (AP) - typically >1.5 times the upper limit of normal
- Elevated gamma-glutamyltranspeptidase (γGT) - typically >3 times the upper limit of normal
- Conjugated hyperbilirubinemia - appears at more advanced stages 1
Laboratory Interpretation Pitfalls
- Isolated γGT elevation has little specificity for cholestasis and may result from enzyme induction by alcohol or drugs 1
- Isolated AP elevation can occur in non-cholestatic conditions including rapid bone growth in children, Paget's disease, or pregnancy 1
Classification
By duration:
- Acute cholestasis: <6 months duration
- Chronic cholestasis: >6 months duration 1
By anatomical location:
- Intrahepatic: Most chronic cholestatic diseases are purely intrahepatic 1
- Extrahepatic: Mechanical obstruction of bile ducts
- Mixed: Sclerosing cholangitis may affect small and large intrahepatic and/or extrahepatic bile ducts 1
Underlying Causes
The differential diagnosis is extensive and varies by age:
In adults, intrahepatic cholestasis includes: 1
- Hepatocellular causes: sepsis-induced, viral hepatitis, alcoholic/non-alcoholic steatohepatitis, drug-induced
- Cholangiocellular causes: primary biliary cirrhosis, primary sclerosing cholangitis, IgG4-associated cholangitis
- Infiltrative disorders: sarcoidosis, malignancy, storage diseases
- Genetic disorders: BRIC, PFIC, ABCB4 deficiency
In infants and children: 1
- Metabolic diseases (α1-antitrypsin deficiency, cystic fibrosis)
- Bile acid synthesis/secretion defects
- Biliary atresia
- Infections
- Genetic syndromes (Alagille syndrome)
Clinical Significance
Cholestasis is always pathological and requires investigation. 2 The retained bile acids cause liver damage and systemic effects, while diminished bile delivery to the gastrointestinal tract leads to malabsorption of fat-soluble vitamins and other complications 3. Early detection is crucial as it improves prognosis for many underlying diseases, particularly biliary atresia in infants 2.
Portal hypertension can develop early in chronic cholestatic liver disease, sometimes occurring before cirrhosis develops 3.