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Small-Duct Primary Sclerosing Cholangitis
HISTORICAL BACKGROUND The recognition of small-duct primary sclerosing cholangitis (PSC) can be traced to publications by Vinnik and Kern in 1963' and by Mistilis in 1965,' in which pericholangitis was described in patients with chronic ulcerative colitis (CUC). Earlier authors are quoted in these articles but the contents of their studies are difficult to elucidate. Thus, Mistilis stated that pericholangitis had been described by Klemperer et a1 as early as 1926,3 but 1 have been unable to find that term or a convincing corresponding description of the lesion in that article. In 1949, however, the terms "chronic pericholangitis" and "pericholangiolitic cirrhosis" indeed were used; MacMahon and Thannhauser applied them in their description of "xanthomatous biliary cirrhosis."" In this classic account of present-day primary biliary cirrhosis (PBC), the authors did not distinguish between cholangioles (bile ductules) and interlobular bile ducts and thus, for them, pericholangiolitis and pericholangitis may have had the same meaning. However, in later studies of PBC, the distinction indeed was made.5 The destructive inflammatory lesions of interlobular bile ducts in PBC were distinguished from an inflammation of the cholangioles. Because the significance of the ductular changes was misinterpreted, the name "cholangiolitic hepatitis" was used to describe the precirrhotic stages of the disease. In any event, between 1950 and 1965, the term "pericholangitis" became established in the literature,'," although no clear morphologic justification was provided; the meaning of the term remained vague. At that time (and for many pathologists and clinicians, until today), pericholangitis appeared to have been a designation for nonsuppurative portal and periportal inflammation, not necessarily concentrated around bile ducts. Most authors seemed to believe that the inflammation was the result of bile duct disease, even without unequivocal evidence of cholangitis. Thus, the term "pericholangitis" was intended to convey a pathogenetic concept as well as a morphologic finding, specifically in PBC, large-duct biliary obstruction, and some infectious diseases. After Vinnik and Kern,' as well as Mistilis' had
From the Depurrmrnt of' Luborutory Medicine und Puthology, Muyo Clinic and Muyo Foundation, Rochester, Minnesoru Reprint requests: Dr. Ludwig, Section of Medical Pathology, Mayo Clinic, Rochester, M N 55905
called attention to the association between pericholangitis and CUC, the name for this putative liver condition again changed its focus: pericholangitis became a morphologic and clinical designation for chronic hepatitis, usually with cholestatic biochemical features, in patients with CUC. Although the name was rejected by the Fogarty Conference7 because precise morphologic criteria or a justification for this diagnosis had not been established, use of the term "pericholangitis" has become common practice. In current t e x t b o ~ k s , ~ ~ Q hdilemma is often is recognized by placing the term pericholangitis in quotation marks. The concept that classic (or large-duct) PSC and pericholangitis might be parts of a disease spectrum emerged in the late 1960s"'," and found strong support in 1981 in a study of 43 patients with classic, cholangiographically proven PSC, with and without CUC, and of 19 patients with CUC, elevated alkaline phosphatase levels, and absence of large duct disease (confirmed by cholangiography in 14 patients or surgery or autopsy in 5 patients)." Biopsy findings were the same in both groups although, collectively, specimens from patients with large-duct PSC had more cholestatic features. A related retrospective review that provided further support for the concept of small-duct PSC was published in 1985. For this publication, 107 patients with CUC had been studied." Unfortunately, endoscopic retrograde cholangiograms could not be reviewed in most of these patients because the procedure had not been available 10 to 15 years earlier when the disease was diagnosed or treated. Despite this limitation, evidence again was obtained that the features of pericholangitis in patients without demonstrable large-duct disease were the same as those in specimens from patients with classic (largeduct) PSC. Furthermore, 6 of 18 patients who eventually developed classic (large-duct) PSC had biopsy evidence of pericholangitis 1 to 12 years earlier. Additional evidence was provided by the observation that bile duct carcinomas (cholangiocarcinomas and related malignancies) developed not only in long-standing classic (largeduct) PSC, but also in pericholangitis without large-duct involvement. l 4 All of these findings became the basis for the suggestion to: ( I ) consider the microscopic changes in small ducts, and the cholangiographic changes in large ducts as part of the PSC syndrome; and (2) to replace the term "pericholangitis" by the name "small-duct PSC" (as opposed to large-duct PSC). I am not aware of a more recent publication dealing specifically with small-duct PSC.
Copyright O 1991 by Thierne Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.
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JURGEN LUDWIG, M.D.
SUGGESTED TERMINOLOGY AND DEFINITIONS Based on the considerations described above, the author proposes the following terminology. Primary Sclerosing Cholangitis (PSC):A disease or syndrome of unknown cause characterized by chronic inflammation and fibrosis of the entire biliary ductal system or of segments or parts within this system. Large-Duct PSC: Involvement of cholangiographically identifiable bile ducts in PSC. Large-duct PSC is the classic manifestation of the disease and thus a synonym for the term PSC as it is customarily used. The condition may be accompanied by small-duct PSC. Small-Duct PSC: Involvement of only microscopically identifiable (interlobular and septal) bile ducts in PSC. Changes in large, cholangiographically definable bile ducts may accompany small-duct PSC. Of these three terms and definitions, only large-duct PSC would be uniformly acceptable at this time because, for many clinicians and pathologists, only changes in large, cholangiographically identifiable bile ducts qualify for the diagnosis of PSC. In the suggested first definition, both macroscopic and microscopic bile ducts can be affected by PSC, and only ductules (cholangioles) and bile canaliculi would remain excluded. (Definitions for bile ductules as well as interlobular, septal, and segmental bile ducts have been published previously. 15) Use of the term large-duct PSC is particularly helpful when cholangiographic changes are compared with biopsy changes. Thus, in clinical practice, the term "primary sclerosing cholangitis," without further specification, still means classic or large-duct disease but it does not make clear whether biopsy changes of small-duct PSC are present. If only interlobular and septal bile ducts are affected, use of the term "small-duct PSC" is mandatory. To facilitate communication, reports still might state, "small-duct PSC ('pericholangitis')." The constellation of principal diagnostic criteria and suggested types of PSC are shown in Table 1. The clinical diagnosis "primary sclerosing cholangitis" (unspecified) is based primarily on cholangiographic evidence of irregularity and tortuosity of extrahepatic or intrahepatic bile ducts or both, with diffusely
TABLE 1. Suggested Terminology of Duct Disease in the PSC Syndrome* Cholangiographyf
Liver Biopsy
Typical findings
Not diagnostic
Not diagnostic
Typical findings
Typical findings
Typical findings
Diagnostic. Term Large-duct PSC (extrahepatic or intrahepatic) Small-duct PSC (pericholangitis) Combined largeand small-duct PSC (global PSC)
tUsually endoscopic retrograde cholangiopancreatography. *From Ludwig."' Reprinted with permission.
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distributed multifocal strictures." With few exceptions," these changes are associated with a twofold or higher elevation of serum alkaline phosphatase level. Liver biopsy specimens in large-duct PSC (without small-duct involvement) may show near-normal or nonspecific findings, presence of complicating disease such as chronic active viral hepatitis, or evidence of large-duct biliary obstruction as one might see, for instance, in choledocholithiasis. The clinical diagnosis of small-duct PSC must be based on ( 1 ) biopsy changes as described later under "Diagnostic Features and Staging," (2) biochemical abnormalities similar to those in large-duct disease, and (3) presence of one or two accompanying conditions, that is, inflammatory bowel disease (IBD; in particular, CUC) or large-duct PSC or both. Thus, if small-duct PSC is found in a patient with the typical cholangiographic changes of large-duct PSC, the histologic findings establish the diagnosis of combined small-duct and large-duct (global) PSC. The small-duct features are then used to stage the hepatobiliary disorder, as described later. If a patient has IBD, a cholestatic biochemical profile, and a normal endoscopic retrograde cholangiogram, biopsy features still may reveal small-duct PSC. The morphologic confirmation not only serves to exclude other conditions, such as acute viral hepatitis, but also alerts clinicians to the possible development of largeduct PSC, biliary cirrhosis, and hepatobiliary carcinoma. This may become important for treatment protocols and the timing of liver transplantation.
DIAGNOSTIC FEATURES AND STAGING The histologic features of small-duct PSC change dramatically as they progress. With few exceptions, the pathologist cannot predict from the biopsy changes whether large-duct PSC is present also. Therefore biopsy study and cholangiography are complementary examinations and neither can be used alone to evaluate completely the extent of the disease. Even after a diagnostic cholangiogram has established the diagnosis of largeduct PSC, liver biopsy is needed for staging. In general, the prognosis in each case is determined primarily by the parenchymal changes shown in biopsy specimens, not by the degree of duct abnormalities.'' For this reason, staging has been based on biopsy features, that is, the features of small-duct PSC and its complications; cholangiographic findings are not considered for staging. The first signs of small-duct PSC (stage I), with or without large-duct involvement, are portal inflammation with some edema or fibrosis and proliferation of ducts and ductules (Fig. la). Most ducts are normal but some may show degenerative changes (Fig. Ib), periductal fibrosis, and mild nonsuppurative fibrous cholangitis ("onion skin" lesions). The periportal hepatocytes rarely contain a few granules of copper and copper-associated protein. If special stains (rhodanine for copper and orcein for copper-associated protein) show these granules, the diagnosis of small-duct PSC is strengthened.
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FIG. 1. Small-duct primary sclerosing cholangitis (smallduct PSC) in patients with chronic ulcerative colitis but without cholangiographic evidence of large-duct abnormalities. a: Slightly fibrosed portal tract with prominent proliferation of ducts and ductules (asterisks). V: portal vein; A: artery. (Hematoxylin & eosin, x 100.) b: Mild portal hepatitis with degeneration of bile-duct epithelium (arrows); note pyknosis of epithelial cells. Hematoxylin & eosin, x200.) c: Portal tract with ductopenia. Note presence of artery (A) and portal vein (V) and absence of bile duct. Hematoxylin & eosin, x 200.)
Eventually, portal tracts become enlarged (stage 2) because the disease process leads to fibrous piecemeal necrosis and often to the formation of new limiting plates. The enlarged portal tracts may closely resemble normal septal portal tracts of similar size. The main difference is the size of the blood vessels and bile ducts; they appear unexpectedly small in the pathologically enlarged portal tracts. Periductal fibrosis and cholangitis
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may be present but, often, these changes still are inconspicuous. Nevertheless, focal ductopenia already is noted at this stage and, thus, portal tracts with ductal proliferation and portal tracts without a bile duct (Fig. Ic) often are present in the same specimen. This feature is rarely seen in any condition other than small-duct PSC, with or without large-duct involvement. Further progression of the disease (stage 3) is characterized by portal-to-portal bridging with formation of active (fibrous) septa. This process represents typical biliary fibrosis, which merges imperceptively into biliary cirrhosis, that is, appearance of true nodular regeneration. These histologic features usually parallel symptomatic disease. Cholestasis often becomes quite prominent, primarily in periportal and paraseptal hepatocytes, which become edematous as a result of cholate stasis. Mallory bodies and deposits of copper and copper-associated protein often appear in the damaged hepatocytes at these locations. Again, presence of centrilobular hepatocanalicular cholestasis would suggest obstructive large-duct disease; it rarely is a feature of small-duct PSC only. In advanced cases (stage 4), the number of interlobular bile ducts often is markedly decreased, which causes a striking resemblance of biliary cirrhosis in PSC and PBC. Unless obliterative cholangitis (in PSC) or granulomatous cholangitis (in PBC) can be identified, the two conditions cannot be distinguished with certainty by morphologic study alone." Collectively, the inflammatory changes in small-duct PSC are quite mild, whereas PBC often is associated with rather prominent inflammation of portal tracts and septa. Although granulomatous cholangitis is near-diagnostic for PBC and does not occur in PSC, isolated granulomas provide little diagnostic help; they may be found in both conditions. This is in contrast to fibrous-obliterative cholangitis, which is, for all practical purposes, diagnostic for PSC. Unfortunately, the lesion is only rarely found in needle biopsy specimens, and even in surgical wedge specimens, duct changes of this type are rarely found. Thus, fibrous cholangitis, focal ductopenia, and changes associated with biliary fibrosis are the most important morphologic features of small-duct PSC. It should be noted that periductal fibrosis without inflammation is a common biopsy finding in many liver diseases, and even fibrous cholangitis may be quite unrelated to PSC. The rationale for stuging is based on the described histologic observations and on the experience that bile duct changes per se do not determine clinical course and outcome. This is particularly apparent in large-duct PSC where severe cholangiographic abnormalities may coexist with only mild parenchymal abnormalities and clinical wellness. The progression from isolated portal tract changes to cirrhosis determines the course of PSC, whether large ducts are involved or not, and therefore staging of parenchymal changes in any primary biliary disease appears justified. The staging criteria correspond to the progression of the disease from portal to periportal to septal to cirrhotic. The essential and nonessential morphologic features2' are shown in Table 2. It should be noted that the main staging criteria are not diagnostic for PSC; staging can be done only after the diagnosis had been established.
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SMALL-DUCT PRIMARY SCLEROSING CHOLANGITIS-LUDWIG
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TABLE 2. Stcrgr
Stage I (portal stage)
Stage 2 (periportal stage or stage of portal enlargement)
Stage 3 (septal disease)
Stage 4 (cirrhotic stage)
Staging Criteria for Chronic Hepatitis Associated with PSC*+ Critrricr
Portal hepatitis or bile duct abnormalities or both, with little or no periportal intlammation and fibrosis. The portal tracts are not noticeably enlarged Nonessential features: Portal edema and fibrosis may be present. Parenchymal changes tend to be mild or absent Periportal fibrosis with or without periportal hepatitis, or prominent enlargement of portal tracts with seemingly intact newly formed limiting plates. Both conditions may coexist. Biliary and fibrosing piecemeal necrosis may not be identifiable Nonessential features: Portal edema and fibrosis, proliferation of ducts and ductules, and evidence of f~brous, lymphoid, or mixed cell cholangitis Septal fibrosis or bridging necrosis or both Nonessential features: They are the same as in the previous stages. Presence of bridging necrosis is not common. Bile ducts often are severely damage or absent. In the parenchyma. biliary and fibrosing piecemeal necrosis and associated changes, such as prominent copper deposition, may be found Biliary cirrhosis Nonessential features: They may be the same as in the previous stages. but parenchymal changes usually are more prominent than in stage 3. Bile ducts often have disappeared
*From Ludwig et al."' Reprinted with permission. ?These staging criteria are not diagnostic for PSC: they should be applied only after the diagnosis has been established.
CONTROVERSIES IN PATHOGENESIS The concept of small-duct PSC implies that the pathogenetic mechanisms leading to large-duct PSC also can affect small bile ducts. This appears self-evident in small-duct PSC of patients with CUC who also develop cholangiographic changes of large-duct PSC, either simultaneously or months and years after biopsy evidence of small-duct disease had been obtained. However, until the pathogenesis of PSC has been elucidated and unequivocal diagnostic tests have been obtained, for instance, demonstration of a specific integrated viral genome or a unique constellation of immunologic markers, two other interpretations are possible. They will be discussed in the following paragraphs.
Nonspecific Incomplete Biliary Obstruction In patients who have no evidence of PSC or IBD, and whose bile ducts are narrowed by tumor, stones, or postoperative strictures, biopsy changes may be indistinguishable from those seen in small-duct PSC; they include ductal proliferation, fibrous cholangitis, and even duct loss. In a patient with floxuridine-induced cholangitis, we found unexplained ductopenia in small portal tracts in the periphery of the liver, although this partic-
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ular type of sclerosing cholangitis appears to be confined to large perihilar bile ducts; in our patient, these ducts had been affected by obstructive vasculopathy with ischemia." Thus, based on the described experiences, one could speculate that small-duct PSC may be just a response to the involvement of large ducts and that in PSC seemingly confined to small ducts, the narrowing of the large ducts was simply too mild or too diffuse to yield diagnostic cholangiographic changes.
Chronic Active Hepatitis Many patients with CUC had complications or surgical procedures that required blood transfusions. Therefore infection with the hepatitis C virus (or another non-A, non-B virus) must be expected in an appreciable percentage of patients with PSC. The morphologic features of post-transfusion chronic active hepatitis or chronic persistent hepatitis, type C , usually differ from those of small-duct PSC but in some instances much overlap appears to occur and, thus, the morphologic differential diagnosis is not always possible.**The situation is complicated by the likelihood that small-duct PSC and chronic active hepatitis or chronic persistent hepatitis, type C , may coexist. Obviously, severe portal or periportal hepatitis with lymphocytic piecemeal necrosis and lymphocytic or pleomorphic cholangitis would favor chronic hepatitis C infection.".*' However, the features of small-duct PSC could be simulated by hepatitis C infection with severe duct damage" and fibrous cholangitis." Even duct loss might be a feature in some cases.*" Thus, the possibility must be accepted that an unknown number of patients with the diagnosis of small-duct PSC actually have hepatitis C infection with prominent duct involvement. The same holds true for the reversed constellation. Some patients with suspected chronic posttransfusion hepatitis may have small-duct PSC. With the introduction of hepatitis C tests, preliminary steps can be taken toward a distinction between small-duct PSC and hepatitis C , particularly in cases that so far have remained unclassified. Despite the limitations of this firstgeneration test,2s the role of these two etiologic categories will become clearer. The two alternative explanations of putative smallduct PSC-nonspecific response to incomplete obstruction and chronic active hepatitis-have been discussed in the context of coexisting large-duct PSC or CUC. Although such alternative explanations certainly must be entertained, the evidence strongly supports the existence of small-duct PSC. Indeed, the latter condition might even occur as a seemingly new disease-idiopathic adulthood ductopenia. This diagnosis applies to patients who have chronic cholestatic liver disease characterized by biopsy evidence of ductopenia and absence of any of the conditions that are known to cause loss of interlobular and septal bile ducts, in particular, the syndrome of PBC or large-duct PSC. The name "paucity of intrahepatic bile ducts" was not applicable because it already refers to an idiopathic infantile or childhood ductopenia. Therefore we coined the term "idiopathic adulthood duct~penia."'~ Our study as well as study of unpublished cases suggested that idiopathic adulthood ductopenia
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SMALL-DUCT PRIMARY SCLEROSING CHOLANGITIS-LUDWIG
FUTURE STUDIES The need for further studies of small-duct PSC is immediately apparent from the many unanswered questions and speculations discussed in the previous paragraphs. Three problem areas come to mind, namely, incidence and natural history of small-duct PSC, pathogenesis, and treatment.
Incidence and Natural History I am not aware of a study of patients with IBD in whom small-duct PSC was evaluated prospectively. Ideally, this should be accomplished by routine liver biopsy analysis in a very large number of consecutive patients with IBD (or unequivocal CUC). For 74 patients with CUC who had normal liver function, a comparable analysis indeed has been published. As expected, most specimens were normal or had only minor changes but in three instances findings were described that were compatible with small-duct PSC (the authors did not use this term)." No progression was noted in these three cases, 13 to 23 years later. However, another patient who had only fatty changes in 1959 developed symptoms of autoimmune chronic active hepatitis. In that patient, bile duct carcinoma was identified almost 30 years later, suggesting that small-duct or large-duct PSC may have been present after all. Although the study of small-duct PSC was not the purpose of that publication, it did reveal that in patients with CUC and normal liver function tests, progressive PSC, including small-duct PSC, probably
develops in less than 5% of the cases, as was estimated by others. l 3 For a prospective study of small-duct PSC, meaningful results could be obtained even if liver biopsy would only be done in the presence of a predefined biochemical profile, for instance, alkaline phosphatase levels exceeding two times the upper level of normal for more than 2 months. This would identify most, although not all, cases." Some of the patients can be expected to have large-duct PSC at that time but in other cases cholangiographic findings probably would be normal or not diagnostic. The incidence and prognosis of small-duct PSC in such a setting still is largely unknown. In a recent unpublished review of 73 patients with biopsy evidence of small-duct PSC and satisfactory cholangiograms, I found large-duct PSC in 69 patients, cholangiocarcinoma (with large-duct PSC'?) in one patient, and normal bile ducts in three patients. Follow-up information on the three patients with normal cholangiograms is not available. Nevertheless, results from this series suggest that more than 95% of patients with histologic evidence of small-duct PSC also have large-duct disease. These findings certainly need confirmation. In patients with confirmed large-duct PSC, the spectrum of small-duct involvement is much better known. As already described, small-duct PSC and its secondary manifestations are almost always present, at least after some time, and thus can be used to stage the syndrome of PSC."' I am not aware of studies in which the progression and thus the prognosis of small-duct PSC would have been correlated with the severity of the large-duct disease. One reason may be the difficulty of quantitating the severity of cholangiographic changes in PSC and of comparing the results of radiologic methods with morphologic findings. The need for data of this type has become pressing because of the recent interest in survival models for optimal timing of liver transplantation. Such models are in use for PBC,3' but also are being developed for PSC." Such a comparison between radiologic and morphologic findings also would be important for the evaluation of surgical treatment, as described in the next paragraph.
Pathogenesis As discussed earlier, incomplete large-duct obstruction by PSC may in some cases play a role in the development of small-duct disease (secondary small-duct disease). Small-duct damage unrelated to large-duct disease (primary small-duct disease) is unequivocal only in small-duct PSC without or with only minimal large-duct involvement. Thus far, no morphologic features have been described that would help to distinguish between primary and secondary small-duct disease; these two putative pathogenetic mechanisms have not been compared in a published study. Systematic analysis is needed because of its relevance for the hotly debated indication for surgical treatment of large-duct d i ~ e a s e . ~ ' If . ' ~narrowing of extrahepatic and perihilar intrahepatic bile ducts indeed hastens the progression of small-duct PSC, indications for surgical or endoscopic i n t e r ~ e n t i o nwould ~ ~ become much clearer.
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may have several possible etiologies and that in some cases, the condition might represent isolated small-duct PSC-r "pericholangitis" without IBD. This appears likely because the histologic findings are compatible and because all other constellations of the PSC syndrome have been documented. Thus, large-duct PSC occurs, in up to 30% of the cases,2hwithout evidence of an intestinal disorder, and small-duct PSC in patients with IBD may occur without documentable large-duct involvement." Finally, some patients with large-duct PSC but without IBD fail to show significant small-duct involvement. Thus, the three components of the classic PSCsyndrome, namely, large-duct disease, small-duct disease, and IBD, have been documented to occur in any combination or, in cases of large-duct PSC and IBD, each condition may occur alone. The only exception so far is small-duct PSC, which currently is defined as a condition accompanying large-duct PSC, IBD, or both, and which therefore cannot be diagnosed without these external "markers." However, the current definition of small-duct PSC or "pericholangitis" is only historically linked to large-duct PSC and IBD; no valid scientific reason can be found to suggest that small-duct PSC could not occur without large-duct disease and IBD. This has been the impression of other authors also." Thus, it appears very likely that some cases of idiopathic adulthood ductopenia indeed represent small-duct PSC or "pericholangitis" without its customary companion conditions.
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On a more basic level, studies on bile duct epithelium in PSC should be planned, using recently developed isolation t e ~ h n i q u e s . ~ ~Three . " main areas of interest immediately come to mind: (1) Studies of immunoreactivity between bile duct epithelial cells and immunocytes in patients with PSC and IBD, compared with control patients; (2) biochemical and immunologic comparisons of small-duct epithelium with large-duct epithelium; and (3) searches for integrated viral DNA in biliary epithelium in patients with the syndrome of PSC. The ultimate goal of such studies would be the development of diagnostic immunologic tests for early PSC, the clarification of the role of small-duct PSC (primary target versus secondary involvement), and the possible recognition of a virus or viruses that might trigger the subsequent "autoimmune" events characterizing the PSC syndrome. Of particular interest in this context is the possible role of the hepatitis C virus. Recombinant DNA technology which has been used to study the hepatitis B virus genome in human liver tissue," might also be applicable to the study of biliary epithelium.
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Therapy For the evaluation of treatment trials, morphologic staging of small-duct PSC and its complications has proved most useful. The transplant experience has confirmed that hepatic failure in PSC almost always is caused by parenchymal changes related to the small-duct component of the condition. Cases of PSC with largeduct cholangiocarcinoma are an exception. Thus, in previous treatment trials with penicillamine," and in current protocols evaluating ursodeoxycholic acid, cyclosporine, and other agents, biopsy evaluation of small-duct PSC has remained the main method of assessment. Undoubtedly, endoscopic and surgical treatment of largeduct disease must be evaluated in the same fashion.
SUMMARY AND CONCLUSIONS Current evidence suggests that PSC may affect the entire biliary system from interlobular bile ducts to the ampulla of Vater. If the affected bile ducts are too small for cholangiographic identification, the best designation for the condition is small-duct PSC; cholangiographically identifiable duct changes are the hallmark of largeduct PSC. The term "small-duct PSC" should replace the name pericholangitis because that designation lacks a clear definition. Small-duct PSC may occur in combination with large-duct PSC or it may occur alone. The clinical course of patients with PSC depends on the hepatic changes related to small-duct PSC, not primarily on the classic large-duct disease. Therefore the features of small-duct PSC and its complications are used to determine the disease stages of PSC. The incidence of small-duct PSC still is not known and the natural history as well as the pathogenesis of the condition remains obscure. Nevertheless, the role of small-duct disease in the syndrome of PSC has come into focus and the themes for future studies are apparent. Work should commence.
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Morphologic spectrum, clinical correlations and terminology. Liver 4:105-1 16, 1984. Schmid M. Pirovino M. Altorfer J, et al: Acute hepatitis nonA, non-B; are there any specific light microscopic features? Liver 2:61-67, 1982. Ludwig J, Wiesner RH, LaRusso NF: Idiopathic adulthood ductopenia. A cause of chronic cholestatic liver disease and biliary cirrhosis. J Hepatol 7:193-199, 1988. McFarlane 1G. Smith HM,. Johnson PJ, et al: Hepatitis C virus antibodies in chronic active hepatitis: Pathogenetic factor or false-positive result? Lancet 335:754-757, 1990. LaRusso NF, Wiesner RH. Ludwig J, et al.: Primary sclerosing cholangitis. N Engl J Med 310:899-903, 1984. Tuthill RJ. Carey WD: lntrahepatic small duct sclerosing cholangitis. Hepatology 6: 1 192(A). 1986. Bromme U , Glaumann H, Hultcrantz R: Liver histology and follow up of 68 patients with ulcerative colitis and normal liver function tests. Gut 3 1 :468-472, 1990. Clements D, Rhodes JM, Elias E: Severe bile duct lesions without biochemical evidence of cholestasis in a case of sclerosing cholangitis. J Hepatol 3:72-74, 1986. Ludwig J, LaRusso NF, Wiesner RH: The syndrome of primary sclerosing cholangitis. Prog Liver Dis 9:555-566, 1990. Bonsel GJ, Klompmaker IJ, van 'T Veer F, et al: Use of prognostic models for assessment of value of liver transplantation in primary biliary cirrhosis. Lancet 335:493-497, 1990.
17 Wiesner RH, Grambsch PM, Dickson ER, et al: Primary sclerosing cholangitis: Natural history, prognostic factors and survival analysis. Hepatology 10:430-436. 1989. Thompson JS, Wood RP, Burnett DA, et al: The role of nontransplant procedures for sclerosing cholangitis. Am J Surg 156:506-508, 1988. Cameron JL, Pitt HA, Zinner MJ, et al: Resection of hepatic duct bifurcation and transhepatic stenting for sclerosing cholangitis. Ann Surg 207514-622, 1988. Skolkin MD, Alspaugh JP, Casarella WJ, et al: Sclerosing cholangitis: Palliation with percutaneous cholangioplasty. Radiology 170: 199-206, 1989. lshi M, Vroman B, LaRusso NF: lsolation and morphologic characterization of bile duct epithelial cells from normal rat liver. Gastroenterology 97: 1236-1247, 1989. Alpini G. Lenzi R, Zhai W-R, et al: Isolation of a nonparenchymal liver cell fraction enriched in cells with biliary epithelial phenotypes. Gastroenterology 97: 1248-1 260, 1989. Pasquinelli C, Melegari M, Villa E, et al: Detection of hepatitis B virus transcripts in patients with chronic liver disease. J Hepatol 10: 180-185, 1990. LaRusso NF, Wiesner RH, Ludwig J, et al: Prospective trial of penicillamine in primary sclerosing cholangitis. Gastroenterology 95: 1036-1042, 1988. Ludwig J: Surgical pathology of the syndrome of primary sclerosing cholangitis. Am J Surg Pathol 13:43-49. 1989.
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SMALL-DUCT PRIMARY SCLEROSING CHOLANGITIS-LUDWIG
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Small-Duct Primary Sclerosing Cholangitis
HISTORICAL BACKGROUND The recognition of small-duct primary sclerosing cholangitis (PSC) can be traced to publications by Vinnik and Kern in 1963' and by Mistilis in 1965,' in which pericholangitis was described in patients with chronic ulcerative colitis (CUC). Earlier authors are quoted in these articles but the contents of their studies are difficult to elucidate. Thus, Mistilis stated that pericholangitis had been described by Klemperer et a1 as early as 1926,3 but 1 have been unable to find that term or a convincing corresponding description of the lesion in that article. In 1949, however, the terms "chronic pericholangitis" and "pericholangiolitic cirrhosis" indeed were used; MacMahon and Thannhauser applied them in their description of "xanthomatous biliary cirrhosis."" In this classic account of present-day primary biliary cirrhosis (PBC), the authors did not distinguish between cholangioles (bile ductules) and interlobular bile ducts and thus, for them, pericholangiolitis and pericholangitis may have had the same meaning. However, in later studies of PBC, the distinction indeed was made.5 The destructive inflammatory lesions of interlobular bile ducts in PBC were distinguished from an inflammation of the cholangioles. Because the significance of the ductular changes was misinterpreted, the name "cholangiolitic hepatitis" was used to describe the precirrhotic stages of the disease. In any event, between 1950 and 1965, the term "pericholangitis" became established in the literature,'," although no clear morphologic justification was provided; the meaning of the term remained vague. At that time (and for many pathologists and clinicians, until today), pericholangitis appeared to have been a designation for nonsuppurative portal and periportal inflammation, not necessarily concentrated around bile ducts. Most authors seemed to believe that the inflammation was the result of bile duct disease, even without unequivocal evidence of cholangitis. Thus, the term "pericholangitis" was intended to convey a pathogenetic concept as well as a morphologic finding, specifically in PBC, large-duct biliary obstruction, and some infectious diseases. After Vinnik and Kern,' as well as Mistilis' had
From the Depurrmrnt of' Luborutory Medicine und Puthology, Muyo Clinic and Muyo Foundation, Rochester, Minnesoru Reprint requests: Dr. Ludwig, Section of Medical Pathology, Mayo Clinic, Rochester, M N 55905
called attention to the association between pericholangitis and CUC, the name for this putative liver condition again changed its focus: pericholangitis became a morphologic and clinical designation for chronic hepatitis, usually with cholestatic biochemical features, in patients with CUC. Although the name was rejected by the Fogarty Conference7 because precise morphologic criteria or a justification for this diagnosis had not been established, use of the term "pericholangitis" has become common practice. In current t e x t b o ~ k s , ~ ~ Q hdilemma is often is recognized by placing the term pericholangitis in quotation marks. The concept that classic (or large-duct) PSC and pericholangitis might be parts of a disease spectrum emerged in the late 1960s"'," and found strong support in 1981 in a study of 43 patients with classic, cholangiographically proven PSC, with and without CUC, and of 19 patients with CUC, elevated alkaline phosphatase levels, and absence of large duct disease (confirmed by cholangiography in 14 patients or surgery or autopsy in 5 patients)." Biopsy findings were the same in both groups although, collectively, specimens from patients with large-duct PSC had more cholestatic features. A related retrospective review that provided further support for the concept of small-duct PSC was published in 1985. For this publication, 107 patients with CUC had been studied." Unfortunately, endoscopic retrograde cholangiograms could not be reviewed in most of these patients because the procedure had not been available 10 to 15 years earlier when the disease was diagnosed or treated. Despite this limitation, evidence again was obtained that the features of pericholangitis in patients without demonstrable large-duct disease were the same as those in specimens from patients with classic (largeduct) PSC. Furthermore, 6 of 18 patients who eventually developed classic (large-duct) PSC had biopsy evidence of pericholangitis 1 to 12 years earlier. Additional evidence was provided by the observation that bile duct carcinomas (cholangiocarcinomas and related malignancies) developed not only in long-standing classic (largeduct) PSC, but also in pericholangitis without large-duct involvement. l 4 All of these findings became the basis for the suggestion to: ( I ) consider the microscopic changes in small ducts, and the cholangiographic changes in large ducts as part of the PSC syndrome; and (2) to replace the term "pericholangitis" by the name "small-duct PSC" (as opposed to large-duct PSC). I am not aware of a more recent publication dealing specifically with small-duct PSC.
Copyright O 1991 by Thierne Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.
II
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JURGEN LUDWIG, M.D.
SUGGESTED TERMINOLOGY AND DEFINITIONS Based on the considerations described above, the author proposes the following terminology. Primary Sclerosing Cholangitis (PSC):A disease or syndrome of unknown cause characterized by chronic inflammation and fibrosis of the entire biliary ductal system or of segments or parts within this system. Large-Duct PSC: Involvement of cholangiographically identifiable bile ducts in PSC. Large-duct PSC is the classic manifestation of the disease and thus a synonym for the term PSC as it is customarily used. The condition may be accompanied by small-duct PSC. Small-Duct PSC: Involvement of only microscopically identifiable (interlobular and septal) bile ducts in PSC. Changes in large, cholangiographically definable bile ducts may accompany small-duct PSC. Of these three terms and definitions, only large-duct PSC would be uniformly acceptable at this time because, for many clinicians and pathologists, only changes in large, cholangiographically identifiable bile ducts qualify for the diagnosis of PSC. In the suggested first definition, both macroscopic and microscopic bile ducts can be affected by PSC, and only ductules (cholangioles) and bile canaliculi would remain excluded. (Definitions for bile ductules as well as interlobular, septal, and segmental bile ducts have been published previously. 15) Use of the term large-duct PSC is particularly helpful when cholangiographic changes are compared with biopsy changes. Thus, in clinical practice, the term "primary sclerosing cholangitis," without further specification, still means classic or large-duct disease but it does not make clear whether biopsy changes of small-duct PSC are present. If only interlobular and septal bile ducts are affected, use of the term "small-duct PSC" is mandatory. To facilitate communication, reports still might state, "small-duct PSC ('pericholangitis')." The constellation of principal diagnostic criteria and suggested types of PSC are shown in Table 1. The clinical diagnosis "primary sclerosing cholangitis" (unspecified) is based primarily on cholangiographic evidence of irregularity and tortuosity of extrahepatic or intrahepatic bile ducts or both, with diffusely
TABLE 1. Suggested Terminology of Duct Disease in the PSC Syndrome* Cholangiographyf
Liver Biopsy
Typical findings
Not diagnostic
Not diagnostic
Typical findings
Typical findings
Typical findings
Diagnostic. Term Large-duct PSC (extrahepatic or intrahepatic) Small-duct PSC (pericholangitis) Combined largeand small-duct PSC (global PSC)
tUsually endoscopic retrograde cholangiopancreatography. *From Ludwig."' Reprinted with permission.
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distributed multifocal strictures." With few exceptions," these changes are associated with a twofold or higher elevation of serum alkaline phosphatase level. Liver biopsy specimens in large-duct PSC (without small-duct involvement) may show near-normal or nonspecific findings, presence of complicating disease such as chronic active viral hepatitis, or evidence of large-duct biliary obstruction as one might see, for instance, in choledocholithiasis. The clinical diagnosis of small-duct PSC must be based on ( 1 ) biopsy changes as described later under "Diagnostic Features and Staging," (2) biochemical abnormalities similar to those in large-duct disease, and (3) presence of one or two accompanying conditions, that is, inflammatory bowel disease (IBD; in particular, CUC) or large-duct PSC or both. Thus, if small-duct PSC is found in a patient with the typical cholangiographic changes of large-duct PSC, the histologic findings establish the diagnosis of combined small-duct and large-duct (global) PSC. The small-duct features are then used to stage the hepatobiliary disorder, as described later. If a patient has IBD, a cholestatic biochemical profile, and a normal endoscopic retrograde cholangiogram, biopsy features still may reveal small-duct PSC. The morphologic confirmation not only serves to exclude other conditions, such as acute viral hepatitis, but also alerts clinicians to the possible development of largeduct PSC, biliary cirrhosis, and hepatobiliary carcinoma. This may become important for treatment protocols and the timing of liver transplantation.
DIAGNOSTIC FEATURES AND STAGING The histologic features of small-duct PSC change dramatically as they progress. With few exceptions, the pathologist cannot predict from the biopsy changes whether large-duct PSC is present also. Therefore biopsy study and cholangiography are complementary examinations and neither can be used alone to evaluate completely the extent of the disease. Even after a diagnostic cholangiogram has established the diagnosis of largeduct PSC, liver biopsy is needed for staging. In general, the prognosis in each case is determined primarily by the parenchymal changes shown in biopsy specimens, not by the degree of duct abnormalities.'' For this reason, staging has been based on biopsy features, that is, the features of small-duct PSC and its complications; cholangiographic findings are not considered for staging. The first signs of small-duct PSC (stage I), with or without large-duct involvement, are portal inflammation with some edema or fibrosis and proliferation of ducts and ductules (Fig. la). Most ducts are normal but some may show degenerative changes (Fig. Ib), periductal fibrosis, and mild nonsuppurative fibrous cholangitis ("onion skin" lesions). The periportal hepatocytes rarely contain a few granules of copper and copper-associated protein. If special stains (rhodanine for copper and orcein for copper-associated protein) show these granules, the diagnosis of small-duct PSC is strengthened.
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FIG. 1. Small-duct primary sclerosing cholangitis (smallduct PSC) in patients with chronic ulcerative colitis but without cholangiographic evidence of large-duct abnormalities. a: Slightly fibrosed portal tract with prominent proliferation of ducts and ductules (asterisks). V: portal vein; A: artery. (Hematoxylin & eosin, x 100.) b: Mild portal hepatitis with degeneration of bile-duct epithelium (arrows); note pyknosis of epithelial cells. Hematoxylin & eosin, x200.) c: Portal tract with ductopenia. Note presence of artery (A) and portal vein (V) and absence of bile duct. Hematoxylin & eosin, x 200.)
Eventually, portal tracts become enlarged (stage 2) because the disease process leads to fibrous piecemeal necrosis and often to the formation of new limiting plates. The enlarged portal tracts may closely resemble normal septal portal tracts of similar size. The main difference is the size of the blood vessels and bile ducts; they appear unexpectedly small in the pathologically enlarged portal tracts. Periductal fibrosis and cholangitis
13
may be present but, often, these changes still are inconspicuous. Nevertheless, focal ductopenia already is noted at this stage and, thus, portal tracts with ductal proliferation and portal tracts without a bile duct (Fig. Ic) often are present in the same specimen. This feature is rarely seen in any condition other than small-duct PSC, with or without large-duct involvement. Further progression of the disease (stage 3) is characterized by portal-to-portal bridging with formation of active (fibrous) septa. This process represents typical biliary fibrosis, which merges imperceptively into biliary cirrhosis, that is, appearance of true nodular regeneration. These histologic features usually parallel symptomatic disease. Cholestasis often becomes quite prominent, primarily in periportal and paraseptal hepatocytes, which become edematous as a result of cholate stasis. Mallory bodies and deposits of copper and copper-associated protein often appear in the damaged hepatocytes at these locations. Again, presence of centrilobular hepatocanalicular cholestasis would suggest obstructive large-duct disease; it rarely is a feature of small-duct PSC only. In advanced cases (stage 4), the number of interlobular bile ducts often is markedly decreased, which causes a striking resemblance of biliary cirrhosis in PSC and PBC. Unless obliterative cholangitis (in PSC) or granulomatous cholangitis (in PBC) can be identified, the two conditions cannot be distinguished with certainty by morphologic study alone." Collectively, the inflammatory changes in small-duct PSC are quite mild, whereas PBC often is associated with rather prominent inflammation of portal tracts and septa. Although granulomatous cholangitis is near-diagnostic for PBC and does not occur in PSC, isolated granulomas provide little diagnostic help; they may be found in both conditions. This is in contrast to fibrous-obliterative cholangitis, which is, for all practical purposes, diagnostic for PSC. Unfortunately, the lesion is only rarely found in needle biopsy specimens, and even in surgical wedge specimens, duct changes of this type are rarely found. Thus, fibrous cholangitis, focal ductopenia, and changes associated with biliary fibrosis are the most important morphologic features of small-duct PSC. It should be noted that periductal fibrosis without inflammation is a common biopsy finding in many liver diseases, and even fibrous cholangitis may be quite unrelated to PSC. The rationale for stuging is based on the described histologic observations and on the experience that bile duct changes per se do not determine clinical course and outcome. This is particularly apparent in large-duct PSC where severe cholangiographic abnormalities may coexist with only mild parenchymal abnormalities and clinical wellness. The progression from isolated portal tract changes to cirrhosis determines the course of PSC, whether large ducts are involved or not, and therefore staging of parenchymal changes in any primary biliary disease appears justified. The staging criteria correspond to the progression of the disease from portal to periportal to septal to cirrhotic. The essential and nonessential morphologic features2' are shown in Table 2. It should be noted that the main staging criteria are not diagnostic for PSC; staging can be done only after the diagnosis had been established.
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TABLE 2. Stcrgr
Stage I (portal stage)
Stage 2 (periportal stage or stage of portal enlargement)
Stage 3 (septal disease)
Stage 4 (cirrhotic stage)
Staging Criteria for Chronic Hepatitis Associated with PSC*+ Critrricr
Portal hepatitis or bile duct abnormalities or both, with little or no periportal intlammation and fibrosis. The portal tracts are not noticeably enlarged Nonessential features: Portal edema and fibrosis may be present. Parenchymal changes tend to be mild or absent Periportal fibrosis with or without periportal hepatitis, or prominent enlargement of portal tracts with seemingly intact newly formed limiting plates. Both conditions may coexist. Biliary and fibrosing piecemeal necrosis may not be identifiable Nonessential features: Portal edema and fibrosis, proliferation of ducts and ductules, and evidence of f~brous, lymphoid, or mixed cell cholangitis Septal fibrosis or bridging necrosis or both Nonessential features: They are the same as in the previous stages. Presence of bridging necrosis is not common. Bile ducts often are severely damage or absent. In the parenchyma. biliary and fibrosing piecemeal necrosis and associated changes, such as prominent copper deposition, may be found Biliary cirrhosis Nonessential features: They may be the same as in the previous stages. but parenchymal changes usually are more prominent than in stage 3. Bile ducts often have disappeared
*From Ludwig et al."' Reprinted with permission. ?These staging criteria are not diagnostic for PSC: they should be applied only after the diagnosis has been established.
CONTROVERSIES IN PATHOGENESIS The concept of small-duct PSC implies that the pathogenetic mechanisms leading to large-duct PSC also can affect small bile ducts. This appears self-evident in small-duct PSC of patients with CUC who also develop cholangiographic changes of large-duct PSC, either simultaneously or months and years after biopsy evidence of small-duct disease had been obtained. However, until the pathogenesis of PSC has been elucidated and unequivocal diagnostic tests have been obtained, for instance, demonstration of a specific integrated viral genome or a unique constellation of immunologic markers, two other interpretations are possible. They will be discussed in the following paragraphs.
Nonspecific Incomplete Biliary Obstruction In patients who have no evidence of PSC or IBD, and whose bile ducts are narrowed by tumor, stones, or postoperative strictures, biopsy changes may be indistinguishable from those seen in small-duct PSC; they include ductal proliferation, fibrous cholangitis, and even duct loss. In a patient with floxuridine-induced cholangitis, we found unexplained ductopenia in small portal tracts in the periphery of the liver, although this partic-
1 1 , NUMBER 1, 1991
ular type of sclerosing cholangitis appears to be confined to large perihilar bile ducts; in our patient, these ducts had been affected by obstructive vasculopathy with ischemia." Thus, based on the described experiences, one could speculate that small-duct PSC may be just a response to the involvement of large ducts and that in PSC seemingly confined to small ducts, the narrowing of the large ducts was simply too mild or too diffuse to yield diagnostic cholangiographic changes.
Chronic Active Hepatitis Many patients with CUC had complications or surgical procedures that required blood transfusions. Therefore infection with the hepatitis C virus (or another non-A, non-B virus) must be expected in an appreciable percentage of patients with PSC. The morphologic features of post-transfusion chronic active hepatitis or chronic persistent hepatitis, type C , usually differ from those of small-duct PSC but in some instances much overlap appears to occur and, thus, the morphologic differential diagnosis is not always possible.**The situation is complicated by the likelihood that small-duct PSC and chronic active hepatitis or chronic persistent hepatitis, type C , may coexist. Obviously, severe portal or periportal hepatitis with lymphocytic piecemeal necrosis and lymphocytic or pleomorphic cholangitis would favor chronic hepatitis C infection.".*' However, the features of small-duct PSC could be simulated by hepatitis C infection with severe duct damage" and fibrous cholangitis." Even duct loss might be a feature in some cases.*" Thus, the possibility must be accepted that an unknown number of patients with the diagnosis of small-duct PSC actually have hepatitis C infection with prominent duct involvement. The same holds true for the reversed constellation. Some patients with suspected chronic posttransfusion hepatitis may have small-duct PSC. With the introduction of hepatitis C tests, preliminary steps can be taken toward a distinction between small-duct PSC and hepatitis C , particularly in cases that so far have remained unclassified. Despite the limitations of this firstgeneration test,2s the role of these two etiologic categories will become clearer. The two alternative explanations of putative smallduct PSC-nonspecific response to incomplete obstruction and chronic active hepatitis-have been discussed in the context of coexisting large-duct PSC or CUC. Although such alternative explanations certainly must be entertained, the evidence strongly supports the existence of small-duct PSC. Indeed, the latter condition might even occur as a seemingly new disease-idiopathic adulthood ductopenia. This diagnosis applies to patients who have chronic cholestatic liver disease characterized by biopsy evidence of ductopenia and absence of any of the conditions that are known to cause loss of interlobular and septal bile ducts, in particular, the syndrome of PBC or large-duct PSC. The name "paucity of intrahepatic bile ducts" was not applicable because it already refers to an idiopathic infantile or childhood ductopenia. Therefore we coined the term "idiopathic adulthood duct~penia."'~ Our study as well as study of unpublished cases suggested that idiopathic adulthood ductopenia
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FUTURE STUDIES The need for further studies of small-duct PSC is immediately apparent from the many unanswered questions and speculations discussed in the previous paragraphs. Three problem areas come to mind, namely, incidence and natural history of small-duct PSC, pathogenesis, and treatment.
Incidence and Natural History I am not aware of a study of patients with IBD in whom small-duct PSC was evaluated prospectively. Ideally, this should be accomplished by routine liver biopsy analysis in a very large number of consecutive patients with IBD (or unequivocal CUC). For 74 patients with CUC who had normal liver function, a comparable analysis indeed has been published. As expected, most specimens were normal or had only minor changes but in three instances findings were described that were compatible with small-duct PSC (the authors did not use this term)." No progression was noted in these three cases, 13 to 23 years later. However, another patient who had only fatty changes in 1959 developed symptoms of autoimmune chronic active hepatitis. In that patient, bile duct carcinoma was identified almost 30 years later, suggesting that small-duct or large-duct PSC may have been present after all. Although the study of small-duct PSC was not the purpose of that publication, it did reveal that in patients with CUC and normal liver function tests, progressive PSC, including small-duct PSC, probably
develops in less than 5% of the cases, as was estimated by others. l 3 For a prospective study of small-duct PSC, meaningful results could be obtained even if liver biopsy would only be done in the presence of a predefined biochemical profile, for instance, alkaline phosphatase levels exceeding two times the upper level of normal for more than 2 months. This would identify most, although not all, cases." Some of the patients can be expected to have large-duct PSC at that time but in other cases cholangiographic findings probably would be normal or not diagnostic. The incidence and prognosis of small-duct PSC in such a setting still is largely unknown. In a recent unpublished review of 73 patients with biopsy evidence of small-duct PSC and satisfactory cholangiograms, I found large-duct PSC in 69 patients, cholangiocarcinoma (with large-duct PSC'?) in one patient, and normal bile ducts in three patients. Follow-up information on the three patients with normal cholangiograms is not available. Nevertheless, results from this series suggest that more than 95% of patients with histologic evidence of small-duct PSC also have large-duct disease. These findings certainly need confirmation. In patients with confirmed large-duct PSC, the spectrum of small-duct involvement is much better known. As already described, small-duct PSC and its secondary manifestations are almost always present, at least after some time, and thus can be used to stage the syndrome of PSC."' I am not aware of studies in which the progression and thus the prognosis of small-duct PSC would have been correlated with the severity of the large-duct disease. One reason may be the difficulty of quantitating the severity of cholangiographic changes in PSC and of comparing the results of radiologic methods with morphologic findings. The need for data of this type has become pressing because of the recent interest in survival models for optimal timing of liver transplantation. Such models are in use for PBC,3' but also are being developed for PSC." Such a comparison between radiologic and morphologic findings also would be important for the evaluation of surgical treatment, as described in the next paragraph.
Pathogenesis As discussed earlier, incomplete large-duct obstruction by PSC may in some cases play a role in the development of small-duct disease (secondary small-duct disease). Small-duct damage unrelated to large-duct disease (primary small-duct disease) is unequivocal only in small-duct PSC without or with only minimal large-duct involvement. Thus far, no morphologic features have been described that would help to distinguish between primary and secondary small-duct disease; these two putative pathogenetic mechanisms have not been compared in a published study. Systematic analysis is needed because of its relevance for the hotly debated indication for surgical treatment of large-duct d i ~ e a s e . ~ ' If . ' ~narrowing of extrahepatic and perihilar intrahepatic bile ducts indeed hastens the progression of small-duct PSC, indications for surgical or endoscopic i n t e r ~ e n t i o nwould ~ ~ become much clearer.
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may have several possible etiologies and that in some cases, the condition might represent isolated small-duct PSC-r "pericholangitis" without IBD. This appears likely because the histologic findings are compatible and because all other constellations of the PSC syndrome have been documented. Thus, large-duct PSC occurs, in up to 30% of the cases,2hwithout evidence of an intestinal disorder, and small-duct PSC in patients with IBD may occur without documentable large-duct involvement." Finally, some patients with large-duct PSC but without IBD fail to show significant small-duct involvement. Thus, the three components of the classic PSCsyndrome, namely, large-duct disease, small-duct disease, and IBD, have been documented to occur in any combination or, in cases of large-duct PSC and IBD, each condition may occur alone. The only exception so far is small-duct PSC, which currently is defined as a condition accompanying large-duct PSC, IBD, or both, and which therefore cannot be diagnosed without these external "markers." However, the current definition of small-duct PSC or "pericholangitis" is only historically linked to large-duct PSC and IBD; no valid scientific reason can be found to suggest that small-duct PSC could not occur without large-duct disease and IBD. This has been the impression of other authors also." Thus, it appears very likely that some cases of idiopathic adulthood ductopenia indeed represent small-duct PSC or "pericholangitis" without its customary companion conditions.
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On a more basic level, studies on bile duct epithelium in PSC should be planned, using recently developed isolation t e ~ h n i q u e s . ~ ~Three . " main areas of interest immediately come to mind: (1) Studies of immunoreactivity between bile duct epithelial cells and immunocytes in patients with PSC and IBD, compared with control patients; (2) biochemical and immunologic comparisons of small-duct epithelium with large-duct epithelium; and (3) searches for integrated viral DNA in biliary epithelium in patients with the syndrome of PSC. The ultimate goal of such studies would be the development of diagnostic immunologic tests for early PSC, the clarification of the role of small-duct PSC (primary target versus secondary involvement), and the possible recognition of a virus or viruses that might trigger the subsequent "autoimmune" events characterizing the PSC syndrome. Of particular interest in this context is the possible role of the hepatitis C virus. Recombinant DNA technology which has been used to study the hepatitis B virus genome in human liver tissue," might also be applicable to the study of biliary epithelium.
REFERENCES I. 2.
3. 4.
5.
6.
7.
8.
Therapy For the evaluation of treatment trials, morphologic staging of small-duct PSC and its complications has proved most useful. The transplant experience has confirmed that hepatic failure in PSC almost always is caused by parenchymal changes related to the small-duct component of the condition. Cases of PSC with largeduct cholangiocarcinoma are an exception. Thus, in previous treatment trials with penicillamine," and in current protocols evaluating ursodeoxycholic acid, cyclosporine, and other agents, biopsy evaluation of small-duct PSC has remained the main method of assessment. Undoubtedly, endoscopic and surgical treatment of largeduct disease must be evaluated in the same fashion.
SUMMARY AND CONCLUSIONS Current evidence suggests that PSC may affect the entire biliary system from interlobular bile ducts to the ampulla of Vater. If the affected bile ducts are too small for cholangiographic identification, the best designation for the condition is small-duct PSC; cholangiographically identifiable duct changes are the hallmark of largeduct PSC. The term "small-duct PSC" should replace the name pericholangitis because that designation lacks a clear definition. Small-duct PSC may occur in combination with large-duct PSC or it may occur alone. The clinical course of patients with PSC depends on the hepatic changes related to small-duct PSC, not primarily on the classic large-duct disease. Therefore the features of small-duct PSC and its complications are used to determine the disease stages of PSC. The incidence of small-duct PSC still is not known and the natural history as well as the pathogenesis of the condition remains obscure. Nevertheless, the role of small-duct disease in the syndrome of PSC has come into focus and the themes for future studies are apparent. Work should commence.
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SMALL-DUCT PRIMARY SCLEROSING CHOLANGITIS-LUDWIG
