Definition and pathology of primary sclerosing cholangitis

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1 J Hepatobiliary Pancreat Surg (1999) 6: Definition and pathology of primary sclerosing cholangitis Yasuni Nakanuma, Kenichi Harada, Kazuhoshi Katayanagi, Kouichi Tsuneyama, and Motoko Sasaki Second Department of Pathology, Kanazawa University School of Medicine, Kanazawa , Japan Abstract: Although primary sclerosing cholangitis (PSC) is not a common disease, it is important in the differential diagnosis of hepatobiliary tract diseases in clinical practice. A diagnosis of PSC should be made only after the exclusion of similar diseases with well known etiologies or pathogeneses. In this review, the pathology of classical PSC and its variants or related diseases is highlighted. PSC is histologically characterized by progressive periductal fibrosis with luminal stenosis or obliteration, along with the formation of a fibrous core, as well as dilatation (cholangiectasis). Its etiology is unknown. Bacterial ascending cholangitis is superimposed on its long clinical course. Such a heterogeneous distribution of biliary lesions with biliary obliteration and cholangiectasis is responsible for the radiological demonstration of biliary abnormalities, particularly the beaded appearance. Sampling variability is common in needle or wedge biopsied specimens. As a result of biliary damage, the liver shows progressive cholestatic change followed by biliary fibrosis and cirrhosis, and this hepatic progression is divisible into four stages. There are several variants of PSC or related diseases, such as localized biliary sclerosis and stenosis, sclerosing cholangitis associated with inflammatory pseudotumor, and PSC-autoimmune hepatitis overlapping syndrome. Cholelithiasis, including secondary hepatolithiasis and, to a lesser degree, biliary carcinoma and dysplasia, are also known to develop at the perihilar bile ducts as a late complication of PSC. Key words: primary sclerosing cholangitis, biliary tree, autoimmune disease, peribiliary glands Introduction Primary sclerosing cholangitis (PSC) is characterized by nonspecific inflammatory fibrosis in the wall, usually in Offprint requests to: Y. Nakanuma Received for publication on March 8, 1999; accepted on April 30, 1999 both the intrahepatic and extrahepatic biliary tree. 1 This disease is part of the vanishing bile duct syndrome, and presents as chronic cholestatic liver disease followed by biliary fibrosis and cirrhosis. While the cause of PSC remains speculative, prominent lymphocyte infiltrates have been seen in areas of portal destruction, and T cells have been found within the biliary epithelium, 2 suggesting an autoimmune nature involving T cells. 3 There is no doubt that genetic factors play a role in the development of PSC. 4 An increased incidence of HLA B8 and DR2 5 was also noted. In addition to adults, children are also affected by this disease. PSC usually occurs in association with inflammatory bowel diseases, particularly ulcerative colitis. 6 The association rate for inflammatory bowel disease, especially ulcerative colitis, is different between Japan and the West (United States and Europe), being about 10% in Japan and more than 60% in the West. This may reflect heterogeneity in the etiopathogenesis of PSC, and such heterogeneity may be due to geographic factors. For a better understanding of this disease, the anatomy of the intrahepatic biliary tree will be briefly described. The intrahepatic biliary tree proximal to the hepatic duct confluence is classified into the right and left hepatic ducts, segmental ducts, area ducts, and their finer branches. 7,8 The hepatic, segmental, and area ducts and their first and second branches are grossly visible and are termed collectively large intrahepatic bile ducts. Peribiliary glands are present along the large intrahepatic and extrahepatic bile ducts. Bile ductules are tubular structures in the peripheral zone of the portal tract with a diameter of 20 µm; interlobular bile ducts have a diameter of µm, and can be subdivided into medium-sized (diameter, µm) and smaller (diameter, µm) types. Septal bile ducts are larger than the interlobular bile ducts. The wall of the bile duct consists of a hypocellular, collagenous band lined by a single layer of biliary epithelium. The

2 334 Y. Nakanuma et al.: Primary sclerosing cholangitis periductal tissue is a loose connective tissue around the bile duct wall. Septal and large intrahepatic bile ducts have their own bile duct wall and are lined by a single layer of high columnar epithelium, while the interlobular bile ducts and bile ductules are lined by a single layer of low columnar or cuboidal epithelium. In this review, interlobular bile ducts and bile ductules are referred to as small bile ducts, and bile ducts around the hepatic hilus as perihilar bile ducts. Definition of primary sclerosing cholangitis PSC is characterized by non-specific inflammation and fibrosis of the intrahepatic and extrahepatic biliary tree, leading to luminal narrowing or obliteration as well as dilatation of the affected bile ducts. 9 This disease is also called chronic fibrosing obliterative cholangitis, 10 and affects both sexes. The small bile duct, mediumsized and large intrahepatic bile duct, and extrahepatic bile duct involvement occur independently and heterogeneously, but with progression of the disease, almost all segments of the biliary tree may be affected. 11 Specimens from patients with extrahepatic PSC were indistinguishable from those of patients with combined extra- and intrahepatic PSC. As a consequence of the biliary damage, the liver shows progressive cholestatic changes, followed by biliary fibrosis and cirrhosis. The changes in the biliary tree are grossly recognizable, and are visible and identifiable by cholangiography as stricture and diminution, as well as dilatation, of the biliary tree ( beaded appearance ) (Figs. 1 and 2). 1 In addition to typical or classical PSC, there are many kinds of diseases presenting with radiologic and histopathologic changes similar to these in PSC, such as cholangiocarcinoma, 1 and also several variants or related diseases such as PSC-auto immune hepatitis (AIH) overlap syndrome. Because of the lack of pathognomonic changes in pathology and radiology at present, this disease should be diagnosed by the exclusion of these similar or related diseases. In practice, PSC is diagnosed by cholangiography and also by needle or wedge biopsy of the liver and, occasionally, bile ducts. The bile duct lesions characterizing PSC may be present in fewer than 40% of biopsy specimens. Surgical biopsy and endoscopic punch biopsy of extrahepatic bile ducts provide useful information, although their application is very limited. 1,12 Pathology of primary sclerosing cholangitis The pathology of classical PSC and then that of its variants or related diseases will be described. The immunopathology of PSC is also briefly discussed. Fig. 1. Endoscopic retrograde cholangiopancreatography of primary sclerosing cholangitis. The extrahepatic and intrahepatic biliary tree shows alternating stenosis and dilatation (beaded appearance). G, Gallbladder; D, duodenum Fig. 2. Cut surface of autopsied liver of patient with primary sclerosing cholangitis. The bile ducts show dilatation (arrows) and also are embedded in fibrous tissues. Portal vein shows occlusive thromboembolism and phlebosclerosis

3 Y. Nakanuma et al.: Primary sclerosing cholangitis 335 Pathology and histopathology of classical PSC The histopathology of the bile duct differs according to the anatomical level(s) of the biliary tree. Pathology of the intrahepatic large bile duct and extrahepatic biliary tree. Macroscopically, the intrahepatic large bile duct and extrahepatic bile duct show gross fibrous thickening of the duct wall with luminal narrowing or obliteration, as well as dilatation (intrahepatic cholangiectasis) (Fig. 3a,b and Fig. 4). There are annular scars or fibrous cords which alternate with tubular or saccular cholangiectases of the bile duct. Fibrous scar around the hepatic hilus may show yellow discoloration due to the presence of xanthomatous aggregates. Grossly, the affected portal tracts are sclerotic (Fig. 2). Histologically, these affected duct walls show, variably, lymphoplasmacytic infiltration and, occasionally, lymph follicle formation (Fig. 5). Myofibroblastic proliferation is also seen variably, Clusters of eosinophils are also encountered in some cases. The activity of these inflammatory changes is dyssynchrous or heterogeneous along the biliary tree, and some parts are acellular and hyalinous while others are cellular and show active inflammation. In spite of the periductal fibrosis, the damage to biliary lining epithelia is relatively mild. However, these epithelia show variable degenerative or atrophic changes, and the biliary mucosa occasionally shows erosions or ulceration with accumulation of foamy macrophages (Fig. 6). Bile extravasation or bile impregnation is occasionally found, with a xanthogranulomatous reaction. The basement membrane is often thickened instead of destroyed. On serial section observations, the intrahepatic large bile ducts were found to have disappeared Fig. 4. Intrahepatic large bile duct of primary sclerosing cholangitis shows luminal dilatation. There are protrusions of duct wall (arrowheads) into the lumen. L, Bile duct lumen. H&E, 75 a b Fig. 3a b. Intrahepatic large bile duct of primary sclerosing cholangitis. a The bile duct (arrows) shows luminal narrowing, proliferation of intramural peribiliary glands (arrowhead), and fibrous thickening of the duct wall. b On serial section observation, this bile duct is obliterated with dense fibrous tissue H&E, 150 Fig. 5. Extrahepatic bile ducts in primary sclerosing cholangitis show marked thickening of the duct wall, composed of marked infiltration of lymphoid cells with germinal center and fibrosis (asterisk). However, some parts are not severely involved. L, Bile duct lumen

4 336 Y. Nakanuma et al.: Primary sclerosing cholangitis Fig. 6. The bile duct surface in primary sclerosing cholangitis shows focal erosion and accumulation of pigmented macrophages or foamy cells. L, Bile duct lumen H&E, 250 Fig. 7. The liver shows fibrous enlargement of portal tracts (P) and P-P fibrous bridging. The regenerative activity of hepatic parenchyma is weak. H&E, 100 in the fibrotic tissue, and remnants of peribiliary glands were identifiable at the site of bile duct disappearance. Obliteration of segmental or main left or right hepatic ducts may occasionally lead to a cirrhosis confined to the more affected parts of the liver. At the perihilar bile ducts, the peribiliary glands proliferate and also show fibrosis and necroinflammation, The peribiliary glands show also cystic change which could be detectable as a diverticulum along the biliary tree on imaging modalities. These findings suggest that the disease process for PSC extends to the peribiliary glands. 13 Gallbladder disease in PSC is common but, again, histologic findings are not diagnostic. As to the mechanism of bile duct fibrosis of the intrahepatic large bile duct and extrahepatic biliary tree, several fibrogenetic factors may be involved. Among them, c-kit-expressing mast cells are involved in the bile duct fibrosis. 14 These mast cells are known to synthesize and secrete fibrogenetic factors, such as basic fibroblast growth factor and tryptase, and these factors may stimulate fibroblasts and then fiber deposition. Pathology of small bile ducts, periportal regions, and hepatic parenchyma. In small portal tracts, periductal fibrosis and inflammation, portal edema and fibrosis, focal proliferation of bile ducts and ductules, and loss of bile ducts are seen variably (Fig. 7). The relationship between the pathology and pathogenesis of PSC in the large and small bile ducts remains uncertain. 11 Septal and, to a lesser degree, interlobular bile ducts show periductal lamellar fibrosis, an onion-skin type fibrosis (Fig. 8a,b). These biliary lesions are accompanied by loss the of interlobular bile ducts (Fig. 9). Proliferation of bile ducts in some portal tracts and absence of bile duct in others are the most characteristic combination in PSC; when bile ducts disappear, their Fig. 8a b. a In primary sclerosing cholangitis, the septal bile duct (arrow) shows lamellar fibrosis, while biliary epithelial changes show no severe damage. H&E, 200 b In primary sclerosing cholangitis, the interlobular bile duct (arrow) shows periductal fibrosis and biliary epithelial damage. There is lymphoid cell infiltration. H&E, 250 a b

5 Y. Nakanuma et al.: Primary sclerosing cholangitis 337 Fig. 9. In primary sclerosing cholangitis, portal vein and hepatic arterial branch are identifiable in this fibrous portal tract with mild lymphoid cell infiltration. However, interlobular bile duct is missing. In the suspected place of bile duct loss, there are indistinct fibrous scars (arrow). H&E, 200 former sites are indicated either by small aggregates of lymphocytes or by macrophages, or round scars. The hepatic parenchyma shows nonspecific changes. However, along with the progression of the disease or bile duct damage, there occur cholestatic parenchymal changes, such as deposition of copper or copper-binding protein, bile plugs, and cholate stasis. 15 Bile plugs are rather frequently seen in spite of the lack of small bile ducts, probably due to the large bile duct PSC. Hepatic copper content, measured by atomic absorption spectrophotometry, was higher in specimens from patients with PSC. So-called biliary piecemeal necrosis with destruction of the limiting plates of the hepatic lobules seems to be important to this progression. Compared with primary biliary cirrhosis (PBC) or chronic viral hepatitis, inflammatory changes appeared mild, yet biliary cirrhosis may eventually develop in most patients with PSC. Di-PAS-positive cells are also seen in portal tracts and hepatic parenchyma. PSC in children The majority of children with PSC were diagnosed in their second decade. 16 More than half of the patients had inflammatory bowel disease (IBD), all with colitis, particularly ulcerative colitis. Intrahepatic disease predominated; in a few patients, a common bile duct stricture was identified, requiring stenting. Findings in the initial liver biopsy were classifiable according to Ludwig s criteria for staging PSC (see below). Staging of PSC Liver biopsy study in PSC is recommended not only for diagnostic purposes but also for histologic staging. Staging is used for determining the prognosis of a patient and the therapeutic approaches, particularly in the decision-making process for liver transplantation. The histological changes of PSC may be divided into four stages, 10 as is done in PBC: portal (stage 1), periportal (stage 2), septal (stage 3), and cirrhotic (stage 4). The concept of this staging is similar to that done in PBC. However, the pattern of cirrhosis is more irregular than that of PBC, reflecting the larger caliber of the ducts involved in PSC. This staging is based on the progressive cholestasis and associated necroinflammatory changes. The biliary type of fibrosis and cirrhosis may be due to a substantial loss or stenosis of intrahepatic bile ducts, leading to interference with bile flow. In addition, an interface hepatitis associated with lymphocytic infiltration (piecemeal necrosis) and focal necrosis, as seen in chronic hepatitis, are seen, variably. Stage 1. The inflammatory and fibrotic changes are confined within the boundaries of portal tracts. A diffuse mixed inflammatory cell infiltrate of lymphocytes, plasma cells, and neutrophils is found in the portal tracts, particularly around the bile ducts. Lymphoid follicles or aggregates may be present. Epithelioid granuloma is only occasionally found in portal tracts. Small bile ducts may show degenerative epithelial changes, and may be surrounded by a ring of edematous or hyaline fibrosis. Stage 2. Portal tracts are enlarged, with disruption of the limiting plates. The histologic picture varies, presumably depending on the severity of the biliary obstruction, extent of the PSC process, and cholestatic changes. Superimposed bacterial cholangitis may also influence the histologic picture. Biliary piecemeal necrosis with focal ductular proliferation may predominate (Fig. 10). Sometimes, dense portal tract inflammation is associated with interface hepatitis, mimicking AIH. In many instances, the inflammation seems to have subsided, and the mildly fibrotic portal tracts have a stellate shape due to short and thin radiating septa. Stages 3 and 4. Increasing portal fibrosis with the formation of portal-to-portal linking septa and eventual development of biliary fibrosis (stage 3) and cirrhosis (stage 4). The regenerative activities of hepatic parenchyma are weak compared with those in viral cirrhosis, and these parenchymal changes are jigsaw puzzle-like in appearance. As the disease advances, the inflammation has a tendency to subside, leaving a combination of portal and septal fibrosis. Portal tract and septal fibroses are very dense and collagenous, and are associated with edema, focal ductular proliferation, and with periseptal biliary piecemeal necrosis with copper accumulation, Mallory bodies, and halo formation around the regenerative nodules. The interlobular bile ducts are reduced.

6 338 Y. Nakanuma et al.: Primary sclerosing cholangitis specifically found in the serum. It is proposed that there is cross reactivity against the intestinal tropomyosin isoform to biliary epithelial cells for PSC. In addition, HSP is also suspected as an autoantigen in PSC. A cross-reactive peptide in small and large bile duct cholangiocytes, as well as in colonic epithelial cells, may be an important target antigen. 23 Complications of PSC Fig. 10. In primary sclerosing cholangitis, portal tract is fibrously enlarged and there is marked ductular proliferation. There bile ductules are positive for CK 19, a bile duct-specific cytokeratin. Some hepatocytes facing fibrously enlarged portal tracts also variously express this cytokeratin. P, Portal tract; H, hepatic parenchyma. Immunostaining of CK 19 and hematoxylin, 200 Immunopathology of PSC Current evidence suggests that immunologic factors also play a significant pathogenetic role in PSC. Microenvironments around the biliary tree. Immunopathologically, HLA class II antigens and intracellular adhesion molecule (ICAM-1) are aberrantly expressed by biliary epithelial cells. 17 Subtyping of the lymphocytes in the liver tissue shows a predominance of CD4-positive T cells over CD8-positive cells. 17 T Cells accumulate at the sites of the bile duct inflammation in PSC. 18 Helper T cell populations comprise functionally distinct subsets characterized by the cytokines they produce. Determination of lymphocytes by cytokines to Th1 or Th2 subtype showed a majority of Th1 lymphocytes in PSC. Enhanced autoreactivity by portal T cells, increased numbers of circulating T cells, and the occurrence of autoantibodies are noted. 19,20 Ultrastructurally, there are point and broad contacts between infiltrating lymphoid cells and biliary epithelial cells. 2 Humoral immune abnormalities. These include the classic autoantibodies, anti-nuclear antibodies and antismooth muscle antibody. Autoimmunity may be linked to an antibody that recognizes a cross-reactive peptide in small and large bile duct cholangiocytes, as well as in colonic epithelial cells. 21 Anti-neutrophil cytoplasmic antibody (ANCA) was positive in about half of PSC patients. Target antigens. Some antigens, such as colonocyte protein of 40 kd (an intestinal isoform of tropomyosin, shared by biliary epithelial cells and colonic mucosa) 22 and heat shock protein (HSP), are regarded as target antigens. In PSC, antibodies to a colonocyte protein are Bacterial cholangitis. During the long clinical course of PSC, bacterial cholangitis may superimpose, and this may lead to suppurative cholangitis and cholangitic abscess. Olsson et al. 6 recently reported a strikingly high positivity rate for bacterial isolates in the bile ducts in PSC. Biliary sludge and hepatolithiasis. In prolonged disease, biliary sludge and even calcium bilirubinate stones are frequently detectable in the cholangiectatic parts of the biliary tree. Hepatobiliary malignancy. PSC is associated with hepatobiliary maligancies in 10% to 36% of patients at the endstage. The majority of such cases are of cholangiocarcinoma, while, rarely, hepatocellular carcinoma is a complication. Study of the excised liver reveals papillary lesions consisting of abundant fibrovascular stroma covered by biliary epithelium, with low-grade and high-grade dysplasia in the common hepatic ducts and the right and left hepatic ducts. 24 Some periductal glands were also dysplastic. 24 It is estimated that the prevalence of dysplasia and carcinoma of bile ducts may be less than the 7% 9% reported in the literature for malignancies associated with PSC. Portal venous thromboembolism. This complication eventually develops, and could be a cause of death. This may be due to the local influence of parallel running bile ducts showing inflammation. Variants of PSC or related diseases Small bile duct PSC (pericholangitis) Current evidence suggests that PSC affects the entire biliary system from interlobular bile ducts to the ampulla of Vater. Pathology of the large bile ducts in PSC (large bile duct PSC) is well established, with cholangiographically identifiable duct change a hallmark. However, the pathology of small bile duct lesions, particularly the lesions of interlobular bile ducts and bile ductules in PSC, remains uncertain. This lesion shows mixed inflammatory changes in portal and periportal regions with small bile duct damage (proliferation, loss, and periductal fibrosis). Small bile

7 Y. Nakanuma et al.: Primary sclerosing cholangitis 339 duct PSC may be secondary cholestatic and inflammatory changes due to the large bile duct lesion. These changes are too small for cholangiographic identification. The term small-duct PSC should be used instead of pericholangitis. 10,11 Small bile duct PSC many occur in combination with large-duct PSC or it may occur alone in patients with ulcerative colitis. The natural history as well as the pathogenesis of small bile duct PSC remains obscure. Acquired or secondary sclerosing cholangitis Acquired forms of sclerosing cholangitis in which cholangiographic findings are similar to those in PSC are increasingly being identified. The condition may occur in patients with primary or acquired immunodeficiency syndrome and in whom biliary infection is probably involved in the pathogenesis. Sclerosing cholangitis has occurred following rupture of hydatid cysts into the biliary tree. Ischemic cholangiopathy is also included in this category. During therapy using transarterial embolization (TAE) or hepatic arterial chemoinfusion (HAI), the bile ducts show sclerosing cholangitis. Sclerosing cholangitis has also been observed in about half of patients receiving HAI of fluorodesocyridine (FUDR) for palliative treatment of liver metastases. 25 In addition to the ischemic effects, the toxic effects of the drug itself are important. The bile duct shows dense sclerosis of the bile duct wall, while inflammatory changes are relatively mild, In addition to the biliary tree, portal tracts show dense sclerosis and obliteration of portal vein branches. The exclusive supply of hepatic arterial blood to the biliary system may be why the bile duct shows sclerotic change when peribiliary vascular plexus (PVP) or hepatic arterial branches are damaged. Sclerosing and proliferative cholangitis localized to some segments of the biliary tree In patients who have not had previous biliary tract surgery, choledocholithiasis, congenital abnormality of the biliary tract, bile duct carcinoma, or pancreatic disease, sclerosing cholangitis affecting some parts of the biliary tree, particularly the extrahepatic biliary tree, has been reported. 26 Such patients may be treated by surgical operation. These cases are associated with dilation of the intrahepatic bile ducts, and endoscopic retrograde cholangiopancreatography revealed a short, ring-like stenosis. The final diagnosis was mild, localized, chronic cholangitis. This category may be diverse in terms of etiology and pathogenesis, and include some variants of PSC. The proliferative cholangitis 27,28 which usually affects females and is not associated with chronic inflammatory bowel disease is characterized by the florid proliferation of the peribiliary glands of intramural types along parts of the extrahepatic biliary tree, with intense inflammatory components. This may be a variant of PSC. Sclerosing cholangitis with inflammatory pseudotumor To date, there have been several reports of inflammatory pseudotumor along or involving the biliary tree in infants and adults. 29 Histologically, these tumors consisted of an admixed proliferation of lymphocytes, plasma cells, and fibroblasts with variable hyaline fibrosis. The phenotypes of lymphocytes and plasma cells within the tumor were immunohistochemically heterogeneous. Bile ducts and peribiliary glands embedded within these tumors showed nonspecific fibrosis and inflammation, and inflammatory changes in the bile ducts were imperceptibly merged with those in the inflammatory tumor, raising the possibility that these tumors arose in relation to cholangitis. The bile ducts adjacent to the tumor also showed similar but milder nonspecific inflammatory changes. Biliary tract disease(s) should be explored as the etiology of hepatic inflammatory pseudotumor. In patients in whom the inflammatory pseudotumor was solitary, the tumor was present in the hepatic hilar region, and had been misdiagnosed as cholangiocarcinoma by imaging modalities and/or gross pathologic examination. Pancreatic involvement in PSC is an extremely rare condition, and its pathologic features are poorly documented. Kawaguchi et al. 30 reported two cases of an unusual lymphoplasmacytic sclerosing inflammatory disease involving the total pancreas, common bile duct, and gallbladder. The gross appearance of the pancreas showed firm and mass-like enlargement with regional lymph node swelling. Histologic findings were characterized by diffuse lymphoplasmacytic infiltration with marked interstitial fibrosis and acinar atrophy, obliterated phlebitis of the pancreatic veins, and involvement of the portal vein. Similar inflammatory processes involved the bile duct and the gallbladder. Lymphoplasmacytic sclerosing pancreatitis with cholangitis is thought to be a more appropriate term of this condition. PSC and AIH overlap syndrome In about a third of PSC patients, autoantibodies, particularly antinuclear antibodies, are detectable in serum. Histologically, a moderate to marked degree of interface hepatitis (lymphocytic piecemeal necrosis) and focal hepatocellular necrosis are also noted in some cases of PSC. There cases should be called overlapping syndrome of PSC and AIH. This overlap syndrome is more common in children with PSC. Nine of 32 children

8 340 Y. Nakanuma et al.: Primary sclerosing cholangitis with PSC presented with features similar to those of AIH. Differential diagnosis In clinical practice, differential diagnosis is essential in PSC. Representative diseases which resemble PSC radiologically and pathologically are described below. Intrahepatic stones (hepatolithiasis) As a late complication of PSC, calcium bilirubinate stones or biliary sludge develop in the biliary tree, particularly in the cholangiectatic parts. Differentiation of such cases from primary hepatolithiasis is occasionally difficult. PBC PBC and PSC share many clinical and pathologic features. 5 Distinguishing between PSC and PBC based on histologic appearances alone may be difficult, 31 and the distinction is even more difficult on the basis of a single biopsy and where the size of the portal tracts contained in the biopsy specimen may determine the pattern of the histological lesions seen. Cholestasis is an earlier and more frequent finding in PSC than in PBC. Periductal fibrosis or ductal replacement by fibrous cords with or without superimposed acute cholangitis favor PSC, whereas granulomas are mostly found in PBC. Central to the symptoms and biochemical alterations in both conditions is a substantial loss of intrahepatic bile ducts, leading to interference with bile flow. However, the two diseases differ serologically. This pathologic change may ultimately result in cirrhosis of the biliary type. In addition, however, biopsy specimens usually show an element of liver-cell destruction and associated inflammation, mainly interface hepatitis. This finding is more pronounced in PBC than in PSC but can lead, in both diseases, to features that resemble those of cirrhosis as a result of hepatitis virus infection. The resemblance often leads to diagnostic confusion, which is easily dispelled by attention to the clinical, radiologic, serologic, and biochemical context. Biliary tract malignancy As a late complication of PSC, biliary malignancy may develop. However, the cholangiographic and even pathologic changes of PSC and peribiliary infiltrating cholangiocarcinoma (sclerosing bile duct carcinoma) resemble each other. Liver biopsy is a useful method for differentiation, although sampling errors should be avoided. Histiocytosis X may produce a picture of sclerosing cholangitis, both in children and adults. This seems to follow infiltration of the bile ducts by granulation tissue with Langerhans cells. Hematopoietic malignancy In patients with T-cell malignancy or human T- lymphotropic type 1 (HTLV-1)-associated myelopathy (HAM), PSC-like features develop. 18,32 These patients present with intrahepatic cholestasis, cholangitis, weight loss, lassitude, and diarrhea. Cholangiographic changes are similar to those in PSC. Liver histology also demonstrates concentric fibrosis of the bile ducts ( onion skin lesions, with an inflammatory cell infiltrate and lymphoid aggregates). This may be medicated by the effect of cytokines released by the infiltrating T cells into the portal circulation or may be a manifestation of immune disorders in these diseases. Polycystic disease and peribiliary multiple cysts In adult polycystic disease of the kidney, there are numerous hepatic cysts in the hepatic parenchyma and hepatic hilus. This PSC-like cholangiographic feature is seen in 67% of patients with this adult-type polycystic disease. 33 These cysts compress the intrahepatic large bile ducts and create cholangiographic features resembling those of PSC. 30 Such changes are also seen in the extrahepatic biliary tree. Rarely, peribiliary multiple hilar cysts 34 also present with similar cholangiographic changes. 35 However, histopathologically, these diseases are easily differentiated from PSC. Portal venous thomboembolism PSC-like clinical and radiological findings may develop in patients with portal venous thromboembolism. The changes are due to the fully developed peribiliary varices bypassing the occluded portal vein. 36 Hemobilia may result from the rupture of these varices. Other conditions According to our postmortem findings on intrahepatic cholangiography in 154 liver autopsy specimens. 37 PSClike cholangiographic changes were seen in diseases such as liver cirrhosis with hepatocellular carcinoma (67%), submassive hepatic necrosis (40%), amyloidosis (50%), metastatic carcinomas (23%), and leukemia/ lymphoma infiltration (17%). Histologically, in livers with a PSC-like cholangiographic appearance, the intrahepatic bile ducts were compressed by fibrosis, inflammatory infiltrates, cancer cell infiltration, amyloid deposition, or portal thrombi. Dilated ducts had less

9 Y. Nakanuma et al.: Primary sclerosing cholangitis 341 pronounced changes than strictured ducts. In these hepatobiliary diseases, changes in the intrahepatic bile ducts were much less marked in livers without the PSClike cholangiographic appearance than in the livers with this appearance. These results suggest that the PSC-like intrahepatic cholangiographic appearance is present in several hepatobiliary diseases in autopsy cases, although such cholangiographic changes are not visible or reproducible in clinical practice. 38 Summary PSC is still a rare disease in Japan. However, it is very important in the differential diagnosis of hepatobiliary diseases, and its variants or related diseases are being noted in clinical practice. A precise diagnosis in these patients is mandatory for choosing therapy. References 1. Ludwig J (1989) Surgical pathology of the syndrome of primary sclerosing cholangitis. 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Semin Liver Dis 5: Terasaki S, Nakanuma Y, Unoura M, Kaneko S, Kobayashi K (1997) Involvement of peribiliary glands in primary sclerosing cholangitis: a histopathologic study. Int Med 36: Tsuneyama K, Kono N, Yamashiro M, Sabit A, Sasaki M, Nakanuma Y. Aberrant expression of stem cell factor on biliary epithelial cells and peribiliary infiltration of c-kit-expressing mast cells in hepatolithiasis and primary sclerosing cholangitis: a possible contribution to bile duct fibrosis. J Pathol (in press), Ludwig J, Barham SS, LaRusso NF, Elveback LR, Wiesner RH, McCall JT (1981) Morphologic features of chronic hepatitis associated with primary sclerosing cholangitis and chronic ulcerative colitis. Hepatology 1: Wilschanski M, Chait P, Wade JA, Davis L, Corey M, St Louis P, Griffiths M, Blendis LM, Moroz SP, Scrully L (1995) Primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with survival analysis. 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