Pathological patterns of biliary disease

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Abbreviations

AIP

autoimmune pancreatitis

AMA

antimitochondrial antibody

DILI

drug‐induced liver injury

GVHD

graft‐versus‐host disease

IgG4

immunoglobulin G4

ISC

IgG4‐related sclerosing cholangitis

PBC

primary biliary cholangitis

PSC

primary sclerosing cholangitis

Pathological Patterns of Biliary Disease

Disorders of the biliary tree may be either primary or secondary and involve the extrahepatic system, intrahepatic system, or a combination of the two. Nonspecific histological findings present in all forms of chronic biliary disease include ductopenia, ductular reaction, and cholestasis (Fig. 1). When the disease process involves only the large, extrahepatic ducts (e.g., secondary sclerosing cholangitis), these may be the only changes seen on needle biopsy. In such situations, clinical correlation is essential to arrive at the correct diagnosis. All forms of chronic biliary disease are staged on a four‐tier system: stage 1 is confined to the portal tract, with portal‐based inflammation and expansion; stage 2 is characterized by irregular periportal fibrosis and interface inflammation; stage 3 is defined by the presence of portal‐portal bridging fibrosis; and stage 4 is cirrhosis, with bridging fibrosis and regenerative nodule formation. This review focuses on the primary autoimmune cholangiopathies, followed by a brief discussion of several miscellaneous conditions. The three primary cholangiopathies include primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and immunoglobulin G4 (IgG4)‐related sclerosing cholangitis (ISC).1

Figure 1.

Late‐stage chronic biliary disease of any cause may demonstrate ductular reaction (black arrow) and hepatocanalicular cholestasis (white arrow). Yellow‐brown bile concretions are present within ductules (cholangitis lenta), which is associated with sepsis, uremia, and shock.

Each disease has a characteristic histology, although the microscopic changes in PBC and PSC are not pathognomonic or present in all tissue samples. ISC may be diagnosed entirely upon histology, whereas PBC and PSC have diagnostic serological or radiological tests, respectively. In all of the diseases, characteristic features are better seen in early stages, when the pattern and morphology of duct injury can be observed.

Primary Biliary Cholangitis

PBC is an autoimmune‐mediated process that involves the small, intrahepatic bile ducts. The classic patient is a middle‐aged woman (female/male ratio, 9‐10:1) found to have an elevated alkaline phosphatase level.2 The antimitochondrial antibody (AMA) is the diagnostic test for PBC, which is present in 90% to 95% of patients.3 As such, needle biopsy is usually undertaken for staging, to rule out a PBC‐autoimmune overlap or other conditions (e.g., steatosis) or to diagnose AMA‐negative PBC. The latter is a variant of PBC that comprises 5% to 10% of patients. The clinical, serological, and histological features are identical to typical cases, except for an absent AMA.

The florid duct lesion, defined as a granulomatous destruction of the bile ducts, is the histological hallmark of PBC (Fig. 2).4 Because PBC preferentially affects small ducts, florid duct lesions are often sampled in percutaneous needle biopsy specimens of early‐stage disease. The granulomatous inflammation may be either well‐formed or vague, and is accompanied by lymphocytes and variable numbers of plasma cells, all of which are centered on the bile duct. Due to its focal nature, florid duct lesions are identified in less than 40% of PBC biopsy samples when all stages are considered together.1

Figure 2.

(A) Florid duct lesion characterized by granulomatous and lymphocytic portal inflammation centered on the interlobular bile ducts. (B) Lymphocytic cholangitis (black arrow) associated with loose aggregates of histiocytes (white arrows), which constitute the granulomatous component.

Primary Sclerosing Cholangitis

PSC is a fibroinflammatory process that preferentially affects the large, intrahepatic and/or extrahepatic biliary tree. The disease is most common in younger men (male/female ratio, 2:1), and there is a strong association with inflammatory bowel disease, present in more than 75% of cases.1, 5 Radiography is the diagnostic test for PSC. Because of the lower complication rate, magnetic resonance cholangiopancreatography is preferred over endoscopic retrograde cholangiopancreatography.6 In approximately 5% of cases, the fibroinflammatory process is restricted to small, intrahepatic bile ducts that are not visualized by imaging.6 This variant is referred to as small‐duct PSC. These patients will typically have a cholestatic profile with a history of inflammatory bowel disease. Biopsy is necessary only for staging, to rule out an overlap syndrome or superimposed process, and to diagnose small‐duct PSC.

The fibro‐obliterative lesion is the histological hallmark of PSC (Fig. 3). It begins as concentric rings of fibrosis, known as onion‐skinning, around bile ducts. With time, this concentric fibrosis squeezes off and obliterates the bile duct lumen, leaving behind a fibrous plug or scar. There is often a mild lymphocytic infiltrate that accompanies the fibrosis, although the inflammation is much less prominent than in PBC.

Figure 3.

(A) Onion skin fibrosis characterized by concentric rings of collagen and fibroblasts (arrows) surrounding a bile duct branch. (B) Fibrous plug (arrow) is the only indicator that a bile duct was present in this septal tract. Portal vein and hepatic artery branches are intact.

IgG4‐Related Sclerosing Cholangitis

ISC represents biliary tract involvement by IgG4‐related disease, resulting in diffuse thickening of the bile duct wall, stricture formation, or an inflammatory pseudotumor. The disease preferentially affects men (80%) older than 50 years.7 Although inflammation may be restricted to the bile ducts in a subset of patients (2%), the majority of cases arise in the setting of autoimmune pancreatitis (AIP).8 There is such a strong association with AIP that its identification provides supporting evidence for the diagnosis of ISC versus other conditions, such as PSC. Elevation of serum IgG4 is present in the majority of patients, with levels greater than two times normal (i.e., >280 mg/dL) considered very specific for ISC.9 Importantly, other conditions may show elevated IgG4 levels, including PSC and cholangiocarcinoma. Patients are diagnosed using the HISORt criteria (histology, imaging, serum IgG4, other organ involvement, and response to steroid therapy).9

ISC is characterized by dense lymphoplasmacytic infiltrates containing increased numbers of IgG4⁺ plasma cells. Inflammation is accompanied by a unique pattern of storiform fibrosis and destruction of veins (obliterative phlebitis). Immunostain demonstrates more than 10 IgG4⁺ cells per high‐power field in biopsy specimens and more than 50 IgG4⁺ cells per high‐power field in surgical specimens.10

Miscellaneous Conditions

Drug‐Induced Liver Injury

Drug‐induced liver injury (DILI) may manifest as a hepatitis, as a cholestatic process, or as a combination of the two. When the biliary tree is affected, there is often a robust ductular reaction associated with a mixed portal‐based infiltrate. Although fibrosis may occur, DILI is typically an acute or subacute phenomenon. Because of this, there is often some degree of portal edema that may mimic an acute large‐duct obstruction (Fig. 4). The absence of scarring favors DILI over other causes of chronic biliary disease.

Figure 4.

Biliary pattern of injury in a case of DILI. There is portal edema (black arrow) and marked ductular reaction around the periphery (white arrow) of the portal tracts. Acute large‐duct obstruction can have a similar appearance.

Secondary Sclerosing Cholangitis

Any process that obstructs or injures the extrahepatic biliary tree may result in histological changes upstream that are indistinguishable from PSC, including periductal onion‐skinning fibrosis, ductular reaction, cholestasis, ductopenia, and biliary‐type scarring. Because the microscopic changes are not autoimmune mediated, but are instead the sequelae of downstream pathology, they are classified under the heading of secondary sclerosing cholangitis. Possible causative factors include obstruction from a cholelith or external compression by a neoplasm (e.g., pancreatic carcinoma), trauma, ischemic injury, portal vein abnormality, and infection.11 As mentioned earlier, acute large‐duct obstruction is characteristically associated with portal edema.

Graft‐Versus‐Host Disease

Hepatic graft‐versus‐host disease (GVHD) usually occurs in the setting of systemic GVHD. Bile duct injury is the defining feature. Typical changes include lymphocytic cholangitis associated with alterations to the bile duct epithelial cells, eventually leading to ductopenia.11, 12 Unlike most other causes of biliary disease, there is usually no significant ductular reaction and only mild fibrosis.

Idiopathic Adulthood Ductopenia

Idiopathic adulthood ductopenia is a diagnosis of exclusion characterized by absence of interlobular bile ducts in more than 50% of portal tracts in a patient with a cholestatic serologic profile.13 All other known causes of biliary disease must be excluded by imaging and serology, and no specific features can be present in the liver biopsy, such as granulomas. There can be no known history of malignancy or exposure to drugs known to cause biliary injury. Because of the strict criteria for diagnosis, it is an extremely rare condition.