Viral Hepatitis and Liver Disease Website Course

Evaluating Liver Test Abnormalities

Understanding the Pathophysiology of Liver Disease

for Health Care Providers

Chronic Cholestasis

Abnormal liver test > Cholestatic pattern > More than six months > Chronic cholestasis


The differential diagnosis for chronic cholestasis is wide and depends on the clinical setting and therefore careful history and physical examination are of great importance. The main cause of chronic cholestasis is drug-induced liver injury (intrahepatic cholestasis), but there are additional diagnostic possibilities.

Any chronic liver injury may progress to cirrhosis. Therefore, in addition to determining a possible cause of chronic cholestatic injury, it is essential to assess whether cirrhosis is present.

Intrahepatic cholestasis:

  • Drug-induced liver injury
  • Primary biliary cirrhosis
  • Primary sclerosing cholangitis (small duct)
  • Total parenteral nutrition
  • Infiltrative diseases
    • Sarcoidosis
    • Amyloidosis
    • Neoplasia
    • Infection (e.g. mycobacterial)
  • Liver allograft rejection
  • Graft disease
  • Liver flow abnormalities leading to nodular regenerative hyperplasia

Extrahepatic cholestasis:

  • Biliary obstruction
    • Malignancy
    • Pancreatitis
  • Primary sclerosing cholangitis
  • Secondary sclerosing cholangitis (mostly iatrogenic)
  • Biliary ischemia
  • Opportunistic viral or parasitic bile duct infections (e.g. AIDS cholangiopathy)

Medications (Not a complete list):

  • Antibiotics (Penicillins, Sulfonamides, Macrolides, Fluoroquinolones, Tetracyclines)
  • Antifungals (Terbinafine, Griseofulvin, Ketoconazole, Itraconazole)
  • Anabolic steroids
  • Anti-inflammatories(some)
  • Azathioprine
  • Barbiturates
  • Cyclosporine
  • Isoniazid
  • Oral contraceptives
  • Psychotropics (some)
  • Phenytoin
  • Rifampin
  • Tamoxifen


The clinical hallmark of cholestasis is the presence of PRURITUS. Patients should be specifically asked about the presence of pruritus. In general, pruritus presents earlier in cases of intrahepatic cholestasis. Initial questions aimed at determining the possible etiology of acute cholestatic injury are:

To investigate drug-induced liver injury:

Detailed medication history including over-the-counter medications, herbal remedies and health food supplements, particularly regarding recently prescribed medications.

To investigate primary biliary cirrhosis:

Presence of other autoimmune disorders such as thyroid disease, Raynaud's phenomenon, Sjogren's syndrome, or arthralgias

To investigate primary sclerosing cholangitis:

Presence of symptoms suggestive of inflammatory bowel disease.

To investigate biliary obstruction:

Weight loss, anorexia or thromboembolic events suggest malignancy. History of bile duct surgery suggests iatrogenic bile duct obstruction leading to secondary sclerosing cholangitis.

To investigate biliary ischemia

Procedures or illnesses involving the hepatic artery (embolization, ligation, chemotherapy, arteriovenous shunting) will lead to biliary ischemia and cholestasis.

To investigate nodular regenerative hyperplasia

Procedures or illnesses that affect flow to the liver (hypercoagulable or hyperviscosity states, portal vein thrombosis, arteriovenous shunts).

To investigate total parenteral nutrition (TPN):

History of TPN administration for more than 2-3 weeks.

In addition to history directed at determining a possible etiology of chronic hepatocellular injury (below), history should include questions directed at determining the presence of cirrhosis (ascites, gastrointestinal hemorrhage, encephalopathy).

Physical examination

Primary biliary cirrhosis may be associate with xanthomas or xanthelasma as well as hyperpigmentation and features compatible with Raynaud's phenomenon. A palpable gallbladder suggests malignant biliary obstruction. Hepatomegaly will be present in an infiltrative disease. Stigmata of chronic liver disease may be present, such as palmar erythema, vascular spiders and muscle hypotrophy, particularly if cirrhosis is present.

Laboratory Investigation

Initial investigation should be directed at distinguishing between an intrahepatic or an extrahepatic acute cholestasis. The initial test is therefore abdominal ultrasonography to look for bile duct dilatation. The presence of bile duct dilatation on ultrasonography indicates that cholestasis is extrahepatic.

Liver biopsy is indicated in intrahepatic chronic cholestatic injury as it will not only be useful in determining the etiology of the injury but also will be important in staging the disease, that is, in determining the amount of fibrosis present. However, contrary to what occurs in chronic hepatocellular injury, in chronic cholestatic injury, such as PBC or PSC, changes are more heterogeneous and staging is more unreliable.

To investigate primary biliary cirrhosis:

  • Antimitochondrial antibodies (AMA)

To investigate primary sclerosing cholangitis

  • MRCP
  • pANCA

In addition to laboratory investigations directed at determining a possible etiology of chronic hepatocellular injury, platelets, albumin and prothrombin time/INR should be obtained. The presence of the followings is suggestive of cirrhosis:

  • Thrombocytopenia, hypoalbuminemia, or prolonged prothrombin time/INR