Biopsy Interpretation of the Liver, 2nd ed

18. Large Bile Duct Disorders

Disorders affecting the large extrahepatic bile ducts are common. Modern biochemical tests and sophisticated imaging techniques often make liver biopsy unnecessary in contrast with past years when large duct obstruction (LDO) was one of the most important indications for liver biopsy.

LARGE DUCT OBSTRUCTION

Acute Large Bile Duct Obstruction

Acute large bile duct obstruction (LDO) often has a dramatic clinical presentation with sudden onset of jaundice and right upper quadrant abdominal pain, generally due to obstruction of the common hepatic duct or the ampulla of Vater.

Histopathologic changes are characteristic but not pathognomonic. They can be seen with obstruction of the right or left hepatic ducts as well as the smaller intrahepatic ducts into which portal tract interlobular ducts drain. When either intrahepatic duct obstruction or obstruction above the point of juncture of the right and left hepatic ducts is suspected, biopsy of tissue from both liver lobes may be useful. Changes will be bilateral with obstructions below the juncture of the right and left hepatic ducts, but will be one-sided when only one is involved or when the obstructed duct is intrahepatic.

Acute LDO is most commonly associated with gallstones and can persist after passage of the gallstone. Any process causing obstruction or stenosis of the bile ducts can lead to similar changes, including neoplasms (13), strictures following surgical procedures (8), and congenital biliary atresia (see Chapter 6), for example. Rare causes include inflammatory bile duct polyps, choledochal cyst or diverticulum, parasites such as Clonorchis sinensis, annular pancreas compressing the common duct, and pancreatitis and its complications (7,10,11,16,21,23).

PATHOLOGY. The earliest change, seen as early as 2 or 3 days after onset, is canalicular cholestasis, predominantly in zone 3 of the acinus (Fig. 18.1). The bile is visible as green or brown-green pigment in the form of bile plugs or bile thrombi. In addition, the perivenular (zone 3) area has prominent, bile-laden Kupffer cells. In resolving acute LDO, the bile plugs disappear first, but pigment-rich Kupffer cells may persist for weeks. Periodic acid-Schiff-positive Kupffer cells may be the only remaining evidence of cholestasis after resolution of the obstruction (23).

In acute LDO, hepatocytes are not primarily damaged. If obstruction and cholestasis persist, however, secondary reactive changes become prominent (4). Cholestasis up-regulates class I human leukocyte antigen expression in hepatocytes leading to focal liver cell injury and necrosis (6). Zone 3 hepatocytes have distended, swollen cytoplasm, and liver cell nuclei vary in size with nuclear hyperchromasia. The cytoplasm of some hepatocytes becomes rarified with fine, weblike reticulation, traditionally recognized, and described as “feathery degeneration” (Fig. 18.2). Individual liver cells may be necrotic (acidophilic bodies). Mitoses are common. Ultrastructurally there is hypertrophy of endoplasmic reticulum.

In the first week after onset of LDO, portal tracts are edematous, with pale, loose connective tissue and early fibroblast proliferation (Fig. 18.3, e-Figs. 18.1-18.4). Interlobular or septal bile ducts can show reactive epithelial changes including irregularity of epithelium, variation in size and nuclear hyperchromasia, and, occasionally, true necrosis. Bile duct epithelium may later become atrophic, particularly once periductal fibrosis is well developed. In spite of this, interlobular bile duct loss is exceedingly rare (Fig. 18.4).

The portal tract inflammatory infiltrate varies. Early, there is little or no inflammatory cell accumulation. When present, lymphoid and histiocytic cells predominate (Fig. 18.4). As LDO persists, the number of polymorphonuclear leukocytes (PMNs) increases in number, usually accompanying so-called marginal bile ductular proliferation. Proliferating bile ductules are themselves chemotactic and nonspecifically stimulate a PMN response in many conditions associated with ductular proliferation.

Marginal bile ductular reaction (proliferation) is a reliable, but not pathognomonic, feature of LDO, seen in more than 80% of portal tracts (e-Fig. 18.4). Although proliferated bile ductules may have a dilated lumen, there is usually no visible bile. When dilated ductules are prominent, sepsis and septicemia should also be considered (17). Superimposed acute cholangitis with intraluminal PMNs and chronic inflammatory cells focally infiltrating the bile duct epithelium can be seen. Proliferated ductules, especially before a luminal space is apparent, can be highlighted with keratin immunohistochemistry, using CK19 or keratin AE 1,3.

The origin of ductules is controversial. Possibilities include (a) multiplication of pre-existing bile ductules, (b) proliferation from a putative progenitor (stem) cell, and (c) metaplasia of periportal hepatocytes. It may be that they are all active at different stages (9,24,27,29,30,31). Multiplication of the preexisting bile ductules seems more important in acute cholestasis, whereas ductular periportal metaplasia is more often associated with chronic cholangiopathies, including primary biliary cirrhosis and primary sclerosing cholangitis. Hepatocytes undergo phenotypic changes with expression of biliary-type cytokeratin, integrins, blood group antigens, and tissue peptide antigen (20,29,30,31). Cholestatic rosette formation is commonly seen (Fig. 18.5).

Periportal bile lakes or bile infarcts are the hallmark of LDO, although seen in only a small percentage of patients. Bile within the bile lake is often admixed with fibrin. Hepatocytes immediately adjacent show variable degrees of degeneration and lytic-type necrosis. Bile can escape from bile ducts into portal tracts as bile extravasation with local histiocytic phagocytic reaction, sometimes causing giant cell reaction (Fig. 18.6).

Long-Standing Large Duct Obstruction

The clinical diagnosis of long-standing LDO obstruction is rarely problematic.

PATHOLOGY. In long-standing LDO, lasting weeks to months, fibrosis gradually replaces the portal inflammatory infiltrate. A characteristic pattern of periductal, concentric fibrosis, similar to that of primary sclerosing cholangitis, develops (Figs. 18.7, 18.8). Portal-to-portal fibrous bridging ensues, and secondary biliary cirrhosis eventually develops. Liver cell injury is not prominent, and fibrous septa are highly irregular. The nodules that form are not circular as are typical regenerative nodules of cirrhosis following hepatitis and have a geographic or jigsaw-puzzle appearance (e-Figs. 18.5, 18.6) (5,7,8). In the absence of portal-to-central shunting and true regenerative nodules, secondary biliary cirrhosis is not a true cirrhosis and initially manifests as portal hypertension without hepatocellular dysfunction (see Chapter 20). Cholestasis has an inhibitory effect on liver cell regeneration by interfering with expression of growth-promoting genes (4,28). The term biliary fibrosis is more appropriate than biliary cirrhosis in these cases.

Other parenchymal changes can be seen with long-standing cholestasis secondary to LDO. Feathery degeneration (Fig. 18.2), and cholestatic rosettes (Fig. 18.5), representing a circular arrangement of hepatocytes around a central bile plug, may be seen. Antibody directed against cytokeratin CAM 5.2 will highlight these tubule-like structures. Clusters of foamy (xanthomatous) cells are seen. Perpiportal or paraseptal hepatocytes are pale and rarified (cholate stasis). These hepatocytes often have increased copper-associated protein, demonstrated with Victoria blue or orcein (Shikata) stain (14,25,26). Mallory hyalin can be present (Fig. 18.9), but, unlike in alcoholic liver disease, the intracytoplasmic hyalin is almost invariably periportal or paraseptal and not distributed throughout the lobule (see Chapter 13). Portal and periportal fibrosis develops (e-Figs. 18.7-18.9). Fibrous septa are usually regular, broad, and paucicellular, with loosely arranged collagen fibers.

The changes of acute LDO are entirely reversible. When LDO is eliminated, the inflammatory and reactive changes and the cholestasis resolve within a few weeks. However, the reversibility of established fibrosis is somewhat controversial (1,5). Extensive fibrosis of established secondary biliary cirrhosis is probably irreversible, but there have been reports of resolution of biliary cirrhosis in children (32).

Cholangitis Associated with Bile Duct Obstruction

PMNs accompany bile ductular proliferation following prolonged LDO in the connective tissue (acute pericholangitis). True acute ascending cholangitis, rare with modern antibiotic therapy, should be diagnosed only when numerous PMNs fill the bile duct lumen. In ascending cholangitis there may also be suppurative necrosis of the bile duct epithelium and eventual abscess formation.

Differential Diagnosis of Intrahepatic Cholestasis

Cholestasis is the presence of visible bile in liver tissue and can be canalicular (intracanalicular), intracellular (intrahepatocytic) or can involve ducts and/or ductules.

Canalicular (intracanalicular) cholestasis is the most frequently observed form of acute cholestasis. In LDO, canalicular cholestasis is seen within a few days of onset. Green or green-yellow bile plugs are in dilated canaliculi, particularly in zone 3. Histochemical stains can be used to demonstrate bile, but canalicular cholestasis is generally easily recognized with hematoxylin-eosin. In prolonged cholestasis, the cytoplasm of liver cells also contains bile pigment (intracytoplasmic cholestasis). With excessive accumulation of bile, liver cells form tubular, glandlike structures (cholestatic liver cell rosettes) (19).

Canalicular cholestasis is not pathognomonic for LDO and can be seen in other conditions, including acute hepatitis, whether viral or drug-induced, preservation (harvesting) injury in liver transplantation patients, and “pure” cholestatic syndromes associated with oral contraceptives, benign recurrent cholestasis, pregnancy, sepsis, and some malignancies including Hodgkin disease and other lymphoproliferative disorders. Several drugs can also cause a pure cholestatic jaundice in the absence of other morphologic changes (15).

Chronic cholestasis is often associated with long-standing chronic biliary diseases. Even in the absence of bile in the canaliculi and hepatocytes, cytoplasmic changes develop secondary to compromised bile flow, so-called cholate stasis (22). The term and the concept of cholate stasis are not universally accepted, despite the constellation of changes that are easily recognized, including swelling and rarefaction of the hepatocytes in periportal or paraseptal areas. These swollen cells contain a variable amount of finely granular copper-associated protein within autophagic vacuoles, demonstrated with Victoria blue or orcein stains (14,25,26). There may also be excessive metallic copper, stainable with rubeanic acid or rhodamine methods. Hepatocytes can contain Mallory hyaline-like material (12).

Cholate stasis is seen as a pale rim of hepatocytes at the periphery of the nodule. There is usually associated ductular proliferation.

Ductal and, when present, ductular cholestasis are commonly seen in sepsis, as well as in acute pancreatitis, and can follow ischemic cholangitis in the early posttransplantation period. In congenital hepatic fibrosis and bile duct hamartomas, larger bile duct-like structures can contain bile in their lumen in the absence of obstructive changes, hepatitis, or other causes of cholestasis.

Intrahepatic Cholestasis

The list of conditions contributing to intrahepatic cholestasis is extensive and includes congenital and inherited syndromes as well as various acquired disorders (see Chapter 26) (8,18).

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