Cholestasis is defined as impaired bile flow. It may be secondary to either hepatocyte abnormalities or compromise of the biliary tree.1
From an etiologic perspective, compromise of the biliary tree can be primary or secondary, and from an anatomic standpoint either intra- and/or extrahepatic. Biliary tract compromise typically leads to a characteristic constellation of portal-based changes (see below).1
Clinically, cholestasis is characterized by hyperbilirubinemia and an elevated alkaline phosphatase and γ-glutamyltransferase (GGT). Because GGT can be elevated in other conditions, alkaline phosphatase is the more specific indicator. Importantly, clinical and histologic cholestasis may not occur simultaneously. It is not uncommon for there to be an elevated alkaline phosphatase with no histologic features of cholestasis.
There are five elements to assess when considering a diagnosis of cholestatic or chronic biliary disease. The combination of these features will vary with the type and stage of disease.
Bile can be identified in hepatocytes, Kupffer cells, canaliculi, proliferative bile ductules, or bile ducts (Fig. 13.1
). Cholate stasis
is the term given to the cytologic changes which occur in
hepatocytes secondary to the toxic effects of retained bile: cytoplasmic swelling with protein condensation (feathery degeneration) and Mallory-Denk bodies (Figs. 13.2
In severe cases, foci of hepatocyte necrosis with extravasated bile can be seen, which is referred as bile infarcts. In chronic biliary disease, cholestasis is typically not seen until late in the course of the disease.
Figure 13.1 Cholestasis. Canaliculi are not visible under normal circumstances but can be seen in cholestasis when they become dilated with inspissated bile plugs.
2. Ductular reaction:
A reactive process that consists of a mixture of ductular proliferation, inflammation, and stromal cells along the limiting plate.2
Ductular reactions can occur in many types of disease, and the morphology does not always indicate the precise cause.2
It may be seen as a secondary pattern in cases of fulminant necrosis or chronic hepatitis in which it is accompanied by other significant portal and lobular changes.2
Conversely, a primary injury pattern of ductular reaction is one of the earliest and most sensitive indicators of bile flow impairment. With obstruction,
there is a visible proliferation of ductules along the perimeter of the portal tracts (Figs. 13.4
). The lumina of the ductules are typically not visualized unless they are expanded by bile plugs. Bile plugs within ductules (ductular or cholangiolar cholestasis) is termed cholangitis lenta
. Although this pattern may be seen in late stage chronic biliary disease, it is also present in other conditions such as sepsis, shock, or uremia (Figs. 13.6
When the obstruction is acute onset and involves a large duct, ductular reaction is typically accompanied by portal edema. With chronicity, the edema subsides and is replaced by fibrosis.2
Inflammatory cells, including lymphocytes, plasma cells, and neutrophils, are an integral component of ductular reaction. The presence of neutrophils along the limiting plate can serve as a valuable clue to the presence of ductular reaction.
Figure 13.2 Cholestasis. Bile pigment can be identified as golden granular material within hepatocytes or as phagocytosed debris within Kupffer cells. Cholate stasis is characterized by feathery degeneration (cytoplasmic swelling with protein condensation) of hepatocytes. Mallory-Denk bodies are often present.
Figure 13.3 Cholestasis. Cholate stasis preferentially affects periportal and periseptal hepatocytes.
Figure 13.4 Ductular reaction. Marked ductular reaction characterized by an irregular mass of ductules along the limiting plate and focally extending into the periportal lobule. No well-formed lumina are seen in this field. Neutrophilic pericholangitis is present. Note the cholate stasis within the periportal hepatocytes to the left.
Figure 13.5 Ductular reaction. Ductular reaction is not always pronounced. In the center of the field, there is a subtle ductular reaction extending vertically along the interface of the lobule and the portal tract. There is a poorly formed lumen present within one of the ductule profiles.
Figure 13.6 Cholangitis lenta. Cholangitis lenta in a case of sepsis. Proliferating ductules along the perimeter of the portal tract are dilated and contain inspissated bile plugs (ductular or cholangiolar cholestasis). There is no significant fibrosis. This finding is often idiopathic but can also be seen in shock, uremia, or any debilitating illness.
Figure 13.7 Ductular cholestasis. Ductular cholestasis is seen in this case of primary biliary cirrhosis. With prolonged cholestasis of any etiology, bile plugs can be seen within the proliferating ductules. This finding is most commonly seen in the setting of end-stage disease and clinical decompensation.
3. Ductopenia: Ductopenia
is defined as the absence of a bile duct branch in at least 50% of portal tracts.3
The number of portal tracts needed for an adequate specimen varies by institution. From a practical standpoint, 8 to 10 portal tracts are usually sufficient to determine if there is significant ductopenia. Because the bile duct branch travels with the hepatic artery, the presence of an artery without a bile duct is a helpful indicator of bile duct loss within that portal tract3
). Normally, 70% to 80% of arteries have an associated bile duct.3
At times, portal inflammation may be so dense that it is difficult to identify normal structures. Cytokeratin 7 (CK7) immunostains can aid by highlighting ducts in this situation. Though not typically utilized for this purpose, periodic acid-Schiff diastase (PASD) highlights the basement membranes of bile ducts and can be used to assess for ductopenia. Table 13.1
contains a list of disease processes which can result in ductopenia.
Figure 13.8 Ductopenia. The portal tract contains a portal vein and hepatic artery branch but no bile duct.
4. Copper accumulation:
In early stage disease, the presence of periportal copper is highly suggestive of a chronic biliary disease. Though rare in chronic hepatitis and steatohepatitis, copper accumulation can be found in a small percent of these cases when there is advanced fibrosis (<10%).4
In chronic biliary disease, the amount of copper increases with the stage of the disease, such that the absence of copper in the cirrhotic liver is unusual for chronic biliary disease (Figs. 13.9
At Mayo Clinic, rhodanine stain is performed on 10-um thick sections. The orcein stain for copper-associated protein is another commonly utilized stain at other medical centers.
Chronic biliary disease has a characteristic pattern of scarring, termed jigsaw puzzle-like
, in which there is an irregular shape to the cirrhotic nodules (Fig. 13.11
). In addition, fibrosis is often unevenly distributed within the liver in early stage disease. When present, fibrosis of any degree
indicates a chronic disorder and argues against an acute process, such as a cholestatic drug reaction or acute large duct obstruction.
Table 13.1 Common causes of ductopenia in adults
Primary biliary cirrhosis
Primary sclerosing cholangitis
Secondary sclerosing cholangitis
Graft versus host disease
Liver allograft rejection
Idiopathic adulthood ductopenia
Figure 13.9 Rhodanine stain. In this case of primary biliary cirrhosis, the copper appears as rust-colored granules within hepatocytes. The amount of copper generally increases with the stage of disease and the severity of cholestasis.
Figure 13.10 Rhodanine stain. In early cholestatic liver disease, copper deposits can be very focal, identified in only rare periportal hepatocytes, requiring careful high-power examination.
Figure 13.11 Biliary pattern of cirrhosis. In this case of end-stage primary sclerosing cholangitis, there is an irregular pattern of scarring such that the lobular parenchyma appears to fit together like pieces of a puzzle, hence the term jigsaw puzzle-like. This pattern is not universally present, and some cases may demonstrate more classic regenerative nodules.
Older scoring systems for chronic biliary disease did not give a separate grade and stage for the disease. Instead, inflammation and fibrosis were combined into an overall staging system. For example, the one used historically at the Mayo Clinic was created by Ludwig et al.5
Stage 1: Portal stage—all disease activity is confined to the portal tract; limiting plate intact.
Stage 2: Periportal stage—limiting plate disrupted by lymphocytic interface activity and/or ductular reaction; portal tracts have irregular shape.
Stage 3: Septal stage—fibrous septa (portal-portal bridging fibrosis).
Stage 4: Cirrhotic stage—fibrous septa and parenchymal distortion.
These staging systems are not widely used anymore, but can be encountered in older pathology reports on prior specimens. Currently, at the Mayo Clinic and at most medical centers, fibrosis in biliary tract disease is staged using a standard system such as the Batts-Ludwig, Ishak, or Metavir.
The majority of this chapter will focus on the three main causes of primary chronic biliary tract disease: primary biliary cirrhosis, primary sclerosing cholangitis, and Immunoglobulin G4 (IgG4)-related disease (Table 13.2
), followed by brief discussions of secondary causes.
Table 13.2 Clinicopathologic features of the three major autoimmune cholangiopathies
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
IgG4-related Sclerosing Cholangitis
Peak incidence (age)
Key diagnostic test
Florid duct lesion
Large duct obstructive disease; fibro-obliterative duct lesions (not always present)
Dense lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, increased IgG4+ plasma cell//hpf
Sjogren syndrome, scleroderma, hemolytic anemia, celiac disease, and hypothyroidism
Inflammatory bowel disease