EASL Clinical Practice Guidelines

Diagnostic approach to cholestasis

Cholestasis is an impairment of bile formation and/or bile flow which may clinically present with fatigue, pruritus and, in its most overt form, jaundice. Early biochemical markers in often asymptomatic patients include increases in serum alkaline phosphatase (AP) and γ-glutamyltranspeptidase (γGT) followed by conjugated hyperbilirubinemia at more advanced stages. Cholestasis may be classified as intrahepatic or extrahepatic. Intrahepatic cholestasis may result from hepatocellular functional defects or from obstructive lesions of the intrahepatic biliary tract distal from bile canaliculi. Cholestasis may also be related to mixed mechanisms in diseases such as lymphoma [2]. By convention, cholestasis is considered chronic if it lasts >6 months. Most chronic cholestatic diseases are purely intrahepatic, whereas sclerosing cholangitis may affect small and large intrahepatic and/or extrahepatic bile ducts. Asymptomatic patients are generally identified when routine laboratory tests are being performed or during work-up for another disease when an increase is noted in the serum level of AP and/or γGT. Isolated serum γGT elevation has little specificity for cholestasis, and may also result from enzyme induction in response to alcohol or drug intake. Isolated serum AP elevation is seen in cholestatic liver diseases including certain rare disorders (e.g., progressive familial intrahepatic cholestasis (PFIC) 1 & 2, bile acid synthesis defects), but may also result from rapid bone growth (e.g., in children), bone disease (e.g., Paget's disease), or pregnancy. The cut-off levels of serum AP and γGT requiring diagnostic work-up are debated: AP levels higher than 1.5 times the upper limit of normal (ULN) and γGT levels >3× ULN have been proposed. The differential diagnosis of cholestatic disorders can be wide (Table 2a, Table 2b). Nevertheless, the first critical step is to differentiate intra- and extrahepatic cholestasis.

Table 2a
Causes of intrahepatic cholestasis in adulthood.

Hepatocellular cholestasis
Sepsis-, endotoxemia-induced cholestasis
Cholestatic variety of viral hepatitis
Alcoholic or non-alcoholic steatohepatitis
Drug- or parenteral nutrition-induced cholestasis
Genetic disorders: e.g., BRIC, PFIC, ABCB4 deficiency, intrahepatic cholestasis of pregnancy (ICP), erythropoietic protoporphyria
Malignant infiltrating disorders: e.g., hematologic diseases, metastatic cancer
Benign infiltrating disorders: e.g., amyloidosis, sarcoidosis hepatis and other granulomatoses, storage diseases
Paraneoplastic syndromes: e.g., Hodgkin disease, renal carcinoma
Ductal plate malformations: e.g., congenital hepatic fibrosis
Nodular regenerative hyperplasia
Vascular disorders: e.g., Budd–Chiari syndrome, veno-occlusive disease, congestive hepatopathy
Cirrhosis (any cause)
Cholangiocellular cholestasis
Primary biliary cirrhosis (AMA+/AMA−)
Primary sclerosing cholangitis
Overlap syndromes of PBC and PSC with AIH
IgG4-associated cholangitis
Idiopathic adulthood ductopenia
Ductal plate malformations: biliary hamartoma, Caroli syndrome Cystic fibrosis
Drug-induced cholangiopathy
Graft vs. host disease
Secondary sclerosing cholangitis: e.g., due to various forms of cholangiolithiasis, ischemic choangiopathies (hereditary hemorragic telangiectasia, polyarteritis nodosa and other forms of vasculitis), infectious cholangitis related to AIDS and other forms of immunodepression, etc.

Table 2b
Causes of intrahepatic cholestasis in infancy and childhood [2].


Metabolic disease
 – with biliary tract involvement: α1-antitrypsin storage disease, cystic fibrosis
 – without biliary tract involvement: galactosemia, tyrosinemia, fatty acid oxidation defects, lipid and glycogen storage disorders, peroxisomal disorders
 – specific defects in biliary function:
  disorders of bile acid biosynthesis and conjugation
  disorders of canalicular secretion (PFIC)
Paucity of bile ducts
 – syndromic: Alagille syndrome (Jagged 1 defect)
 – non-syndromic
Ductal plate malformations
Infections: bacterial, viral
Toxic: parenteral nutrition, drugs
Idiopathic neonatal hepatitis
Cirrhosis (any cause)

Careful patient history and physical examination are essential in the diagnostic process and may provide valuable information so that an experienced clinician can predict the nature of cholestasis in many cases [3]. Presence of extrahepatic diseases has to be recorded. A thorough occupational and drug history is imperative and any medications taken within 6 weeks of presentation may be incriminated (and discontinued); this includes herbal medicines, vitamins and other substances. A history of fever, especially when accompanied by rigors or right upper quadrant abdominal pain is suggestive of cholangitis due to obstructive diseases (particularly choledocholithiasis), but may be seen in alcoholic disease and rarely, viral hepatitis. A history of prior biliary surgery also increases the likelihood that biliary obstruction is present. Finally, a family history of cholestatic liver disease suggests a possibility of a hereditary disorder. Some cholestatic disorders are observed only under certain circumstances (e.g., pregnancy, childhood, liver transplantation, HIV-infection), and may require specific investigations that are not relevant in other populations.

Abdominal ultrasonography is usually the first step to exclude dilated intra- and extrahepatic ducts and mass lesions because it is rather sensitive and specific, non-invasive, portable and relatively inexpensive. Its disadvantages are that its findings are operator-dependent and abnormalities of bile ducts such as those observed in sclerosing cholangitis may be missed. Furthermore, the lower common bile duct and pancreas are usually not well depicted. Computed tomography of the abdomen is less interpreter-dependent, but is associated with radiation exposure and may be not as good as ultrasound at delineating the biliary tree.

If bile duct abnormalities are present, further work-up depends on the presumed cause. From a purely diagnostic perspective, magnetic resonance cholangiopancreatography (MRCP) is a safe option to explore the biliary tree. Its accuracy for detecting biliary tract obstruction approaches that of endoscopic retrograde cholangiopancreatography (ERCP) when performed in experienced centres with state-of-the-art technology. Endoscopic ultrasound (EUS) is equivalent to MRCP in the detection of bile duct stones and lesions causing extrahepatic obstruction and may be preferred to MRCP in endoscopic units.

Extrahepatic biliary obstruction may be caused by stones, tumours, cysts, or strictures. The gold standard for visualizing the biliary tract and treating extrahepatic biliary obstruction is endoscopic retrograde cholangiopancreatography (ERCP), but even in experienced hands it carries a significant complication rate (pancreatitis in 3–5% of cases; when combined with sphincterotomy, bleeding 2%, cholangitis 1%, procedure-related mortality 0.4% [4]). Thus, when extrahepatic obstruction is considered and the need for endoscopic intervention is unclear, MRCP or EUS should be performed in order to avoid ERCP if it is not needed [3].

If imaging studies do not demonstrate mechanical obstruction, a diagnosis of intrahepatic cholestasis can be reasonably made. However, in an individual whose history suggests an extrahepatic cause (like early pancreatic or ampullary carcinoma), clinical judgment should be pursued and repeat ultrasound or another imaging procedure should be performed [3].

When extrahepatic obstruction has been reasonably excluded, further work-up of intrahepatic cholestasis (Table 2a, Table 2b) depends on the clinical setting.

In adult patients with chronic intrahepatic cholestasis, the next step is testing for serum antimitochondrial antibodies (AMA) since the diagnosis of PBC, which is the major cause of small-duct biliary diseases [5], can be made with confidence in a patient with high-titer AMA (⩾1/40) and a cholestatic serum enzyme profile in the absence of an alternative explanation [6]. A liver biopsy may still be appropriate in selected patients. If AMA and PBC-specific antinuclear antibodies (ANA) are negative, MRCP (in a specialized centre) may be the next diagnostic step for most patients with chronic intrahepatic cholestasis of unknown cause.

Subsequently, a liver biopsy should be performed when the diagnosis is still unclear. Particular attention to the condition of bile ducts is critical in the histologic evaluation and a biopsy of adequate quality should contain ⩾10 portal fields because of the high degree of sampling variability in patients with small bile duct disease. Biopsy findings should be classified under (i) disorders involving bile ducts (for typical biliary lesions, see Table 3) the main causes being AMA-negative PBC, isolated small duct PSC, ABCB4 deficiency, sarcoidosis, idiopathic ductopenia or prolonged drug-induced cholestasis; (ii) disorders not involving bile ducts, the main causes being a variety of storage or infiltrative liver diseases, hepatic granulomas (without cholangitis), nodular regenerative hyperplasia, peliosis, sinusoidal dilatation and cirrhosis; and (iii) hepatocellular cholestasis with only minimal histologic abnormalities as observed in benign recurrent intrahepatic cholestasis (BRIC), estrogen or anabolic steroid therapy, sepsis, total parenteral nutrition or as a paraneoplastic phenomenon.


Table 3
Typical biliary lesions and their main causes (liver transplant setting excluded) [2].


1. Nonsuppurative destructive cholangitis
  Primary biliary cirrhosis
  Primary sclerosing cholangitis
  Autoimmune hepatitis
  Drug-induced cholangitis
  Sarcoidosis
  ABCB4 deficiency
  (Hepatitis C, B, E)
2. Fibrous obliterative cholangitis
  Primary sclerosing cholangitis
  Secondary sclerosing cholangitis
  IgG4-associated cholangitis
  Sarcoidosis
3. Other cholangitis (unusual)
  Malignant cholangitis
  Lymphoma (Hodgkin or non-Hodgkin)
  Systemic mastocytosis
  Langerhans cell histiocytosis
  Neutrophilic cholangitis: neutrophilic dermatosis
4. Ductal plate malformations
  Biliary hamartomas (von Meyenburg complexes)
  Caroli syndrome
  Congenital hepatic fibrosis

A general algorithm for evaluating the adult patient with cholestasis is presented in Fig. 1.



Fig. 1 Diagnostic approach to cholestasis in adult patients. Abbreviations: US, ultrasound; CT, computed tomography; AMA, antimitochondrial antibodies; ANA, antinuclear antibodies; MRCP, magnetic resonance cholangiopancreatography; ERCP, endoscopic retrograde cholangiopancreatography; PBC, primary biliary cirrhosis; SC, sclerosing cholangitis.
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Recommendations

  1. A detailed history and physical examination are essential (III/C1).
  2. Ultrasound is the first-line non-invasive imaging procedure in order to differentiate intra- from extrahepatic cholestasis (III/C1).
  3. Testing for serum antimitochondrial antibodies (AMA) is mandatory in adults with chronic intrahepatic cholestasis (III/C1).
  4. Magnetic resonance cholangiopancreatography (MRCP) is the next step to be considered in patients with unexplained cholestasis (III/C1).
  5. Endoscopic ultrasound (EUS) is an alternative to MRCP for evaluation of distal biliary tract obstruction (II-2/B1).
  6. Diagnostic endoscopic retrograde cholangiopancreatography (ERCP) should be reserved for highly selected cases (II-2/A1). If the need for a therapeutic maneuver is not anticipated, MRCP or EUS should be preferred to ERCP because of the morbidity and mortality related to ERCP (II-2/A1).
  7. A liver biopsy should be considered in patients with otherwise unexplained intrahepatic cholestasis and a negative AMA test (III/C1).
  8. Genetic testing for ABCB4 (encoding the canalicular phospholipid export pump), when available, should be considered in patients with a negative AMA test and biopsy findings that might be compatible with PBC or PSC.