Biological cholestasis

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"Biological Cholestasis" is defined as a simultaneous increase in serum levels of Gamma Glutamyl Transpeptidases (GGT), alkaline phosphatase (ALP) activity, and bilirubin. Its evolution can be acute or chronic depending on its etiology.

It corresponds to the biological manifestations of cholestasis, defined as a decrease in the flow of bile into the duodenum.

Classification and Etiologies

Traditionally, the causes of cholestasis are classified based on whether the anomaly is intrahepatic or extrahepatic. Here is a (non-exhaustive) list:

Intrahepatic Cholestasis

  • Viral Hepatitis
  • Drug-induced and Toxic Hepatitis
  • Alcoholic Hepatitis and Cirrhosis
  • Primary Biliary Cirrhosis
  • Pregnancy-Related Cholestasis
  • Hepatic Metastases and Tumors
  • Hepatic Vasculitis (e.g., common in Horton's disease and sometimes in isolated pseudo-rheumatoid polyarthritis)

Extrahepatic Cholestasis (involvement of extrahepatic bile ducts)

  • Biliary Stones
  • Tumors (especially neoplasms) of the pancreatic head
  • Benign stenosis of the main bile duct (often post-surgical)
  • Bile Duct Cancer
  • Pancreatitis and Pancreatic Pseudocysts
  • Sclerosing Cholangitis
  • Angiocholitis

Biological cholestasis can also occur in various other situations: benign recurrent cholestasis (both clinical and biological with mildly altered GGT, starting in young adults), parenteral nutrition (more than 20% of patients on parenteral nutrition develop multifactorial cholestasis), neonatal cholestatses (due to biliary tract atresia, infections, congenital metabolic abnormalities, etc.).

Some prefer an etiological classification based on the type of mechanism, whether metabolic or obstructive.

Clinical Presentation

  • Key Manifestations:
    • Jaundice (bilirubin) and pruritus (bile acids), dark urine and pale stools
  • Other Possible Manifestations:
    • Xanthomas and xanthelasma (local lipid accumulations, often on the eyelids)
    • Kayser-Fleischer Ring (brownish ring at the periphery of the iris due to copper buildup)
    • Signs of malabsorption (bile acids): steatorrhea and weight loss (fats), night blindness (vitamin A), osteomalacia (vitamin D), neuromyelopathy (vitamin E), bleeding tendencies (vitamin K), weight loss
  • Manifestations vary depending on the cause: fever, deterioration of general condition, signs of hepatic insufficiency and encephalopathy, abdominal pain, signs of portal hypertension, hepatomegaly, lymphadenopathy, headaches, visual disturbances, shoulder pain, etc.

Kayser-Fleischer ring

Icterus (jaundice) with pronounced conjunctival icterus

Etiological Diagnosis

In most cases, the clinical context, basic laboratory tests, and abdominal ultrasound are sufficient to establish the etiology of cholestasis.

  • Medical History (treatment, drugs, alcohol, hepatitis risk factors, abdominal surgery, HIV, travel history) and clinical examination
  • Laboratory tests: increased GGT, ALP, conjugated bilirubin (= biological cholestasis), and 5'-nucleotidase (more specific than ALP), cholesterol, bile acids, (+- coagulation abnormalities), CRP, ESR, complete blood count.
    • Hyperneutrophilia → angiocholitis? alcoholic hepatitis?
    • Leukopenia → viral hepatitis?
    • Hypereosinophilia → drug-induced hepatitis?
    • Anemia → bleeding or cancer?
    • Polycythemia → paraneoplastic?
    • Transaminases:
      • Very high → hepatitis (CMV, EBV, HAV should be particularly considered in cholestatic hepatitis)? (GOT > GPT suggests an alcoholic origin)
      • Elevated → biliary obstruction?
      • Moderately elevated: can be encountered in cholestasis of all types
    • Hypergammaglobulinemia: chronic liver disease?
    • Viral hepatitis serology
    • Search for autoantibodies (anti-smooth muscle, anti-mitochondria, anti-LKM)
    • Ceruloplasmin and Cu, biological signs of alcoholism, α-1-antitrypsin, etc.
    • Elevated ESR → nonspecific, always consider Horton's disease or PPR in elderly subjects
  • Exclusion of emergencies in acute contexts: angiocholitis (triad of jaundice, abdominal pain, fever! Present in full in only 1/3 of cases, hyperneutrophilia) (ultrasound or cholangio-RMN in case of doubt), acute hepatitis (very high transaminases)
  • Evocative contexts:
    • History of cholecystectomy for gallstones: common bile duct stone
    • Progressive jaundice with deterioration of general condition (often large gallbladder and pruritus): neoplasm of the pancreatic head or bile ducts
    • Alcoholism and pseudo-angiocholitic clinical picture: alcoholic hepatitis
    • Known liver disease: search for decompensation cause
    • Pregnancy: acute gravidic steatosis (3rd trimester, abdominal pain, fever, jaundice, high blood pressure, hypertransaminasemia, factor V drop), intrahepatic gravidic cholestasis, preeclampsia
    • If HIV+ or immunocompromised: rule out Gram-negative infection, CMV, and cryptosporidiosis
    • Parenteral nutrition
    • Acute headaches or visual disturbances → Horton's disease?
    • Shoulder pain → pseudo-rheumatoid polyarthritis?
    • Known heart disease: stasis liver (painful hepatomegaly, hepato-jugular reflux)
    • CREST syndrome: primary biliary cirrhosis?
    • Crohn's disease or UC: sclerosing cholangitis?
    • Sarcoidosis or collagenosis: granulomatous involvement?
  • Abdominal ultrasound:
    • Mainly useful for detecting bile duct dilation (extrahepatic cholestasis)
    • Allows diagnosis in 75% of cases
  • Cholangio-MRI:
    • Can be useful for stones, tumors, pancreatitis, and pancreatic cysts
  • Endoscopic ultrasound:
    • Can be useful for ampullary tumors and stones in the common bile duct
    • (Puncture)-Liver biopsy:
    • Rarely performed, especially useful in unexplained chronic cholestasis (primary biliary cirrhosis? primary sclerosing cholangitis? sarcoidosis or other granulomatosis?)
  • Injected abdominal CT-scan:
    • Same usefulness and effectiveness as ultrasound but also allows for a distant tumor assessment and is more efficient in establishing complications
  • ERCP (endoscopic retrograde cholangiopancreatography):
    • Especially useful for diagnosis (and treatment) of bile duct obstructions

Therapeutic Management - Treatments

  • Etiological if possible
  • Symptomatic if necessary
    • Pruritus:
      • Cholestyramine (Questran)
      • Antihistamines: contested usefulness
      • Rifampicin: effective but exposes the patient to hypersensitivity risk
      • In case of refractory pruritus: consider opioid antagonists
    • In case of significant malnutrition: consider prescribing medium-chain fatty acids
  • Supplements in case of significant malnutrition or treatment with cholestyramine: vitamins (K, A, D), calcium gluconate.


Dr Shanan Khairi, MD


Friedman LS, Approach to the patient with abnormal liver biochemical and function tests, UpToDate, 2022

Longo DL et al., Harrison - Principes de médecine interne, 18e éd., Lavoisier, 2013